You have a 54-year-old black patient with gout, diabetes mellitus, hypertension, and chronic kidney disease (CKD). He has an acute gout flare involving his right knee. In the past year he has had four attacks of gout in the ankles and knees, which you treated with intra-articular glucocorticoid injections. He has been on allopurinol (Zyloprim) 200 mg daily, but his last serum urate level was 9.4 mg/dL (reference range 3.0–8.0). His creatinine clearance is 45 mL/minute (reference range 85–125).
In view of his kidney disease, you are concerned about increasing his dose of allopurinol, but also about the need to treat his frequent attacks. How should you manage this patient?
GOUT IS CHALLENGING TO TREAT IN PATIENTS WITH KIDNEY DISEASE
A major challenge in treating patients with gout is to avoid therapeutic interactions with common comorbidities, including hypertension, insulin resistance, coronary artery disease, heart failure, and especially CKD.1
In this paper, we discuss approaches to and controversies in the management of gout and hyperuricemia in patients with CKD. Unfortunately, the evidence from clinical trials to guide treatment decisions is limited; therefore, decisions must often be based on experience and pathophysiologic principles.
GENERAL GOALS OF GOUT THERAPY
Depending on the patient and the stage of the disease, the goals in treating patients with gout are to:
Terminate acute attacks as promptly and safely as possible
Prevent recurrences of acute gout attacks
Prevent or reverse complications resulting from deposition of monosodium urate in the joints, in the kidneys, or at other sites.
These goals are more difficult to achieve in patients with CKD because of the potential complications from many of the available drugs.
TERMINATING ACUTE GOUT FLARES
In patients with acute gout, treatment is aimed at quickly resolving pain and inflammation.
Several types of drugs can terminate acute gout flares. The choice in most situations is colchicine (Colcrys); a nonsteroidal anti-inflammatory drug (NSAID); a corticosteroid; or corticotropin (ACTH).
However, in patients with CKD, there are concerns about using colchicine or NSAIDs, and corticotropin is very expensive; thus, corticosteroids are often used.
Colchicine’s clearance is reduced in CKD
Colchicine is somewhat effective in treating acute gout attacks and probably more effective in preventing attacks.
Due to concerns about inappropriate dosing and reported deaths,2 the intravenous formulation is not available in many countries, including the United States.
After oral administration, colchicine is rapidly absorbed, with a bioavailability of up to 50%. It undergoes metabolism by the liver, and its metabolites are excreted by renal and biliary-intestinal routes. Up to 20% of the active drug is excreted by the kidneys.3
Colchicine’s clearance is significantly reduced in patients with renal or hepatic insufficiency, and the drug may accumulate in cells, with resultant toxicity.4 Colchicine-induced toxicity has been observed when the drug was used for acute treatment, as well as for chronic prophylaxis of gout in patients with CKD; thus, alternative agents for treating acute attacks should be considered.5,6 With prolonged use, reversible colchicine-induced axonal neuropathy, neutropenia, and vacuolar myopathy can develop in patients with CKD.7
In a trial in patients with normal renal function, nearly 100% who received an initial dose of 1 mg followed by 0.5 mg every 2 hours developed diarrhea at a median time of 24 hours.8 Emesis may also occur.
A lower dose of 1.8 mg (two 0.6-mg pills followed by one pill an hour later) was well tolerated but only moderately effective in treating acute gout, causing at least a 50% reduction in pain at 24 hours in only 38% of patients.9 This study does not clarify the dosage to use to completely resolve attacks. Using additional colchicine likely will increase the response rate, but will also increase side effects. Patients with CKD were not included.
Some patients, as shown in the above trial, can abort attacks by taking only one or two colchicine tablets when they feel the first “twinge” of an attack. This approach is likely to be safe in CKD, but it may be of value to only a few patients.
Nonsteroidal anti-inflammatory drugs can worsen chronic kidney disease
NSAIDs in high doses can effectively treat the pain and inflammation of acute gout. Indomethacin (Indocin) 50 mg three times daily has been standard NSAID therapy.
Other nonselective NSAIDs and NSAIDs that selectively inhibit cyclooxygenase 2 (COX-2) are effective, but all can cause acute renal toxicity or worsen CKD.10 Renal side effects include salt and water retention, acute tubular necrosis, acute interstitial nephritis, proteinuria, hypertension, hyperkalemia, and chronic renal injury.11
Even short-term use of high-dose NSAIDs should generally be avoided in patients with preexisting CKD, for whom there is no established safe threshold dose. When NSAIDs (including selective COX-2 inhibitors) are used, renal function should be monitored closely and the duration limited as much as possible.
Corticosteroids are often used to treat acute attacks
Due to the concerns about NSAIDs or colchicine to treat acute gout attacks in patients with CKD, corticosteroids are often used in this setting.
Intra-articular steroid injections are useful in treating acute gout limited to a single joint or bursa.12 However, one should first make sure that the joint is not infected: septic arthritis should ideally be excluded by arthrocentesis, particularly in immunosuppressed patients13 or those with end-stage renal disease, who are predisposed to bacteremia.
Oral, intramuscular, or intravenous steroids can provide complete relief from acute gout, although high doses (eg, prednisone 30–60 mg/day or the equivalent) are often needed. Common errors resulting in inefficacy include using too low a dose or not treating for a sufficient time before tapering or stopping. Groff and colleagues14 described 13 patients who received oral or intravenous steroids for acute gout. Nine patients received an initial single dose of prednisone ranging from 20 to 50 mg, with tapering over a mean of 10 days. Twelve of the 13 patients had improvement within 48 hours, and the signs and symptoms of acute gout resolved completely within 7 to 10 days.
We often give prednisone 40 mg daily until a day after the acute attack resolves and then taper over another 7 to 10 days. There are no data to guide steroid dosing in an evidence-based way, but we believe too short a course of therapy may result in return of symptoms.
Corticotropin and other agents: Effective but costly
Corticotropin shares the same indications as systemic corticosteroids, being used to treat flares when NSAIDs, intra-articular steroids, and colchicine are contraindicated. However, corticotropin is far more expensive than generic corticosteroids, costing nearly $2,000 for a single 80-IU dose, which may need to be repeated.
Corticotropin is available for subcutaneous or intramuscular injection. A single intramuscular injection of corticotropin gel (H.P. Acthar, 25–80 IU) may terminate an acute gout attack.15 However, many patients need another injection after 24 to 72 hours, which would require another visit to the physician. This treatment has been touted by some as being more effective than corticosteroid therapy, possibly because of a unique peripheral mechanism of action in addition to stimulating cortisol release.16
We rarely use corticotropin, in view of its cost as well as concerns about excessive sodium and water retention due to the release of multiple hormones from the adrenal gland. This may be especially deleterious in patients with CKD or congestive heart failure.17
Parenteral anti-tumor necrosis factor agents or interleukin 1 antagonists can be dramatically effective but are also expensive.18,19 For example, anakinra (Kineret) 100 mg costs about $73, and multiple daily doses may be necessary.
Under unique conditions in which they can be safely used (eg, patients with CKD, diabetes mellitus, liver disease), they may be cost-effective if they can shorten the stay of a hospitalized patient with acute gout.
PROPHYLACTIC ANTI-INFLAMMATORY THERAPY FOR PATIENTS WITH GOUT
Between attacks, the goal is to prevent new attacks through prophylactic management, which may include anti-inflammatory and hypouricemic therapy along with dietary instruction (such as avoiding excessive beer, liquor, and fructose ingestion).
Colchicine can be used as prophylaxis, with caution and monitoring
Although colchicine is not 100% effective, it markedly reduces the flare rate when started in low doses at the time hypouricemic therapy is initiated.20,21 (Hypouricemic therapy is discussed below.) We generally try to continue this prophylactic therapy, if the patient tolerates it, for at least 6 months—longer if tophi are still present or if attacks continue to occur.
If renal function is intact, colchicine can be prescribed at a dosage of 0.6 mg orally once or twice daily.21 In CKD, since the clearance of colchicine is reduced,4 the dosage should be reduced. Patients on colchicine for prophylaxis must be carefully monitored if the glomerular filtration rate is less than 50 mL/minute, or colchicine should be avoided altogether.6 Laboratory testing for colchicine levels is not routinely available and may be of limited value in predicting adverse effects; thus, recommendations about dose adjustments in CKD are empiric.
Wallace et al22 recommended a dose of 0.6 mg once daily if the creatinine clearance is 35 to 49 mL/minute and 0.6 mg every 2 to 3 days if it is 10 to 34 mL/minute, but there are no published long-term safety or efficacy data validating these reasonable (based on available information) dosing regimens.
Even with dose adjustment, caution is needed. Low-dose daily colchicine may be associated with reversible neuromyopathy and bone marrow suppression.7,23 Patients with neuromyopathy may complain of myalgias, proximal muscle weakness, and numbness and may have areflexia and decreased sensation. Laboratory findings include elevated creatine kinase and aminotransferase levels. We regularly check for leukopenia or elevated creatine kinase and aspartate aminotransferase levels in patients with CKD who are receiving colchicine in any dose.
Prolonged colchicine therapy should probably be avoided in patients on hemodialysis, as this drug is not removed by dialysis or by exchange transfusion, and the risk of toxicity under these circumstances may be high.22 When there is no viable alternative and the drug is given, patients should be closely monitored for signs of toxicity.
Concurrent (even short-term) treatment with most macrolide antibiotics, particularly clarithromycin (Biaxin), most statin drugs, ketoconazole (Nizoral), cyclosporine, and likely other drugs predisposes to colchicine toxicity by altering its distribution and elimination, and can in rare cases cause morbidity or death.24–26
NSAIDs are not optimal as prophylaxis in patients with chronic kidney disease
Little information has been published about using NSAIDs chronically to prevent flares, but they are not the optimal drugs to use in patients with CKD, as discussed above. In patients with end-stage renal disease, there are also concerns about NSAID-induced gastric and intestinal bleeding.
Low-dose steroids may not be effective as prophylaxis
Lower doses of steroids may not be effective as prophylaxis against gout flares, consistent with the common observation that gout flares still occur in organ transplant recipients who are taking maintenance doses of prednisone.13
PREVENTING FLARES BY LOWERING SERUM URATE LEVELS
If tophi are present, if radiography shows evidence of damage, if attacks are frequent or disabling, or if there are relative contraindications to the drugs that would be needed to treat acute attacks, then hypouricemic therapy should be strongly considered to reduce the burden of urate in the body, resorb tophi, and ultimately reduce the frequency of gout flares.20
Although intermittent therapy for attacks or prolonged prophylactic use of colchicine may prevent recurrent episodes of gouty arthritis and may be reasonable for many patients, this approach does not prevent continued urate deposition, with the potential development of bony erosions, tophaceous deposits, and chronic arthritis.
The definitive therapy for gouty arthritis is to deplete the periarticular deposits of urate by maintaining a low serum urate level. Urate-lowering therapy, when indicated, is almost always lifelong.
Four strategies for lowering serum urate
The serum urate concentration can be lowered in four ways:
Increasing renal uric acid excretion
Altering the diet
Decreasing urate synthesis
Converting urate to a more soluble metabolite.
Increasing uric acid excretion is rarely effective if renal function is impaired
Probenecid, sulfinpyrazone (Anturane), and losartan (Cozaar) modestly increase uric acid secretion and reduce serum urate levels, but they are rarely effective if the creatinine clearance rate is less than 60 mL/minute, and they require significant fluid intake for maximal efficacy.
Uricosuric drugs probably should be avoided in patients who excrete more than 1,000 mg of uric acid per day on a normal diet, since urinary uric acid stones may form. In practice, however, patients are given losartan to treat hypertension without attention to uric acid excretion.
More-potent urocosuric drugs are being tested in clinical trials.
Altering the diet: Traditional advice confirmed
The Health Professionals Follow-up Study27,28 prospectively examined the relation between diet and gout over 12 years in 47,150 men. The study confirmed some long-standing beliefs, such as that consuming meat, seafood, beer, and liquor increases the risk. Other risk factors were consumption of sugar-sweetened soft drinks and fructose, adiposity, weight gain, hypertension, and diuretic use. On the other hand, protein, wine, and purine-rich vegetables were not associated with gout flares. Low-fat dairy products may have a protective effect. Weight loss was found to be protective.
Low-purine diets are not very palatable, are difficult to adhere to, and are at best only minimally effective, lowering serum urate by 1 to 2 mg/dL. Low-protein diets designed to slow progression of CKD will likely also have only a slight effect on serum urate. Dietary change alone is not likely to dramatically lower serum urate levels.
Metabolizing urate with exogenous uricase
Rasburicase (Elitek) effectively converts urate to allantoin, which is more soluble, but rasburicase is fraught with allergic reactions and cannot be used as chronic therapy.
A pegylated intravenous uricase29 has just been approved by the US Food and Drug Administration (FDA); the retail cost is not yet known. It is dramatically effective in those patients able to use it chronically, but it has not been fully evaluated in patients with CKD.
Decreasing urate synthesis with allopurinol
Allopurinol acts by competitively inhibiting xanthine oxidase, the enzyme that converts hypoxanthine to xanthine and xanthine to uric acid. The drug, a structural analogue of hypoxanthine, is converted by xanthine oxidase to oxypurinol, which is an even more effective inhibitor of xanthine oxidase than allopurinol.
Allopurinol is metabolized in the liver and has a half-life of 1 to 3 hours, but oxypurinol, which is excreted in the urine, has a half-life of 12 to 17 hours. Because of these pharmacokinetic properties, allopurinol can usually be given once daily, and the dosage required to reduce serum urate levels should in theory be lower in patients with lower glomerular filtration rates.
Allopurinol (100- and 300-mg tablets) is approved by the FDA in doses of up to 800 mg/day to treat hyperuricemia in patients with gout,30 while guidelines from the British Society of Rheumatology advocate a maximum dose of 900 mg/day.31 These maximum doses are based on the limited amount of data with higher doses, not on documented toxicity.
Practice survey data in the United States indicate that most physicians prescribe no greater than 300 mg daily, although this dosage is likely to reduce the serum urate to less than 6 mg/dL—the goal level—in fewer than 50% of patients.20,32 Patients with normal renal function occasionally require more than 1,000 mg daily to reduce the serum urate level to less than 6 mg/dL.
How low should the serum urate level be?
Ideally, therapy should keep the serum urate level significantly below 6.7 mg/dL, the approximate saturation point of urate in physiologic fluids.
Lowering the serum urate level from 10 mg/dL to 7 mg/dL may seem encouraging, and the urate level may be in the laboratory “normal” range; however, urate may continue to precipitate in tissues if the concentration is greater than 6.7 mg/dL. A target of 6 mg/dL, used in clinical studies, is far enough below the saturation level to provide some margin for fluctuations in serum levels. A serum level of 6.0 mg/dL has thus been arbitrarily proposed as a reasonable therapeutic target.
The lower the serum urate level achieved during hypouricemic therapy, the faster the reduction in tophaceous deposits. With adequate urate lowering, tophi can be visibly reduced in less than a year of hypouricemic therapy.33,34
We have as yet no convincing evidence that lowering the serum urate level to less than 6.0 mg/dL is harmful, despite theoretical concerns that urate is a beneficial circulating antioxidant and epidemiologic observations that urate levels have been inversely correlated with progression of Parkinson disease.
Start low, go slow to avoid a flare
Rapid reduction of the serum urate level in a patient with chronic hyperuricemia and gout is likely to induce an acute flare.20 We have traditionally used a “start low and increase slowly” approach to escalating hypouricemic therapy in hopes of reducing the likelihood of causing a gout flare.
Without anti-inflammatory prophylaxis, acute flares associated with urate-lowering are extremely likely. In a 28-week trial of allopurinol, febuxostat, and placebo by Schumacher et al,33 during the first 8 weeks, when prophylaxis against gout flare was provided with either colchicine 0.6 mg once daily or naproxen (Naprosyn) 250 mg twice daily, the proportion of patients requiring treatment of gout flares was still 23% to 46%. When prophylaxis was stopped, the flare rate increased further.33
The more we acutely lower serum urate levels, the more likely flares are to occur. In the study by Schumacher et al,33 the percentage of patients needing treatment for gout flares during the first 8 weeks of the study, despite gout flare prophylaxis, was related to the percent reduction in serum urate by week 28 of the trial (Table 2).
IS IT NECESSARY TO ADJUST THE ALLOPURINOL DOSE IN CHRONIC KIDNEY DISEASE?
In 1984, Hande et al35 proposed that allopurinol doses be lower in patients with renal insufficiency, with a dosage scale based on creatinine clearance.
Their thoughtful proposal was based on data from six of their own patients and 72 others with severe allopurinol toxicity, mainly allopurinol hypersensitivity syndrome, reported in the literature.
Perez-Ruiz et al36 noted that patients who had experienced adverse effects from allopurinol in their series were likely to have had received “higher” doses of allopurinol, if the dosage was corrected for reduced oxypurinol elimination based on their estimated creatinine clearance.
However, most of these reactions occurred soon after initiating therapy, a temporal pattern more typical of non-dose-dependent allergic reactions. Additionally, allopurinol hypersensitivity has been linked to T-cell-mediated immune reactions to oxypurinol,37 a mechanism not likely linked to drug levels.
Arguments against dose adjustment
Despite the compelling information that allopurinol reactions are more common in CKD, adjusting the dosage of allopurinol has not been clearly shown to reduce the frequency of these reactions.
In a small retrospective analysis, Vázquez-Mellado et al38 reported that adjusting the allopurinol dosage according to creatinine clearance did not decrease the incidence of allopurinol hypersensitivity.
In a study in 250 patients, Dalbeth et al39 showed that the overall incidence of hypersensitivity reaction was 1.6%, and the incidence of allergic reactions did not decrease when allopurinol was given according to the dosing guidelines proposed by Hande et al.35 However, it is worth noting that, of the patients who received the recommended lower doses, only 19% achieved the target serum urate level of 6 mg/dL.39
Silverberg et al40 found that of 15 patients who developed hypersensitivity reactions to allopurinol, 10 had received doses that were low or appropriate according to the guidelines of Hande et al.35
More recently, Stamp et al41 found that gradually increasing the allopurinol dose above the proposed creatinine clearance-based dose was safe and effective. Thirty-one (89%) of the 35 patients who completed the study achieved the target serum urate level of 6 mg/dL, while only 3 of 45 who started the study developed rashes, which were not serious.
The small number of patients in these studies limits any strong conclusion, but at present there is no interventional study showing that allopurinol dosing adjustment based on glomerular filtration rate is effective or safer than dosing based on the serum urate level.
Our view on allopurinol dosing adjustment
We believe the initial observations of Hande et al35 and the subsequent meticulous data from Perez-Ruiz et al36 suggest a relationship between CKD and the occurrence of severe allopurinol reactions. However, these observations do not prove that dose adjustment will prevent these reactions.
In patients with normal kidney function, the FDA30 and the European League Against Rheumatism (EULAR)42 recommend slow upward titration, starting with 100 to 200 mg/day, which we agree should decrease the frequency of acute gout flares. The dose is increased by increments of 100 mg/day at intervals of 1 week (FDA recommendation) or 2 to 4 weeks (EULAR recommendation) until the serum urate level is lower than 6 mg/dL.
We believe the optimal approach to allopurinol dosing in patients with CKD remains uncertain. We generally escalate the dose slowly, with ongoing frequent laboratory and clinical monitoring, and we do not limit the maximal dose as suggested by Hande et al.35
An alternative strategy is to use the newer, far more expensive xanthine oxidase inhibitor febuxostat in patients with CKD, since it is not excreted by the kidney. We usually first try escalating doses of allopurinol.
FEBUXOSTAT, AN ALTERNATIVE TO ALLOPURINOL
Febuxostat is an oral nonpurine inhibitor of xanthine oxidase.43 Approved by the FDA in 2009, it is available in 40- and 80-mg tablets.
Unlike allopurinol, febuxostat is metabolized primarily by hepatic glucuronide formation and oxidation and then excreted in stool and urine,44 making it in theory an attractive agent in patients with renal insufficiency, bypassing the controversial dose-adjustment issue with allopurinol.
In the Febuxostat Versus Allopurinol Controlled Trial (FACT),20 a 52-week randomized, double-blind study in hyperuricemic patients with gout, serum urate levels were reduced to less than 6.0 mg/dL in over 50% of patients receiving febuxostat 80 mg or 120 mg once daily, while only 21% of patients receiving 300 mg of allopurinol achieved this goal. This does not imply that allopurinol at higher doses, as should be used in clinical practice,45 would not be equally effective. Patients with CKD were not included in this trial.
In the study by Schumacher et al,33 febuxostat 80, 120, or 240 mg once daily reduced serum urate. A small subset (35 patients) had mild to moderate renal insufficiency (serum creatinine 1.5–2 mg/dL).33 The number of patients with renal insufficiency who achieved the primary end point of a serum urate level lower than 6 mg/dL was 4 (44%) of 9 in the febuxostat 80-mg group, 5 (46%) of 11 in the 120-mg group, and 3 (60%) of 5 in the 240-mg group, while none of the 10 patients in the dose-adjusted allopurinol group achieved the primary end point (P < .05). Of note, 41% of the patients with normal renal function who received allopurinol achieved the primary end point.33 As proposed above, if the allopurinol dose had been slowly increased in the patients with renal insufficiency, it might have been equally effective.
Febuxostat has not been thoroughly evaluated in patients with severe CKD or in patients on hemodialysis.
A presumed niche indication of febuxostat is in patients allergic to allopurinol, since the drugs are not similar in chemical structure. However, at present, experience with this use is limited. Allopurinol-allergic patients were excluded from the clinical trials; thus, if there is any allergic overlap, it would not likely have been recognized in those studies. The FDA has received reports of patients who were allergic to allopurinol also having reactions to febuxostat, and it is currently evaluating these reports (personal communication).
Concern was raised over cardiovascular adverse events in patients treated with febuxostat during clinical trials. In the FACT trial, two patients died of cardiac causes.20 In the study by Schumacher et al,33 11 of 670 patients experienced cardiac adverse events in the febuxostat group vs 3 of 268 in the allopurinol group. Events included atrial fibrillation, chest pain, coronary artery disease, and myocardial infarction. However, this difference was not statistically significant.
Febuxostat costs much more than allopurinol. Currently, patients pay $153.88 for 1 month of febuxostat 40 or 80 mg from Cleveland Clinic pharmacy; 1 month of allopurinol costs $17.45 (300 mg) or $14.00 (100 mg). We believe febuxostat should be reserved for patients with documented intolerance to allopurinol in effective doses.
Monitoring serum urate levels is important in all patients on hypouricemic therapy so that dosage adjustments can be made until the target serum urate concentration is reached. In patients failing to meet target serum urate levels, patient adherence with the prescribed dosing should be specifically addressed because as many as 50% of patients do not adhere to their prescribed regimen.
DOES URATE-LOWERING THERAPY HAVE BENEFITS BEYOND GOUT?
Despite experimental animal data and a strong epidemiologic association between hyperuri-cemia and hypertension,46 metabolic syndrome, and rates of cardiovascular and all-cause mortality,47 the evidence from interventional trials so far does not support the routine use of hypo-uricemic therapy to prevent these outcomes.
Similarly, hyperuricemia has long been associated with renal disease, and there has been debate as to whether hyperuricemia is a result of kidney dysfunction or a contributing factor.46,48–51 A few studies have documented improvement of renal function after initiation of hypouricemic therapy.52 However, treating asymptomatic hyperuricemia to preserve kidney function remains controversial.
A recent study indicates that lowering the serum urate level with allopurinol can lower the blood pressure in hyperuricemic adolescents who have newly diagnosed primary hypertension.53 This does not indicate, however, that initiating hypouricemic therapy in patients with preexisting, long-standing hypertension will be successful.
RECOMMENDED FOR OUR PATIENT
As for our diabetic patient with an acute gout flare and creatinine clearance rate of 45 mL/minute, we would recommend:
Aspirating the knee, sending the fluid for bacterial culture, and then treating it with a local glucocorticoid injection
Starting colchicine 0.6 mg every day, with frequent monitoring for signs of toxicity (muscle pain, weakness, leukopenia, and elevations of creatine kinase and aspartate aminotransferase)
Increasing his allopurinol dose by 100 mg every 2 to 4 weeks until the target serum urate level of less than 6.0 mg/dL is reached
If he cannot tolerate allopurinol or if the target serum urate level is not achieved despite adequate doses of allopurinol (about 800 mg), we would switch to febuxostat 40 mg and increase the dose as needed to achieve the desired urate level.
References
Vázquez-Mellado J, García CG, Vázquez SG, et al. Metabolic syndrome and ischemic heart disease in gout. J Clin Rheumatol2004; 10:105–109.
Bonnel RA, Villalba ML, Karwoski CB, Beitz J. Deaths associated with inappropriate intravenous colchicine administration. J Emerg Med2002; 22:385–387.
Achtert G, Scherrmann JM, Christen MO. Pharmacokinetics/bioavailability of colchicine in healthy male volunteers. Eur J Drug Metab Pharmacokinet1989; 14:317–322.
Ben-Chetrit E, Scherrmann JM, Zylber-Katz E, Levy M. Colchicine disposition in patients with familial Mediterranean fever with renal impairment. J Rheumatol1994; 21:710–713.
Putterman C, Ben-Chetrit E, Caraco Y, Levy M. Colchicine intoxication: clinical pharmacology, risk factors, features, and management. Semin Arthritis Rheum1991; 21:143–155.
Aronoff G, Brater DC, Schrier R, Bennett WM. Use of drugs in patients with renal insufficiency. Workshop report. Blood Purif1994; 12:14–19.
Kuncl RW, Duncan G, Watson D, Alderson K, Rogawski MA, Peper M. Colchicine myopathy and neuropathy. N Engl J Med1987; 316:1562–1568.
Ahern MJ, Reid C, Gordon TP, McCredie M, Brooks PM, Jones M. Does colchicine work? The results of the first controlled study in acute gout. Aust N Z J Med1987; 17:301–304.
Terkeltaub R, Furst D, Bennett K, Kook K, Crockett RS, Davis WM. High versus low dosing of oral colchicine for early acute gout flare: twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. Arthritis Rheum2010, 62:1060–1068.
Whelton A. Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications. Am J Med1999; 106:13S–24S.
Wali RK, Henrich WL. Recent developments in toxic nephropathy. Curr Opin Nephrol Hypertens2002; 11:155–163.
Fernández C, Noguera R, González JA, Pascual E. Treatment of acute attacks of gout with a small dose of intraarticular triamcinolone acetonide. J Rheumatol1999; 26:2285–2286.
Clive DM. Renal transplant-associated hyperuricemia and gout. J Am Soc Nephrol2000; 11:974–979.
Groff GD, Franck WA, Raddatz DA. Systemic steroid therapy for acute gout: a clinical trial and review of the literature. Semin Arthritis Rheum1990; 19:329–336.
Ritter J, Kerr LD, Valeriano-Marcet J, Spiera H. ACTH revisited: effective treatment for acute crystal induced synovitis in patients with multiple medical problems. J Rheumatol1994; 21:696–699.
Getting SJ, Christian HC, Flower RJ, Perretti M. Activation of melanocortin type 3 receptor as a molecular mechanism for adrenocorticotropic hormone efficacy in gouty arthritis. Arthritis Rheum2002; 46:2765–2775.
Connell JM, Whitworth JA, Davies DL, Lever AF, Richards AM, Fraser R. Effects of ACTH and cortisol administration on blood pressure, electrolyte metabolism, atrial natriuretic peptide and renal function in normal man. J Hypertens1987; 5:425–433.
Tausche AK, Richter K, Grässler A, Hänsel S, Roch B, Schröder HE. Severe gouty arthritis refractory to anti-inflammatory drugs: treatment with anti-tumour necrosis factor alpha as a new therapeutic option. Ann Rheum Dis2004; 63:1351–1352.
So A, De Smedt T, Revaz S, Tschopp J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther2007; 9:R28.
Becker MA, Schumacher HR, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med2005; 353:2450–2461.
Borstad GC, Bryant LR, Abel MP, Scroggie DA, Harris MD, Alloway JA. Colchicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J Rheumatol2004; 31:2429–2432.
Wallace SL, Singer JZ, Duncan GJ, Wigley FM, Kuncl RW. Renal function predicts colchicine toxicity: guidelines for the prophylactic use of colchicine in gout. J Rheumatol1991; 18:264–269.
Wilbur K, Makowsky M. Colchicine myotoxicity: case reports and literature review. Pharmacotherapy2004; 24:1784–1792.
Hung IF, Wu AK, Cheng VC, et al. Fatal interaction between clarithromycin and colchicine in patients with renal insufficiency: a retrospective study. Clin Infect Dis2005; 41:291–300.
Alayli G, Cengiz K, Cantürk F, Durmus D, Akyol Y, Menekse EB. Acute myopathy in a patient with concomitant use of pravastatin and colchicine. Ann Pharmacother2005; 39:1358–1361.
Ducloux D, Schuller V, Bresson-Vautrin C, Chalopin JM. Colchicine myopathy in renal transplant recipients on cyclosporin. Nephrol Dial Transplant1997; 12:2389–2392.
Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Purine-rich foods, dairy and protein intake, and the risk of gout in men. N Engl J Med2004; 350:1093–1103.
Choi HK, Curhan G. Soft drinks, fructose consumption, and the risk of gout in men: prospective cohort study. BMJ2008; 336:309–312.
Sundy JS, Becker MA, Baraf HS, et al; Pegloticase Phase 2 Study Investigators. Reduction of plasma urate levels following treatment with multiple doses of pegloticase (polyethylene glycol-conjugated uricase) in patients with treatment-failure gout: results of a phase II randomized study. Arthritis Rheum2008; 58:2882–2891.
Jordan KM, Cameron JS, Snaith M, et al; British Society for Rheumatology and British Health Professionals in Rheumatology Standards, Guidelines and Audit Working Group (SGAWG). British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of gout. Rheumatology (Oxford)2007; 46:1372–1374.
Perez-Ruiz F, Alonso-Ruiz A, Calabozo M, Herrero-Beites A, García-Erauskin G, Ruiz-Lucea E. Efficacy of allopurinol and benzbromarone for the control of hyperuricaemia. A pathogenic approach to the treatment of primary chronic gout. Ann Rheum Dis1998; 57:545–549.
Schumacher HR, Becker MA, Wortmann RL, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum2008; 59:1540–1548.
Perez-Ruiz F, Calabozo M, Pijoan JI, Herrero-Beites AM, Ruibal A. Effect of urate-lowering therapy on the velocity of size reduction of tophi in chronic gout. Arthritis Rheum2002; 47:356–360.
Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Am J Med1984; 76:47–56.
Perez-Ruiz F, Hernando I, Villar I, Nolla JM. Correction of allopurinol dosing should be based on clearance of creatinine, but not plasma creatinine levels: another insight to allopurinol-related toxicity. J Clin Rheumatol2005; 11:129–133.
Hung SI, Chung WH, Liou LB, et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A2005; 102:4134–4139.
Vázquez-Mellado J, Morales EM, Pacheco-Tena C, Burgos-Vargas R. Relation between adverse events associated with allopurinol and renal function in patients with gout. Ann Rheum Dis2001; 60:981–983.
Dalbeth N, Kumar S, Stamp L, Gow P. Dose adjustment of allopurinol according to creatinine clearance does not provide adequate control of hyperuricemia in patients with gout. J Rheumatol2006; 33:1646–1650.
Silverberg MS, Mallela R, Lesse AJ, Bonner MR, Baer AN, Li C. Allopurinol hypersensitivity reactions: a case-control study of the role of renal dosing (abstract). Arthritis Rheum2009; 60(suppl 10):1106.
Stamp LK, O'Donnell JL, Zhang M, et al. Using allopurinol above the dose based on creatinine clearance is effective and safe in chronic gout, including in those with renal impairment. Arthritis Rhem2010; doi:10.1002/art.30119. E-pub ahead of print. Accessed 10/29/2010.
Zhang W, Doherty M, Bardin T, et al; EULAR Standing Committee for International Clinical Studies Including Therapeutics. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis2006; 65:1312–1324.
Okamoto K, Eger BT, Nishino T, Kondo S, Pai EF, Nishino T. An extremely potent inhibitor of xanthine oxidoreductase. Crystal structure of the enzyme-inhibitor complex and mechanism of inhibition. J Biol Chem2003; 278:1848–1855.
Khosravan R, Grabowski BA, Wu JT, Joseph-Ridge N, Vernillet L. Pharmacokinetics, pharmacodynamics and safety of febuxostat, a non-purine selective inhibitor of xanthine oxidase, in a dose escalation study in healthy subjects. Clin Pharmacokinet2006; 45:821–841.
Reinders MK, Haagsma C, Jansen TL, et al. A randomised controlled trial on the efficacy and tolerability with dose escalation of allopurinol 300–600 mg/day versus benzbromarone 100–200 mg/day in patients with gout. Ann Rheum Dis2009; 68:892–897.
Mazzali M, Hughes J, Kim YG, et al. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension2001; 38:1101–1106.
Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med2008; 359:1811–1821.
Beck LH. Requiem for gouty nephropathy. Kidney Int1986; 30:280–287.
Tomita M, Mizuno S, Yamanaka H, et al. Does hyperuricemia affect mortality? A prospective cohort study of Japanese male workers. J Epidemiol2000; 10:403–409.
Kang DH, Nakagawa T. Uric acid and chronic renal disease: possible implication of hyperuricemia on progression of renal disease. Semin Nephrol2005; 25:43–49.
Iseki K, Oshiro S, Tozawa M, Iseki C, Ikemiya Y, Takishita S. Significance of hyperuricemia on the early detection of renal failure in a cohort of screened subjects. Hypertens Res2001; 24:691–697.
Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia. Risks and consequences in the Normative Aging Study. Am J Med1987; 82:421–426.
Siu YP, Leung KT, Tong MK, Kwan TH. Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level. Am J Kidney Dis2006; 47:51–59.
Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. JAMA2008; 300:924–932.
Hossam El-Zawawy, MD, MS Assistant Professor, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton; Associate Staff, Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Weston, FL
Brian F. Mandell, MD, PhD Chairman, Department of Medicine, Education Institute, Cleveland Clinic; Professor of Medicine, Lerner College of Medicine of Case Western Reserve University, Cleveland, OH; Department of Rheumatic and Immunologic Diseases, Cleveland Clinic; and Editor-in-Chief, Cleveland Clinic Journal of Medicine
Address: Brian F. Mandell, MD, PhD, Education Institute, NA10, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]
Dr. Mandell has disclosed that he has been a consultant for Takeda Pharmaceutical Company and has conducted a clinical trial for Savient Pharmaceuticals.
Hossam El-Zawawy, MD, MS Assistant Professor, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton; Associate Staff, Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Weston, FL
Brian F. Mandell, MD, PhD Chairman, Department of Medicine, Education Institute, Cleveland Clinic; Professor of Medicine, Lerner College of Medicine of Case Western Reserve University, Cleveland, OH; Department of Rheumatic and Immunologic Diseases, Cleveland Clinic; and Editor-in-Chief, Cleveland Clinic Journal of Medicine
Address: Brian F. Mandell, MD, PhD, Education Institute, NA10, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]
Dr. Mandell has disclosed that he has been a consultant for Takeda Pharmaceutical Company and has conducted a clinical trial for Savient Pharmaceuticals.
Author and Disclosure Information
Hossam El-Zawawy, MD, MS Assistant Professor, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton; Associate Staff, Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Weston, FL
Brian F. Mandell, MD, PhD Chairman, Department of Medicine, Education Institute, Cleveland Clinic; Professor of Medicine, Lerner College of Medicine of Case Western Reserve University, Cleveland, OH; Department of Rheumatic and Immunologic Diseases, Cleveland Clinic; and Editor-in-Chief, Cleveland Clinic Journal of Medicine
Address: Brian F. Mandell, MD, PhD, Education Institute, NA10, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]
Dr. Mandell has disclosed that he has been a consultant for Takeda Pharmaceutical Company and has conducted a clinical trial for Savient Pharmaceuticals.
You have a 54-year-old black patient with gout, diabetes mellitus, hypertension, and chronic kidney disease (CKD). He has an acute gout flare involving his right knee. In the past year he has had four attacks of gout in the ankles and knees, which you treated with intra-articular glucocorticoid injections. He has been on allopurinol (Zyloprim) 200 mg daily, but his last serum urate level was 9.4 mg/dL (reference range 3.0–8.0). His creatinine clearance is 45 mL/minute (reference range 85–125).
In view of his kidney disease, you are concerned about increasing his dose of allopurinol, but also about the need to treat his frequent attacks. How should you manage this patient?
GOUT IS CHALLENGING TO TREAT IN PATIENTS WITH KIDNEY DISEASE
A major challenge in treating patients with gout is to avoid therapeutic interactions with common comorbidities, including hypertension, insulin resistance, coronary artery disease, heart failure, and especially CKD.1
In this paper, we discuss approaches to and controversies in the management of gout and hyperuricemia in patients with CKD. Unfortunately, the evidence from clinical trials to guide treatment decisions is limited; therefore, decisions must often be based on experience and pathophysiologic principles.
GENERAL GOALS OF GOUT THERAPY
Depending on the patient and the stage of the disease, the goals in treating patients with gout are to:
Terminate acute attacks as promptly and safely as possible
Prevent recurrences of acute gout attacks
Prevent or reverse complications resulting from deposition of monosodium urate in the joints, in the kidneys, or at other sites.
These goals are more difficult to achieve in patients with CKD because of the potential complications from many of the available drugs.
TERMINATING ACUTE GOUT FLARES
In patients with acute gout, treatment is aimed at quickly resolving pain and inflammation.
Several types of drugs can terminate acute gout flares. The choice in most situations is colchicine (Colcrys); a nonsteroidal anti-inflammatory drug (NSAID); a corticosteroid; or corticotropin (ACTH).
However, in patients with CKD, there are concerns about using colchicine or NSAIDs, and corticotropin is very expensive; thus, corticosteroids are often used.
Colchicine’s clearance is reduced in CKD
Colchicine is somewhat effective in treating acute gout attacks and probably more effective in preventing attacks.
Due to concerns about inappropriate dosing and reported deaths,2 the intravenous formulation is not available in many countries, including the United States.
After oral administration, colchicine is rapidly absorbed, with a bioavailability of up to 50%. It undergoes metabolism by the liver, and its metabolites are excreted by renal and biliary-intestinal routes. Up to 20% of the active drug is excreted by the kidneys.3
Colchicine’s clearance is significantly reduced in patients with renal or hepatic insufficiency, and the drug may accumulate in cells, with resultant toxicity.4 Colchicine-induced toxicity has been observed when the drug was used for acute treatment, as well as for chronic prophylaxis of gout in patients with CKD; thus, alternative agents for treating acute attacks should be considered.5,6 With prolonged use, reversible colchicine-induced axonal neuropathy, neutropenia, and vacuolar myopathy can develop in patients with CKD.7
In a trial in patients with normal renal function, nearly 100% who received an initial dose of 1 mg followed by 0.5 mg every 2 hours developed diarrhea at a median time of 24 hours.8 Emesis may also occur.
A lower dose of 1.8 mg (two 0.6-mg pills followed by one pill an hour later) was well tolerated but only moderately effective in treating acute gout, causing at least a 50% reduction in pain at 24 hours in only 38% of patients.9 This study does not clarify the dosage to use to completely resolve attacks. Using additional colchicine likely will increase the response rate, but will also increase side effects. Patients with CKD were not included.
Some patients, as shown in the above trial, can abort attacks by taking only one or two colchicine tablets when they feel the first “twinge” of an attack. This approach is likely to be safe in CKD, but it may be of value to only a few patients.
Nonsteroidal anti-inflammatory drugs can worsen chronic kidney disease
NSAIDs in high doses can effectively treat the pain and inflammation of acute gout. Indomethacin (Indocin) 50 mg three times daily has been standard NSAID therapy.
Other nonselective NSAIDs and NSAIDs that selectively inhibit cyclooxygenase 2 (COX-2) are effective, but all can cause acute renal toxicity or worsen CKD.10 Renal side effects include salt and water retention, acute tubular necrosis, acute interstitial nephritis, proteinuria, hypertension, hyperkalemia, and chronic renal injury.11
Even short-term use of high-dose NSAIDs should generally be avoided in patients with preexisting CKD, for whom there is no established safe threshold dose. When NSAIDs (including selective COX-2 inhibitors) are used, renal function should be monitored closely and the duration limited as much as possible.
Corticosteroids are often used to treat acute attacks
Due to the concerns about NSAIDs or colchicine to treat acute gout attacks in patients with CKD, corticosteroids are often used in this setting.
Intra-articular steroid injections are useful in treating acute gout limited to a single joint or bursa.12 However, one should first make sure that the joint is not infected: septic arthritis should ideally be excluded by arthrocentesis, particularly in immunosuppressed patients13 or those with end-stage renal disease, who are predisposed to bacteremia.
Oral, intramuscular, or intravenous steroids can provide complete relief from acute gout, although high doses (eg, prednisone 30–60 mg/day or the equivalent) are often needed. Common errors resulting in inefficacy include using too low a dose or not treating for a sufficient time before tapering or stopping. Groff and colleagues14 described 13 patients who received oral or intravenous steroids for acute gout. Nine patients received an initial single dose of prednisone ranging from 20 to 50 mg, with tapering over a mean of 10 days. Twelve of the 13 patients had improvement within 48 hours, and the signs and symptoms of acute gout resolved completely within 7 to 10 days.
We often give prednisone 40 mg daily until a day after the acute attack resolves and then taper over another 7 to 10 days. There are no data to guide steroid dosing in an evidence-based way, but we believe too short a course of therapy may result in return of symptoms.
Corticotropin and other agents: Effective but costly
Corticotropin shares the same indications as systemic corticosteroids, being used to treat flares when NSAIDs, intra-articular steroids, and colchicine are contraindicated. However, corticotropin is far more expensive than generic corticosteroids, costing nearly $2,000 for a single 80-IU dose, which may need to be repeated.
Corticotropin is available for subcutaneous or intramuscular injection. A single intramuscular injection of corticotropin gel (H.P. Acthar, 25–80 IU) may terminate an acute gout attack.15 However, many patients need another injection after 24 to 72 hours, which would require another visit to the physician. This treatment has been touted by some as being more effective than corticosteroid therapy, possibly because of a unique peripheral mechanism of action in addition to stimulating cortisol release.16
We rarely use corticotropin, in view of its cost as well as concerns about excessive sodium and water retention due to the release of multiple hormones from the adrenal gland. This may be especially deleterious in patients with CKD or congestive heart failure.17
Parenteral anti-tumor necrosis factor agents or interleukin 1 antagonists can be dramatically effective but are also expensive.18,19 For example, anakinra (Kineret) 100 mg costs about $73, and multiple daily doses may be necessary.
Under unique conditions in which they can be safely used (eg, patients with CKD, diabetes mellitus, liver disease), they may be cost-effective if they can shorten the stay of a hospitalized patient with acute gout.
PROPHYLACTIC ANTI-INFLAMMATORY THERAPY FOR PATIENTS WITH GOUT
Between attacks, the goal is to prevent new attacks through prophylactic management, which may include anti-inflammatory and hypouricemic therapy along with dietary instruction (such as avoiding excessive beer, liquor, and fructose ingestion).
Colchicine can be used as prophylaxis, with caution and monitoring
Although colchicine is not 100% effective, it markedly reduces the flare rate when started in low doses at the time hypouricemic therapy is initiated.20,21 (Hypouricemic therapy is discussed below.) We generally try to continue this prophylactic therapy, if the patient tolerates it, for at least 6 months—longer if tophi are still present or if attacks continue to occur.
If renal function is intact, colchicine can be prescribed at a dosage of 0.6 mg orally once or twice daily.21 In CKD, since the clearance of colchicine is reduced,4 the dosage should be reduced. Patients on colchicine for prophylaxis must be carefully monitored if the glomerular filtration rate is less than 50 mL/minute, or colchicine should be avoided altogether.6 Laboratory testing for colchicine levels is not routinely available and may be of limited value in predicting adverse effects; thus, recommendations about dose adjustments in CKD are empiric.
Wallace et al22 recommended a dose of 0.6 mg once daily if the creatinine clearance is 35 to 49 mL/minute and 0.6 mg every 2 to 3 days if it is 10 to 34 mL/minute, but there are no published long-term safety or efficacy data validating these reasonable (based on available information) dosing regimens.
Even with dose adjustment, caution is needed. Low-dose daily colchicine may be associated with reversible neuromyopathy and bone marrow suppression.7,23 Patients with neuromyopathy may complain of myalgias, proximal muscle weakness, and numbness and may have areflexia and decreased sensation. Laboratory findings include elevated creatine kinase and aminotransferase levels. We regularly check for leukopenia or elevated creatine kinase and aspartate aminotransferase levels in patients with CKD who are receiving colchicine in any dose.
Prolonged colchicine therapy should probably be avoided in patients on hemodialysis, as this drug is not removed by dialysis or by exchange transfusion, and the risk of toxicity under these circumstances may be high.22 When there is no viable alternative and the drug is given, patients should be closely monitored for signs of toxicity.
Concurrent (even short-term) treatment with most macrolide antibiotics, particularly clarithromycin (Biaxin), most statin drugs, ketoconazole (Nizoral), cyclosporine, and likely other drugs predisposes to colchicine toxicity by altering its distribution and elimination, and can in rare cases cause morbidity or death.24–26
NSAIDs are not optimal as prophylaxis in patients with chronic kidney disease
Little information has been published about using NSAIDs chronically to prevent flares, but they are not the optimal drugs to use in patients with CKD, as discussed above. In patients with end-stage renal disease, there are also concerns about NSAID-induced gastric and intestinal bleeding.
Low-dose steroids may not be effective as prophylaxis
Lower doses of steroids may not be effective as prophylaxis against gout flares, consistent with the common observation that gout flares still occur in organ transplant recipients who are taking maintenance doses of prednisone.13
PREVENTING FLARES BY LOWERING SERUM URATE LEVELS
If tophi are present, if radiography shows evidence of damage, if attacks are frequent or disabling, or if there are relative contraindications to the drugs that would be needed to treat acute attacks, then hypouricemic therapy should be strongly considered to reduce the burden of urate in the body, resorb tophi, and ultimately reduce the frequency of gout flares.20
Although intermittent therapy for attacks or prolonged prophylactic use of colchicine may prevent recurrent episodes of gouty arthritis and may be reasonable for many patients, this approach does not prevent continued urate deposition, with the potential development of bony erosions, tophaceous deposits, and chronic arthritis.
The definitive therapy for gouty arthritis is to deplete the periarticular deposits of urate by maintaining a low serum urate level. Urate-lowering therapy, when indicated, is almost always lifelong.
Four strategies for lowering serum urate
The serum urate concentration can be lowered in four ways:
Increasing renal uric acid excretion
Altering the diet
Decreasing urate synthesis
Converting urate to a more soluble metabolite.
Increasing uric acid excretion is rarely effective if renal function is impaired
Probenecid, sulfinpyrazone (Anturane), and losartan (Cozaar) modestly increase uric acid secretion and reduce serum urate levels, but they are rarely effective if the creatinine clearance rate is less than 60 mL/minute, and they require significant fluid intake for maximal efficacy.
Uricosuric drugs probably should be avoided in patients who excrete more than 1,000 mg of uric acid per day on a normal diet, since urinary uric acid stones may form. In practice, however, patients are given losartan to treat hypertension without attention to uric acid excretion.
More-potent urocosuric drugs are being tested in clinical trials.
Altering the diet: Traditional advice confirmed
The Health Professionals Follow-up Study27,28 prospectively examined the relation between diet and gout over 12 years in 47,150 men. The study confirmed some long-standing beliefs, such as that consuming meat, seafood, beer, and liquor increases the risk. Other risk factors were consumption of sugar-sweetened soft drinks and fructose, adiposity, weight gain, hypertension, and diuretic use. On the other hand, protein, wine, and purine-rich vegetables were not associated with gout flares. Low-fat dairy products may have a protective effect. Weight loss was found to be protective.
Low-purine diets are not very palatable, are difficult to adhere to, and are at best only minimally effective, lowering serum urate by 1 to 2 mg/dL. Low-protein diets designed to slow progression of CKD will likely also have only a slight effect on serum urate. Dietary change alone is not likely to dramatically lower serum urate levels.
Metabolizing urate with exogenous uricase
Rasburicase (Elitek) effectively converts urate to allantoin, which is more soluble, but rasburicase is fraught with allergic reactions and cannot be used as chronic therapy.
A pegylated intravenous uricase29 has just been approved by the US Food and Drug Administration (FDA); the retail cost is not yet known. It is dramatically effective in those patients able to use it chronically, but it has not been fully evaluated in patients with CKD.
Decreasing urate synthesis with allopurinol
Allopurinol acts by competitively inhibiting xanthine oxidase, the enzyme that converts hypoxanthine to xanthine and xanthine to uric acid. The drug, a structural analogue of hypoxanthine, is converted by xanthine oxidase to oxypurinol, which is an even more effective inhibitor of xanthine oxidase than allopurinol.
Allopurinol is metabolized in the liver and has a half-life of 1 to 3 hours, but oxypurinol, which is excreted in the urine, has a half-life of 12 to 17 hours. Because of these pharmacokinetic properties, allopurinol can usually be given once daily, and the dosage required to reduce serum urate levels should in theory be lower in patients with lower glomerular filtration rates.
Allopurinol (100- and 300-mg tablets) is approved by the FDA in doses of up to 800 mg/day to treat hyperuricemia in patients with gout,30 while guidelines from the British Society of Rheumatology advocate a maximum dose of 900 mg/day.31 These maximum doses are based on the limited amount of data with higher doses, not on documented toxicity.
Practice survey data in the United States indicate that most physicians prescribe no greater than 300 mg daily, although this dosage is likely to reduce the serum urate to less than 6 mg/dL—the goal level—in fewer than 50% of patients.20,32 Patients with normal renal function occasionally require more than 1,000 mg daily to reduce the serum urate level to less than 6 mg/dL.
How low should the serum urate level be?
Ideally, therapy should keep the serum urate level significantly below 6.7 mg/dL, the approximate saturation point of urate in physiologic fluids.
Lowering the serum urate level from 10 mg/dL to 7 mg/dL may seem encouraging, and the urate level may be in the laboratory “normal” range; however, urate may continue to precipitate in tissues if the concentration is greater than 6.7 mg/dL. A target of 6 mg/dL, used in clinical studies, is far enough below the saturation level to provide some margin for fluctuations in serum levels. A serum level of 6.0 mg/dL has thus been arbitrarily proposed as a reasonable therapeutic target.
The lower the serum urate level achieved during hypouricemic therapy, the faster the reduction in tophaceous deposits. With adequate urate lowering, tophi can be visibly reduced in less than a year of hypouricemic therapy.33,34
We have as yet no convincing evidence that lowering the serum urate level to less than 6.0 mg/dL is harmful, despite theoretical concerns that urate is a beneficial circulating antioxidant and epidemiologic observations that urate levels have been inversely correlated with progression of Parkinson disease.
Start low, go slow to avoid a flare
Rapid reduction of the serum urate level in a patient with chronic hyperuricemia and gout is likely to induce an acute flare.20 We have traditionally used a “start low and increase slowly” approach to escalating hypouricemic therapy in hopes of reducing the likelihood of causing a gout flare.
Without anti-inflammatory prophylaxis, acute flares associated with urate-lowering are extremely likely. In a 28-week trial of allopurinol, febuxostat, and placebo by Schumacher et al,33 during the first 8 weeks, when prophylaxis against gout flare was provided with either colchicine 0.6 mg once daily or naproxen (Naprosyn) 250 mg twice daily, the proportion of patients requiring treatment of gout flares was still 23% to 46%. When prophylaxis was stopped, the flare rate increased further.33
The more we acutely lower serum urate levels, the more likely flares are to occur. In the study by Schumacher et al,33 the percentage of patients needing treatment for gout flares during the first 8 weeks of the study, despite gout flare prophylaxis, was related to the percent reduction in serum urate by week 28 of the trial (Table 2).
IS IT NECESSARY TO ADJUST THE ALLOPURINOL DOSE IN CHRONIC KIDNEY DISEASE?
In 1984, Hande et al35 proposed that allopurinol doses be lower in patients with renal insufficiency, with a dosage scale based on creatinine clearance.
Their thoughtful proposal was based on data from six of their own patients and 72 others with severe allopurinol toxicity, mainly allopurinol hypersensitivity syndrome, reported in the literature.
Perez-Ruiz et al36 noted that patients who had experienced adverse effects from allopurinol in their series were likely to have had received “higher” doses of allopurinol, if the dosage was corrected for reduced oxypurinol elimination based on their estimated creatinine clearance.
However, most of these reactions occurred soon after initiating therapy, a temporal pattern more typical of non-dose-dependent allergic reactions. Additionally, allopurinol hypersensitivity has been linked to T-cell-mediated immune reactions to oxypurinol,37 a mechanism not likely linked to drug levels.
Arguments against dose adjustment
Despite the compelling information that allopurinol reactions are more common in CKD, adjusting the dosage of allopurinol has not been clearly shown to reduce the frequency of these reactions.
In a small retrospective analysis, Vázquez-Mellado et al38 reported that adjusting the allopurinol dosage according to creatinine clearance did not decrease the incidence of allopurinol hypersensitivity.
In a study in 250 patients, Dalbeth et al39 showed that the overall incidence of hypersensitivity reaction was 1.6%, and the incidence of allergic reactions did not decrease when allopurinol was given according to the dosing guidelines proposed by Hande et al.35 However, it is worth noting that, of the patients who received the recommended lower doses, only 19% achieved the target serum urate level of 6 mg/dL.39
Silverberg et al40 found that of 15 patients who developed hypersensitivity reactions to allopurinol, 10 had received doses that were low or appropriate according to the guidelines of Hande et al.35
More recently, Stamp et al41 found that gradually increasing the allopurinol dose above the proposed creatinine clearance-based dose was safe and effective. Thirty-one (89%) of the 35 patients who completed the study achieved the target serum urate level of 6 mg/dL, while only 3 of 45 who started the study developed rashes, which were not serious.
The small number of patients in these studies limits any strong conclusion, but at present there is no interventional study showing that allopurinol dosing adjustment based on glomerular filtration rate is effective or safer than dosing based on the serum urate level.
Our view on allopurinol dosing adjustment
We believe the initial observations of Hande et al35 and the subsequent meticulous data from Perez-Ruiz et al36 suggest a relationship between CKD and the occurrence of severe allopurinol reactions. However, these observations do not prove that dose adjustment will prevent these reactions.
In patients with normal kidney function, the FDA30 and the European League Against Rheumatism (EULAR)42 recommend slow upward titration, starting with 100 to 200 mg/day, which we agree should decrease the frequency of acute gout flares. The dose is increased by increments of 100 mg/day at intervals of 1 week (FDA recommendation) or 2 to 4 weeks (EULAR recommendation) until the serum urate level is lower than 6 mg/dL.
We believe the optimal approach to allopurinol dosing in patients with CKD remains uncertain. We generally escalate the dose slowly, with ongoing frequent laboratory and clinical monitoring, and we do not limit the maximal dose as suggested by Hande et al.35
An alternative strategy is to use the newer, far more expensive xanthine oxidase inhibitor febuxostat in patients with CKD, since it is not excreted by the kidney. We usually first try escalating doses of allopurinol.
FEBUXOSTAT, AN ALTERNATIVE TO ALLOPURINOL
Febuxostat is an oral nonpurine inhibitor of xanthine oxidase.43 Approved by the FDA in 2009, it is available in 40- and 80-mg tablets.
Unlike allopurinol, febuxostat is metabolized primarily by hepatic glucuronide formation and oxidation and then excreted in stool and urine,44 making it in theory an attractive agent in patients with renal insufficiency, bypassing the controversial dose-adjustment issue with allopurinol.
In the Febuxostat Versus Allopurinol Controlled Trial (FACT),20 a 52-week randomized, double-blind study in hyperuricemic patients with gout, serum urate levels were reduced to less than 6.0 mg/dL in over 50% of patients receiving febuxostat 80 mg or 120 mg once daily, while only 21% of patients receiving 300 mg of allopurinol achieved this goal. This does not imply that allopurinol at higher doses, as should be used in clinical practice,45 would not be equally effective. Patients with CKD were not included in this trial.
In the study by Schumacher et al,33 febuxostat 80, 120, or 240 mg once daily reduced serum urate. A small subset (35 patients) had mild to moderate renal insufficiency (serum creatinine 1.5–2 mg/dL).33 The number of patients with renal insufficiency who achieved the primary end point of a serum urate level lower than 6 mg/dL was 4 (44%) of 9 in the febuxostat 80-mg group, 5 (46%) of 11 in the 120-mg group, and 3 (60%) of 5 in the 240-mg group, while none of the 10 patients in the dose-adjusted allopurinol group achieved the primary end point (P < .05). Of note, 41% of the patients with normal renal function who received allopurinol achieved the primary end point.33 As proposed above, if the allopurinol dose had been slowly increased in the patients with renal insufficiency, it might have been equally effective.
Febuxostat has not been thoroughly evaluated in patients with severe CKD or in patients on hemodialysis.
A presumed niche indication of febuxostat is in patients allergic to allopurinol, since the drugs are not similar in chemical structure. However, at present, experience with this use is limited. Allopurinol-allergic patients were excluded from the clinical trials; thus, if there is any allergic overlap, it would not likely have been recognized in those studies. The FDA has received reports of patients who were allergic to allopurinol also having reactions to febuxostat, and it is currently evaluating these reports (personal communication).
Concern was raised over cardiovascular adverse events in patients treated with febuxostat during clinical trials. In the FACT trial, two patients died of cardiac causes.20 In the study by Schumacher et al,33 11 of 670 patients experienced cardiac adverse events in the febuxostat group vs 3 of 268 in the allopurinol group. Events included atrial fibrillation, chest pain, coronary artery disease, and myocardial infarction. However, this difference was not statistically significant.
Febuxostat costs much more than allopurinol. Currently, patients pay $153.88 for 1 month of febuxostat 40 or 80 mg from Cleveland Clinic pharmacy; 1 month of allopurinol costs $17.45 (300 mg) or $14.00 (100 mg). We believe febuxostat should be reserved for patients with documented intolerance to allopurinol in effective doses.
Monitoring serum urate levels is important in all patients on hypouricemic therapy so that dosage adjustments can be made until the target serum urate concentration is reached. In patients failing to meet target serum urate levels, patient adherence with the prescribed dosing should be specifically addressed because as many as 50% of patients do not adhere to their prescribed regimen.
DOES URATE-LOWERING THERAPY HAVE BENEFITS BEYOND GOUT?
Despite experimental animal data and a strong epidemiologic association between hyperuri-cemia and hypertension,46 metabolic syndrome, and rates of cardiovascular and all-cause mortality,47 the evidence from interventional trials so far does not support the routine use of hypo-uricemic therapy to prevent these outcomes.
Similarly, hyperuricemia has long been associated with renal disease, and there has been debate as to whether hyperuricemia is a result of kidney dysfunction or a contributing factor.46,48–51 A few studies have documented improvement of renal function after initiation of hypouricemic therapy.52 However, treating asymptomatic hyperuricemia to preserve kidney function remains controversial.
A recent study indicates that lowering the serum urate level with allopurinol can lower the blood pressure in hyperuricemic adolescents who have newly diagnosed primary hypertension.53 This does not indicate, however, that initiating hypouricemic therapy in patients with preexisting, long-standing hypertension will be successful.
RECOMMENDED FOR OUR PATIENT
As for our diabetic patient with an acute gout flare and creatinine clearance rate of 45 mL/minute, we would recommend:
Aspirating the knee, sending the fluid for bacterial culture, and then treating it with a local glucocorticoid injection
Starting colchicine 0.6 mg every day, with frequent monitoring for signs of toxicity (muscle pain, weakness, leukopenia, and elevations of creatine kinase and aspartate aminotransferase)
Increasing his allopurinol dose by 100 mg every 2 to 4 weeks until the target serum urate level of less than 6.0 mg/dL is reached
If he cannot tolerate allopurinol or if the target serum urate level is not achieved despite adequate doses of allopurinol (about 800 mg), we would switch to febuxostat 40 mg and increase the dose as needed to achieve the desired urate level.
You have a 54-year-old black patient with gout, diabetes mellitus, hypertension, and chronic kidney disease (CKD). He has an acute gout flare involving his right knee. In the past year he has had four attacks of gout in the ankles and knees, which you treated with intra-articular glucocorticoid injections. He has been on allopurinol (Zyloprim) 200 mg daily, but his last serum urate level was 9.4 mg/dL (reference range 3.0–8.0). His creatinine clearance is 45 mL/minute (reference range 85–125).
In view of his kidney disease, you are concerned about increasing his dose of allopurinol, but also about the need to treat his frequent attacks. How should you manage this patient?
GOUT IS CHALLENGING TO TREAT IN PATIENTS WITH KIDNEY DISEASE
A major challenge in treating patients with gout is to avoid therapeutic interactions with common comorbidities, including hypertension, insulin resistance, coronary artery disease, heart failure, and especially CKD.1
In this paper, we discuss approaches to and controversies in the management of gout and hyperuricemia in patients with CKD. Unfortunately, the evidence from clinical trials to guide treatment decisions is limited; therefore, decisions must often be based on experience and pathophysiologic principles.
GENERAL GOALS OF GOUT THERAPY
Depending on the patient and the stage of the disease, the goals in treating patients with gout are to:
Terminate acute attacks as promptly and safely as possible
Prevent recurrences of acute gout attacks
Prevent or reverse complications resulting from deposition of monosodium urate in the joints, in the kidneys, or at other sites.
These goals are more difficult to achieve in patients with CKD because of the potential complications from many of the available drugs.
TERMINATING ACUTE GOUT FLARES
In patients with acute gout, treatment is aimed at quickly resolving pain and inflammation.
Several types of drugs can terminate acute gout flares. The choice in most situations is colchicine (Colcrys); a nonsteroidal anti-inflammatory drug (NSAID); a corticosteroid; or corticotropin (ACTH).
However, in patients with CKD, there are concerns about using colchicine or NSAIDs, and corticotropin is very expensive; thus, corticosteroids are often used.
Colchicine’s clearance is reduced in CKD
Colchicine is somewhat effective in treating acute gout attacks and probably more effective in preventing attacks.
Due to concerns about inappropriate dosing and reported deaths,2 the intravenous formulation is not available in many countries, including the United States.
After oral administration, colchicine is rapidly absorbed, with a bioavailability of up to 50%. It undergoes metabolism by the liver, and its metabolites are excreted by renal and biliary-intestinal routes. Up to 20% of the active drug is excreted by the kidneys.3
Colchicine’s clearance is significantly reduced in patients with renal or hepatic insufficiency, and the drug may accumulate in cells, with resultant toxicity.4 Colchicine-induced toxicity has been observed when the drug was used for acute treatment, as well as for chronic prophylaxis of gout in patients with CKD; thus, alternative agents for treating acute attacks should be considered.5,6 With prolonged use, reversible colchicine-induced axonal neuropathy, neutropenia, and vacuolar myopathy can develop in patients with CKD.7
In a trial in patients with normal renal function, nearly 100% who received an initial dose of 1 mg followed by 0.5 mg every 2 hours developed diarrhea at a median time of 24 hours.8 Emesis may also occur.
A lower dose of 1.8 mg (two 0.6-mg pills followed by one pill an hour later) was well tolerated but only moderately effective in treating acute gout, causing at least a 50% reduction in pain at 24 hours in only 38% of patients.9 This study does not clarify the dosage to use to completely resolve attacks. Using additional colchicine likely will increase the response rate, but will also increase side effects. Patients with CKD were not included.
Some patients, as shown in the above trial, can abort attacks by taking only one or two colchicine tablets when they feel the first “twinge” of an attack. This approach is likely to be safe in CKD, but it may be of value to only a few patients.
Nonsteroidal anti-inflammatory drugs can worsen chronic kidney disease
NSAIDs in high doses can effectively treat the pain and inflammation of acute gout. Indomethacin (Indocin) 50 mg three times daily has been standard NSAID therapy.
Other nonselective NSAIDs and NSAIDs that selectively inhibit cyclooxygenase 2 (COX-2) are effective, but all can cause acute renal toxicity or worsen CKD.10 Renal side effects include salt and water retention, acute tubular necrosis, acute interstitial nephritis, proteinuria, hypertension, hyperkalemia, and chronic renal injury.11
Even short-term use of high-dose NSAIDs should generally be avoided in patients with preexisting CKD, for whom there is no established safe threshold dose. When NSAIDs (including selective COX-2 inhibitors) are used, renal function should be monitored closely and the duration limited as much as possible.
Corticosteroids are often used to treat acute attacks
Due to the concerns about NSAIDs or colchicine to treat acute gout attacks in patients with CKD, corticosteroids are often used in this setting.
Intra-articular steroid injections are useful in treating acute gout limited to a single joint or bursa.12 However, one should first make sure that the joint is not infected: septic arthritis should ideally be excluded by arthrocentesis, particularly in immunosuppressed patients13 or those with end-stage renal disease, who are predisposed to bacteremia.
Oral, intramuscular, or intravenous steroids can provide complete relief from acute gout, although high doses (eg, prednisone 30–60 mg/day or the equivalent) are often needed. Common errors resulting in inefficacy include using too low a dose or not treating for a sufficient time before tapering or stopping. Groff and colleagues14 described 13 patients who received oral or intravenous steroids for acute gout. Nine patients received an initial single dose of prednisone ranging from 20 to 50 mg, with tapering over a mean of 10 days. Twelve of the 13 patients had improvement within 48 hours, and the signs and symptoms of acute gout resolved completely within 7 to 10 days.
We often give prednisone 40 mg daily until a day after the acute attack resolves and then taper over another 7 to 10 days. There are no data to guide steroid dosing in an evidence-based way, but we believe too short a course of therapy may result in return of symptoms.
Corticotropin and other agents: Effective but costly
Corticotropin shares the same indications as systemic corticosteroids, being used to treat flares when NSAIDs, intra-articular steroids, and colchicine are contraindicated. However, corticotropin is far more expensive than generic corticosteroids, costing nearly $2,000 for a single 80-IU dose, which may need to be repeated.
Corticotropin is available for subcutaneous or intramuscular injection. A single intramuscular injection of corticotropin gel (H.P. Acthar, 25–80 IU) may terminate an acute gout attack.15 However, many patients need another injection after 24 to 72 hours, which would require another visit to the physician. This treatment has been touted by some as being more effective than corticosteroid therapy, possibly because of a unique peripheral mechanism of action in addition to stimulating cortisol release.16
We rarely use corticotropin, in view of its cost as well as concerns about excessive sodium and water retention due to the release of multiple hormones from the adrenal gland. This may be especially deleterious in patients with CKD or congestive heart failure.17
Parenteral anti-tumor necrosis factor agents or interleukin 1 antagonists can be dramatically effective but are also expensive.18,19 For example, anakinra (Kineret) 100 mg costs about $73, and multiple daily doses may be necessary.
Under unique conditions in which they can be safely used (eg, patients with CKD, diabetes mellitus, liver disease), they may be cost-effective if they can shorten the stay of a hospitalized patient with acute gout.
PROPHYLACTIC ANTI-INFLAMMATORY THERAPY FOR PATIENTS WITH GOUT
Between attacks, the goal is to prevent new attacks through prophylactic management, which may include anti-inflammatory and hypouricemic therapy along with dietary instruction (such as avoiding excessive beer, liquor, and fructose ingestion).
Colchicine can be used as prophylaxis, with caution and monitoring
Although colchicine is not 100% effective, it markedly reduces the flare rate when started in low doses at the time hypouricemic therapy is initiated.20,21 (Hypouricemic therapy is discussed below.) We generally try to continue this prophylactic therapy, if the patient tolerates it, for at least 6 months—longer if tophi are still present or if attacks continue to occur.
If renal function is intact, colchicine can be prescribed at a dosage of 0.6 mg orally once or twice daily.21 In CKD, since the clearance of colchicine is reduced,4 the dosage should be reduced. Patients on colchicine for prophylaxis must be carefully monitored if the glomerular filtration rate is less than 50 mL/minute, or colchicine should be avoided altogether.6 Laboratory testing for colchicine levels is not routinely available and may be of limited value in predicting adverse effects; thus, recommendations about dose adjustments in CKD are empiric.
Wallace et al22 recommended a dose of 0.6 mg once daily if the creatinine clearance is 35 to 49 mL/minute and 0.6 mg every 2 to 3 days if it is 10 to 34 mL/minute, but there are no published long-term safety or efficacy data validating these reasonable (based on available information) dosing regimens.
Even with dose adjustment, caution is needed. Low-dose daily colchicine may be associated with reversible neuromyopathy and bone marrow suppression.7,23 Patients with neuromyopathy may complain of myalgias, proximal muscle weakness, and numbness and may have areflexia and decreased sensation. Laboratory findings include elevated creatine kinase and aminotransferase levels. We regularly check for leukopenia or elevated creatine kinase and aspartate aminotransferase levels in patients with CKD who are receiving colchicine in any dose.
Prolonged colchicine therapy should probably be avoided in patients on hemodialysis, as this drug is not removed by dialysis or by exchange transfusion, and the risk of toxicity under these circumstances may be high.22 When there is no viable alternative and the drug is given, patients should be closely monitored for signs of toxicity.
Concurrent (even short-term) treatment with most macrolide antibiotics, particularly clarithromycin (Biaxin), most statin drugs, ketoconazole (Nizoral), cyclosporine, and likely other drugs predisposes to colchicine toxicity by altering its distribution and elimination, and can in rare cases cause morbidity or death.24–26
NSAIDs are not optimal as prophylaxis in patients with chronic kidney disease
Little information has been published about using NSAIDs chronically to prevent flares, but they are not the optimal drugs to use in patients with CKD, as discussed above. In patients with end-stage renal disease, there are also concerns about NSAID-induced gastric and intestinal bleeding.
Low-dose steroids may not be effective as prophylaxis
Lower doses of steroids may not be effective as prophylaxis against gout flares, consistent with the common observation that gout flares still occur in organ transplant recipients who are taking maintenance doses of prednisone.13
PREVENTING FLARES BY LOWERING SERUM URATE LEVELS
If tophi are present, if radiography shows evidence of damage, if attacks are frequent or disabling, or if there are relative contraindications to the drugs that would be needed to treat acute attacks, then hypouricemic therapy should be strongly considered to reduce the burden of urate in the body, resorb tophi, and ultimately reduce the frequency of gout flares.20
Although intermittent therapy for attacks or prolonged prophylactic use of colchicine may prevent recurrent episodes of gouty arthritis and may be reasonable for many patients, this approach does not prevent continued urate deposition, with the potential development of bony erosions, tophaceous deposits, and chronic arthritis.
The definitive therapy for gouty arthritis is to deplete the periarticular deposits of urate by maintaining a low serum urate level. Urate-lowering therapy, when indicated, is almost always lifelong.
Four strategies for lowering serum urate
The serum urate concentration can be lowered in four ways:
Increasing renal uric acid excretion
Altering the diet
Decreasing urate synthesis
Converting urate to a more soluble metabolite.
Increasing uric acid excretion is rarely effective if renal function is impaired
Probenecid, sulfinpyrazone (Anturane), and losartan (Cozaar) modestly increase uric acid secretion and reduce serum urate levels, but they are rarely effective if the creatinine clearance rate is less than 60 mL/minute, and they require significant fluid intake for maximal efficacy.
Uricosuric drugs probably should be avoided in patients who excrete more than 1,000 mg of uric acid per day on a normal diet, since urinary uric acid stones may form. In practice, however, patients are given losartan to treat hypertension without attention to uric acid excretion.
More-potent urocosuric drugs are being tested in clinical trials.
Altering the diet: Traditional advice confirmed
The Health Professionals Follow-up Study27,28 prospectively examined the relation between diet and gout over 12 years in 47,150 men. The study confirmed some long-standing beliefs, such as that consuming meat, seafood, beer, and liquor increases the risk. Other risk factors were consumption of sugar-sweetened soft drinks and fructose, adiposity, weight gain, hypertension, and diuretic use. On the other hand, protein, wine, and purine-rich vegetables were not associated with gout flares. Low-fat dairy products may have a protective effect. Weight loss was found to be protective.
Low-purine diets are not very palatable, are difficult to adhere to, and are at best only minimally effective, lowering serum urate by 1 to 2 mg/dL. Low-protein diets designed to slow progression of CKD will likely also have only a slight effect on serum urate. Dietary change alone is not likely to dramatically lower serum urate levels.
Metabolizing urate with exogenous uricase
Rasburicase (Elitek) effectively converts urate to allantoin, which is more soluble, but rasburicase is fraught with allergic reactions and cannot be used as chronic therapy.
A pegylated intravenous uricase29 has just been approved by the US Food and Drug Administration (FDA); the retail cost is not yet known. It is dramatically effective in those patients able to use it chronically, but it has not been fully evaluated in patients with CKD.
Decreasing urate synthesis with allopurinol
Allopurinol acts by competitively inhibiting xanthine oxidase, the enzyme that converts hypoxanthine to xanthine and xanthine to uric acid. The drug, a structural analogue of hypoxanthine, is converted by xanthine oxidase to oxypurinol, which is an even more effective inhibitor of xanthine oxidase than allopurinol.
Allopurinol is metabolized in the liver and has a half-life of 1 to 3 hours, but oxypurinol, which is excreted in the urine, has a half-life of 12 to 17 hours. Because of these pharmacokinetic properties, allopurinol can usually be given once daily, and the dosage required to reduce serum urate levels should in theory be lower in patients with lower glomerular filtration rates.
Allopurinol (100- and 300-mg tablets) is approved by the FDA in doses of up to 800 mg/day to treat hyperuricemia in patients with gout,30 while guidelines from the British Society of Rheumatology advocate a maximum dose of 900 mg/day.31 These maximum doses are based on the limited amount of data with higher doses, not on documented toxicity.
Practice survey data in the United States indicate that most physicians prescribe no greater than 300 mg daily, although this dosage is likely to reduce the serum urate to less than 6 mg/dL—the goal level—in fewer than 50% of patients.20,32 Patients with normal renal function occasionally require more than 1,000 mg daily to reduce the serum urate level to less than 6 mg/dL.
How low should the serum urate level be?
Ideally, therapy should keep the serum urate level significantly below 6.7 mg/dL, the approximate saturation point of urate in physiologic fluids.
Lowering the serum urate level from 10 mg/dL to 7 mg/dL may seem encouraging, and the urate level may be in the laboratory “normal” range; however, urate may continue to precipitate in tissues if the concentration is greater than 6.7 mg/dL. A target of 6 mg/dL, used in clinical studies, is far enough below the saturation level to provide some margin for fluctuations in serum levels. A serum level of 6.0 mg/dL has thus been arbitrarily proposed as a reasonable therapeutic target.
The lower the serum urate level achieved during hypouricemic therapy, the faster the reduction in tophaceous deposits. With adequate urate lowering, tophi can be visibly reduced in less than a year of hypouricemic therapy.33,34
We have as yet no convincing evidence that lowering the serum urate level to less than 6.0 mg/dL is harmful, despite theoretical concerns that urate is a beneficial circulating antioxidant and epidemiologic observations that urate levels have been inversely correlated with progression of Parkinson disease.
Start low, go slow to avoid a flare
Rapid reduction of the serum urate level in a patient with chronic hyperuricemia and gout is likely to induce an acute flare.20 We have traditionally used a “start low and increase slowly” approach to escalating hypouricemic therapy in hopes of reducing the likelihood of causing a gout flare.
Without anti-inflammatory prophylaxis, acute flares associated with urate-lowering are extremely likely. In a 28-week trial of allopurinol, febuxostat, and placebo by Schumacher et al,33 during the first 8 weeks, when prophylaxis against gout flare was provided with either colchicine 0.6 mg once daily or naproxen (Naprosyn) 250 mg twice daily, the proportion of patients requiring treatment of gout flares was still 23% to 46%. When prophylaxis was stopped, the flare rate increased further.33
The more we acutely lower serum urate levels, the more likely flares are to occur. In the study by Schumacher et al,33 the percentage of patients needing treatment for gout flares during the first 8 weeks of the study, despite gout flare prophylaxis, was related to the percent reduction in serum urate by week 28 of the trial (Table 2).
IS IT NECESSARY TO ADJUST THE ALLOPURINOL DOSE IN CHRONIC KIDNEY DISEASE?
In 1984, Hande et al35 proposed that allopurinol doses be lower in patients with renal insufficiency, with a dosage scale based on creatinine clearance.
Their thoughtful proposal was based on data from six of their own patients and 72 others with severe allopurinol toxicity, mainly allopurinol hypersensitivity syndrome, reported in the literature.
Perez-Ruiz et al36 noted that patients who had experienced adverse effects from allopurinol in their series were likely to have had received “higher” doses of allopurinol, if the dosage was corrected for reduced oxypurinol elimination based on their estimated creatinine clearance.
However, most of these reactions occurred soon after initiating therapy, a temporal pattern more typical of non-dose-dependent allergic reactions. Additionally, allopurinol hypersensitivity has been linked to T-cell-mediated immune reactions to oxypurinol,37 a mechanism not likely linked to drug levels.
Arguments against dose adjustment
Despite the compelling information that allopurinol reactions are more common in CKD, adjusting the dosage of allopurinol has not been clearly shown to reduce the frequency of these reactions.
In a small retrospective analysis, Vázquez-Mellado et al38 reported that adjusting the allopurinol dosage according to creatinine clearance did not decrease the incidence of allopurinol hypersensitivity.
In a study in 250 patients, Dalbeth et al39 showed that the overall incidence of hypersensitivity reaction was 1.6%, and the incidence of allergic reactions did not decrease when allopurinol was given according to the dosing guidelines proposed by Hande et al.35 However, it is worth noting that, of the patients who received the recommended lower doses, only 19% achieved the target serum urate level of 6 mg/dL.39
Silverberg et al40 found that of 15 patients who developed hypersensitivity reactions to allopurinol, 10 had received doses that were low or appropriate according to the guidelines of Hande et al.35
More recently, Stamp et al41 found that gradually increasing the allopurinol dose above the proposed creatinine clearance-based dose was safe and effective. Thirty-one (89%) of the 35 patients who completed the study achieved the target serum urate level of 6 mg/dL, while only 3 of 45 who started the study developed rashes, which were not serious.
The small number of patients in these studies limits any strong conclusion, but at present there is no interventional study showing that allopurinol dosing adjustment based on glomerular filtration rate is effective or safer than dosing based on the serum urate level.
Our view on allopurinol dosing adjustment
We believe the initial observations of Hande et al35 and the subsequent meticulous data from Perez-Ruiz et al36 suggest a relationship between CKD and the occurrence of severe allopurinol reactions. However, these observations do not prove that dose adjustment will prevent these reactions.
In patients with normal kidney function, the FDA30 and the European League Against Rheumatism (EULAR)42 recommend slow upward titration, starting with 100 to 200 mg/day, which we agree should decrease the frequency of acute gout flares. The dose is increased by increments of 100 mg/day at intervals of 1 week (FDA recommendation) or 2 to 4 weeks (EULAR recommendation) until the serum urate level is lower than 6 mg/dL.
We believe the optimal approach to allopurinol dosing in patients with CKD remains uncertain. We generally escalate the dose slowly, with ongoing frequent laboratory and clinical monitoring, and we do not limit the maximal dose as suggested by Hande et al.35
An alternative strategy is to use the newer, far more expensive xanthine oxidase inhibitor febuxostat in patients with CKD, since it is not excreted by the kidney. We usually first try escalating doses of allopurinol.
FEBUXOSTAT, AN ALTERNATIVE TO ALLOPURINOL
Febuxostat is an oral nonpurine inhibitor of xanthine oxidase.43 Approved by the FDA in 2009, it is available in 40- and 80-mg tablets.
Unlike allopurinol, febuxostat is metabolized primarily by hepatic glucuronide formation and oxidation and then excreted in stool and urine,44 making it in theory an attractive agent in patients with renal insufficiency, bypassing the controversial dose-adjustment issue with allopurinol.
In the Febuxostat Versus Allopurinol Controlled Trial (FACT),20 a 52-week randomized, double-blind study in hyperuricemic patients with gout, serum urate levels were reduced to less than 6.0 mg/dL in over 50% of patients receiving febuxostat 80 mg or 120 mg once daily, while only 21% of patients receiving 300 mg of allopurinol achieved this goal. This does not imply that allopurinol at higher doses, as should be used in clinical practice,45 would not be equally effective. Patients with CKD were not included in this trial.
In the study by Schumacher et al,33 febuxostat 80, 120, or 240 mg once daily reduced serum urate. A small subset (35 patients) had mild to moderate renal insufficiency (serum creatinine 1.5–2 mg/dL).33 The number of patients with renal insufficiency who achieved the primary end point of a serum urate level lower than 6 mg/dL was 4 (44%) of 9 in the febuxostat 80-mg group, 5 (46%) of 11 in the 120-mg group, and 3 (60%) of 5 in the 240-mg group, while none of the 10 patients in the dose-adjusted allopurinol group achieved the primary end point (P < .05). Of note, 41% of the patients with normal renal function who received allopurinol achieved the primary end point.33 As proposed above, if the allopurinol dose had been slowly increased in the patients with renal insufficiency, it might have been equally effective.
Febuxostat has not been thoroughly evaluated in patients with severe CKD or in patients on hemodialysis.
A presumed niche indication of febuxostat is in patients allergic to allopurinol, since the drugs are not similar in chemical structure. However, at present, experience with this use is limited. Allopurinol-allergic patients were excluded from the clinical trials; thus, if there is any allergic overlap, it would not likely have been recognized in those studies. The FDA has received reports of patients who were allergic to allopurinol also having reactions to febuxostat, and it is currently evaluating these reports (personal communication).
Concern was raised over cardiovascular adverse events in patients treated with febuxostat during clinical trials. In the FACT trial, two patients died of cardiac causes.20 In the study by Schumacher et al,33 11 of 670 patients experienced cardiac adverse events in the febuxostat group vs 3 of 268 in the allopurinol group. Events included atrial fibrillation, chest pain, coronary artery disease, and myocardial infarction. However, this difference was not statistically significant.
Febuxostat costs much more than allopurinol. Currently, patients pay $153.88 for 1 month of febuxostat 40 or 80 mg from Cleveland Clinic pharmacy; 1 month of allopurinol costs $17.45 (300 mg) or $14.00 (100 mg). We believe febuxostat should be reserved for patients with documented intolerance to allopurinol in effective doses.
Monitoring serum urate levels is important in all patients on hypouricemic therapy so that dosage adjustments can be made until the target serum urate concentration is reached. In patients failing to meet target serum urate levels, patient adherence with the prescribed dosing should be specifically addressed because as many as 50% of patients do not adhere to their prescribed regimen.
DOES URATE-LOWERING THERAPY HAVE BENEFITS BEYOND GOUT?
Despite experimental animal data and a strong epidemiologic association between hyperuri-cemia and hypertension,46 metabolic syndrome, and rates of cardiovascular and all-cause mortality,47 the evidence from interventional trials so far does not support the routine use of hypo-uricemic therapy to prevent these outcomes.
Similarly, hyperuricemia has long been associated with renal disease, and there has been debate as to whether hyperuricemia is a result of kidney dysfunction or a contributing factor.46,48–51 A few studies have documented improvement of renal function after initiation of hypouricemic therapy.52 However, treating asymptomatic hyperuricemia to preserve kidney function remains controversial.
A recent study indicates that lowering the serum urate level with allopurinol can lower the blood pressure in hyperuricemic adolescents who have newly diagnosed primary hypertension.53 This does not indicate, however, that initiating hypouricemic therapy in patients with preexisting, long-standing hypertension will be successful.
RECOMMENDED FOR OUR PATIENT
As for our diabetic patient with an acute gout flare and creatinine clearance rate of 45 mL/minute, we would recommend:
Aspirating the knee, sending the fluid for bacterial culture, and then treating it with a local glucocorticoid injection
Starting colchicine 0.6 mg every day, with frequent monitoring for signs of toxicity (muscle pain, weakness, leukopenia, and elevations of creatine kinase and aspartate aminotransferase)
Increasing his allopurinol dose by 100 mg every 2 to 4 weeks until the target serum urate level of less than 6.0 mg/dL is reached
If he cannot tolerate allopurinol or if the target serum urate level is not achieved despite adequate doses of allopurinol (about 800 mg), we would switch to febuxostat 40 mg and increase the dose as needed to achieve the desired urate level.
References
Vázquez-Mellado J, García CG, Vázquez SG, et al. Metabolic syndrome and ischemic heart disease in gout. J Clin Rheumatol2004; 10:105–109.
Bonnel RA, Villalba ML, Karwoski CB, Beitz J. Deaths associated with inappropriate intravenous colchicine administration. J Emerg Med2002; 22:385–387.
Achtert G, Scherrmann JM, Christen MO. Pharmacokinetics/bioavailability of colchicine in healthy male volunteers. Eur J Drug Metab Pharmacokinet1989; 14:317–322.
Ben-Chetrit E, Scherrmann JM, Zylber-Katz E, Levy M. Colchicine disposition in patients with familial Mediterranean fever with renal impairment. J Rheumatol1994; 21:710–713.
Putterman C, Ben-Chetrit E, Caraco Y, Levy M. Colchicine intoxication: clinical pharmacology, risk factors, features, and management. Semin Arthritis Rheum1991; 21:143–155.
Aronoff G, Brater DC, Schrier R, Bennett WM. Use of drugs in patients with renal insufficiency. Workshop report. Blood Purif1994; 12:14–19.
Kuncl RW, Duncan G, Watson D, Alderson K, Rogawski MA, Peper M. Colchicine myopathy and neuropathy. N Engl J Med1987; 316:1562–1568.
Ahern MJ, Reid C, Gordon TP, McCredie M, Brooks PM, Jones M. Does colchicine work? The results of the first controlled study in acute gout. Aust N Z J Med1987; 17:301–304.
Terkeltaub R, Furst D, Bennett K, Kook K, Crockett RS, Davis WM. High versus low dosing of oral colchicine for early acute gout flare: twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. Arthritis Rheum2010, 62:1060–1068.
Whelton A. Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications. Am J Med1999; 106:13S–24S.
Wali RK, Henrich WL. Recent developments in toxic nephropathy. Curr Opin Nephrol Hypertens2002; 11:155–163.
Fernández C, Noguera R, González JA, Pascual E. Treatment of acute attacks of gout with a small dose of intraarticular triamcinolone acetonide. J Rheumatol1999; 26:2285–2286.
Clive DM. Renal transplant-associated hyperuricemia and gout. J Am Soc Nephrol2000; 11:974–979.
Groff GD, Franck WA, Raddatz DA. Systemic steroid therapy for acute gout: a clinical trial and review of the literature. Semin Arthritis Rheum1990; 19:329–336.
Ritter J, Kerr LD, Valeriano-Marcet J, Spiera H. ACTH revisited: effective treatment for acute crystal induced synovitis in patients with multiple medical problems. J Rheumatol1994; 21:696–699.
Getting SJ, Christian HC, Flower RJ, Perretti M. Activation of melanocortin type 3 receptor as a molecular mechanism for adrenocorticotropic hormone efficacy in gouty arthritis. Arthritis Rheum2002; 46:2765–2775.
Connell JM, Whitworth JA, Davies DL, Lever AF, Richards AM, Fraser R. Effects of ACTH and cortisol administration on blood pressure, electrolyte metabolism, atrial natriuretic peptide and renal function in normal man. J Hypertens1987; 5:425–433.
Tausche AK, Richter K, Grässler A, Hänsel S, Roch B, Schröder HE. Severe gouty arthritis refractory to anti-inflammatory drugs: treatment with anti-tumour necrosis factor alpha as a new therapeutic option. Ann Rheum Dis2004; 63:1351–1352.
So A, De Smedt T, Revaz S, Tschopp J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther2007; 9:R28.
Becker MA, Schumacher HR, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med2005; 353:2450–2461.
Borstad GC, Bryant LR, Abel MP, Scroggie DA, Harris MD, Alloway JA. Colchicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J Rheumatol2004; 31:2429–2432.
Wallace SL, Singer JZ, Duncan GJ, Wigley FM, Kuncl RW. Renal function predicts colchicine toxicity: guidelines for the prophylactic use of colchicine in gout. J Rheumatol1991; 18:264–269.
Wilbur K, Makowsky M. Colchicine myotoxicity: case reports and literature review. Pharmacotherapy2004; 24:1784–1792.
Hung IF, Wu AK, Cheng VC, et al. Fatal interaction between clarithromycin and colchicine in patients with renal insufficiency: a retrospective study. Clin Infect Dis2005; 41:291–300.
Alayli G, Cengiz K, Cantürk F, Durmus D, Akyol Y, Menekse EB. Acute myopathy in a patient with concomitant use of pravastatin and colchicine. Ann Pharmacother2005; 39:1358–1361.
Ducloux D, Schuller V, Bresson-Vautrin C, Chalopin JM. Colchicine myopathy in renal transplant recipients on cyclosporin. Nephrol Dial Transplant1997; 12:2389–2392.
Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Purine-rich foods, dairy and protein intake, and the risk of gout in men. N Engl J Med2004; 350:1093–1103.
Choi HK, Curhan G. Soft drinks, fructose consumption, and the risk of gout in men: prospective cohort study. BMJ2008; 336:309–312.
Sundy JS, Becker MA, Baraf HS, et al; Pegloticase Phase 2 Study Investigators. Reduction of plasma urate levels following treatment with multiple doses of pegloticase (polyethylene glycol-conjugated uricase) in patients with treatment-failure gout: results of a phase II randomized study. Arthritis Rheum2008; 58:2882–2891.
Jordan KM, Cameron JS, Snaith M, et al; British Society for Rheumatology and British Health Professionals in Rheumatology Standards, Guidelines and Audit Working Group (SGAWG). British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of gout. Rheumatology (Oxford)2007; 46:1372–1374.
Perez-Ruiz F, Alonso-Ruiz A, Calabozo M, Herrero-Beites A, García-Erauskin G, Ruiz-Lucea E. Efficacy of allopurinol and benzbromarone for the control of hyperuricaemia. A pathogenic approach to the treatment of primary chronic gout. Ann Rheum Dis1998; 57:545–549.
Schumacher HR, Becker MA, Wortmann RL, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum2008; 59:1540–1548.
Perez-Ruiz F, Calabozo M, Pijoan JI, Herrero-Beites AM, Ruibal A. Effect of urate-lowering therapy on the velocity of size reduction of tophi in chronic gout. Arthritis Rheum2002; 47:356–360.
Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Am J Med1984; 76:47–56.
Perez-Ruiz F, Hernando I, Villar I, Nolla JM. Correction of allopurinol dosing should be based on clearance of creatinine, but not plasma creatinine levels: another insight to allopurinol-related toxicity. J Clin Rheumatol2005; 11:129–133.
Hung SI, Chung WH, Liou LB, et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A2005; 102:4134–4139.
Vázquez-Mellado J, Morales EM, Pacheco-Tena C, Burgos-Vargas R. Relation between adverse events associated with allopurinol and renal function in patients with gout. Ann Rheum Dis2001; 60:981–983.
Dalbeth N, Kumar S, Stamp L, Gow P. Dose adjustment of allopurinol according to creatinine clearance does not provide adequate control of hyperuricemia in patients with gout. J Rheumatol2006; 33:1646–1650.
Silverberg MS, Mallela R, Lesse AJ, Bonner MR, Baer AN, Li C. Allopurinol hypersensitivity reactions: a case-control study of the role of renal dosing (abstract). Arthritis Rheum2009; 60(suppl 10):1106.
Stamp LK, O'Donnell JL, Zhang M, et al. Using allopurinol above the dose based on creatinine clearance is effective and safe in chronic gout, including in those with renal impairment. Arthritis Rhem2010; doi:10.1002/art.30119. E-pub ahead of print. Accessed 10/29/2010.
Zhang W, Doherty M, Bardin T, et al; EULAR Standing Committee for International Clinical Studies Including Therapeutics. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis2006; 65:1312–1324.
Okamoto K, Eger BT, Nishino T, Kondo S, Pai EF, Nishino T. An extremely potent inhibitor of xanthine oxidoreductase. Crystal structure of the enzyme-inhibitor complex and mechanism of inhibition. J Biol Chem2003; 278:1848–1855.
Khosravan R, Grabowski BA, Wu JT, Joseph-Ridge N, Vernillet L. Pharmacokinetics, pharmacodynamics and safety of febuxostat, a non-purine selective inhibitor of xanthine oxidase, in a dose escalation study in healthy subjects. Clin Pharmacokinet2006; 45:821–841.
Reinders MK, Haagsma C, Jansen TL, et al. A randomised controlled trial on the efficacy and tolerability with dose escalation of allopurinol 300–600 mg/day versus benzbromarone 100–200 mg/day in patients with gout. Ann Rheum Dis2009; 68:892–897.
Mazzali M, Hughes J, Kim YG, et al. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension2001; 38:1101–1106.
Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med2008; 359:1811–1821.
Beck LH. Requiem for gouty nephropathy. Kidney Int1986; 30:280–287.
Tomita M, Mizuno S, Yamanaka H, et al. Does hyperuricemia affect mortality? A prospective cohort study of Japanese male workers. J Epidemiol2000; 10:403–409.
Kang DH, Nakagawa T. Uric acid and chronic renal disease: possible implication of hyperuricemia on progression of renal disease. Semin Nephrol2005; 25:43–49.
Iseki K, Oshiro S, Tozawa M, Iseki C, Ikemiya Y, Takishita S. Significance of hyperuricemia on the early detection of renal failure in a cohort of screened subjects. Hypertens Res2001; 24:691–697.
Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia. Risks and consequences in the Normative Aging Study. Am J Med1987; 82:421–426.
Siu YP, Leung KT, Tong MK, Kwan TH. Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level. Am J Kidney Dis2006; 47:51–59.
Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. JAMA2008; 300:924–932.
References
Vázquez-Mellado J, García CG, Vázquez SG, et al. Metabolic syndrome and ischemic heart disease in gout. J Clin Rheumatol2004; 10:105–109.
Bonnel RA, Villalba ML, Karwoski CB, Beitz J. Deaths associated with inappropriate intravenous colchicine administration. J Emerg Med2002; 22:385–387.
Achtert G, Scherrmann JM, Christen MO. Pharmacokinetics/bioavailability of colchicine in healthy male volunteers. Eur J Drug Metab Pharmacokinet1989; 14:317–322.
Ben-Chetrit E, Scherrmann JM, Zylber-Katz E, Levy M. Colchicine disposition in patients with familial Mediterranean fever with renal impairment. J Rheumatol1994; 21:710–713.
Putterman C, Ben-Chetrit E, Caraco Y, Levy M. Colchicine intoxication: clinical pharmacology, risk factors, features, and management. Semin Arthritis Rheum1991; 21:143–155.
Aronoff G, Brater DC, Schrier R, Bennett WM. Use of drugs in patients with renal insufficiency. Workshop report. Blood Purif1994; 12:14–19.
Kuncl RW, Duncan G, Watson D, Alderson K, Rogawski MA, Peper M. Colchicine myopathy and neuropathy. N Engl J Med1987; 316:1562–1568.
Ahern MJ, Reid C, Gordon TP, McCredie M, Brooks PM, Jones M. Does colchicine work? The results of the first controlled study in acute gout. Aust N Z J Med1987; 17:301–304.
Terkeltaub R, Furst D, Bennett K, Kook K, Crockett RS, Davis WM. High versus low dosing of oral colchicine for early acute gout flare: twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. Arthritis Rheum2010, 62:1060–1068.
Whelton A. Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications. Am J Med1999; 106:13S–24S.
Wali RK, Henrich WL. Recent developments in toxic nephropathy. Curr Opin Nephrol Hypertens2002; 11:155–163.
Fernández C, Noguera R, González JA, Pascual E. Treatment of acute attacks of gout with a small dose of intraarticular triamcinolone acetonide. J Rheumatol1999; 26:2285–2286.
Clive DM. Renal transplant-associated hyperuricemia and gout. J Am Soc Nephrol2000; 11:974–979.
Groff GD, Franck WA, Raddatz DA. Systemic steroid therapy for acute gout: a clinical trial and review of the literature. Semin Arthritis Rheum1990; 19:329–336.
Ritter J, Kerr LD, Valeriano-Marcet J, Spiera H. ACTH revisited: effective treatment for acute crystal induced synovitis in patients with multiple medical problems. J Rheumatol1994; 21:696–699.
Getting SJ, Christian HC, Flower RJ, Perretti M. Activation of melanocortin type 3 receptor as a molecular mechanism for adrenocorticotropic hormone efficacy in gouty arthritis. Arthritis Rheum2002; 46:2765–2775.
Connell JM, Whitworth JA, Davies DL, Lever AF, Richards AM, Fraser R. Effects of ACTH and cortisol administration on blood pressure, electrolyte metabolism, atrial natriuretic peptide and renal function in normal man. J Hypertens1987; 5:425–433.
Tausche AK, Richter K, Grässler A, Hänsel S, Roch B, Schröder HE. Severe gouty arthritis refractory to anti-inflammatory drugs: treatment with anti-tumour necrosis factor alpha as a new therapeutic option. Ann Rheum Dis2004; 63:1351–1352.
So A, De Smedt T, Revaz S, Tschopp J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res Ther2007; 9:R28.
Becker MA, Schumacher HR, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med2005; 353:2450–2461.
Borstad GC, Bryant LR, Abel MP, Scroggie DA, Harris MD, Alloway JA. Colchicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J Rheumatol2004; 31:2429–2432.
Wallace SL, Singer JZ, Duncan GJ, Wigley FM, Kuncl RW. Renal function predicts colchicine toxicity: guidelines for the prophylactic use of colchicine in gout. J Rheumatol1991; 18:264–269.
Wilbur K, Makowsky M. Colchicine myotoxicity: case reports and literature review. Pharmacotherapy2004; 24:1784–1792.
Hung IF, Wu AK, Cheng VC, et al. Fatal interaction between clarithromycin and colchicine in patients with renal insufficiency: a retrospective study. Clin Infect Dis2005; 41:291–300.
Alayli G, Cengiz K, Cantürk F, Durmus D, Akyol Y, Menekse EB. Acute myopathy in a patient with concomitant use of pravastatin and colchicine. Ann Pharmacother2005; 39:1358–1361.
Ducloux D, Schuller V, Bresson-Vautrin C, Chalopin JM. Colchicine myopathy in renal transplant recipients on cyclosporin. Nephrol Dial Transplant1997; 12:2389–2392.
Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Purine-rich foods, dairy and protein intake, and the risk of gout in men. N Engl J Med2004; 350:1093–1103.
Choi HK, Curhan G. Soft drinks, fructose consumption, and the risk of gout in men: prospective cohort study. BMJ2008; 336:309–312.
Sundy JS, Becker MA, Baraf HS, et al; Pegloticase Phase 2 Study Investigators. Reduction of plasma urate levels following treatment with multiple doses of pegloticase (polyethylene glycol-conjugated uricase) in patients with treatment-failure gout: results of a phase II randomized study. Arthritis Rheum2008; 58:2882–2891.
Jordan KM, Cameron JS, Snaith M, et al; British Society for Rheumatology and British Health Professionals in Rheumatology Standards, Guidelines and Audit Working Group (SGAWG). British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of gout. Rheumatology (Oxford)2007; 46:1372–1374.
Perez-Ruiz F, Alonso-Ruiz A, Calabozo M, Herrero-Beites A, García-Erauskin G, Ruiz-Lucea E. Efficacy of allopurinol and benzbromarone for the control of hyperuricaemia. A pathogenic approach to the treatment of primary chronic gout. Ann Rheum Dis1998; 57:545–549.
Schumacher HR, Becker MA, Wortmann RL, et al. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum2008; 59:1540–1548.
Perez-Ruiz F, Calabozo M, Pijoan JI, Herrero-Beites AM, Ruibal A. Effect of urate-lowering therapy on the velocity of size reduction of tophi in chronic gout. Arthritis Rheum2002; 47:356–360.
Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Am J Med1984; 76:47–56.
Perez-Ruiz F, Hernando I, Villar I, Nolla JM. Correction of allopurinol dosing should be based on clearance of creatinine, but not plasma creatinine levels: another insight to allopurinol-related toxicity. J Clin Rheumatol2005; 11:129–133.
Hung SI, Chung WH, Liou LB, et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A2005; 102:4134–4139.
Vázquez-Mellado J, Morales EM, Pacheco-Tena C, Burgos-Vargas R. Relation between adverse events associated with allopurinol and renal function in patients with gout. Ann Rheum Dis2001; 60:981–983.
Dalbeth N, Kumar S, Stamp L, Gow P. Dose adjustment of allopurinol according to creatinine clearance does not provide adequate control of hyperuricemia in patients with gout. J Rheumatol2006; 33:1646–1650.
Silverberg MS, Mallela R, Lesse AJ, Bonner MR, Baer AN, Li C. Allopurinol hypersensitivity reactions: a case-control study of the role of renal dosing (abstract). Arthritis Rheum2009; 60(suppl 10):1106.
Stamp LK, O'Donnell JL, Zhang M, et al. Using allopurinol above the dose based on creatinine clearance is effective and safe in chronic gout, including in those with renal impairment. Arthritis Rhem2010; doi:10.1002/art.30119. E-pub ahead of print. Accessed 10/29/2010.
Zhang W, Doherty M, Bardin T, et al; EULAR Standing Committee for International Clinical Studies Including Therapeutics. EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis2006; 65:1312–1324.
Okamoto K, Eger BT, Nishino T, Kondo S, Pai EF, Nishino T. An extremely potent inhibitor of xanthine oxidoreductase. Crystal structure of the enzyme-inhibitor complex and mechanism of inhibition. J Biol Chem2003; 278:1848–1855.
Khosravan R, Grabowski BA, Wu JT, Joseph-Ridge N, Vernillet L. Pharmacokinetics, pharmacodynamics and safety of febuxostat, a non-purine selective inhibitor of xanthine oxidase, in a dose escalation study in healthy subjects. Clin Pharmacokinet2006; 45:821–841.
Reinders MK, Haagsma C, Jansen TL, et al. A randomised controlled trial on the efficacy and tolerability with dose escalation of allopurinol 300–600 mg/day versus benzbromarone 100–200 mg/day in patients with gout. Ann Rheum Dis2009; 68:892–897.
Mazzali M, Hughes J, Kim YG, et al. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension2001; 38:1101–1106.
Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med2008; 359:1811–1821.
Beck LH. Requiem for gouty nephropathy. Kidney Int1986; 30:280–287.
Tomita M, Mizuno S, Yamanaka H, et al. Does hyperuricemia affect mortality? A prospective cohort study of Japanese male workers. J Epidemiol2000; 10:403–409.
Kang DH, Nakagawa T. Uric acid and chronic renal disease: possible implication of hyperuricemia on progression of renal disease. Semin Nephrol2005; 25:43–49.
Iseki K, Oshiro S, Tozawa M, Iseki C, Ikemiya Y, Takishita S. Significance of hyperuricemia on the early detection of renal failure in a cohort of screened subjects. Hypertens Res2001; 24:691–697.
Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia. Risks and consequences in the Normative Aging Study. Am J Med1987; 82:421–426.
Siu YP, Leung KT, Tong MK, Kwan TH. Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level. Am J Kidney Dis2006; 47:51–59.
Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. JAMA2008; 300:924–932.
Owing to concerns about using colchicine and nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with CKD, glucocorticoids (local injections or systemic therapy) are often used to treat acute attacks. Corticotropin (Acthar), anti-tumor necrosis factor agents, and interleukin 1 antagonists are effective but expensive.
Colchicine can be used in low doses as prophylaxis, with caution and appropriate monitoring. NSAIDs should be avoided, and glucocorticoids may not be effective for this purpose.
Whether the dosage of allopurinol should be lower in patients with CKD remains controversial. We start with a low dose and slowly increase it, with a goal serum urate level of less than 6.0 mg/dL.
Febuxostat (Uloric), like allopurinol, is a xanthine oxidase inhibitor, but the elimination of the active drug is not by the kidney. Nevertheless, we try allopurinol in escalating doses first, due to major cost differences.
Patients often ask primary care physicians and cardiologists about the measurement of biomarkers for cardiovascular disease and about the efficacy of preventive measures.
Although studies have shown that elevated homocysteine is a risk factor for cardiovascular and peripheral arterial disease1–3 and that supplementation with folic acid, vitamin B6, and vitamin B12 lowers homocysteine levels,4,5 it is unclear whether such supplementation prevents cardiovascular events. As a result, there is no consensus about whose homocysteine levels should be measured and who, if anyone, should receive homocysteine-lowering therapies.
The aim of this paper is to examine whether the evidence is sufficient to recommend homocysteine testing to guide the prevention and treatment of cardiovascular disease, or to recommend using folic acid, vitamin B6, and vitamin B12 for primary or secondary prevention of cardiovascular disease.
HISTORY OF HOMOCYSTEINE AS A RISK MARKER
Homocysteine is an amino acid formed from the metabolism of methionine, an essential amino acid derived from dietary protein. Although homocysteine was first isolated by Butz and du Vigneaud in 1932,6 it was not until 1964 that Gibson et al7 reported that patients with homocystinuria (more about this below) had vascular anomalies and arterial thrombosis. In 1969, McCully8 made the connection between elevated homocysteine levels and the risk of atherosclerosis.
Several possible mechanisms for the association between homocysteine and atherosclerosis have been demonstrated in experimental models. These include stimulation of smooth muscle growth, reduction in endothelial cell growth, impaired endothelial cell relaxation, decreased synthesis of high-density lipoprotein, promotion of autoimmune response, and accumulation of inflammatory monocytes in atherosclerotic plaques.3,9,10
In view of these findings, researchers have been evaluating whether homocysteine-lowering therapies decrease the risk of cardiovascular disease.
CAUSES OF ELEVATED PLASMA HOMOCYSTEINE
An elevated plasma homocysteine level can result from many different factors, including vitamin deficiencies, renal impairment, and inborn errors of homocysteine metabolism (Table 1).9,11,12
Vitamin deficiencies. Vitamin B6 (pyridoxine), vitamin B12 (cyanocobalamin), and folic acid are cofactors required for homocysteine metabolism, and deficiency in any or all of these leads to disruption of the relevant metabolic pathways.
Renal impairment. A low glomerular filtration rate has also been correlated with an elevated plasma homocysteine concentration. This makes sense, since the kidneys perform up to 70% of the clearance of homocysteine, although a cause-and-effect relationship is unclear.13
Inborn errors of homocysteine metabolism.Homocystinuria, ie, an abnormal elevation of homocysteine in the urine, is caused by several autosomal recessive disorders. People with these genetic variations have extremely high homocysteine levels.
A deficiency in the enzyme cystathionine beta-synthase is quite rare (the incidence in newborn babies has been found to be 1 in 344,000 worldwide and 1 in 65,000 in Ireland and Australia14), but leads to homocysteine levels greater than 100 μmol/L and often causes cardiovascular disease by the age of 30 years.15
A deficiency in the enzyme methylene tetrahydrofolate reductase (MTHFR) is a more common cause of mildly to moderately elevated plasma homocysteine levels.16 The MTHFR deficiency involves a variation at position 677 in the MTHFR gene in which cytosine is replaced by thymidine (thus called C677T or 677C>T).17 Ten percent of the population are homozygous for this variant (TT), 43% are heterozygous (CT), and 47% are unaffected (CC). Heterozygotes have slightly higher homocysteine levels than unaffected people, while people with the TT genotype have approximately 20% higher homocysteine levels.17
ELEVATED HOMOCYSTEINE IS COMMON
In a study of a population in Norway from 1992 to 1993, 8.5% had mild elevations in homocysteine (plasma levels 15–29.99 μmol/L), 0.8% had moderate elevations (30–99.99 μmol/L), and 0.02% had severe elevations (≥ 100 μmol/L).13,18 The prevalence of hyperhomocysteinemia in the United States is probably much lower, given that supplementation of white flour and cereal grains with folic acid has been mandatory since 1998, but this is not well described in the literature.
HOW GREAT IS THE RISK?
Studies over the past 10 to 20 years have shown that elevated homocysteine is a marker of risk of cardiovascular disease. The association was first noted in patients with cystathionine beta-synthase deficiency, who tend to have premature cardiovascular disease.
However, studies of patients with MTHFR 677C>T have yielded mixed results. Although several meta-analyses found up to a 42% higher rate of ischemic heart disease and stroke in patients homozygous for MTHFR 677C>T (the TT genotype) than in those with the CC genotype,17,19,20 two other large meta-analyses did not find an association between this variant and vascular risk.21,22
Nonetheless, in a meta-analysis of the association between homocysteine and cardiovascular disease, Wald et al17 found that for every 5-μmol/L increase in serum homocysteine concentration, the risk of ischemic heart disease increased 20% to 30%.
TRIALS OF HOMOCYSTEINE-LOWERING THERAPY HAVE HAD MIXED RESULTS
Primary prevention of cardiovascular disease
Given the finding that treatment with folic acid lowers homocysteine—initially noted in patients with homocystinuria—researchers hypothesized that treatment with folic acid, vitamin B6, and vitamin B12 would decrease the risk of cardiovascular disease.
Little evidence currently exists to guide recommendations for homocysteine-lowering therapy to prevent first attacks of cardiovascular disease. The few studies published to date have been observational studies of dietary intake (not vitamin supplementation), and many were performed before folic acid fortification was mandated for flour and cereal (Table 2).23–27 Although the studies suggest that higher B-vitamin intake correlates with less vascular disease and its sequelae, there is uncertainty as to whether it is folic acid, vitamin B6, or vitamin B12 that is responsible, and also whether supplements would provide the same protective benefit as the presence of these nutrients in a varied diet.
Thus, in its recent evaluation of novel risk markers of cardiovascular disease, the United States Preventive Services Task Force 28,29 does not recommend measuring the plasma homocysteine level in the evaluation of either low-risk or intermediate-risk populations, finding no evidence that it adds any useful information in predicting major coronary events beyond what one could get from calculating the Framingham Risk Score. The task force also found no evidence that treating people who have elevated homocysteine levels decreases their risk of subsequent cardiovascular events.
In addition, a recent Cochrane Database review of eight randomized controlled trials in patients at low risk did not find a lower risk of myocardial infarction (fatal or nonfatal), stroke, or death from any cause in patients receiving B-complex vitamins.30
Secondary prevention of cardiovascular disease
Results have been mixed with regard to the ability of B vitamins to prevent cardiovascular events in patients with known cardiovascular disease (Table 3).4,5,11,12,31–46
Bazzano et al,47 in a meta-analysis published in 2006, evaluated 12 randomized controlled trials of folic acid supplementation in patients with known cardiovascular disease and did not find that treated patients had better cardiovascular outcomes. The mean homocysteine level was elevated (> 15 μmol/L) at baseline in only 4 of the 12 trials. However, in 1 of these 4 trials, there was no difference in outcomes comparing those with and without elevated homocysteine.31
Albert et al4 more recently evaluated the effect of a combination pill containing folic acid, vitamin B6, and vitamin B12 on cardiovascular events in women at high risk, ie, those with a history of cardiovascular disease or having three or more coronary risk factors. Treatment did not decrease the rate of the composite outcome of cardiovascular disease mortality, stroke, myocardial infarction, or coronary revascularization, although the homocysteine level decreased by a mean of 30% in the treated group. However, only 27.7% of the participants had an elevated homocysteine level. One might not expect patients to benefit from such treatment if they had normal homocysteine levels to begin with.
Ebbing et al,5 in a trial published in 2008, investigated the effect of folic acid, vitamin B12, and vitamin B6 supplements on the risks of death from any cause and of cardiovascular events in patients undergoing coronary angiography. Outcomes were no better in the treatment group than in the control group, despite a mean decrease in homocysteine level of 19%. However, over 90% of the participants had a normal homocysteine level.
Mager et al,32 in a study published in 2009, looked specifically at whether patients with coronary artery disease and elevated homocysteine levels (> 15 μmol/L) would benefit from folate-based vitamin therapy. In this subset, the incidence of death from any cause was lower in the treated group than in the control group (4% vs 32%, P < .001), an association that was not present in patients with normal homocysteine levels.
The SEARCH trial (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine),33 recently published, was a double-blind, randomized controlled trial of vitamin B12 and folic acid treatment in 12,064 patients who had survived a myocardial infarction. Although those who received the vitamin therapy had a 28% reduction in homocysteine level, no clinical benefit was demonstrated. Of note, 66% of the patients had a homocysteine level lower than 14 μmol/L at baseline.
Restenosis after angioplasty
Results are also mixed regarding whether folic acid supplements modify the risk of restenosis after coronary angioplasty.
Namazi et al48 evaluated the effect of folic acid supplementation on in-stent restenosis in 200 patients and found no difference between the treatment and placebo groups in the rates of either restenosis or target-vessel revascularization.
Schnyder et al49 evaluated the effect of folic acid, vitamin B6, and vitamin B12 treatment on the rate of coronary restenosis (in cases of balloon angioplasty) or in-stent restenosis (if a stent was used). Patients receiving treatment had lower rates of restenosis or instent restenosis (40% vs 48%, P = .01) and of need for target-vessel revascularization (11% vs 22%, P = .047). The mean homocysteine level was not elevated in this study either, and the researchers did not analyze the outcomes according to whether patients had high or normal homocysteine levels.
Lange et al35 also evaluated the effect of folic acid, vitamin B6, and vitamin B12 treatment on coronary in-stent restenosis. Paradoxically, the rate was higher with treatment in the overall group (mean homocysteine level 12.2 μmol/L), leading to a higher incidence of target-vessel revascularization. Patients who had a baseline elevation in homocysteine level had a nonsignificant trend toward a lower rate of in-stent restenosis.
Cerebrovascular and peripheral arterial disease
The evidence is also mixed for using folic acid and other B vitamins to prevent cerebrovascular disease and peripheral vascular disease. Although a 2007 meta-analysis found that folic acid supplementation decreased the risk of a first stroke by 18% (P = .045),50 a later meta-analysis contradicts this finding.51
A 2009 meta-analysis found that patients with peripheral arterial disease had higher homocysteine levels than controls, but it did not find any benefit from supplementation, owing to heterogeneity of the clinical end points used.52 Indeed, a 2009 Cochrane Database Systematic Review found that there were no adequate trials of the treatment of patients with peripheral vascular disease who have elevated plasma homocysteine.53
However, immediately after the Cochrane review was published, Khandanpour et al36 published the results of a trial of the effect of folic acid and 5-methyltetrahydrofolate (an active form of folic acid) supplementation on the ankle-brachial pressure index and the pulse-wave velocity in patients with peripheral arterial disease. These measures improved with 16 weeks of treatment. For the ankle-brachial pressure index, the P value was less than .01 for folic acid and .009 for 5-methyltetrahydrofolate; for the pulse-wave velocity, the P value was .051 for folic acid and .011 for 5-methyltetrahydrofolate.
Kidney disease
One could postulate that patients with end-stage renal disease or chronic kidney disease might benefit the most from folic acid supplementation, given the correlation of elevations in homocysteine levels with decline in glomerular filtration rate.
However, only one study found a lower rate of cardiovascular events with folic acid supplementation in dialysis patients, and the difference was not statistically significant (25% vs 36%, P < .08).31 Further, several studies found no benefit of folic acid supplementation in patients with chronic kidney disease.11,12,37
FUTURE DIRECTIONS AND RECOMMENDATIONS
Many experts have suggested that the existing evidence indicates that the homocysteine-lowering therapies folic acid, vitamin B6, and vitamin B12 do not lower the risk of cardiovascular disease.38,54–59 Indeed, the American Heart Association guidelines for cardiovascular disease prevention in women do not recommend folic acid supplementation to prevent cardiovascular disease.60 (Recommendations for men are the same as for women.) However, most of the clinical trials have not selected and treated patients with elevated homocysteine levels, but have instead included all patients regardless of homocysteine level.
At least two large ongoing trials are currently evaluating B-vitamin therapy for secondary prevention, but neither trial is looking specifically at patients with elevated homocysteine levels.61,62
Thus, instead of concluding that no patients could benefit from homocysteine-lowering treatment, future studies need to clarify:
Whether patients with elevated homocysteine would benefit from such treatment
At what level it would be appropriate to start treatment
The appropriate target homocysteine level with treatment.
Particularly given the recent finding that folic acid supplementation may increase cancer risk,63 these questions need closer scrutiny.
References
Humphrey LL, Fu R, Rogers K, Freeman M, Helfand M. Homocysteine level and coronary heart disease incidence: a systematic review and meta-analysis. Mayo Clin Proc2008; 83:1203–1212.
Boers GH. The case for mild hyperhomocysteinaemia as a risk factor. J Inherit Metab Dis1997; 20:301–306.
Austin RC, Lentz SR, Werstuck GH. Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease. Cell Death Differ2004; 11(suppl 1):S56–S64.
Albert CM, Cook NR, Gaziano JM, et al. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA2008; 299:2027–2036.
Ebbing M, Bleie Ø, Ueland PM, et al. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. JAMA2008; 300:795–804.
Butz LW, du Vigneaud V. The formation of a homologue of cystine by the decompensation of methionine with sulphuric acid. J Biol Chem1932; 99:135–142.
McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol1969; 56:111–128.
Zhang D, Jiang X, Fang P, et al. Hyperhomocysteinemia promotes inflammatory monocyte generation and accelerates atherosclerosis in transgenic cystathionine beta-synthase-deficient mice. Circulation2009; 120:1893–1902.
Woo KS, Chook P, Lolin YI, Sanderson JE, Metreweli C, Celermajer DS. Folic acid improves arterial endothelial function in adults with hyperhomocystinemia. J Am Coll Cardiol1999; 34:2002–2006.
Righetti M, Ferrario GM, Milani S, et al. Effects of folic acid treatment on homocysteine levels and vascular disease in hemodialysis patients. Med Sci Monit2003; 9:PI19–PI24.
Zoungas S, McGrath BP, Branley P, et al. Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renal failure: a multicenter, randomized, controlled trial. J Am Coll Cardiol2006; 47:1108–1116.
Carmel R, Jacobsen DW, editors. Homocysteine in Health and Disease. Cambridge, UK: Cambridge University Press, 2001.
Yap S, Boers GH, Wilcken B, et al. Vascular outcome in patients with homocystinuria due to cystathionine beta-synthase deficiency treated chronically: a multicenter observational study. Arterioscler Thromb Vasc Biol2001; 21:2080–2085.
McKusick V. 236200 Homocystinuria. In:McKusick V, editor. Mendelian Inheritance in Man. 10th ed. Baltimore, MD: The Johns Hopkins University Press, 1992:1444–1446.
McKusick V. 236250 Homocystinuria due to deficiency of N(5,10)-methylenetetrahydrofolate reductase activity. In:McKusick V, editor. Mendelian Inheritance in Man. Baltimore, MD: The Johns Hopkins University Press, 1992:1447–1448.
Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ2002; 325:1202.
Nygård O, Vollset SE, Refsum H, et al. Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. JAMA1995; 274:1526–1533.
Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG; MTHFR Studies Collaboration Group. MTHFR 677C-->T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA2002; 288:2023–2031.
Kelly PJ, Rosand J, Kistler JP, et al. Homocysteine, MTHFR 677C-->T polymorphism, and risk of ischemic stroke: results of a meta-analysis. Neurology2002; 59:529–536.
Lewis SJ, Ebrahim S, Davey Smith G. Meta-analysis of MTHFR 677C->T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate?BMJ2005; 331:1053.
Brattström L, Wilcken DE, Ohrvik J, Brudin L. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: the result of a meta-analysis. Circulation1998; 98:2520–2526.
Cui R, Iso H, Date C, Kikuchi S, Tamakoshi A; Japan Collaborative Cohort Study Group. Dietary folate and vitamin B6 and B12 intake in relation to mortality from cardiovascular diseases: Japan Collaborative Cohort Study. Stroke2010; 41:1285–1289.
Liu S, Stampfer MJ, Hu FB, et al. Whole-grain consumption and risk of coronary heart disease: results from the Nurses’ Health Study. Am J Clin Nutr1999; 70:412–419.
Liu S, Manson JE, Stampfer MJ, et al. Whole grain consumption and risk of ischemic stroke in women: a prospective study. JAMA2000; 284:1534–1540.
Merchant AT, Hu FB, Spiegelman D, Willett WC, Rimm EB, Ascherio A. The use of B vitamin supplements and peripheral arterial disease risk in men are inversely related. J Nutr2003; 133:2863–2867.
Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA1998; 279:359–364.
US Preventive Services Task Force. Using nontraditional risk factors in coronary heart disease risk assessment: US Preventive Services Task Force recommendation statement. Ann Intern Med2009; 151:474–482.
Helfand M, Buckley DI, Freeman M, et al. Emerging risk factors for coronary heart disease: a summary of systematic reviews conducted for the US Preventive Services Task Force. Ann Intern Med2009; 151:496–507.
Martí-Carvajal AJ, Solà I, Lathyris D, Salanti G. Homocysteine lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev2009; ( 4):CD006612.
Righetti M, Serbelloni P, Milani S, Ferrario G. Homocysteine-lowering vitamin B treatment decreases cardiovascular events in hemodialysis patients. Blood Purif2006; 24:379–386.
Mager A, Orvin K, Koren-Morag N, et al. Impact of homocysteine-lowering vitamin therapy on long-term outcome of patients with coronary artery disease. Am J Cardiol2009; 104:745–749.
Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group; Armitage JM, Bowman L, Clarke RJ, et al. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA2010; 303:2486–2494.
Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and percutaneous coronary intervention: the Swiss Heart Study: a randomized controlled trial. JAMA2002; 288:973–979.
Lange H, Suryapranata H, De Luca G, et al. Folate therapy and in-stent restenosis after coronary stenting. N Engl J Med2004; 350:2673–2781.
Khandanpour N, Armon MP, Jennings B, et al. Randomized clinical trial of folate supplementation in patients with peripheral arterial disease. Br J Surg2009; 96:990–998.
Wrone EM, Hornberger JM, Zehnder JL, McCann LM, Coplon NS, Fortmann SP. Randomized trial of folic acid for prevention of cardiovascular events in end-stage renal disease. J Am Soc Nephrol2004; 15:420–426.
Loscalzo J. Homocysteine trials—clear outcomes for complex reasons. N Engl J Med2006; 354:1629–1632.
Bønaa KH, Njølstad I, Ueland PM, et al; NORVIT Trial Investigators. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med2006; 354:1578–1588.
Carrero JJ, López-Huertas E, Salmerón LM, Baró L, Ros E. Daily supplementation with (n-3) PUFAs, oleic acid, folic acid, and vitamins B-6 and E increases pain-free walking distance and improves risk factors in men with peripheral vascular disease. J Nutr2005; 135:1393–1399.
Liem AH, van Boven AJ, Veeger NJ, et al; Folic Acid on Risk Diminishment After Acute Myocarial Infarction Study Group. Efficacy of folic acid when added to statin therapy in patients with hypercholesterolemia following acute myocardial infarction: a randomised pilot trial. Int J Cardiol2004; 93:175–179.
Liem A, Reynierse-Buitenwerf GH, Zwinderman AH, Jukema JW, van Veldhuisen DJ. Secondary prevention with folic acid: results of the Goes extension study. Heart2005; 91:1213–1214.
Lonn E, Yusuf S, Arnold MJ, et al; Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med2006; 354:1567–1577.
Sydow K, Schwedhelm E, Arakawa N, et al. ADMA and oxidative stress are responsible for endothelial dysfunction in hyperhomocyst(e)inemia: effects of L-arginine and B vitamins. Cardiovasc Res2003; 57:244–252.
Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA2004; 291:565–575.
Jamison RL, Hartigan P, Kaufman JS, et al; Veterans Affairs Site Investigators. Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial. JAMA2007; 2989:1163–1170. Erratum in JAMA 2008;300:170.
Bazzano LA, Reynolds K, Holder KN, He J. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. JAMA2006; 296:2720–2726.
Namazi MH, Motamedi MR, Safi M, Vakili H, Saadat H, Nazari N. Efficacy of folic acid therapy for prevention of in-stent restenosis: a randomized clinical trial. Arch Iran Med2006; 9:108–110.
Schnyder G, Roffi M, Pin R, et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med2001; 345:1593–1600.
Wang X, Qin X, Demirtas H, et al. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet2007; 369:1876–1882.
Lee M, Hong KS, Chang SC, Saver JL. Efficacy of homocysteine-lowering therapy with folic Acid in stroke prevention: a meta-analysis. Stroke2010; 41:1205–1212.
Khandanpour N, Loke YK, Meyer FJ, Jennings B, Armon MP. Homocysteine and peripheral arterial disease: systematic review and meta-analysis. Eur J Vasc Endovasc Surg2009; 38:316–322.
Hansrani M, Stansby G. Homocysteine lowering interventions for peripheral arterial disease and bypass grafts. Cochrane Database Syst Rev2002; ( 3):CD003285.
Mosca L. Novel cardiovascular risk factors: do they add value to your practice?Am Fam Physician2003; 67:264,266.
Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction. J Am Coll Cardiol2007; 50:e1–e157.
Lonn E. Homocysteine-lowering B vitamin therapy in cardiovascular prevention—wrong again?JAMA2008; 299:2086–2087.
Milani RV, Lavie CJ. Homocysteine: the Rubik’s cube of cardiovascular risk factors. Mayo Clin Proc2008; 83:1200–1202.
Bazzano LA. Folic acid supplementation and cardiovascular disease: the state of the art. Am J Med Sci2009; 338:48–49.
Ntaios G, Savopoulos C, Grekas D, Hatzitolios A. The controversial role of B-vitamins in cardiovascular risk: an update. Arch Cardiovasc Dis2009; 102:847–854.
Mosca L, Banka CL, Benjamin EJ; Expert Panel/Writing Group. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation2007; 115:1481–1501.
Bassuk SS, Albert CM, Cook NR, et al. The Women’s Antioxidant Cardiovascular Study: design and baseline characteristics of participants. J Womens Health (Larchmt)2004; 13:99–117.
SEARCH Study Collaborative Group; Bowman L, Armitage J, Bulbulia R, Parish S, Collins R. Study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH): characteristics of a randomized trial among 12064 myocardial infarction survivors. Am Heart J2007; 154:815–823,823.e1–e6.
Ebbing M, Bønaa KH, Nygård O, et al. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA2009; 302:2119–2126.
Patients often ask primary care physicians and cardiologists about the measurement of biomarkers for cardiovascular disease and about the efficacy of preventive measures.
Although studies have shown that elevated homocysteine is a risk factor for cardiovascular and peripheral arterial disease1–3 and that supplementation with folic acid, vitamin B6, and vitamin B12 lowers homocysteine levels,4,5 it is unclear whether such supplementation prevents cardiovascular events. As a result, there is no consensus about whose homocysteine levels should be measured and who, if anyone, should receive homocysteine-lowering therapies.
The aim of this paper is to examine whether the evidence is sufficient to recommend homocysteine testing to guide the prevention and treatment of cardiovascular disease, or to recommend using folic acid, vitamin B6, and vitamin B12 for primary or secondary prevention of cardiovascular disease.
HISTORY OF HOMOCYSTEINE AS A RISK MARKER
Homocysteine is an amino acid formed from the metabolism of methionine, an essential amino acid derived from dietary protein. Although homocysteine was first isolated by Butz and du Vigneaud in 1932,6 it was not until 1964 that Gibson et al7 reported that patients with homocystinuria (more about this below) had vascular anomalies and arterial thrombosis. In 1969, McCully8 made the connection between elevated homocysteine levels and the risk of atherosclerosis.
Several possible mechanisms for the association between homocysteine and atherosclerosis have been demonstrated in experimental models. These include stimulation of smooth muscle growth, reduction in endothelial cell growth, impaired endothelial cell relaxation, decreased synthesis of high-density lipoprotein, promotion of autoimmune response, and accumulation of inflammatory monocytes in atherosclerotic plaques.3,9,10
In view of these findings, researchers have been evaluating whether homocysteine-lowering therapies decrease the risk of cardiovascular disease.
CAUSES OF ELEVATED PLASMA HOMOCYSTEINE
An elevated plasma homocysteine level can result from many different factors, including vitamin deficiencies, renal impairment, and inborn errors of homocysteine metabolism (Table 1).9,11,12
Vitamin deficiencies. Vitamin B6 (pyridoxine), vitamin B12 (cyanocobalamin), and folic acid are cofactors required for homocysteine metabolism, and deficiency in any or all of these leads to disruption of the relevant metabolic pathways.
Renal impairment. A low glomerular filtration rate has also been correlated with an elevated plasma homocysteine concentration. This makes sense, since the kidneys perform up to 70% of the clearance of homocysteine, although a cause-and-effect relationship is unclear.13
Inborn errors of homocysteine metabolism.Homocystinuria, ie, an abnormal elevation of homocysteine in the urine, is caused by several autosomal recessive disorders. People with these genetic variations have extremely high homocysteine levels.
A deficiency in the enzyme cystathionine beta-synthase is quite rare (the incidence in newborn babies has been found to be 1 in 344,000 worldwide and 1 in 65,000 in Ireland and Australia14), but leads to homocysteine levels greater than 100 μmol/L and often causes cardiovascular disease by the age of 30 years.15
A deficiency in the enzyme methylene tetrahydrofolate reductase (MTHFR) is a more common cause of mildly to moderately elevated plasma homocysteine levels.16 The MTHFR deficiency involves a variation at position 677 in the MTHFR gene in which cytosine is replaced by thymidine (thus called C677T or 677C>T).17 Ten percent of the population are homozygous for this variant (TT), 43% are heterozygous (CT), and 47% are unaffected (CC). Heterozygotes have slightly higher homocysteine levels than unaffected people, while people with the TT genotype have approximately 20% higher homocysteine levels.17
ELEVATED HOMOCYSTEINE IS COMMON
In a study of a population in Norway from 1992 to 1993, 8.5% had mild elevations in homocysteine (plasma levels 15–29.99 μmol/L), 0.8% had moderate elevations (30–99.99 μmol/L), and 0.02% had severe elevations (≥ 100 μmol/L).13,18 The prevalence of hyperhomocysteinemia in the United States is probably much lower, given that supplementation of white flour and cereal grains with folic acid has been mandatory since 1998, but this is not well described in the literature.
HOW GREAT IS THE RISK?
Studies over the past 10 to 20 years have shown that elevated homocysteine is a marker of risk of cardiovascular disease. The association was first noted in patients with cystathionine beta-synthase deficiency, who tend to have premature cardiovascular disease.
However, studies of patients with MTHFR 677C>T have yielded mixed results. Although several meta-analyses found up to a 42% higher rate of ischemic heart disease and stroke in patients homozygous for MTHFR 677C>T (the TT genotype) than in those with the CC genotype,17,19,20 two other large meta-analyses did not find an association between this variant and vascular risk.21,22
Nonetheless, in a meta-analysis of the association between homocysteine and cardiovascular disease, Wald et al17 found that for every 5-μmol/L increase in serum homocysteine concentration, the risk of ischemic heart disease increased 20% to 30%.
TRIALS OF HOMOCYSTEINE-LOWERING THERAPY HAVE HAD MIXED RESULTS
Primary prevention of cardiovascular disease
Given the finding that treatment with folic acid lowers homocysteine—initially noted in patients with homocystinuria—researchers hypothesized that treatment with folic acid, vitamin B6, and vitamin B12 would decrease the risk of cardiovascular disease.
Little evidence currently exists to guide recommendations for homocysteine-lowering therapy to prevent first attacks of cardiovascular disease. The few studies published to date have been observational studies of dietary intake (not vitamin supplementation), and many were performed before folic acid fortification was mandated for flour and cereal (Table 2).23–27 Although the studies suggest that higher B-vitamin intake correlates with less vascular disease and its sequelae, there is uncertainty as to whether it is folic acid, vitamin B6, or vitamin B12 that is responsible, and also whether supplements would provide the same protective benefit as the presence of these nutrients in a varied diet.
Thus, in its recent evaluation of novel risk markers of cardiovascular disease, the United States Preventive Services Task Force 28,29 does not recommend measuring the plasma homocysteine level in the evaluation of either low-risk or intermediate-risk populations, finding no evidence that it adds any useful information in predicting major coronary events beyond what one could get from calculating the Framingham Risk Score. The task force also found no evidence that treating people who have elevated homocysteine levels decreases their risk of subsequent cardiovascular events.
In addition, a recent Cochrane Database review of eight randomized controlled trials in patients at low risk did not find a lower risk of myocardial infarction (fatal or nonfatal), stroke, or death from any cause in patients receiving B-complex vitamins.30
Secondary prevention of cardiovascular disease
Results have been mixed with regard to the ability of B vitamins to prevent cardiovascular events in patients with known cardiovascular disease (Table 3).4,5,11,12,31–46
Bazzano et al,47 in a meta-analysis published in 2006, evaluated 12 randomized controlled trials of folic acid supplementation in patients with known cardiovascular disease and did not find that treated patients had better cardiovascular outcomes. The mean homocysteine level was elevated (> 15 μmol/L) at baseline in only 4 of the 12 trials. However, in 1 of these 4 trials, there was no difference in outcomes comparing those with and without elevated homocysteine.31
Albert et al4 more recently evaluated the effect of a combination pill containing folic acid, vitamin B6, and vitamin B12 on cardiovascular events in women at high risk, ie, those with a history of cardiovascular disease or having three or more coronary risk factors. Treatment did not decrease the rate of the composite outcome of cardiovascular disease mortality, stroke, myocardial infarction, or coronary revascularization, although the homocysteine level decreased by a mean of 30% in the treated group. However, only 27.7% of the participants had an elevated homocysteine level. One might not expect patients to benefit from such treatment if they had normal homocysteine levels to begin with.
Ebbing et al,5 in a trial published in 2008, investigated the effect of folic acid, vitamin B12, and vitamin B6 supplements on the risks of death from any cause and of cardiovascular events in patients undergoing coronary angiography. Outcomes were no better in the treatment group than in the control group, despite a mean decrease in homocysteine level of 19%. However, over 90% of the participants had a normal homocysteine level.
Mager et al,32 in a study published in 2009, looked specifically at whether patients with coronary artery disease and elevated homocysteine levels (> 15 μmol/L) would benefit from folate-based vitamin therapy. In this subset, the incidence of death from any cause was lower in the treated group than in the control group (4% vs 32%, P < .001), an association that was not present in patients with normal homocysteine levels.
The SEARCH trial (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine),33 recently published, was a double-blind, randomized controlled trial of vitamin B12 and folic acid treatment in 12,064 patients who had survived a myocardial infarction. Although those who received the vitamin therapy had a 28% reduction in homocysteine level, no clinical benefit was demonstrated. Of note, 66% of the patients had a homocysteine level lower than 14 μmol/L at baseline.
Restenosis after angioplasty
Results are also mixed regarding whether folic acid supplements modify the risk of restenosis after coronary angioplasty.
Namazi et al48 evaluated the effect of folic acid supplementation on in-stent restenosis in 200 patients and found no difference between the treatment and placebo groups in the rates of either restenosis or target-vessel revascularization.
Schnyder et al49 evaluated the effect of folic acid, vitamin B6, and vitamin B12 treatment on the rate of coronary restenosis (in cases of balloon angioplasty) or in-stent restenosis (if a stent was used). Patients receiving treatment had lower rates of restenosis or instent restenosis (40% vs 48%, P = .01) and of need for target-vessel revascularization (11% vs 22%, P = .047). The mean homocysteine level was not elevated in this study either, and the researchers did not analyze the outcomes according to whether patients had high or normal homocysteine levels.
Lange et al35 also evaluated the effect of folic acid, vitamin B6, and vitamin B12 treatment on coronary in-stent restenosis. Paradoxically, the rate was higher with treatment in the overall group (mean homocysteine level 12.2 μmol/L), leading to a higher incidence of target-vessel revascularization. Patients who had a baseline elevation in homocysteine level had a nonsignificant trend toward a lower rate of in-stent restenosis.
Cerebrovascular and peripheral arterial disease
The evidence is also mixed for using folic acid and other B vitamins to prevent cerebrovascular disease and peripheral vascular disease. Although a 2007 meta-analysis found that folic acid supplementation decreased the risk of a first stroke by 18% (P = .045),50 a later meta-analysis contradicts this finding.51
A 2009 meta-analysis found that patients with peripheral arterial disease had higher homocysteine levels than controls, but it did not find any benefit from supplementation, owing to heterogeneity of the clinical end points used.52 Indeed, a 2009 Cochrane Database Systematic Review found that there were no adequate trials of the treatment of patients with peripheral vascular disease who have elevated plasma homocysteine.53
However, immediately after the Cochrane review was published, Khandanpour et al36 published the results of a trial of the effect of folic acid and 5-methyltetrahydrofolate (an active form of folic acid) supplementation on the ankle-brachial pressure index and the pulse-wave velocity in patients with peripheral arterial disease. These measures improved with 16 weeks of treatment. For the ankle-brachial pressure index, the P value was less than .01 for folic acid and .009 for 5-methyltetrahydrofolate; for the pulse-wave velocity, the P value was .051 for folic acid and .011 for 5-methyltetrahydrofolate.
Kidney disease
One could postulate that patients with end-stage renal disease or chronic kidney disease might benefit the most from folic acid supplementation, given the correlation of elevations in homocysteine levels with decline in glomerular filtration rate.
However, only one study found a lower rate of cardiovascular events with folic acid supplementation in dialysis patients, and the difference was not statistically significant (25% vs 36%, P < .08).31 Further, several studies found no benefit of folic acid supplementation in patients with chronic kidney disease.11,12,37
FUTURE DIRECTIONS AND RECOMMENDATIONS
Many experts have suggested that the existing evidence indicates that the homocysteine-lowering therapies folic acid, vitamin B6, and vitamin B12 do not lower the risk of cardiovascular disease.38,54–59 Indeed, the American Heart Association guidelines for cardiovascular disease prevention in women do not recommend folic acid supplementation to prevent cardiovascular disease.60 (Recommendations for men are the same as for women.) However, most of the clinical trials have not selected and treated patients with elevated homocysteine levels, but have instead included all patients regardless of homocysteine level.
At least two large ongoing trials are currently evaluating B-vitamin therapy for secondary prevention, but neither trial is looking specifically at patients with elevated homocysteine levels.61,62
Thus, instead of concluding that no patients could benefit from homocysteine-lowering treatment, future studies need to clarify:
Whether patients with elevated homocysteine would benefit from such treatment
At what level it would be appropriate to start treatment
The appropriate target homocysteine level with treatment.
Particularly given the recent finding that folic acid supplementation may increase cancer risk,63 these questions need closer scrutiny.
Patients often ask primary care physicians and cardiologists about the measurement of biomarkers for cardiovascular disease and about the efficacy of preventive measures.
Although studies have shown that elevated homocysteine is a risk factor for cardiovascular and peripheral arterial disease1–3 and that supplementation with folic acid, vitamin B6, and vitamin B12 lowers homocysteine levels,4,5 it is unclear whether such supplementation prevents cardiovascular events. As a result, there is no consensus about whose homocysteine levels should be measured and who, if anyone, should receive homocysteine-lowering therapies.
The aim of this paper is to examine whether the evidence is sufficient to recommend homocysteine testing to guide the prevention and treatment of cardiovascular disease, or to recommend using folic acid, vitamin B6, and vitamin B12 for primary or secondary prevention of cardiovascular disease.
HISTORY OF HOMOCYSTEINE AS A RISK MARKER
Homocysteine is an amino acid formed from the metabolism of methionine, an essential amino acid derived from dietary protein. Although homocysteine was first isolated by Butz and du Vigneaud in 1932,6 it was not until 1964 that Gibson et al7 reported that patients with homocystinuria (more about this below) had vascular anomalies and arterial thrombosis. In 1969, McCully8 made the connection between elevated homocysteine levels and the risk of atherosclerosis.
Several possible mechanisms for the association between homocysteine and atherosclerosis have been demonstrated in experimental models. These include stimulation of smooth muscle growth, reduction in endothelial cell growth, impaired endothelial cell relaxation, decreased synthesis of high-density lipoprotein, promotion of autoimmune response, and accumulation of inflammatory monocytes in atherosclerotic plaques.3,9,10
In view of these findings, researchers have been evaluating whether homocysteine-lowering therapies decrease the risk of cardiovascular disease.
CAUSES OF ELEVATED PLASMA HOMOCYSTEINE
An elevated plasma homocysteine level can result from many different factors, including vitamin deficiencies, renal impairment, and inborn errors of homocysteine metabolism (Table 1).9,11,12
Vitamin deficiencies. Vitamin B6 (pyridoxine), vitamin B12 (cyanocobalamin), and folic acid are cofactors required for homocysteine metabolism, and deficiency in any or all of these leads to disruption of the relevant metabolic pathways.
Renal impairment. A low glomerular filtration rate has also been correlated with an elevated plasma homocysteine concentration. This makes sense, since the kidneys perform up to 70% of the clearance of homocysteine, although a cause-and-effect relationship is unclear.13
Inborn errors of homocysteine metabolism.Homocystinuria, ie, an abnormal elevation of homocysteine in the urine, is caused by several autosomal recessive disorders. People with these genetic variations have extremely high homocysteine levels.
A deficiency in the enzyme cystathionine beta-synthase is quite rare (the incidence in newborn babies has been found to be 1 in 344,000 worldwide and 1 in 65,000 in Ireland and Australia14), but leads to homocysteine levels greater than 100 μmol/L and often causes cardiovascular disease by the age of 30 years.15
A deficiency in the enzyme methylene tetrahydrofolate reductase (MTHFR) is a more common cause of mildly to moderately elevated plasma homocysteine levels.16 The MTHFR deficiency involves a variation at position 677 in the MTHFR gene in which cytosine is replaced by thymidine (thus called C677T or 677C>T).17 Ten percent of the population are homozygous for this variant (TT), 43% are heterozygous (CT), and 47% are unaffected (CC). Heterozygotes have slightly higher homocysteine levels than unaffected people, while people with the TT genotype have approximately 20% higher homocysteine levels.17
ELEVATED HOMOCYSTEINE IS COMMON
In a study of a population in Norway from 1992 to 1993, 8.5% had mild elevations in homocysteine (plasma levels 15–29.99 μmol/L), 0.8% had moderate elevations (30–99.99 μmol/L), and 0.02% had severe elevations (≥ 100 μmol/L).13,18 The prevalence of hyperhomocysteinemia in the United States is probably much lower, given that supplementation of white flour and cereal grains with folic acid has been mandatory since 1998, but this is not well described in the literature.
HOW GREAT IS THE RISK?
Studies over the past 10 to 20 years have shown that elevated homocysteine is a marker of risk of cardiovascular disease. The association was first noted in patients with cystathionine beta-synthase deficiency, who tend to have premature cardiovascular disease.
However, studies of patients with MTHFR 677C>T have yielded mixed results. Although several meta-analyses found up to a 42% higher rate of ischemic heart disease and stroke in patients homozygous for MTHFR 677C>T (the TT genotype) than in those with the CC genotype,17,19,20 two other large meta-analyses did not find an association between this variant and vascular risk.21,22
Nonetheless, in a meta-analysis of the association between homocysteine and cardiovascular disease, Wald et al17 found that for every 5-μmol/L increase in serum homocysteine concentration, the risk of ischemic heart disease increased 20% to 30%.
TRIALS OF HOMOCYSTEINE-LOWERING THERAPY HAVE HAD MIXED RESULTS
Primary prevention of cardiovascular disease
Given the finding that treatment with folic acid lowers homocysteine—initially noted in patients with homocystinuria—researchers hypothesized that treatment with folic acid, vitamin B6, and vitamin B12 would decrease the risk of cardiovascular disease.
Little evidence currently exists to guide recommendations for homocysteine-lowering therapy to prevent first attacks of cardiovascular disease. The few studies published to date have been observational studies of dietary intake (not vitamin supplementation), and many were performed before folic acid fortification was mandated for flour and cereal (Table 2).23–27 Although the studies suggest that higher B-vitamin intake correlates with less vascular disease and its sequelae, there is uncertainty as to whether it is folic acid, vitamin B6, or vitamin B12 that is responsible, and also whether supplements would provide the same protective benefit as the presence of these nutrients in a varied diet.
Thus, in its recent evaluation of novel risk markers of cardiovascular disease, the United States Preventive Services Task Force 28,29 does not recommend measuring the plasma homocysteine level in the evaluation of either low-risk or intermediate-risk populations, finding no evidence that it adds any useful information in predicting major coronary events beyond what one could get from calculating the Framingham Risk Score. The task force also found no evidence that treating people who have elevated homocysteine levels decreases their risk of subsequent cardiovascular events.
In addition, a recent Cochrane Database review of eight randomized controlled trials in patients at low risk did not find a lower risk of myocardial infarction (fatal or nonfatal), stroke, or death from any cause in patients receiving B-complex vitamins.30
Secondary prevention of cardiovascular disease
Results have been mixed with regard to the ability of B vitamins to prevent cardiovascular events in patients with known cardiovascular disease (Table 3).4,5,11,12,31–46
Bazzano et al,47 in a meta-analysis published in 2006, evaluated 12 randomized controlled trials of folic acid supplementation in patients with known cardiovascular disease and did not find that treated patients had better cardiovascular outcomes. The mean homocysteine level was elevated (> 15 μmol/L) at baseline in only 4 of the 12 trials. However, in 1 of these 4 trials, there was no difference in outcomes comparing those with and without elevated homocysteine.31
Albert et al4 more recently evaluated the effect of a combination pill containing folic acid, vitamin B6, and vitamin B12 on cardiovascular events in women at high risk, ie, those with a history of cardiovascular disease or having three or more coronary risk factors. Treatment did not decrease the rate of the composite outcome of cardiovascular disease mortality, stroke, myocardial infarction, or coronary revascularization, although the homocysteine level decreased by a mean of 30% in the treated group. However, only 27.7% of the participants had an elevated homocysteine level. One might not expect patients to benefit from such treatment if they had normal homocysteine levels to begin with.
Ebbing et al,5 in a trial published in 2008, investigated the effect of folic acid, vitamin B12, and vitamin B6 supplements on the risks of death from any cause and of cardiovascular events in patients undergoing coronary angiography. Outcomes were no better in the treatment group than in the control group, despite a mean decrease in homocysteine level of 19%. However, over 90% of the participants had a normal homocysteine level.
Mager et al,32 in a study published in 2009, looked specifically at whether patients with coronary artery disease and elevated homocysteine levels (> 15 μmol/L) would benefit from folate-based vitamin therapy. In this subset, the incidence of death from any cause was lower in the treated group than in the control group (4% vs 32%, P < .001), an association that was not present in patients with normal homocysteine levels.
The SEARCH trial (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine),33 recently published, was a double-blind, randomized controlled trial of vitamin B12 and folic acid treatment in 12,064 patients who had survived a myocardial infarction. Although those who received the vitamin therapy had a 28% reduction in homocysteine level, no clinical benefit was demonstrated. Of note, 66% of the patients had a homocysteine level lower than 14 μmol/L at baseline.
Restenosis after angioplasty
Results are also mixed regarding whether folic acid supplements modify the risk of restenosis after coronary angioplasty.
Namazi et al48 evaluated the effect of folic acid supplementation on in-stent restenosis in 200 patients and found no difference between the treatment and placebo groups in the rates of either restenosis or target-vessel revascularization.
Schnyder et al49 evaluated the effect of folic acid, vitamin B6, and vitamin B12 treatment on the rate of coronary restenosis (in cases of balloon angioplasty) or in-stent restenosis (if a stent was used). Patients receiving treatment had lower rates of restenosis or instent restenosis (40% vs 48%, P = .01) and of need for target-vessel revascularization (11% vs 22%, P = .047). The mean homocysteine level was not elevated in this study either, and the researchers did not analyze the outcomes according to whether patients had high or normal homocysteine levels.
Lange et al35 also evaluated the effect of folic acid, vitamin B6, and vitamin B12 treatment on coronary in-stent restenosis. Paradoxically, the rate was higher with treatment in the overall group (mean homocysteine level 12.2 μmol/L), leading to a higher incidence of target-vessel revascularization. Patients who had a baseline elevation in homocysteine level had a nonsignificant trend toward a lower rate of in-stent restenosis.
Cerebrovascular and peripheral arterial disease
The evidence is also mixed for using folic acid and other B vitamins to prevent cerebrovascular disease and peripheral vascular disease. Although a 2007 meta-analysis found that folic acid supplementation decreased the risk of a first stroke by 18% (P = .045),50 a later meta-analysis contradicts this finding.51
A 2009 meta-analysis found that patients with peripheral arterial disease had higher homocysteine levels than controls, but it did not find any benefit from supplementation, owing to heterogeneity of the clinical end points used.52 Indeed, a 2009 Cochrane Database Systematic Review found that there were no adequate trials of the treatment of patients with peripheral vascular disease who have elevated plasma homocysteine.53
However, immediately after the Cochrane review was published, Khandanpour et al36 published the results of a trial of the effect of folic acid and 5-methyltetrahydrofolate (an active form of folic acid) supplementation on the ankle-brachial pressure index and the pulse-wave velocity in patients with peripheral arterial disease. These measures improved with 16 weeks of treatment. For the ankle-brachial pressure index, the P value was less than .01 for folic acid and .009 for 5-methyltetrahydrofolate; for the pulse-wave velocity, the P value was .051 for folic acid and .011 for 5-methyltetrahydrofolate.
Kidney disease
One could postulate that patients with end-stage renal disease or chronic kidney disease might benefit the most from folic acid supplementation, given the correlation of elevations in homocysteine levels with decline in glomerular filtration rate.
However, only one study found a lower rate of cardiovascular events with folic acid supplementation in dialysis patients, and the difference was not statistically significant (25% vs 36%, P < .08).31 Further, several studies found no benefit of folic acid supplementation in patients with chronic kidney disease.11,12,37
FUTURE DIRECTIONS AND RECOMMENDATIONS
Many experts have suggested that the existing evidence indicates that the homocysteine-lowering therapies folic acid, vitamin B6, and vitamin B12 do not lower the risk of cardiovascular disease.38,54–59 Indeed, the American Heart Association guidelines for cardiovascular disease prevention in women do not recommend folic acid supplementation to prevent cardiovascular disease.60 (Recommendations for men are the same as for women.) However, most of the clinical trials have not selected and treated patients with elevated homocysteine levels, but have instead included all patients regardless of homocysteine level.
At least two large ongoing trials are currently evaluating B-vitamin therapy for secondary prevention, but neither trial is looking specifically at patients with elevated homocysteine levels.61,62
Thus, instead of concluding that no patients could benefit from homocysteine-lowering treatment, future studies need to clarify:
Whether patients with elevated homocysteine would benefit from such treatment
At what level it would be appropriate to start treatment
The appropriate target homocysteine level with treatment.
Particularly given the recent finding that folic acid supplementation may increase cancer risk,63 these questions need closer scrutiny.
References
Humphrey LL, Fu R, Rogers K, Freeman M, Helfand M. Homocysteine level and coronary heart disease incidence: a systematic review and meta-analysis. Mayo Clin Proc2008; 83:1203–1212.
Boers GH. The case for mild hyperhomocysteinaemia as a risk factor. J Inherit Metab Dis1997; 20:301–306.
Austin RC, Lentz SR, Werstuck GH. Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease. Cell Death Differ2004; 11(suppl 1):S56–S64.
Albert CM, Cook NR, Gaziano JM, et al. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA2008; 299:2027–2036.
Ebbing M, Bleie Ø, Ueland PM, et al. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. JAMA2008; 300:795–804.
Butz LW, du Vigneaud V. The formation of a homologue of cystine by the decompensation of methionine with sulphuric acid. J Biol Chem1932; 99:135–142.
McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol1969; 56:111–128.
Zhang D, Jiang X, Fang P, et al. Hyperhomocysteinemia promotes inflammatory monocyte generation and accelerates atherosclerosis in transgenic cystathionine beta-synthase-deficient mice. Circulation2009; 120:1893–1902.
Woo KS, Chook P, Lolin YI, Sanderson JE, Metreweli C, Celermajer DS. Folic acid improves arterial endothelial function in adults with hyperhomocystinemia. J Am Coll Cardiol1999; 34:2002–2006.
Righetti M, Ferrario GM, Milani S, et al. Effects of folic acid treatment on homocysteine levels and vascular disease in hemodialysis patients. Med Sci Monit2003; 9:PI19–PI24.
Zoungas S, McGrath BP, Branley P, et al. Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renal failure: a multicenter, randomized, controlled trial. J Am Coll Cardiol2006; 47:1108–1116.
Carmel R, Jacobsen DW, editors. Homocysteine in Health and Disease. Cambridge, UK: Cambridge University Press, 2001.
Yap S, Boers GH, Wilcken B, et al. Vascular outcome in patients with homocystinuria due to cystathionine beta-synthase deficiency treated chronically: a multicenter observational study. Arterioscler Thromb Vasc Biol2001; 21:2080–2085.
McKusick V. 236200 Homocystinuria. In:McKusick V, editor. Mendelian Inheritance in Man. 10th ed. Baltimore, MD: The Johns Hopkins University Press, 1992:1444–1446.
McKusick V. 236250 Homocystinuria due to deficiency of N(5,10)-methylenetetrahydrofolate reductase activity. In:McKusick V, editor. Mendelian Inheritance in Man. Baltimore, MD: The Johns Hopkins University Press, 1992:1447–1448.
Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ2002; 325:1202.
Nygård O, Vollset SE, Refsum H, et al. Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. JAMA1995; 274:1526–1533.
Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG; MTHFR Studies Collaboration Group. MTHFR 677C-->T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA2002; 288:2023–2031.
Kelly PJ, Rosand J, Kistler JP, et al. Homocysteine, MTHFR 677C-->T polymorphism, and risk of ischemic stroke: results of a meta-analysis. Neurology2002; 59:529–536.
Lewis SJ, Ebrahim S, Davey Smith G. Meta-analysis of MTHFR 677C->T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate?BMJ2005; 331:1053.
Brattström L, Wilcken DE, Ohrvik J, Brudin L. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: the result of a meta-analysis. Circulation1998; 98:2520–2526.
Cui R, Iso H, Date C, Kikuchi S, Tamakoshi A; Japan Collaborative Cohort Study Group. Dietary folate and vitamin B6 and B12 intake in relation to mortality from cardiovascular diseases: Japan Collaborative Cohort Study. Stroke2010; 41:1285–1289.
Liu S, Stampfer MJ, Hu FB, et al. Whole-grain consumption and risk of coronary heart disease: results from the Nurses’ Health Study. Am J Clin Nutr1999; 70:412–419.
Liu S, Manson JE, Stampfer MJ, et al. Whole grain consumption and risk of ischemic stroke in women: a prospective study. JAMA2000; 284:1534–1540.
Merchant AT, Hu FB, Spiegelman D, Willett WC, Rimm EB, Ascherio A. The use of B vitamin supplements and peripheral arterial disease risk in men are inversely related. J Nutr2003; 133:2863–2867.
Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA1998; 279:359–364.
US Preventive Services Task Force. Using nontraditional risk factors in coronary heart disease risk assessment: US Preventive Services Task Force recommendation statement. Ann Intern Med2009; 151:474–482.
Helfand M, Buckley DI, Freeman M, et al. Emerging risk factors for coronary heart disease: a summary of systematic reviews conducted for the US Preventive Services Task Force. Ann Intern Med2009; 151:496–507.
Martí-Carvajal AJ, Solà I, Lathyris D, Salanti G. Homocysteine lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev2009; ( 4):CD006612.
Righetti M, Serbelloni P, Milani S, Ferrario G. Homocysteine-lowering vitamin B treatment decreases cardiovascular events in hemodialysis patients. Blood Purif2006; 24:379–386.
Mager A, Orvin K, Koren-Morag N, et al. Impact of homocysteine-lowering vitamin therapy on long-term outcome of patients with coronary artery disease. Am J Cardiol2009; 104:745–749.
Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group; Armitage JM, Bowman L, Clarke RJ, et al. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA2010; 303:2486–2494.
Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and percutaneous coronary intervention: the Swiss Heart Study: a randomized controlled trial. JAMA2002; 288:973–979.
Lange H, Suryapranata H, De Luca G, et al. Folate therapy and in-stent restenosis after coronary stenting. N Engl J Med2004; 350:2673–2781.
Khandanpour N, Armon MP, Jennings B, et al. Randomized clinical trial of folate supplementation in patients with peripheral arterial disease. Br J Surg2009; 96:990–998.
Wrone EM, Hornberger JM, Zehnder JL, McCann LM, Coplon NS, Fortmann SP. Randomized trial of folic acid for prevention of cardiovascular events in end-stage renal disease. J Am Soc Nephrol2004; 15:420–426.
Loscalzo J. Homocysteine trials—clear outcomes for complex reasons. N Engl J Med2006; 354:1629–1632.
Bønaa KH, Njølstad I, Ueland PM, et al; NORVIT Trial Investigators. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med2006; 354:1578–1588.
Carrero JJ, López-Huertas E, Salmerón LM, Baró L, Ros E. Daily supplementation with (n-3) PUFAs, oleic acid, folic acid, and vitamins B-6 and E increases pain-free walking distance and improves risk factors in men with peripheral vascular disease. J Nutr2005; 135:1393–1399.
Liem AH, van Boven AJ, Veeger NJ, et al; Folic Acid on Risk Diminishment After Acute Myocarial Infarction Study Group. Efficacy of folic acid when added to statin therapy in patients with hypercholesterolemia following acute myocardial infarction: a randomised pilot trial. Int J Cardiol2004; 93:175–179.
Liem A, Reynierse-Buitenwerf GH, Zwinderman AH, Jukema JW, van Veldhuisen DJ. Secondary prevention with folic acid: results of the Goes extension study. Heart2005; 91:1213–1214.
Lonn E, Yusuf S, Arnold MJ, et al; Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med2006; 354:1567–1577.
Sydow K, Schwedhelm E, Arakawa N, et al. ADMA and oxidative stress are responsible for endothelial dysfunction in hyperhomocyst(e)inemia: effects of L-arginine and B vitamins. Cardiovasc Res2003; 57:244–252.
Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA2004; 291:565–575.
Jamison RL, Hartigan P, Kaufman JS, et al; Veterans Affairs Site Investigators. Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial. JAMA2007; 2989:1163–1170. Erratum in JAMA 2008;300:170.
Bazzano LA, Reynolds K, Holder KN, He J. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. JAMA2006; 296:2720–2726.
Namazi MH, Motamedi MR, Safi M, Vakili H, Saadat H, Nazari N. Efficacy of folic acid therapy for prevention of in-stent restenosis: a randomized clinical trial. Arch Iran Med2006; 9:108–110.
Schnyder G, Roffi M, Pin R, et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med2001; 345:1593–1600.
Wang X, Qin X, Demirtas H, et al. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet2007; 369:1876–1882.
Lee M, Hong KS, Chang SC, Saver JL. Efficacy of homocysteine-lowering therapy with folic Acid in stroke prevention: a meta-analysis. Stroke2010; 41:1205–1212.
Khandanpour N, Loke YK, Meyer FJ, Jennings B, Armon MP. Homocysteine and peripheral arterial disease: systematic review and meta-analysis. Eur J Vasc Endovasc Surg2009; 38:316–322.
Hansrani M, Stansby G. Homocysteine lowering interventions for peripheral arterial disease and bypass grafts. Cochrane Database Syst Rev2002; ( 3):CD003285.
Mosca L. Novel cardiovascular risk factors: do they add value to your practice?Am Fam Physician2003; 67:264,266.
Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction. J Am Coll Cardiol2007; 50:e1–e157.
Lonn E. Homocysteine-lowering B vitamin therapy in cardiovascular prevention—wrong again?JAMA2008; 299:2086–2087.
Milani RV, Lavie CJ. Homocysteine: the Rubik’s cube of cardiovascular risk factors. Mayo Clin Proc2008; 83:1200–1202.
Bazzano LA. Folic acid supplementation and cardiovascular disease: the state of the art. Am J Med Sci2009; 338:48–49.
Ntaios G, Savopoulos C, Grekas D, Hatzitolios A. The controversial role of B-vitamins in cardiovascular risk: an update. Arch Cardiovasc Dis2009; 102:847–854.
Mosca L, Banka CL, Benjamin EJ; Expert Panel/Writing Group. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation2007; 115:1481–1501.
Bassuk SS, Albert CM, Cook NR, et al. The Women’s Antioxidant Cardiovascular Study: design and baseline characteristics of participants. J Womens Health (Larchmt)2004; 13:99–117.
SEARCH Study Collaborative Group; Bowman L, Armitage J, Bulbulia R, Parish S, Collins R. Study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH): characteristics of a randomized trial among 12064 myocardial infarction survivors. Am Heart J2007; 154:815–823,823.e1–e6.
Ebbing M, Bønaa KH, Nygård O, et al. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA2009; 302:2119–2126.
References
Humphrey LL, Fu R, Rogers K, Freeman M, Helfand M. Homocysteine level and coronary heart disease incidence: a systematic review and meta-analysis. Mayo Clin Proc2008; 83:1203–1212.
Boers GH. The case for mild hyperhomocysteinaemia as a risk factor. J Inherit Metab Dis1997; 20:301–306.
Austin RC, Lentz SR, Werstuck GH. Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease. Cell Death Differ2004; 11(suppl 1):S56–S64.
Albert CM, Cook NR, Gaziano JM, et al. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA2008; 299:2027–2036.
Ebbing M, Bleie Ø, Ueland PM, et al. Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. JAMA2008; 300:795–804.
Butz LW, du Vigneaud V. The formation of a homologue of cystine by the decompensation of methionine with sulphuric acid. J Biol Chem1932; 99:135–142.
McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol1969; 56:111–128.
Zhang D, Jiang X, Fang P, et al. Hyperhomocysteinemia promotes inflammatory monocyte generation and accelerates atherosclerosis in transgenic cystathionine beta-synthase-deficient mice. Circulation2009; 120:1893–1902.
Woo KS, Chook P, Lolin YI, Sanderson JE, Metreweli C, Celermajer DS. Folic acid improves arterial endothelial function in adults with hyperhomocystinemia. J Am Coll Cardiol1999; 34:2002–2006.
Righetti M, Ferrario GM, Milani S, et al. Effects of folic acid treatment on homocysteine levels and vascular disease in hemodialysis patients. Med Sci Monit2003; 9:PI19–PI24.
Zoungas S, McGrath BP, Branley P, et al. Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renal failure: a multicenter, randomized, controlled trial. J Am Coll Cardiol2006; 47:1108–1116.
Carmel R, Jacobsen DW, editors. Homocysteine in Health and Disease. Cambridge, UK: Cambridge University Press, 2001.
Yap S, Boers GH, Wilcken B, et al. Vascular outcome in patients with homocystinuria due to cystathionine beta-synthase deficiency treated chronically: a multicenter observational study. Arterioscler Thromb Vasc Biol2001; 21:2080–2085.
McKusick V. 236200 Homocystinuria. In:McKusick V, editor. Mendelian Inheritance in Man. 10th ed. Baltimore, MD: The Johns Hopkins University Press, 1992:1444–1446.
McKusick V. 236250 Homocystinuria due to deficiency of N(5,10)-methylenetetrahydrofolate reductase activity. In:McKusick V, editor. Mendelian Inheritance in Man. Baltimore, MD: The Johns Hopkins University Press, 1992:1447–1448.
Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ2002; 325:1202.
Nygård O, Vollset SE, Refsum H, et al. Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. JAMA1995; 274:1526–1533.
Klerk M, Verhoef P, Clarke R, Blom HJ, Kok FJ, Schouten EG; MTHFR Studies Collaboration Group. MTHFR 677C-->T polymorphism and risk of coronary heart disease: a meta-analysis. JAMA2002; 288:2023–2031.
Kelly PJ, Rosand J, Kistler JP, et al. Homocysteine, MTHFR 677C-->T polymorphism, and risk of ischemic stroke: results of a meta-analysis. Neurology2002; 59:529–536.
Lewis SJ, Ebrahim S, Davey Smith G. Meta-analysis of MTHFR 677C->T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate?BMJ2005; 331:1053.
Brattström L, Wilcken DE, Ohrvik J, Brudin L. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: the result of a meta-analysis. Circulation1998; 98:2520–2526.
Cui R, Iso H, Date C, Kikuchi S, Tamakoshi A; Japan Collaborative Cohort Study Group. Dietary folate and vitamin B6 and B12 intake in relation to mortality from cardiovascular diseases: Japan Collaborative Cohort Study. Stroke2010; 41:1285–1289.
Liu S, Stampfer MJ, Hu FB, et al. Whole-grain consumption and risk of coronary heart disease: results from the Nurses’ Health Study. Am J Clin Nutr1999; 70:412–419.
Liu S, Manson JE, Stampfer MJ, et al. Whole grain consumption and risk of ischemic stroke in women: a prospective study. JAMA2000; 284:1534–1540.
Merchant AT, Hu FB, Spiegelman D, Willett WC, Rimm EB, Ascherio A. The use of B vitamin supplements and peripheral arterial disease risk in men are inversely related. J Nutr2003; 133:2863–2867.
Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA1998; 279:359–364.
US Preventive Services Task Force. Using nontraditional risk factors in coronary heart disease risk assessment: US Preventive Services Task Force recommendation statement. Ann Intern Med2009; 151:474–482.
Helfand M, Buckley DI, Freeman M, et al. Emerging risk factors for coronary heart disease: a summary of systematic reviews conducted for the US Preventive Services Task Force. Ann Intern Med2009; 151:496–507.
Martí-Carvajal AJ, Solà I, Lathyris D, Salanti G. Homocysteine lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev2009; ( 4):CD006612.
Righetti M, Serbelloni P, Milani S, Ferrario G. Homocysteine-lowering vitamin B treatment decreases cardiovascular events in hemodialysis patients. Blood Purif2006; 24:379–386.
Mager A, Orvin K, Koren-Morag N, et al. Impact of homocysteine-lowering vitamin therapy on long-term outcome of patients with coronary artery disease. Am J Cardiol2009; 104:745–749.
Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group; Armitage JM, Bowman L, Clarke RJ, et al. Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA2010; 303:2486–2494.
Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Effect of homocysteine-lowering therapy with folic acid, vitamin B12, and percutaneous coronary intervention: the Swiss Heart Study: a randomized controlled trial. JAMA2002; 288:973–979.
Lange H, Suryapranata H, De Luca G, et al. Folate therapy and in-stent restenosis after coronary stenting. N Engl J Med2004; 350:2673–2781.
Khandanpour N, Armon MP, Jennings B, et al. Randomized clinical trial of folate supplementation in patients with peripheral arterial disease. Br J Surg2009; 96:990–998.
Wrone EM, Hornberger JM, Zehnder JL, McCann LM, Coplon NS, Fortmann SP. Randomized trial of folic acid for prevention of cardiovascular events in end-stage renal disease. J Am Soc Nephrol2004; 15:420–426.
Loscalzo J. Homocysteine trials—clear outcomes for complex reasons. N Engl J Med2006; 354:1629–1632.
Bønaa KH, Njølstad I, Ueland PM, et al; NORVIT Trial Investigators. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med2006; 354:1578–1588.
Carrero JJ, López-Huertas E, Salmerón LM, Baró L, Ros E. Daily supplementation with (n-3) PUFAs, oleic acid, folic acid, and vitamins B-6 and E increases pain-free walking distance and improves risk factors in men with peripheral vascular disease. J Nutr2005; 135:1393–1399.
Liem AH, van Boven AJ, Veeger NJ, et al; Folic Acid on Risk Diminishment After Acute Myocarial Infarction Study Group. Efficacy of folic acid when added to statin therapy in patients with hypercholesterolemia following acute myocardial infarction: a randomised pilot trial. Int J Cardiol2004; 93:175–179.
Liem A, Reynierse-Buitenwerf GH, Zwinderman AH, Jukema JW, van Veldhuisen DJ. Secondary prevention with folic acid: results of the Goes extension study. Heart2005; 91:1213–1214.
Lonn E, Yusuf S, Arnold MJ, et al; Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med2006; 354:1567–1577.
Sydow K, Schwedhelm E, Arakawa N, et al. ADMA and oxidative stress are responsible for endothelial dysfunction in hyperhomocyst(e)inemia: effects of L-arginine and B vitamins. Cardiovasc Res2003; 57:244–252.
Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA2004; 291:565–575.
Jamison RL, Hartigan P, Kaufman JS, et al; Veterans Affairs Site Investigators. Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial. JAMA2007; 2989:1163–1170. Erratum in JAMA 2008;300:170.
Bazzano LA, Reynolds K, Holder KN, He J. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. JAMA2006; 296:2720–2726.
Namazi MH, Motamedi MR, Safi M, Vakili H, Saadat H, Nazari N. Efficacy of folic acid therapy for prevention of in-stent restenosis: a randomized clinical trial. Arch Iran Med2006; 9:108–110.
Schnyder G, Roffi M, Pin R, et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med2001; 345:1593–1600.
Wang X, Qin X, Demirtas H, et al. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet2007; 369:1876–1882.
Lee M, Hong KS, Chang SC, Saver JL. Efficacy of homocysteine-lowering therapy with folic Acid in stroke prevention: a meta-analysis. Stroke2010; 41:1205–1212.
Khandanpour N, Loke YK, Meyer FJ, Jennings B, Armon MP. Homocysteine and peripheral arterial disease: systematic review and meta-analysis. Eur J Vasc Endovasc Surg2009; 38:316–322.
Hansrani M, Stansby G. Homocysteine lowering interventions for peripheral arterial disease and bypass grafts. Cochrane Database Syst Rev2002; ( 3):CD003285.
Mosca L. Novel cardiovascular risk factors: do they add value to your practice?Am Fam Physician2003; 67:264,266.
Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction. J Am Coll Cardiol2007; 50:e1–e157.
Lonn E. Homocysteine-lowering B vitamin therapy in cardiovascular prevention—wrong again?JAMA2008; 299:2086–2087.
Milani RV, Lavie CJ. Homocysteine: the Rubik’s cube of cardiovascular risk factors. Mayo Clin Proc2008; 83:1200–1202.
Bazzano LA. Folic acid supplementation and cardiovascular disease: the state of the art. Am J Med Sci2009; 338:48–49.
Ntaios G, Savopoulos C, Grekas D, Hatzitolios A. The controversial role of B-vitamins in cardiovascular risk: an update. Arch Cardiovasc Dis2009; 102:847–854.
Mosca L, Banka CL, Benjamin EJ; Expert Panel/Writing Group. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation2007; 115:1481–1501.
Bassuk SS, Albert CM, Cook NR, et al. The Women’s Antioxidant Cardiovascular Study: design and baseline characteristics of participants. J Womens Health (Larchmt)2004; 13:99–117.
SEARCH Study Collaborative Group; Bowman L, Armitage J, Bulbulia R, Parish S, Collins R. Study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH): characteristics of a randomized trial among 12064 myocardial infarction survivors. Am Heart J2007; 154:815–823,823.e1–e6.
Ebbing M, Bønaa KH, Nygård O, et al. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA2009; 302:2119–2126.
Factors that can cause the plasma homocysteine concentration to be high include deficiencies of vitamin B6, vitamin B12, and folic acid; renal insufficiency; and genetic variants in enzymes responsible for homocysteine metabolism.
Higher plasma homocysteine levels are associated with a higher risk of cardiovascular, cerebrovascular, and peripheral arterial disease.
Supplementation of B vitamins and folic acid can lower plasma homocysteine levels.
Randomized controlled trials of supplementation to prevent cardiovascular events and other adverse outcomes have had mostly negative results. However, most patients in these trials had normal baseline plasma homocysteine levels.
Needed are randomized trials to see if supplementation improves outcomes in patients with high homocysteine levels.
Vitamin D is viewed as a promising supplement by the medical, public health, and lay communities, potentially offering many health benefits. But enthusiasm for a new intervention too often gets far ahead of the evidence, as was the case with beta-carotene, selenium, folic acid, and vitamins C and E.
Despite the enthusiasm for vitamin D, there have been no large-scale primary prevention trials that have had either cardiovascular disease or cancer as a prespecified primary outcome. Previous randomized trials of vitamin D have focused primarily on osteoporosis, fracture, falls, and physical function. Although the investigators often reported their findings on vitamin D and cardiovascular disease or cancer, these outcomes were generally secondary or tertiary end points that were not prespecified. These studies should be viewed as hypothesis-generating rather than hypothesis-testing. The increasing prevalence of use of vitamin D supplements underscores the need for rigorous and conclusive evidence from randomized clinical trials that have cardiovascular disease and cancer as primary outcomes.
This article will explain the rationale for a large-scale, randomized clinical trial to evaluate the role of vitamin D in the prevention of cardiovascular disease and cancer. It will also describe the biological mechanisms and currently available evidence relating vitamin D to potential health benefits. Finally, the design, dosage considerations, and logistics of the Vitamin D and Omega-3 Trial (VITAL) will be presented.
EVIDENCE IS MOUNTING FOR VITAMIN D’S BIOLOGICAL IMPORTANCE
Vitamin D is undoubtedly important to health: not only is it produced endogenously, but at least 500 genes have been identified with vitamin D response elements. The vitamin D receptor is found in nearly all cells in the body, and the 1-alpha-hydroxylase enzyme is present in many tissues. Some studies suggest that almost 10% of the human genome may be at least partially regulated by vitamin D.
From Hajjar V, et al. Does vitamin D deficiency play a role in the pathogenesis of chronic heart failure? Do supplements improve survival? Cleve Clin J Med 2010; 77:290–293.
Figure 1.Vitamin D is a prohormone, and people obtain it both endogenously and exogenously (Figure 1). With exposure to ultraviolet B light, 7-dehydrocholesterol in the skin converts to vitamin D3. We also obtain it through diet or supplements. The plant form (vitamin D2) and the animal form (vitamin D3) undergo 25-hydroxylation in the liver. Then, 1-alpha-hydroxylase converts the 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3, primarily in the kidney. Increasing evidence shows that 1-alpha-hydroxylase is present in many other cells and tissues, and that 1,25-dihydroxyvitamin D3 may be locally produced and possibly even have autocrine effects (acting on surface receptors of the same cell it is secreted by) and paracrine effects (acting on adjacent cells).
Although we know vitamin D is important, what our optimal intake and our blood level of 25-hydroxyvitamin D3 should be are key unknowns.
RECOMMENDATIONS FOR VITAMIN D INTAKE
During winter, late fall, and early spring, people who live above the 37th parallel (geographically, about one-half of the contiguous United States) do not get enough ultraviolet B energy from the sun to make all the vitamin D they need, even if they spend several hours outside every day. In addition, dark skin pigmentation serves as a sun block, as do sunscreens.
The Institute of Medicine (IOM) provided guidelines for vitamin D intake in 1997 and, most recently, in 2010. However, these guidelines are based on the amount of vitamin D required for bone health and do not address the amount that may be of benefit for prevention of cancer and cardiovascular disease. The latter outcomes are not addressed because the IOM committee believed that evidence was insufficient to determine the role of vitamin D in the prevention of cardiovascular disease, cancer, and other chronic diseases. Thus, current IOM guidelines, which generally recommend less than 1,000 IU of vitamin D daily, are relevant to bone health but not necessarily to other health outcomes. More research is needed to understand whether the guidelines should be modified for the prevention of other chronic diseases.
Moreover, whether or not everyone should be screened for 25-hydroxyvitamin D3 blood levels is controversial. Most experts agree that a level less than 20 ng/mL is deficient or insufficient. Conversely, potentially harmful are levels 150 ng/mL or more (> 375 nmol/L), which entail the risk of hypercalcemia, vascular soft tissue calcification, and hyperphosphatemia.
People do not reach toxic levels with ultraviolet light exposure because the amount of 25-hydroxyvitamin D3 synthesis is well regulated. Dietary supplements, however, can bring about toxic levels, and patients taking high doses need to be monitored carefully. The level that should be considered optimal is controversial and requires further study.
RISK FACTORS FOR LOW VITAMIN D LEVELS
Risk factors for low vitamin D levels include older age, living in northern latitudes, sun avoidance, dark skin pigmentation, obesity, low dietary intake, and various medical conditions, especially malabsorption syndromes. Some of these are also risk factors for cardiovascular disease, cancer, and other chronic diseases, and potentially confound outcomes in many studies. Older age, which is usually adjusted for in multivariate models, is important to recognize as a major risk factor for vitamin D deficiency, owing to reduced absorption and synthesis, less time outdoors, and low dietary intake.
Wearing sunscreen decreases the synthesis of vitamin D in the skin, but because ultra-violet light has been clearly classified as a carcinogen, it is a not advisable to increase sun exposure for the sake of increasing vitamin D levels. That is a poor trade-off, given the high incidence rate of skin cancer and the adverse effects of solar radiation on skin aging.
Obesity is a risk factor for vitamin D deficiency because vitamin D is fat-soluble and becomes sequestered in fat tissue. Vitamin D may also play a role in the differentiation of adipocytes and may affect their function. In observational studies, it is very important for researchers to adjust for body mass index, physical activity (which may be correlated with more time outdoors), and other potential confounders in their analyses.
HOW VITAMIN D MAY LOWER CANCER RISK
Because of the important effect of vitamin D in regulating cell differentiation and cell growth, there are multiple ways that it may affect cancer risk. Laboratory, cell culture, and animal studies suggest that vitamin D may lower cancer risk by inhibiting cell proliferation, angiogenesis, metastasis, and inflammation and inducing apoptosis and cellular differentiation. Several of these mechanisms are also relevant to atherosclerosis and cardiovascular disease. Although VITAL is addressing the role of vitamin D in preventing both cancer and cardiovascular disease, the remainder of this article will focus on cardiovascular outcomes.
HOW VITAMIN D MAY REDUCE CARDIOVASCULAR RISK
Vitamin D may lower cardiovascular risk via several mechanisms:
Inhibiting inflammation. Vitamin D has a powerful immunomodulatory effect: laboratory studies show that it inhibits prostaglandin and cyclooxygenase 2 pathways, reduces matrix metalloproteinase 9 and several proinflammatory cytokines, and increases interleukin 10, all of which result in suppressed inflammation.1
Inhibiting vascular muscle proliferation and vascular calcification. Animal studies indicate that in moderate doses vitamin D decreases calcium cellular influx and increases matrix Gla protein, which inhibits vascular smooth muscle proliferation and vascular calcification. These protective effects contrast with the hypercalcemia associated with a high intake of vitamin D, especially in the context of renal failure or other risk factors, which may lead to increased vascular calcification.1
Regulates blood pressure. Vitamin D decreases renin gene expression and the synthesis of renin, which reduces activity of the renin-angiotensin-aldosterone system, leading to a reduction of blood pressure and a favorable effect on volume homeostasis.1
Regulates glucose metabolism. Limited evidence shows that vitamin D may increase insulin sensitivity and regulate glucose metabolism.1
Vitamin D and cardiac hypertrophy
The vitamin D receptor is present in virtually all tissues, including cardiac myocytes and endothelial cells. Animals with vitamin D deficiency have higher blood pressures, and animals genetically altered to have no vitamin D receptors (knock-out models) develop left ventricular hypertrophy and heart failure.
Animals genetically altered to have no 1-alpha-hydroxylase (so that the most active form of vitamin D is not made) also develop left ventricular hypertrophy. They can be rescued by the administration of 1,25-dihydroxy vitamin D3.1
These findings are consistent with what is observed in patients with end-stage renal disease, who produce very little 1,25-dihydroxyvitamin D3: they often develop left ventricular hypertrophy, diastolic heart failure, atherosclerosis, and vascular calcification.
EVIDENCE FOR CARDIOVASCULAR DISEASE REDUCTION
Wang et al1 recently reviewed available prospective cohort and randomized clinical trials from 1966 to 2009 that examined vitamin D or calcium supplementation and cardiovascular disease. Comparing people with the lowest to the highest levels of serum 25-hydroxyvitamin D3 indicated that a low level is a risk factor for coronary artery disease and cardiovascular death. Unfortunately, most studies were not designed to assess primary effects on cardiovascular outcomes, and so have many potential confounders.
Prospective observational studies
Observational studies suggest that vitamin D deficiency is associated with an increased risk of cardiovascular disease. Some examples:
The Framingham Offspring Study2 followed 1,739 men and women with a mean age of 59 for 5.4 years. The study compared the incidence of cardiovascular events in those with a serum 25-dihydroxyvitamin D level of at least 37.5 nmol/L vs those with lower levels. The risk of cardiovascular disease was 1.62 times higher in those with the lowest levels of vitamin D, a statistically significant difference. However, a threshold effect was apparent (discussed below).
The Health Professionals Follow-up Study3 prospectively evaluated more than 18,000 men ages 40 to 75 for 10 years. The study compared men with a low serum level of vitamin D (< 37.5 nmol/L) to those with a more optimal level (> 75 nmol/L). The incidence of cardiovascular events was 2.09 times higher in men with low levels of vitamin D, a difference that was statistically significant.
The Third National Health and Nutrition Examination Survey (NHANES III) included data for more than 13,300 men and women age 20 years and older. Using a cohort that was followed for 8.7 years, Melamed et al4 compared the quartile with the lowest serum vitamin D level (< 44.4 nmol/L) against the quartile with the highest level (> 80.1 nmol/L). The associations were modest: those with low levels had a 1.20-times higher rate of death from cardiovascular disease and a statistically significant 1.26-times higher rate of death from all causes.
Randomized clinical trials
A meta-analysis of 18 randomized trials5 of vitamin D supplementation (300–2,000 IU/day, mean 528 IU/day vs placebo), including 57,311 participants, evaluated the rate of death from all causes and found a modest but significant reduction in risk (relative risk 0.93, 95% confidence interval [CI] 0.87–0.99). These were generally trials looking at fracture rates or physical performance, and a dose-response relationship was not evident. A recent systematic review of randomized controlled trials of vitamin D1 that included cardiovascular disease as a secondary outcome found a pooled relative risk for cardiovascular disease of 0.90 (95% CI 0.77–1.05) for vitamin D supplementation compared with placebo and 1.04 (95% CI 0.92–1.18) for combination vitamin D plus calcium supplementation vs placebo.1 Two individual trials are discussed below.
Trivedi et al6 randomized 2,686 British men and women to vitamin D3 100,000 IU given every 4 months over 5 years (equivalent to 800 IU/day) or placebo. The relative risk of cardiovascular events was 0.90 (95% CI 0.77–1.06) and of cardiovascular deaths 0.84 (95% CI 0.65–1.10). Although the results were promising, the trial was designed to assess fracture risk and was not large enough for the differences in cardiovascular outcomes to reach statistical significance.
The Women’s Health Initiative,7,8 which included 36,282 postmenopausal women aged 50 to 79, tested combined vitamin D3 (400 IU/day) with calcium (1,000 mg/day) vs placebo. No benefit was seen for preventing coronary events or stroke, which may be due to the low dosage of vitamin D. The hazard ratio for coronary disease was 1.04 (0.92–1.18). Regarding mortality, the hazard ratio for cardiovascular death was 0.92, for cerebrovascular death 0.89, for cancer death 0.89, and for other deaths 0.95. None of these hazard ratios reached statistical significance.
MORE MAY NOT BE BETTER
As is probably true for everything in biological systems, there apparently is an optimal level of intake to meet vitamin D needs.
The Framingham Offspring Study,2 which found a higher risk with vitamin D deficiency, also found a suggestion of a threshold. Participants who had levels of 50 to 65 nmol/L had the lowest risk. Higher levels did not confer lower risk and even suggested a slight upturn.
Evidence from the Women’s Health Initiative8 also indicates that high dosages may not be better than moderate dosages. The meta-analysis of vitamin D and all-cause mortality5 found a relative risk of 0.93, but one of the largest studies in that meta-analysis tested only 400 IU a day and found a similar relative risk of 0.91 (95% confidence interval, 0.83–1.01).
Moreover, the NHANES study found that with increasing serum 25-hydroxyvitamin D3 levels, the risk of all-cause mortality fell until about 100 nmol/L, but then plateaued and even increased with higher serum levels.4
VITAL: STUDY DESIGN AND LOGISTICS
In VITAL, the investigators aim to recruit 20,000 healthy men (age 60 and older) and women (65 and older) who are representative of the US population (www.vitalstudy.org). Because it is a primary prevention trial, people with a known history of cardiovascular disease or cancer will be excluded. Participants will be randomized to receive either 2,000 IU of vitamin D3 per day or placebo. Each group will be further randomized to receive either 1 g per day of fish oil (combined eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) or placebo. The mean treatment period will be 5 years. Recruitment began in early 2010.
Blood will be collected in about 80% (ideally 100%) of participants, with follow-up blood collection in at least 2,000.
Primary aims of the trial are to test whether vitamin D3 and the omega-3 fatty acids reduce the risk of total cancer and major cardiovascular events (a composite of myocardial infarction, stroke, and death due to cardiovascular events).
Secondary aims are to test whether these agents lower the risk of:
Site-specific cancer, including colorectal, breast, and prostate cancer, and the total cancer mortality rate
An expanded composite outcome including myocardial infarction, stroke, cardiovascular death, coronary artery bypass grafting, percutaneous coronary intervention, and its individual components.
Tertiary aims are to explore whether vitamin D3 and omega-3 fatty acids have additive effects on the primary and secondary end points. The trial will also explore whether the effects of vitamin D3 and omega-3 fatty acids on cancer and cardiovascular disease vary by baseline blood levels of these nutrients, and whether race, skin pigmentation, or body mass index modify the effects of vitamin D3.
Ancillary studies will assess the effect of the interventions on risk of diabetes, hypertension, cognitive decline, depression, fracture, infections, respiratory disorders, and autoimmune diseases. The primary sponsor of this trial is the National Cancer Institute, and the secondary sponsor is the National Heart, Lung and Blood Institute. Other institutes and agencies also are cosponsors of the study.
The timing of VITAL is optimal
There is a limited window of opportunity for conducting a randomized clinical trial: the evidence must be strong enough to justify mounting a very large trial with enough power to look at cardiovascular events and cancer, but the evidence must not be so strong that it would be unethical to have a placebo group. Thus, there must be a state of equipoise. Our trial allows the study population to have a background intake of vitamin D that is currently recommended by national guidelines. Therefore, even the placebo group should have adequate intake of vitamin D.
The growing use of vitamin D supplementation by the public underscores the need for conclusive evidence of its benefits and risks. No previous large-scale randomized clinical trial has tested moderate to high doses of vitamin D for the primary prevention of cancer and cardiovascular disease.
Setting the dosage
VITAL set the vitamin D3 dosage at 2,000 IU per day (50 μg/day), which is designed to provide the best balance of efficacy and safety. As a general rule, each microgram of vitamin D3 is expected to raise the serum 25-hydroxyvitamin D3 level about 1 nmol/L, although the response is not linear: if baseline levels are lower, the increase is greater. In the United States, people commonly have a baseline level of about 40 nmol/L, so we expect that levels of people treated in the study will reach about 90 nmol/L (range 75–100 nmol/L), about 35 to 50 nmol/L higher than in the placebo group.
The target range of 75 to 100 nmol/L is the level at which greatest efficacy has been suggested in observational studies. Previous randomized trials of vitamin D have not tested high enough doses to achieve this level of 25-hydroxyvitamin D3. VITAL will test whether reaching this serum level lowers the risk of cardiovascular disease, cancer, and other chronic diseases. This level may be associated with benefit and has minimal risk of hypercalcemia. Risk of hypercalcemia may be present in participants with an occult chronic granulomatous condition such as sarcoidosis or Wegener granulomatosis, in which activated macrophages synthesize 1,25-dihydroxyvitamin D3. These conditions are very rare, however, and the risk of hypercalcemia in the trial is exceedingly low.
VITAL participants will also be randomized to take placebo or 1 g per day of combined EPA and DHA, about 5 to 10 times more than most Americans consume.
Nationwide recruitment among senior citizens
We aim to recruit 20,000 people (10,000 men and 10,000 women) nationwide who are willing, eligible, and compliant (ie, who take more than two-thirds of study pills during a 3-month placebo “run-in” phase of the trial). The trial aims to enroll 40,000 in the run-in period, and 20,000 will be randomized. To get this many participants, we will send invitational mailings and screening questionnaires to at least 2.5 million people around the United States, with mailing lists selected by age—ie, members of the American Association of Retired Persons, health professionals, teachers, and subscription lists for selected magazines. A pilot study in 5,000 people has indicated that recruiting and randomizing 20,000 participants via large mailings should be possible.
The trial is expected to be extremely cost-effective because it will be conducted largely by mail. Medication will be mailed in calendar blister packs. Participants report outcomes, which are then confirmed by medical record review. The Centers for Medicare and Medicaid Services and the National Death Index will also be used to ascertain outcomes.
We hope to recruit a more racially diverse study population than is typically seen in US trials: 63% (12,620) whites, 25% (5,000) African Americans, 7% (1,400) Hispanics, 2.5% (500) Asians, 2% (400) American Indians and Alaska natives, and 0.4% (80) native Hawaiian and Pacific Islanders.
Eligibility criteria ensure primary prevention is tested
To enter the study, men must be at least 60 years old and women at least 65. At a minimum, a high school education is required due to the detailed forms and questionnaires to be completed. Because this is a primary prevention trial, anyone with a history of cancer (except nonmelanoma skin cancer) or cardiovascular disease (including myocardial infarction, stroke, or coronary revascularization) will be excluded, as will anyone with a history of kidney stones, renal failure or dialysis, hypercalcemia, hypoparathyroidism or hyperparathyroidism, severe liver disease (eg, cirrhosis), sarcoidosis, tuberculosis, or other granulomatous disease. People with an allergy to fish will also be excluded.
We do not expect that those in the placebo group will develop vitamin D deficiency due to their participation in the study. The trial will allow a background intake in the study population of up to 800 IU of vitamin D and 1,200 mg of calcium per day in supplements. Assuming they also get about 200 IU of vitamin D in the diet, the background intake in the placebo group may be close to 1,000 IU of vitamin D. Assuming that the active treatment group has a similar background intake, their total intake will be about 3,000 IU per day (about 1,000 IU/day from background intake plus 2,000 IU/day from the intervention).
Cohort power sufficient to see effect in 5 years
The trial is expected to have sufficient power to evaluate cardiovascular disease and cancer end points as primary outcomes during 5 years of follow-up. The trial is designed to have a power of 91% to 92% to detect a relative risk of 0.85 for the primary cancer end point of total cancer incidence and 0.80 for the cardiovascular disease end point of myocardial infarction, stroke, and cardiovascular mortality. Power will be even greater for the expanded composite outcome for cardiovascular disease.
Ancillary studies
Ancillary studies include evaluating the interventions’ role in preventing diabetes and glucose intolerance, hypertension, heart failure, atrial fibrillation, cognitive decline, mood disorders, osteoporosis and fractures, asthma and respiratory diseases, infections, macular degeneration, rheumatoid arthritis, systemic lupus erythematosus, and a composite of autoimmune diseases. Imaging studies also are planned, including dual energy x-ray absorptiometry, mammographic density, and non-invasive vascular imaging (carotid intima medial thickness, coronary calcium measurements, and two-dimensional echocardiography to assess cardiac function).
Several biomarker and genetic studies will also be carried out. We intend to perform genetic studies on most of the study population to evaluate gene variants in the vitamin D receptor, vitamin D binding protein, and other vitamin-D-related genes that may contribute to lower baseline levels of 25-hydroxyvitamin D3 or different responses to the interventions.
Clinical and Translational Science Center visits are planned to provide more detailed assessments of 1,000 participants, including blood pressure measurements, height, weight, waist circumference, other anthropometric measurements, a 2-hour glucose tolerance test, a fasting blood collection, hemoglobin A1c measurements, spirometry, and assessment of physical performance, strength, frailty, cognitive function, mood, and depression. Dual-energy x-ray absorptiometry and noninvasive vascular imaging studies are also planned for those visits.
References
Wang L, Manson JE, Song Y, Sesso HD. Systematic review: vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med2010; 152:315–323.
Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation2008; 117:503–511.
Giovannucci E, Liu Y, Hollis BW, Rimm EB. 25-Hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Arch Intern Med2008; 168:1174–1180.
Melamed ML, Michos ED, Post W, Astor B. 25-Hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med2008; 168:1629–1637.
Autier P, Gandini S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med2007; 167:1730–1737.
Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ2003; 326:469.
Hsia J, Heiss G, Ren H, et al; Women’s Health Initiative Investigators. Calcium/vitamin D supplementation and cardiovascular events. Circulation2007; 115:846–854.
LaCroix AZ, Kotchen J, Anderson G, et al. Calcium plus vitamin D supplementation and mortality in postmenopausal women: the Women’s Health Initiative calcium-vitamin D randomized controlled trial. J Gerontol A Biol Sci Med Sci2009; 64:559–567.
Joann E. Manson, MD, DrPH, FAHA Chief, Division of Preventive Medicine; Co-Director, Connors Center for Women’s Health and Gender Biology, Brigham and Women’s Hospital; Professor of Medicine, Harvard Medical School, Boston, MA; Principal Investigator, Vitamin D and Omega-3 Trial (VITAL)
Address: JoAnn E. Manson, MD, DrPH, Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, 900 Commonwealth Avenue, Boston, MA 02215; email [email protected]
Dr. Manson has received funding from the National Institutes of Health to conduct a large-scale randomized trial of vitamin D and omega-3 fatty acids for the prevention of cardiovascular disease and cancer.
Joann E. Manson, MD, DrPH, FAHA Chief, Division of Preventive Medicine; Co-Director, Connors Center for Women’s Health and Gender Biology, Brigham and Women’s Hospital; Professor of Medicine, Harvard Medical School, Boston, MA; Principal Investigator, Vitamin D and Omega-3 Trial (VITAL)
Address: JoAnn E. Manson, MD, DrPH, Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, 900 Commonwealth Avenue, Boston, MA 02215; email [email protected]
Dr. Manson has received funding from the National Institutes of Health to conduct a large-scale randomized trial of vitamin D and omega-3 fatty acids for the prevention of cardiovascular disease and cancer.
Author and Disclosure Information
Joann E. Manson, MD, DrPH, FAHA Chief, Division of Preventive Medicine; Co-Director, Connors Center for Women’s Health and Gender Biology, Brigham and Women’s Hospital; Professor of Medicine, Harvard Medical School, Boston, MA; Principal Investigator, Vitamin D and Omega-3 Trial (VITAL)
Address: JoAnn E. Manson, MD, DrPH, Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, 900 Commonwealth Avenue, Boston, MA 02215; email [email protected]
Dr. Manson has received funding from the National Institutes of Health to conduct a large-scale randomized trial of vitamin D and omega-3 fatty acids for the prevention of cardiovascular disease and cancer.
Vitamin D is viewed as a promising supplement by the medical, public health, and lay communities, potentially offering many health benefits. But enthusiasm for a new intervention too often gets far ahead of the evidence, as was the case with beta-carotene, selenium, folic acid, and vitamins C and E.
Despite the enthusiasm for vitamin D, there have been no large-scale primary prevention trials that have had either cardiovascular disease or cancer as a prespecified primary outcome. Previous randomized trials of vitamin D have focused primarily on osteoporosis, fracture, falls, and physical function. Although the investigators often reported their findings on vitamin D and cardiovascular disease or cancer, these outcomes were generally secondary or tertiary end points that were not prespecified. These studies should be viewed as hypothesis-generating rather than hypothesis-testing. The increasing prevalence of use of vitamin D supplements underscores the need for rigorous and conclusive evidence from randomized clinical trials that have cardiovascular disease and cancer as primary outcomes.
This article will explain the rationale for a large-scale, randomized clinical trial to evaluate the role of vitamin D in the prevention of cardiovascular disease and cancer. It will also describe the biological mechanisms and currently available evidence relating vitamin D to potential health benefits. Finally, the design, dosage considerations, and logistics of the Vitamin D and Omega-3 Trial (VITAL) will be presented.
EVIDENCE IS MOUNTING FOR VITAMIN D’S BIOLOGICAL IMPORTANCE
Vitamin D is undoubtedly important to health: not only is it produced endogenously, but at least 500 genes have been identified with vitamin D response elements. The vitamin D receptor is found in nearly all cells in the body, and the 1-alpha-hydroxylase enzyme is present in many tissues. Some studies suggest that almost 10% of the human genome may be at least partially regulated by vitamin D.
From Hajjar V, et al. Does vitamin D deficiency play a role in the pathogenesis of chronic heart failure? Do supplements improve survival? Cleve Clin J Med 2010; 77:290–293.
Figure 1.Vitamin D is a prohormone, and people obtain it both endogenously and exogenously (Figure 1). With exposure to ultraviolet B light, 7-dehydrocholesterol in the skin converts to vitamin D3. We also obtain it through diet or supplements. The plant form (vitamin D2) and the animal form (vitamin D3) undergo 25-hydroxylation in the liver. Then, 1-alpha-hydroxylase converts the 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3, primarily in the kidney. Increasing evidence shows that 1-alpha-hydroxylase is present in many other cells and tissues, and that 1,25-dihydroxyvitamin D3 may be locally produced and possibly even have autocrine effects (acting on surface receptors of the same cell it is secreted by) and paracrine effects (acting on adjacent cells).
Although we know vitamin D is important, what our optimal intake and our blood level of 25-hydroxyvitamin D3 should be are key unknowns.
RECOMMENDATIONS FOR VITAMIN D INTAKE
During winter, late fall, and early spring, people who live above the 37th parallel (geographically, about one-half of the contiguous United States) do not get enough ultraviolet B energy from the sun to make all the vitamin D they need, even if they spend several hours outside every day. In addition, dark skin pigmentation serves as a sun block, as do sunscreens.
The Institute of Medicine (IOM) provided guidelines for vitamin D intake in 1997 and, most recently, in 2010. However, these guidelines are based on the amount of vitamin D required for bone health and do not address the amount that may be of benefit for prevention of cancer and cardiovascular disease. The latter outcomes are not addressed because the IOM committee believed that evidence was insufficient to determine the role of vitamin D in the prevention of cardiovascular disease, cancer, and other chronic diseases. Thus, current IOM guidelines, which generally recommend less than 1,000 IU of vitamin D daily, are relevant to bone health but not necessarily to other health outcomes. More research is needed to understand whether the guidelines should be modified for the prevention of other chronic diseases.
Moreover, whether or not everyone should be screened for 25-hydroxyvitamin D3 blood levels is controversial. Most experts agree that a level less than 20 ng/mL is deficient or insufficient. Conversely, potentially harmful are levels 150 ng/mL or more (> 375 nmol/L), which entail the risk of hypercalcemia, vascular soft tissue calcification, and hyperphosphatemia.
People do not reach toxic levels with ultraviolet light exposure because the amount of 25-hydroxyvitamin D3 synthesis is well regulated. Dietary supplements, however, can bring about toxic levels, and patients taking high doses need to be monitored carefully. The level that should be considered optimal is controversial and requires further study.
RISK FACTORS FOR LOW VITAMIN D LEVELS
Risk factors for low vitamin D levels include older age, living in northern latitudes, sun avoidance, dark skin pigmentation, obesity, low dietary intake, and various medical conditions, especially malabsorption syndromes. Some of these are also risk factors for cardiovascular disease, cancer, and other chronic diseases, and potentially confound outcomes in many studies. Older age, which is usually adjusted for in multivariate models, is important to recognize as a major risk factor for vitamin D deficiency, owing to reduced absorption and synthesis, less time outdoors, and low dietary intake.
Wearing sunscreen decreases the synthesis of vitamin D in the skin, but because ultra-violet light has been clearly classified as a carcinogen, it is a not advisable to increase sun exposure for the sake of increasing vitamin D levels. That is a poor trade-off, given the high incidence rate of skin cancer and the adverse effects of solar radiation on skin aging.
Obesity is a risk factor for vitamin D deficiency because vitamin D is fat-soluble and becomes sequestered in fat tissue. Vitamin D may also play a role in the differentiation of adipocytes and may affect their function. In observational studies, it is very important for researchers to adjust for body mass index, physical activity (which may be correlated with more time outdoors), and other potential confounders in their analyses.
HOW VITAMIN D MAY LOWER CANCER RISK
Because of the important effect of vitamin D in regulating cell differentiation and cell growth, there are multiple ways that it may affect cancer risk. Laboratory, cell culture, and animal studies suggest that vitamin D may lower cancer risk by inhibiting cell proliferation, angiogenesis, metastasis, and inflammation and inducing apoptosis and cellular differentiation. Several of these mechanisms are also relevant to atherosclerosis and cardiovascular disease. Although VITAL is addressing the role of vitamin D in preventing both cancer and cardiovascular disease, the remainder of this article will focus on cardiovascular outcomes.
HOW VITAMIN D MAY REDUCE CARDIOVASCULAR RISK
Vitamin D may lower cardiovascular risk via several mechanisms:
Inhibiting inflammation. Vitamin D has a powerful immunomodulatory effect: laboratory studies show that it inhibits prostaglandin and cyclooxygenase 2 pathways, reduces matrix metalloproteinase 9 and several proinflammatory cytokines, and increases interleukin 10, all of which result in suppressed inflammation.1
Inhibiting vascular muscle proliferation and vascular calcification. Animal studies indicate that in moderate doses vitamin D decreases calcium cellular influx and increases matrix Gla protein, which inhibits vascular smooth muscle proliferation and vascular calcification. These protective effects contrast with the hypercalcemia associated with a high intake of vitamin D, especially in the context of renal failure or other risk factors, which may lead to increased vascular calcification.1
Regulates blood pressure. Vitamin D decreases renin gene expression and the synthesis of renin, which reduces activity of the renin-angiotensin-aldosterone system, leading to a reduction of blood pressure and a favorable effect on volume homeostasis.1
Regulates glucose metabolism. Limited evidence shows that vitamin D may increase insulin sensitivity and regulate glucose metabolism.1
Vitamin D and cardiac hypertrophy
The vitamin D receptor is present in virtually all tissues, including cardiac myocytes and endothelial cells. Animals with vitamin D deficiency have higher blood pressures, and animals genetically altered to have no vitamin D receptors (knock-out models) develop left ventricular hypertrophy and heart failure.
Animals genetically altered to have no 1-alpha-hydroxylase (so that the most active form of vitamin D is not made) also develop left ventricular hypertrophy. They can be rescued by the administration of 1,25-dihydroxy vitamin D3.1
These findings are consistent with what is observed in patients with end-stage renal disease, who produce very little 1,25-dihydroxyvitamin D3: they often develop left ventricular hypertrophy, diastolic heart failure, atherosclerosis, and vascular calcification.
EVIDENCE FOR CARDIOVASCULAR DISEASE REDUCTION
Wang et al1 recently reviewed available prospective cohort and randomized clinical trials from 1966 to 2009 that examined vitamin D or calcium supplementation and cardiovascular disease. Comparing people with the lowest to the highest levels of serum 25-hydroxyvitamin D3 indicated that a low level is a risk factor for coronary artery disease and cardiovascular death. Unfortunately, most studies were not designed to assess primary effects on cardiovascular outcomes, and so have many potential confounders.
Prospective observational studies
Observational studies suggest that vitamin D deficiency is associated with an increased risk of cardiovascular disease. Some examples:
The Framingham Offspring Study2 followed 1,739 men and women with a mean age of 59 for 5.4 years. The study compared the incidence of cardiovascular events in those with a serum 25-dihydroxyvitamin D level of at least 37.5 nmol/L vs those with lower levels. The risk of cardiovascular disease was 1.62 times higher in those with the lowest levels of vitamin D, a statistically significant difference. However, a threshold effect was apparent (discussed below).
The Health Professionals Follow-up Study3 prospectively evaluated more than 18,000 men ages 40 to 75 for 10 years. The study compared men with a low serum level of vitamin D (< 37.5 nmol/L) to those with a more optimal level (> 75 nmol/L). The incidence of cardiovascular events was 2.09 times higher in men with low levels of vitamin D, a difference that was statistically significant.
The Third National Health and Nutrition Examination Survey (NHANES III) included data for more than 13,300 men and women age 20 years and older. Using a cohort that was followed for 8.7 years, Melamed et al4 compared the quartile with the lowest serum vitamin D level (< 44.4 nmol/L) against the quartile with the highest level (> 80.1 nmol/L). The associations were modest: those with low levels had a 1.20-times higher rate of death from cardiovascular disease and a statistically significant 1.26-times higher rate of death from all causes.
Randomized clinical trials
A meta-analysis of 18 randomized trials5 of vitamin D supplementation (300–2,000 IU/day, mean 528 IU/day vs placebo), including 57,311 participants, evaluated the rate of death from all causes and found a modest but significant reduction in risk (relative risk 0.93, 95% confidence interval [CI] 0.87–0.99). These were generally trials looking at fracture rates or physical performance, and a dose-response relationship was not evident. A recent systematic review of randomized controlled trials of vitamin D1 that included cardiovascular disease as a secondary outcome found a pooled relative risk for cardiovascular disease of 0.90 (95% CI 0.77–1.05) for vitamin D supplementation compared with placebo and 1.04 (95% CI 0.92–1.18) for combination vitamin D plus calcium supplementation vs placebo.1 Two individual trials are discussed below.
Trivedi et al6 randomized 2,686 British men and women to vitamin D3 100,000 IU given every 4 months over 5 years (equivalent to 800 IU/day) or placebo. The relative risk of cardiovascular events was 0.90 (95% CI 0.77–1.06) and of cardiovascular deaths 0.84 (95% CI 0.65–1.10). Although the results were promising, the trial was designed to assess fracture risk and was not large enough for the differences in cardiovascular outcomes to reach statistical significance.
The Women’s Health Initiative,7,8 which included 36,282 postmenopausal women aged 50 to 79, tested combined vitamin D3 (400 IU/day) with calcium (1,000 mg/day) vs placebo. No benefit was seen for preventing coronary events or stroke, which may be due to the low dosage of vitamin D. The hazard ratio for coronary disease was 1.04 (0.92–1.18). Regarding mortality, the hazard ratio for cardiovascular death was 0.92, for cerebrovascular death 0.89, for cancer death 0.89, and for other deaths 0.95. None of these hazard ratios reached statistical significance.
MORE MAY NOT BE BETTER
As is probably true for everything in biological systems, there apparently is an optimal level of intake to meet vitamin D needs.
The Framingham Offspring Study,2 which found a higher risk with vitamin D deficiency, also found a suggestion of a threshold. Participants who had levels of 50 to 65 nmol/L had the lowest risk. Higher levels did not confer lower risk and even suggested a slight upturn.
Evidence from the Women’s Health Initiative8 also indicates that high dosages may not be better than moderate dosages. The meta-analysis of vitamin D and all-cause mortality5 found a relative risk of 0.93, but one of the largest studies in that meta-analysis tested only 400 IU a day and found a similar relative risk of 0.91 (95% confidence interval, 0.83–1.01).
Moreover, the NHANES study found that with increasing serum 25-hydroxyvitamin D3 levels, the risk of all-cause mortality fell until about 100 nmol/L, but then plateaued and even increased with higher serum levels.4
VITAL: STUDY DESIGN AND LOGISTICS
In VITAL, the investigators aim to recruit 20,000 healthy men (age 60 and older) and women (65 and older) who are representative of the US population (www.vitalstudy.org). Because it is a primary prevention trial, people with a known history of cardiovascular disease or cancer will be excluded. Participants will be randomized to receive either 2,000 IU of vitamin D3 per day or placebo. Each group will be further randomized to receive either 1 g per day of fish oil (combined eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) or placebo. The mean treatment period will be 5 years. Recruitment began in early 2010.
Blood will be collected in about 80% (ideally 100%) of participants, with follow-up blood collection in at least 2,000.
Primary aims of the trial are to test whether vitamin D3 and the omega-3 fatty acids reduce the risk of total cancer and major cardiovascular events (a composite of myocardial infarction, stroke, and death due to cardiovascular events).
Secondary aims are to test whether these agents lower the risk of:
Site-specific cancer, including colorectal, breast, and prostate cancer, and the total cancer mortality rate
An expanded composite outcome including myocardial infarction, stroke, cardiovascular death, coronary artery bypass grafting, percutaneous coronary intervention, and its individual components.
Tertiary aims are to explore whether vitamin D3 and omega-3 fatty acids have additive effects on the primary and secondary end points. The trial will also explore whether the effects of vitamin D3 and omega-3 fatty acids on cancer and cardiovascular disease vary by baseline blood levels of these nutrients, and whether race, skin pigmentation, or body mass index modify the effects of vitamin D3.
Ancillary studies will assess the effect of the interventions on risk of diabetes, hypertension, cognitive decline, depression, fracture, infections, respiratory disorders, and autoimmune diseases. The primary sponsor of this trial is the National Cancer Institute, and the secondary sponsor is the National Heart, Lung and Blood Institute. Other institutes and agencies also are cosponsors of the study.
The timing of VITAL is optimal
There is a limited window of opportunity for conducting a randomized clinical trial: the evidence must be strong enough to justify mounting a very large trial with enough power to look at cardiovascular events and cancer, but the evidence must not be so strong that it would be unethical to have a placebo group. Thus, there must be a state of equipoise. Our trial allows the study population to have a background intake of vitamin D that is currently recommended by national guidelines. Therefore, even the placebo group should have adequate intake of vitamin D.
The growing use of vitamin D supplementation by the public underscores the need for conclusive evidence of its benefits and risks. No previous large-scale randomized clinical trial has tested moderate to high doses of vitamin D for the primary prevention of cancer and cardiovascular disease.
Setting the dosage
VITAL set the vitamin D3 dosage at 2,000 IU per day (50 μg/day), which is designed to provide the best balance of efficacy and safety. As a general rule, each microgram of vitamin D3 is expected to raise the serum 25-hydroxyvitamin D3 level about 1 nmol/L, although the response is not linear: if baseline levels are lower, the increase is greater. In the United States, people commonly have a baseline level of about 40 nmol/L, so we expect that levels of people treated in the study will reach about 90 nmol/L (range 75–100 nmol/L), about 35 to 50 nmol/L higher than in the placebo group.
The target range of 75 to 100 nmol/L is the level at which greatest efficacy has been suggested in observational studies. Previous randomized trials of vitamin D have not tested high enough doses to achieve this level of 25-hydroxyvitamin D3. VITAL will test whether reaching this serum level lowers the risk of cardiovascular disease, cancer, and other chronic diseases. This level may be associated with benefit and has minimal risk of hypercalcemia. Risk of hypercalcemia may be present in participants with an occult chronic granulomatous condition such as sarcoidosis or Wegener granulomatosis, in which activated macrophages synthesize 1,25-dihydroxyvitamin D3. These conditions are very rare, however, and the risk of hypercalcemia in the trial is exceedingly low.
VITAL participants will also be randomized to take placebo or 1 g per day of combined EPA and DHA, about 5 to 10 times more than most Americans consume.
Nationwide recruitment among senior citizens
We aim to recruit 20,000 people (10,000 men and 10,000 women) nationwide who are willing, eligible, and compliant (ie, who take more than two-thirds of study pills during a 3-month placebo “run-in” phase of the trial). The trial aims to enroll 40,000 in the run-in period, and 20,000 will be randomized. To get this many participants, we will send invitational mailings and screening questionnaires to at least 2.5 million people around the United States, with mailing lists selected by age—ie, members of the American Association of Retired Persons, health professionals, teachers, and subscription lists for selected magazines. A pilot study in 5,000 people has indicated that recruiting and randomizing 20,000 participants via large mailings should be possible.
The trial is expected to be extremely cost-effective because it will be conducted largely by mail. Medication will be mailed in calendar blister packs. Participants report outcomes, which are then confirmed by medical record review. The Centers for Medicare and Medicaid Services and the National Death Index will also be used to ascertain outcomes.
We hope to recruit a more racially diverse study population than is typically seen in US trials: 63% (12,620) whites, 25% (5,000) African Americans, 7% (1,400) Hispanics, 2.5% (500) Asians, 2% (400) American Indians and Alaska natives, and 0.4% (80) native Hawaiian and Pacific Islanders.
Eligibility criteria ensure primary prevention is tested
To enter the study, men must be at least 60 years old and women at least 65. At a minimum, a high school education is required due to the detailed forms and questionnaires to be completed. Because this is a primary prevention trial, anyone with a history of cancer (except nonmelanoma skin cancer) or cardiovascular disease (including myocardial infarction, stroke, or coronary revascularization) will be excluded, as will anyone with a history of kidney stones, renal failure or dialysis, hypercalcemia, hypoparathyroidism or hyperparathyroidism, severe liver disease (eg, cirrhosis), sarcoidosis, tuberculosis, or other granulomatous disease. People with an allergy to fish will also be excluded.
We do not expect that those in the placebo group will develop vitamin D deficiency due to their participation in the study. The trial will allow a background intake in the study population of up to 800 IU of vitamin D and 1,200 mg of calcium per day in supplements. Assuming they also get about 200 IU of vitamin D in the diet, the background intake in the placebo group may be close to 1,000 IU of vitamin D. Assuming that the active treatment group has a similar background intake, their total intake will be about 3,000 IU per day (about 1,000 IU/day from background intake plus 2,000 IU/day from the intervention).
Cohort power sufficient to see effect in 5 years
The trial is expected to have sufficient power to evaluate cardiovascular disease and cancer end points as primary outcomes during 5 years of follow-up. The trial is designed to have a power of 91% to 92% to detect a relative risk of 0.85 for the primary cancer end point of total cancer incidence and 0.80 for the cardiovascular disease end point of myocardial infarction, stroke, and cardiovascular mortality. Power will be even greater for the expanded composite outcome for cardiovascular disease.
Ancillary studies
Ancillary studies include evaluating the interventions’ role in preventing diabetes and glucose intolerance, hypertension, heart failure, atrial fibrillation, cognitive decline, mood disorders, osteoporosis and fractures, asthma and respiratory diseases, infections, macular degeneration, rheumatoid arthritis, systemic lupus erythematosus, and a composite of autoimmune diseases. Imaging studies also are planned, including dual energy x-ray absorptiometry, mammographic density, and non-invasive vascular imaging (carotid intima medial thickness, coronary calcium measurements, and two-dimensional echocardiography to assess cardiac function).
Several biomarker and genetic studies will also be carried out. We intend to perform genetic studies on most of the study population to evaluate gene variants in the vitamin D receptor, vitamin D binding protein, and other vitamin-D-related genes that may contribute to lower baseline levels of 25-hydroxyvitamin D3 or different responses to the interventions.
Clinical and Translational Science Center visits are planned to provide more detailed assessments of 1,000 participants, including blood pressure measurements, height, weight, waist circumference, other anthropometric measurements, a 2-hour glucose tolerance test, a fasting blood collection, hemoglobin A1c measurements, spirometry, and assessment of physical performance, strength, frailty, cognitive function, mood, and depression. Dual-energy x-ray absorptiometry and noninvasive vascular imaging studies are also planned for those visits.
Vitamin D is viewed as a promising supplement by the medical, public health, and lay communities, potentially offering many health benefits. But enthusiasm for a new intervention too often gets far ahead of the evidence, as was the case with beta-carotene, selenium, folic acid, and vitamins C and E.
Despite the enthusiasm for vitamin D, there have been no large-scale primary prevention trials that have had either cardiovascular disease or cancer as a prespecified primary outcome. Previous randomized trials of vitamin D have focused primarily on osteoporosis, fracture, falls, and physical function. Although the investigators often reported their findings on vitamin D and cardiovascular disease or cancer, these outcomes were generally secondary or tertiary end points that were not prespecified. These studies should be viewed as hypothesis-generating rather than hypothesis-testing. The increasing prevalence of use of vitamin D supplements underscores the need for rigorous and conclusive evidence from randomized clinical trials that have cardiovascular disease and cancer as primary outcomes.
This article will explain the rationale for a large-scale, randomized clinical trial to evaluate the role of vitamin D in the prevention of cardiovascular disease and cancer. It will also describe the biological mechanisms and currently available evidence relating vitamin D to potential health benefits. Finally, the design, dosage considerations, and logistics of the Vitamin D and Omega-3 Trial (VITAL) will be presented.
EVIDENCE IS MOUNTING FOR VITAMIN D’S BIOLOGICAL IMPORTANCE
Vitamin D is undoubtedly important to health: not only is it produced endogenously, but at least 500 genes have been identified with vitamin D response elements. The vitamin D receptor is found in nearly all cells in the body, and the 1-alpha-hydroxylase enzyme is present in many tissues. Some studies suggest that almost 10% of the human genome may be at least partially regulated by vitamin D.
From Hajjar V, et al. Does vitamin D deficiency play a role in the pathogenesis of chronic heart failure? Do supplements improve survival? Cleve Clin J Med 2010; 77:290–293.
Figure 1.Vitamin D is a prohormone, and people obtain it both endogenously and exogenously (Figure 1). With exposure to ultraviolet B light, 7-dehydrocholesterol in the skin converts to vitamin D3. We also obtain it through diet or supplements. The plant form (vitamin D2) and the animal form (vitamin D3) undergo 25-hydroxylation in the liver. Then, 1-alpha-hydroxylase converts the 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3, primarily in the kidney. Increasing evidence shows that 1-alpha-hydroxylase is present in many other cells and tissues, and that 1,25-dihydroxyvitamin D3 may be locally produced and possibly even have autocrine effects (acting on surface receptors of the same cell it is secreted by) and paracrine effects (acting on adjacent cells).
Although we know vitamin D is important, what our optimal intake and our blood level of 25-hydroxyvitamin D3 should be are key unknowns.
RECOMMENDATIONS FOR VITAMIN D INTAKE
During winter, late fall, and early spring, people who live above the 37th parallel (geographically, about one-half of the contiguous United States) do not get enough ultraviolet B energy from the sun to make all the vitamin D they need, even if they spend several hours outside every day. In addition, dark skin pigmentation serves as a sun block, as do sunscreens.
The Institute of Medicine (IOM) provided guidelines for vitamin D intake in 1997 and, most recently, in 2010. However, these guidelines are based on the amount of vitamin D required for bone health and do not address the amount that may be of benefit for prevention of cancer and cardiovascular disease. The latter outcomes are not addressed because the IOM committee believed that evidence was insufficient to determine the role of vitamin D in the prevention of cardiovascular disease, cancer, and other chronic diseases. Thus, current IOM guidelines, which generally recommend less than 1,000 IU of vitamin D daily, are relevant to bone health but not necessarily to other health outcomes. More research is needed to understand whether the guidelines should be modified for the prevention of other chronic diseases.
Moreover, whether or not everyone should be screened for 25-hydroxyvitamin D3 blood levels is controversial. Most experts agree that a level less than 20 ng/mL is deficient or insufficient. Conversely, potentially harmful are levels 150 ng/mL or more (> 375 nmol/L), which entail the risk of hypercalcemia, vascular soft tissue calcification, and hyperphosphatemia.
People do not reach toxic levels with ultraviolet light exposure because the amount of 25-hydroxyvitamin D3 synthesis is well regulated. Dietary supplements, however, can bring about toxic levels, and patients taking high doses need to be monitored carefully. The level that should be considered optimal is controversial and requires further study.
RISK FACTORS FOR LOW VITAMIN D LEVELS
Risk factors for low vitamin D levels include older age, living in northern latitudes, sun avoidance, dark skin pigmentation, obesity, low dietary intake, and various medical conditions, especially malabsorption syndromes. Some of these are also risk factors for cardiovascular disease, cancer, and other chronic diseases, and potentially confound outcomes in many studies. Older age, which is usually adjusted for in multivariate models, is important to recognize as a major risk factor for vitamin D deficiency, owing to reduced absorption and synthesis, less time outdoors, and low dietary intake.
Wearing sunscreen decreases the synthesis of vitamin D in the skin, but because ultra-violet light has been clearly classified as a carcinogen, it is a not advisable to increase sun exposure for the sake of increasing vitamin D levels. That is a poor trade-off, given the high incidence rate of skin cancer and the adverse effects of solar radiation on skin aging.
Obesity is a risk factor for vitamin D deficiency because vitamin D is fat-soluble and becomes sequestered in fat tissue. Vitamin D may also play a role in the differentiation of adipocytes and may affect their function. In observational studies, it is very important for researchers to adjust for body mass index, physical activity (which may be correlated with more time outdoors), and other potential confounders in their analyses.
HOW VITAMIN D MAY LOWER CANCER RISK
Because of the important effect of vitamin D in regulating cell differentiation and cell growth, there are multiple ways that it may affect cancer risk. Laboratory, cell culture, and animal studies suggest that vitamin D may lower cancer risk by inhibiting cell proliferation, angiogenesis, metastasis, and inflammation and inducing apoptosis and cellular differentiation. Several of these mechanisms are also relevant to atherosclerosis and cardiovascular disease. Although VITAL is addressing the role of vitamin D in preventing both cancer and cardiovascular disease, the remainder of this article will focus on cardiovascular outcomes.
HOW VITAMIN D MAY REDUCE CARDIOVASCULAR RISK
Vitamin D may lower cardiovascular risk via several mechanisms:
Inhibiting inflammation. Vitamin D has a powerful immunomodulatory effect: laboratory studies show that it inhibits prostaglandin and cyclooxygenase 2 pathways, reduces matrix metalloproteinase 9 and several proinflammatory cytokines, and increases interleukin 10, all of which result in suppressed inflammation.1
Inhibiting vascular muscle proliferation and vascular calcification. Animal studies indicate that in moderate doses vitamin D decreases calcium cellular influx and increases matrix Gla protein, which inhibits vascular smooth muscle proliferation and vascular calcification. These protective effects contrast with the hypercalcemia associated with a high intake of vitamin D, especially in the context of renal failure or other risk factors, which may lead to increased vascular calcification.1
Regulates blood pressure. Vitamin D decreases renin gene expression and the synthesis of renin, which reduces activity of the renin-angiotensin-aldosterone system, leading to a reduction of blood pressure and a favorable effect on volume homeostasis.1
Regulates glucose metabolism. Limited evidence shows that vitamin D may increase insulin sensitivity and regulate glucose metabolism.1
Vitamin D and cardiac hypertrophy
The vitamin D receptor is present in virtually all tissues, including cardiac myocytes and endothelial cells. Animals with vitamin D deficiency have higher blood pressures, and animals genetically altered to have no vitamin D receptors (knock-out models) develop left ventricular hypertrophy and heart failure.
Animals genetically altered to have no 1-alpha-hydroxylase (so that the most active form of vitamin D is not made) also develop left ventricular hypertrophy. They can be rescued by the administration of 1,25-dihydroxy vitamin D3.1
These findings are consistent with what is observed in patients with end-stage renal disease, who produce very little 1,25-dihydroxyvitamin D3: they often develop left ventricular hypertrophy, diastolic heart failure, atherosclerosis, and vascular calcification.
EVIDENCE FOR CARDIOVASCULAR DISEASE REDUCTION
Wang et al1 recently reviewed available prospective cohort and randomized clinical trials from 1966 to 2009 that examined vitamin D or calcium supplementation and cardiovascular disease. Comparing people with the lowest to the highest levels of serum 25-hydroxyvitamin D3 indicated that a low level is a risk factor for coronary artery disease and cardiovascular death. Unfortunately, most studies were not designed to assess primary effects on cardiovascular outcomes, and so have many potential confounders.
Prospective observational studies
Observational studies suggest that vitamin D deficiency is associated with an increased risk of cardiovascular disease. Some examples:
The Framingham Offspring Study2 followed 1,739 men and women with a mean age of 59 for 5.4 years. The study compared the incidence of cardiovascular events in those with a serum 25-dihydroxyvitamin D level of at least 37.5 nmol/L vs those with lower levels. The risk of cardiovascular disease was 1.62 times higher in those with the lowest levels of vitamin D, a statistically significant difference. However, a threshold effect was apparent (discussed below).
The Health Professionals Follow-up Study3 prospectively evaluated more than 18,000 men ages 40 to 75 for 10 years. The study compared men with a low serum level of vitamin D (< 37.5 nmol/L) to those with a more optimal level (> 75 nmol/L). The incidence of cardiovascular events was 2.09 times higher in men with low levels of vitamin D, a difference that was statistically significant.
The Third National Health and Nutrition Examination Survey (NHANES III) included data for more than 13,300 men and women age 20 years and older. Using a cohort that was followed for 8.7 years, Melamed et al4 compared the quartile with the lowest serum vitamin D level (< 44.4 nmol/L) against the quartile with the highest level (> 80.1 nmol/L). The associations were modest: those with low levels had a 1.20-times higher rate of death from cardiovascular disease and a statistically significant 1.26-times higher rate of death from all causes.
Randomized clinical trials
A meta-analysis of 18 randomized trials5 of vitamin D supplementation (300–2,000 IU/day, mean 528 IU/day vs placebo), including 57,311 participants, evaluated the rate of death from all causes and found a modest but significant reduction in risk (relative risk 0.93, 95% confidence interval [CI] 0.87–0.99). These were generally trials looking at fracture rates or physical performance, and a dose-response relationship was not evident. A recent systematic review of randomized controlled trials of vitamin D1 that included cardiovascular disease as a secondary outcome found a pooled relative risk for cardiovascular disease of 0.90 (95% CI 0.77–1.05) for vitamin D supplementation compared with placebo and 1.04 (95% CI 0.92–1.18) for combination vitamin D plus calcium supplementation vs placebo.1 Two individual trials are discussed below.
Trivedi et al6 randomized 2,686 British men and women to vitamin D3 100,000 IU given every 4 months over 5 years (equivalent to 800 IU/day) or placebo. The relative risk of cardiovascular events was 0.90 (95% CI 0.77–1.06) and of cardiovascular deaths 0.84 (95% CI 0.65–1.10). Although the results were promising, the trial was designed to assess fracture risk and was not large enough for the differences in cardiovascular outcomes to reach statistical significance.
The Women’s Health Initiative,7,8 which included 36,282 postmenopausal women aged 50 to 79, tested combined vitamin D3 (400 IU/day) with calcium (1,000 mg/day) vs placebo. No benefit was seen for preventing coronary events or stroke, which may be due to the low dosage of vitamin D. The hazard ratio for coronary disease was 1.04 (0.92–1.18). Regarding mortality, the hazard ratio for cardiovascular death was 0.92, for cerebrovascular death 0.89, for cancer death 0.89, and for other deaths 0.95. None of these hazard ratios reached statistical significance.
MORE MAY NOT BE BETTER
As is probably true for everything in biological systems, there apparently is an optimal level of intake to meet vitamin D needs.
The Framingham Offspring Study,2 which found a higher risk with vitamin D deficiency, also found a suggestion of a threshold. Participants who had levels of 50 to 65 nmol/L had the lowest risk. Higher levels did not confer lower risk and even suggested a slight upturn.
Evidence from the Women’s Health Initiative8 also indicates that high dosages may not be better than moderate dosages. The meta-analysis of vitamin D and all-cause mortality5 found a relative risk of 0.93, but one of the largest studies in that meta-analysis tested only 400 IU a day and found a similar relative risk of 0.91 (95% confidence interval, 0.83–1.01).
Moreover, the NHANES study found that with increasing serum 25-hydroxyvitamin D3 levels, the risk of all-cause mortality fell until about 100 nmol/L, but then plateaued and even increased with higher serum levels.4
VITAL: STUDY DESIGN AND LOGISTICS
In VITAL, the investigators aim to recruit 20,000 healthy men (age 60 and older) and women (65 and older) who are representative of the US population (www.vitalstudy.org). Because it is a primary prevention trial, people with a known history of cardiovascular disease or cancer will be excluded. Participants will be randomized to receive either 2,000 IU of vitamin D3 per day or placebo. Each group will be further randomized to receive either 1 g per day of fish oil (combined eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) or placebo. The mean treatment period will be 5 years. Recruitment began in early 2010.
Blood will be collected in about 80% (ideally 100%) of participants, with follow-up blood collection in at least 2,000.
Primary aims of the trial are to test whether vitamin D3 and the omega-3 fatty acids reduce the risk of total cancer and major cardiovascular events (a composite of myocardial infarction, stroke, and death due to cardiovascular events).
Secondary aims are to test whether these agents lower the risk of:
Site-specific cancer, including colorectal, breast, and prostate cancer, and the total cancer mortality rate
An expanded composite outcome including myocardial infarction, stroke, cardiovascular death, coronary artery bypass grafting, percutaneous coronary intervention, and its individual components.
Tertiary aims are to explore whether vitamin D3 and omega-3 fatty acids have additive effects on the primary and secondary end points. The trial will also explore whether the effects of vitamin D3 and omega-3 fatty acids on cancer and cardiovascular disease vary by baseline blood levels of these nutrients, and whether race, skin pigmentation, or body mass index modify the effects of vitamin D3.
Ancillary studies will assess the effect of the interventions on risk of diabetes, hypertension, cognitive decline, depression, fracture, infections, respiratory disorders, and autoimmune diseases. The primary sponsor of this trial is the National Cancer Institute, and the secondary sponsor is the National Heart, Lung and Blood Institute. Other institutes and agencies also are cosponsors of the study.
The timing of VITAL is optimal
There is a limited window of opportunity for conducting a randomized clinical trial: the evidence must be strong enough to justify mounting a very large trial with enough power to look at cardiovascular events and cancer, but the evidence must not be so strong that it would be unethical to have a placebo group. Thus, there must be a state of equipoise. Our trial allows the study population to have a background intake of vitamin D that is currently recommended by national guidelines. Therefore, even the placebo group should have adequate intake of vitamin D.
The growing use of vitamin D supplementation by the public underscores the need for conclusive evidence of its benefits and risks. No previous large-scale randomized clinical trial has tested moderate to high doses of vitamin D for the primary prevention of cancer and cardiovascular disease.
Setting the dosage
VITAL set the vitamin D3 dosage at 2,000 IU per day (50 μg/day), which is designed to provide the best balance of efficacy and safety. As a general rule, each microgram of vitamin D3 is expected to raise the serum 25-hydroxyvitamin D3 level about 1 nmol/L, although the response is not linear: if baseline levels are lower, the increase is greater. In the United States, people commonly have a baseline level of about 40 nmol/L, so we expect that levels of people treated in the study will reach about 90 nmol/L (range 75–100 nmol/L), about 35 to 50 nmol/L higher than in the placebo group.
The target range of 75 to 100 nmol/L is the level at which greatest efficacy has been suggested in observational studies. Previous randomized trials of vitamin D have not tested high enough doses to achieve this level of 25-hydroxyvitamin D3. VITAL will test whether reaching this serum level lowers the risk of cardiovascular disease, cancer, and other chronic diseases. This level may be associated with benefit and has minimal risk of hypercalcemia. Risk of hypercalcemia may be present in participants with an occult chronic granulomatous condition such as sarcoidosis or Wegener granulomatosis, in which activated macrophages synthesize 1,25-dihydroxyvitamin D3. These conditions are very rare, however, and the risk of hypercalcemia in the trial is exceedingly low.
VITAL participants will also be randomized to take placebo or 1 g per day of combined EPA and DHA, about 5 to 10 times more than most Americans consume.
Nationwide recruitment among senior citizens
We aim to recruit 20,000 people (10,000 men and 10,000 women) nationwide who are willing, eligible, and compliant (ie, who take more than two-thirds of study pills during a 3-month placebo “run-in” phase of the trial). The trial aims to enroll 40,000 in the run-in period, and 20,000 will be randomized. To get this many participants, we will send invitational mailings and screening questionnaires to at least 2.5 million people around the United States, with mailing lists selected by age—ie, members of the American Association of Retired Persons, health professionals, teachers, and subscription lists for selected magazines. A pilot study in 5,000 people has indicated that recruiting and randomizing 20,000 participants via large mailings should be possible.
The trial is expected to be extremely cost-effective because it will be conducted largely by mail. Medication will be mailed in calendar blister packs. Participants report outcomes, which are then confirmed by medical record review. The Centers for Medicare and Medicaid Services and the National Death Index will also be used to ascertain outcomes.
We hope to recruit a more racially diverse study population than is typically seen in US trials: 63% (12,620) whites, 25% (5,000) African Americans, 7% (1,400) Hispanics, 2.5% (500) Asians, 2% (400) American Indians and Alaska natives, and 0.4% (80) native Hawaiian and Pacific Islanders.
Eligibility criteria ensure primary prevention is tested
To enter the study, men must be at least 60 years old and women at least 65. At a minimum, a high school education is required due to the detailed forms and questionnaires to be completed. Because this is a primary prevention trial, anyone with a history of cancer (except nonmelanoma skin cancer) or cardiovascular disease (including myocardial infarction, stroke, or coronary revascularization) will be excluded, as will anyone with a history of kidney stones, renal failure or dialysis, hypercalcemia, hypoparathyroidism or hyperparathyroidism, severe liver disease (eg, cirrhosis), sarcoidosis, tuberculosis, or other granulomatous disease. People with an allergy to fish will also be excluded.
We do not expect that those in the placebo group will develop vitamin D deficiency due to their participation in the study. The trial will allow a background intake in the study population of up to 800 IU of vitamin D and 1,200 mg of calcium per day in supplements. Assuming they also get about 200 IU of vitamin D in the diet, the background intake in the placebo group may be close to 1,000 IU of vitamin D. Assuming that the active treatment group has a similar background intake, their total intake will be about 3,000 IU per day (about 1,000 IU/day from background intake plus 2,000 IU/day from the intervention).
Cohort power sufficient to see effect in 5 years
The trial is expected to have sufficient power to evaluate cardiovascular disease and cancer end points as primary outcomes during 5 years of follow-up. The trial is designed to have a power of 91% to 92% to detect a relative risk of 0.85 for the primary cancer end point of total cancer incidence and 0.80 for the cardiovascular disease end point of myocardial infarction, stroke, and cardiovascular mortality. Power will be even greater for the expanded composite outcome for cardiovascular disease.
Ancillary studies
Ancillary studies include evaluating the interventions’ role in preventing diabetes and glucose intolerance, hypertension, heart failure, atrial fibrillation, cognitive decline, mood disorders, osteoporosis and fractures, asthma and respiratory diseases, infections, macular degeneration, rheumatoid arthritis, systemic lupus erythematosus, and a composite of autoimmune diseases. Imaging studies also are planned, including dual energy x-ray absorptiometry, mammographic density, and non-invasive vascular imaging (carotid intima medial thickness, coronary calcium measurements, and two-dimensional echocardiography to assess cardiac function).
Several biomarker and genetic studies will also be carried out. We intend to perform genetic studies on most of the study population to evaluate gene variants in the vitamin D receptor, vitamin D binding protein, and other vitamin-D-related genes that may contribute to lower baseline levels of 25-hydroxyvitamin D3 or different responses to the interventions.
Clinical and Translational Science Center visits are planned to provide more detailed assessments of 1,000 participants, including blood pressure measurements, height, weight, waist circumference, other anthropometric measurements, a 2-hour glucose tolerance test, a fasting blood collection, hemoglobin A1c measurements, spirometry, and assessment of physical performance, strength, frailty, cognitive function, mood, and depression. Dual-energy x-ray absorptiometry and noninvasive vascular imaging studies are also planned for those visits.
References
Wang L, Manson JE, Song Y, Sesso HD. Systematic review: vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med2010; 152:315–323.
Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation2008; 117:503–511.
Giovannucci E, Liu Y, Hollis BW, Rimm EB. 25-Hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Arch Intern Med2008; 168:1174–1180.
Melamed ML, Michos ED, Post W, Astor B. 25-Hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med2008; 168:1629–1637.
Autier P, Gandini S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med2007; 167:1730–1737.
Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ2003; 326:469.
Hsia J, Heiss G, Ren H, et al; Women’s Health Initiative Investigators. Calcium/vitamin D supplementation and cardiovascular events. Circulation2007; 115:846–854.
LaCroix AZ, Kotchen J, Anderson G, et al. Calcium plus vitamin D supplementation and mortality in postmenopausal women: the Women’s Health Initiative calcium-vitamin D randomized controlled trial. J Gerontol A Biol Sci Med Sci2009; 64:559–567.
References
Wang L, Manson JE, Song Y, Sesso HD. Systematic review: vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med2010; 152:315–323.
Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation2008; 117:503–511.
Giovannucci E, Liu Y, Hollis BW, Rimm EB. 25-Hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Arch Intern Med2008; 168:1174–1180.
Melamed ML, Michos ED, Post W, Astor B. 25-Hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med2008; 168:1629–1637.
Autier P, Gandini S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med2007; 167:1730–1737.
Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ2003; 326:469.
Hsia J, Heiss G, Ren H, et al; Women’s Health Initiative Investigators. Calcium/vitamin D supplementation and cardiovascular events. Circulation2007; 115:846–854.
LaCroix AZ, Kotchen J, Anderson G, et al. Calcium plus vitamin D supplementation and mortality in postmenopausal women: the Women’s Health Initiative calcium-vitamin D randomized controlled trial. J Gerontol A Biol Sci Med Sci2009; 64:559–567.
Laboratory evidence suggests that vitamin D may lower cancer risk by inhibiting cell proliferation, angiogenesis, metastasis, and inflammation.
Vitamin D may also reduce cardiovascular risk by inhibiting vascular smooth muscle proliferation, regulating blood pressure and glucose metabolism, and reducing inflammation.
Some observational studies indicate there may be a threshold for vitamin D intake above which there is no increase in benefit and which may increase risk.
The VITAL trial is currently randomizing 20,000 healthy older men and women throughout the United States to receive either 2,000 IU of vitamin D3 (cholecalciferol) per day or placebo, as well as 1 g of marine omega-3 fatty acids per day or placebo, for 5 years.
Alpha-blockers should not be used as first-line therapy for hypertension. However, an alpha-blocker can be considered as a second-line or third-line add-on in a patient whose blood pressure is not under control despite treatment with other drugs.
In addition, alpha-blockers are useful in relieving lower urinary tract symptoms in patients with benign prostatic hypertrophy. However, even in a patient who has both hypertension and benign prostatic hypertrophy, we advise physicians to use alpha-blockers primarily to relieve the urinary symptoms, and we recommend lowering the blood pressure with a drug of a class shown to reduce rates of illness and death.
NOT FIRST-LINE THERAPY
All antihypertensive drugs, including alpha-blockers, lower blood pressure. Alpha-blockers have been approved by the US Food and Drug Administration for treating high blood pressure, and they are just as effective as other antihypertensive drugs—if efficacy is defined as a decrease in millimeters of mercury.
However, lowering the blood pressure is not the main goal of antihypertensive therapy. What we want to achieve when prescribing antihypertensive drugs is to reduce the rates of heart attacks, strokes, and other adverse cardiovascular adverse outcomes, including death.
Unfortunately, alpha-blockers fall short in this regard. In the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack (ALLHAT) trial,1,2 doxazosin (Cardura) was found to carry a higher risk of combined cardiovascular disease (relative risk 1.19, P = .04), mostly stroke. Alarmingly, the incidence of symptomatic heart failure in patients on doxazosin was twice that in patients on chlorthalidone (relative risk 2.04, P < .001). Doxazosin was minimally more effective in lowering blood pressure than chlorthalidone, but the small difference in blood pressure was unlikely to have accounted for the significant difference in the risk of heart failure.3
This experience with doxazosin illustrates a key drawback to surrogate end points: a treatment may produce a favorable outcome in the surrogate end point (blood pressure) but produce little or no benefit in terms of the real end point (stroke, myocardial infarction, and heart failure).4
Based on the ALLHAT data as well as on a Veterans Administration study in patients with chronic heart failure in which survival with prazosin (Minipress) was no better than with placebo,5 it seems reasonable to no longer use alpha-blockers as initial therapy for hypertension. This view is reflected by current European6 and American7 guidelines.
ALPHA-BLOCKERS AS PART OF COMBINATION THERAPY
In several clinical trials, alpha-blockers were allowed8 or were specified9,10 as add-on therapy if other drugs failed to control the blood pressure, but they were not used in a randomized fashion. Thus, we cannot judge their effect on cardiovascular outcomes such as heart attack and stroke.
The choice of drugs for combination therapy very often is still empirical and based on personal preference. Doxazosin as add-on therapy, in general, has been shown to be safe and well tolerated.11 But even if it is acceptable, it is not a preferred combination.
In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT),9 patients received extended-release doxazosin as a third drug if they did not reach their goal blood pressure with either the combination of amlodipine (Norvasc) plus perindopril (Aceon) or atenolol (Tenormin) plus bendroflumethiazide. Extended-release doxazosin was an effective add-on, and there was no apparent excess rate of heart failure in doxazosin users.
In other studies, in patients with uncontrolled hypertension, adding doxazosin as a second- or third-line agent to a gold-standard drug—calcium channel blocker, diuretic, beta-blocker, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or combinations of these—allowed significantly more participants to achieve their blood pressure goal.11
Personally, we consider doxazosin in patients whose blood pressure is not controlled with triple therapy with a renin-angiotensin system blocker, a diuretic, and a calcium channel antagonist in full doses. In patients with stage 3 or stage 4 kidney disease who can no longer tolerate renin-angiotensin system blockers, doxazosin may also be a useful adjunct. Whether the metabolic effects of alpha-blockers, such as a reduction in insulin resistance and a decrease in total and low-density lipoprotein cholesterol, will result in lower rates of morbidity and death has not been conclusively determined.
A point of view somewhat more favorable to the use of alpha-blockers has recently been put forward by Chapman et al.12
ALPHA-BLOCKERS ALLEVIATE SYMPTOMS OF BENIGN PROSTATIC HYPERTROPHY
Doxazosin and other alpha-blockers are commonly used to alleviate lower urinary tract symptoms in patients with benign prostatic hypertrophy.
Both high blood pressure and benign prostatic hypertrophy become more common with advancing age, and it has been estimated that both are present in more than 25% of men over age 60.13 Indeed, two trials documented that a significant reduction in symptoms of benign prostatic hypertrophy and in systolic and diastolic blood pressure can be achieved with an alpha-blocker.13,14
This raises the question whether such a “twofer” (treating two disease states with one drug) should be used in clinical practice. We have to consider that the principle of the twofer has never been tested and agree with Davis et al,3 who, in a further analysis of the ALLHAT data, stated that, “In older men with benign prostatic hypertrophy in whom an [alpha]-adrenergic blocker seems like the best treatment for the uropathy, coexisting hypertension should be treated with another antihypertensive drug as well.”3
Again, this would clearly relegate doxazosin to second-line or third-line status, even in patients with benign prostatic hypertrophy, in whom it has been shown to be indicated.
ADVERSE EFFECTS OF ALPHA-BLOCKERS
Dizziness, fatigue, and somnolence are occasionally reported but appear to be well tolerated. Postural hypotension is much less common with proper titration of standard doxazosin or with the use of controlled-release formulations.9–15 However, in patients with impaired autonomic function, even long-acting alpha-blockers can cause postural hypotension and syncope.
Patients using phosphodiesterase type 5 inhibitors—sildenafil (Viagra), vardenafil (Levitra), or tadalafil (Cialis)—for erectile dysfunction should avoid alpha-blockers because the blood-pressure-lowering effects of the two drug classes may be additive.
References
Messerli FH. Implications of discontinuation of doxazosin arm of ALLHAT. Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (commentary). Lancet2000; 355:863–864.
Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT Collaborative Research Group. JAMA2000; 283:1967–1975.
Davis BR, Cutler JA, Furberg CD, et al; ALLHAT Collaborative Research Group. Relationship of antihypertensive treatment regimens and change in blood pressure to risk for heart failure in hypertensive patients randomly assigned to doxazosin or chlorthalidone: further analyses from the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial. Ann Intern Med2002; 137:313–320.
Messerli FH. Doxazosin and congestive heart failure (viewpoint). J Am Coll Cardiol2001; 38:1295–1296.
Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med1986; 314:1547–1552.
Mancia G, De Backer G, Dominiczak A, et al; ESH-ESC Task Force on the Management of Arterial Hypertension. 2007 ESH-ESC practice guidelines for the management of arterial hypertension: ESH-ESC Task Force on the Management of Arterial Hypertension. J Hypertens2007; 25:1751–1762.
Chobanian AV, Bakris GL, Black HR, et al; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA2003; 289:2560–2572.
Jamerson K, Weber MA, Bakris GL, et al; for the ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med2008; 359:2417–2428.
Chapman N, Chang CL, Dahlöf B, Sever PS, Wedel H, Poulter NR; ASCOT Investigators. Effect of doxazosin gastrointestinal therapeutic system as third-line antihypertensive therapy on blood pressure and lipids in the Anglo-Scandinavian Cardiac Outcomes Trial. Circulation2008; 118:42–48.
de Alvaro F, Hernandez-Presa MAASOCIA Study. Effect of doxazosin gastrointestinal therapeutic system on patients with uncontrolled hypertension: the ASOCIA Study. J Cardiovasc Pharmacol2006; 47:271–276.
Black HR. Doxazosin as combination therapy for patients with stage 1 and stage 2 hypertension. J Cardiovasc Pharmacol2003; 41:866–869.
Chapman N, Chen C-Y, Fujita T, et al. Time to re-appraise the role of alpha-1 adrenoceptor antagonists in the management of hypertension?J Hypertens2010; 28:1796–1803.
Steers WD, Kirby RS. Clinical ease of using doxazosin in BPH patients with and without hypertension. Prostate Cancer Prostatic Dis2005; 8:152–157.
Guthrie RM, Siegel RL. A multicenter, community-based study of doxazosin in the treatment of concomitant hypertension and symptomatic benign prostatic hyperplasia: the Hypertension and BPH Intervention Trial (HABIT). Clin Ther1999; 21:1732–1748.
MacDonald R, Wilt TJ, Howe RW. Doxazosin for treating lower urinary tract symptoms compatible with benign prostatic obstruction: a systematic review of efficacy and adverse effects. BJU Int2004; 94:1263–1270.
Giacomo Rossitto, MD Department of Clinical and Experimental Medicine, University of Padua School of Medicine, Padua, Italy
Ganesh Kamath, MD Department of Medicine, St. Luke’s-Roosevelt Hospital Center, New York, NY
Franz H. Messerli, MD, FACC, FACP Director, Hypertension Program, Professor of Clinical Medicine, Columbia University College of Physicians and Surgeons; Division of Cardiology, St. Luke’s-Roosevelt Hospital Center, New York, NY
Address: Franz H. Messerli, MD, Hypertension Program, Division of Cardiology, St. Luke’s-Roosevelt Hospital Center, 1000 Tenth Avenue, New York, NY 10019; e-mail [email protected]
Giacomo Rossitto, MD Department of Clinical and Experimental Medicine, University of Padua School of Medicine, Padua, Italy
Ganesh Kamath, MD Department of Medicine, St. Luke’s-Roosevelt Hospital Center, New York, NY
Franz H. Messerli, MD, FACC, FACP Director, Hypertension Program, Professor of Clinical Medicine, Columbia University College of Physicians and Surgeons; Division of Cardiology, St. Luke’s-Roosevelt Hospital Center, New York, NY
Address: Franz H. Messerli, MD, Hypertension Program, Division of Cardiology, St. Luke’s-Roosevelt Hospital Center, 1000 Tenth Avenue, New York, NY 10019; e-mail [email protected]
Author and Disclosure Information
Giacomo Rossitto, MD Department of Clinical and Experimental Medicine, University of Padua School of Medicine, Padua, Italy
Ganesh Kamath, MD Department of Medicine, St. Luke’s-Roosevelt Hospital Center, New York, NY
Franz H. Messerli, MD, FACC, FACP Director, Hypertension Program, Professor of Clinical Medicine, Columbia University College of Physicians and Surgeons; Division of Cardiology, St. Luke’s-Roosevelt Hospital Center, New York, NY
Address: Franz H. Messerli, MD, Hypertension Program, Division of Cardiology, St. Luke’s-Roosevelt Hospital Center, 1000 Tenth Avenue, New York, NY 10019; e-mail [email protected]
Alpha-blockers should not be used as first-line therapy for hypertension. However, an alpha-blocker can be considered as a second-line or third-line add-on in a patient whose blood pressure is not under control despite treatment with other drugs.
In addition, alpha-blockers are useful in relieving lower urinary tract symptoms in patients with benign prostatic hypertrophy. However, even in a patient who has both hypertension and benign prostatic hypertrophy, we advise physicians to use alpha-blockers primarily to relieve the urinary symptoms, and we recommend lowering the blood pressure with a drug of a class shown to reduce rates of illness and death.
NOT FIRST-LINE THERAPY
All antihypertensive drugs, including alpha-blockers, lower blood pressure. Alpha-blockers have been approved by the US Food and Drug Administration for treating high blood pressure, and they are just as effective as other antihypertensive drugs—if efficacy is defined as a decrease in millimeters of mercury.
However, lowering the blood pressure is not the main goal of antihypertensive therapy. What we want to achieve when prescribing antihypertensive drugs is to reduce the rates of heart attacks, strokes, and other adverse cardiovascular adverse outcomes, including death.
Unfortunately, alpha-blockers fall short in this regard. In the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack (ALLHAT) trial,1,2 doxazosin (Cardura) was found to carry a higher risk of combined cardiovascular disease (relative risk 1.19, P = .04), mostly stroke. Alarmingly, the incidence of symptomatic heart failure in patients on doxazosin was twice that in patients on chlorthalidone (relative risk 2.04, P < .001). Doxazosin was minimally more effective in lowering blood pressure than chlorthalidone, but the small difference in blood pressure was unlikely to have accounted for the significant difference in the risk of heart failure.3
This experience with doxazosin illustrates a key drawback to surrogate end points: a treatment may produce a favorable outcome in the surrogate end point (blood pressure) but produce little or no benefit in terms of the real end point (stroke, myocardial infarction, and heart failure).4
Based on the ALLHAT data as well as on a Veterans Administration study in patients with chronic heart failure in which survival with prazosin (Minipress) was no better than with placebo,5 it seems reasonable to no longer use alpha-blockers as initial therapy for hypertension. This view is reflected by current European6 and American7 guidelines.
ALPHA-BLOCKERS AS PART OF COMBINATION THERAPY
In several clinical trials, alpha-blockers were allowed8 or were specified9,10 as add-on therapy if other drugs failed to control the blood pressure, but they were not used in a randomized fashion. Thus, we cannot judge their effect on cardiovascular outcomes such as heart attack and stroke.
The choice of drugs for combination therapy very often is still empirical and based on personal preference. Doxazosin as add-on therapy, in general, has been shown to be safe and well tolerated.11 But even if it is acceptable, it is not a preferred combination.
In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT),9 patients received extended-release doxazosin as a third drug if they did not reach their goal blood pressure with either the combination of amlodipine (Norvasc) plus perindopril (Aceon) or atenolol (Tenormin) plus bendroflumethiazide. Extended-release doxazosin was an effective add-on, and there was no apparent excess rate of heart failure in doxazosin users.
In other studies, in patients with uncontrolled hypertension, adding doxazosin as a second- or third-line agent to a gold-standard drug—calcium channel blocker, diuretic, beta-blocker, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or combinations of these—allowed significantly more participants to achieve their blood pressure goal.11
Personally, we consider doxazosin in patients whose blood pressure is not controlled with triple therapy with a renin-angiotensin system blocker, a diuretic, and a calcium channel antagonist in full doses. In patients with stage 3 or stage 4 kidney disease who can no longer tolerate renin-angiotensin system blockers, doxazosin may also be a useful adjunct. Whether the metabolic effects of alpha-blockers, such as a reduction in insulin resistance and a decrease in total and low-density lipoprotein cholesterol, will result in lower rates of morbidity and death has not been conclusively determined.
A point of view somewhat more favorable to the use of alpha-blockers has recently been put forward by Chapman et al.12
ALPHA-BLOCKERS ALLEVIATE SYMPTOMS OF BENIGN PROSTATIC HYPERTROPHY
Doxazosin and other alpha-blockers are commonly used to alleviate lower urinary tract symptoms in patients with benign prostatic hypertrophy.
Both high blood pressure and benign prostatic hypertrophy become more common with advancing age, and it has been estimated that both are present in more than 25% of men over age 60.13 Indeed, two trials documented that a significant reduction in symptoms of benign prostatic hypertrophy and in systolic and diastolic blood pressure can be achieved with an alpha-blocker.13,14
This raises the question whether such a “twofer” (treating two disease states with one drug) should be used in clinical practice. We have to consider that the principle of the twofer has never been tested and agree with Davis et al,3 who, in a further analysis of the ALLHAT data, stated that, “In older men with benign prostatic hypertrophy in whom an [alpha]-adrenergic blocker seems like the best treatment for the uropathy, coexisting hypertension should be treated with another antihypertensive drug as well.”3
Again, this would clearly relegate doxazosin to second-line or third-line status, even in patients with benign prostatic hypertrophy, in whom it has been shown to be indicated.
ADVERSE EFFECTS OF ALPHA-BLOCKERS
Dizziness, fatigue, and somnolence are occasionally reported but appear to be well tolerated. Postural hypotension is much less common with proper titration of standard doxazosin or with the use of controlled-release formulations.9–15 However, in patients with impaired autonomic function, even long-acting alpha-blockers can cause postural hypotension and syncope.
Patients using phosphodiesterase type 5 inhibitors—sildenafil (Viagra), vardenafil (Levitra), or tadalafil (Cialis)—for erectile dysfunction should avoid alpha-blockers because the blood-pressure-lowering effects of the two drug classes may be additive.
Alpha-blockers should not be used as first-line therapy for hypertension. However, an alpha-blocker can be considered as a second-line or third-line add-on in a patient whose blood pressure is not under control despite treatment with other drugs.
In addition, alpha-blockers are useful in relieving lower urinary tract symptoms in patients with benign prostatic hypertrophy. However, even in a patient who has both hypertension and benign prostatic hypertrophy, we advise physicians to use alpha-blockers primarily to relieve the urinary symptoms, and we recommend lowering the blood pressure with a drug of a class shown to reduce rates of illness and death.
NOT FIRST-LINE THERAPY
All antihypertensive drugs, including alpha-blockers, lower blood pressure. Alpha-blockers have been approved by the US Food and Drug Administration for treating high blood pressure, and they are just as effective as other antihypertensive drugs—if efficacy is defined as a decrease in millimeters of mercury.
However, lowering the blood pressure is not the main goal of antihypertensive therapy. What we want to achieve when prescribing antihypertensive drugs is to reduce the rates of heart attacks, strokes, and other adverse cardiovascular adverse outcomes, including death.
Unfortunately, alpha-blockers fall short in this regard. In the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack (ALLHAT) trial,1,2 doxazosin (Cardura) was found to carry a higher risk of combined cardiovascular disease (relative risk 1.19, P = .04), mostly stroke. Alarmingly, the incidence of symptomatic heart failure in patients on doxazosin was twice that in patients on chlorthalidone (relative risk 2.04, P < .001). Doxazosin was minimally more effective in lowering blood pressure than chlorthalidone, but the small difference in blood pressure was unlikely to have accounted for the significant difference in the risk of heart failure.3
This experience with doxazosin illustrates a key drawback to surrogate end points: a treatment may produce a favorable outcome in the surrogate end point (blood pressure) but produce little or no benefit in terms of the real end point (stroke, myocardial infarction, and heart failure).4
Based on the ALLHAT data as well as on a Veterans Administration study in patients with chronic heart failure in which survival with prazosin (Minipress) was no better than with placebo,5 it seems reasonable to no longer use alpha-blockers as initial therapy for hypertension. This view is reflected by current European6 and American7 guidelines.
ALPHA-BLOCKERS AS PART OF COMBINATION THERAPY
In several clinical trials, alpha-blockers were allowed8 or were specified9,10 as add-on therapy if other drugs failed to control the blood pressure, but they were not used in a randomized fashion. Thus, we cannot judge their effect on cardiovascular outcomes such as heart attack and stroke.
The choice of drugs for combination therapy very often is still empirical and based on personal preference. Doxazosin as add-on therapy, in general, has been shown to be safe and well tolerated.11 But even if it is acceptable, it is not a preferred combination.
In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT),9 patients received extended-release doxazosin as a third drug if they did not reach their goal blood pressure with either the combination of amlodipine (Norvasc) plus perindopril (Aceon) or atenolol (Tenormin) plus bendroflumethiazide. Extended-release doxazosin was an effective add-on, and there was no apparent excess rate of heart failure in doxazosin users.
In other studies, in patients with uncontrolled hypertension, adding doxazosin as a second- or third-line agent to a gold-standard drug—calcium channel blocker, diuretic, beta-blocker, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or combinations of these—allowed significantly more participants to achieve their blood pressure goal.11
Personally, we consider doxazosin in patients whose blood pressure is not controlled with triple therapy with a renin-angiotensin system blocker, a diuretic, and a calcium channel antagonist in full doses. In patients with stage 3 or stage 4 kidney disease who can no longer tolerate renin-angiotensin system blockers, doxazosin may also be a useful adjunct. Whether the metabolic effects of alpha-blockers, such as a reduction in insulin resistance and a decrease in total and low-density lipoprotein cholesterol, will result in lower rates of morbidity and death has not been conclusively determined.
A point of view somewhat more favorable to the use of alpha-blockers has recently been put forward by Chapman et al.12
ALPHA-BLOCKERS ALLEVIATE SYMPTOMS OF BENIGN PROSTATIC HYPERTROPHY
Doxazosin and other alpha-blockers are commonly used to alleviate lower urinary tract symptoms in patients with benign prostatic hypertrophy.
Both high blood pressure and benign prostatic hypertrophy become more common with advancing age, and it has been estimated that both are present in more than 25% of men over age 60.13 Indeed, two trials documented that a significant reduction in symptoms of benign prostatic hypertrophy and in systolic and diastolic blood pressure can be achieved with an alpha-blocker.13,14
This raises the question whether such a “twofer” (treating two disease states with one drug) should be used in clinical practice. We have to consider that the principle of the twofer has never been tested and agree with Davis et al,3 who, in a further analysis of the ALLHAT data, stated that, “In older men with benign prostatic hypertrophy in whom an [alpha]-adrenergic blocker seems like the best treatment for the uropathy, coexisting hypertension should be treated with another antihypertensive drug as well.”3
Again, this would clearly relegate doxazosin to second-line or third-line status, even in patients with benign prostatic hypertrophy, in whom it has been shown to be indicated.
ADVERSE EFFECTS OF ALPHA-BLOCKERS
Dizziness, fatigue, and somnolence are occasionally reported but appear to be well tolerated. Postural hypotension is much less common with proper titration of standard doxazosin or with the use of controlled-release formulations.9–15 However, in patients with impaired autonomic function, even long-acting alpha-blockers can cause postural hypotension and syncope.
Patients using phosphodiesterase type 5 inhibitors—sildenafil (Viagra), vardenafil (Levitra), or tadalafil (Cialis)—for erectile dysfunction should avoid alpha-blockers because the blood-pressure-lowering effects of the two drug classes may be additive.
References
Messerli FH. Implications of discontinuation of doxazosin arm of ALLHAT. Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (commentary). Lancet2000; 355:863–864.
Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT Collaborative Research Group. JAMA2000; 283:1967–1975.
Davis BR, Cutler JA, Furberg CD, et al; ALLHAT Collaborative Research Group. Relationship of antihypertensive treatment regimens and change in blood pressure to risk for heart failure in hypertensive patients randomly assigned to doxazosin or chlorthalidone: further analyses from the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial. Ann Intern Med2002; 137:313–320.
Messerli FH. Doxazosin and congestive heart failure (viewpoint). J Am Coll Cardiol2001; 38:1295–1296.
Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med1986; 314:1547–1552.
Mancia G, De Backer G, Dominiczak A, et al; ESH-ESC Task Force on the Management of Arterial Hypertension. 2007 ESH-ESC practice guidelines for the management of arterial hypertension: ESH-ESC Task Force on the Management of Arterial Hypertension. J Hypertens2007; 25:1751–1762.
Chobanian AV, Bakris GL, Black HR, et al; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA2003; 289:2560–2572.
Jamerson K, Weber MA, Bakris GL, et al; for the ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med2008; 359:2417–2428.
Chapman N, Chang CL, Dahlöf B, Sever PS, Wedel H, Poulter NR; ASCOT Investigators. Effect of doxazosin gastrointestinal therapeutic system as third-line antihypertensive therapy on blood pressure and lipids in the Anglo-Scandinavian Cardiac Outcomes Trial. Circulation2008; 118:42–48.
de Alvaro F, Hernandez-Presa MAASOCIA Study. Effect of doxazosin gastrointestinal therapeutic system on patients with uncontrolled hypertension: the ASOCIA Study. J Cardiovasc Pharmacol2006; 47:271–276.
Black HR. Doxazosin as combination therapy for patients with stage 1 and stage 2 hypertension. J Cardiovasc Pharmacol2003; 41:866–869.
Chapman N, Chen C-Y, Fujita T, et al. Time to re-appraise the role of alpha-1 adrenoceptor antagonists in the management of hypertension?J Hypertens2010; 28:1796–1803.
Steers WD, Kirby RS. Clinical ease of using doxazosin in BPH patients with and without hypertension. Prostate Cancer Prostatic Dis2005; 8:152–157.
Guthrie RM, Siegel RL. A multicenter, community-based study of doxazosin in the treatment of concomitant hypertension and symptomatic benign prostatic hyperplasia: the Hypertension and BPH Intervention Trial (HABIT). Clin Ther1999; 21:1732–1748.
MacDonald R, Wilt TJ, Howe RW. Doxazosin for treating lower urinary tract symptoms compatible with benign prostatic obstruction: a systematic review of efficacy and adverse effects. BJU Int2004; 94:1263–1270.
References
Messerli FH. Implications of discontinuation of doxazosin arm of ALLHAT. Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (commentary). Lancet2000; 355:863–864.
Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ALLHAT Collaborative Research Group. JAMA2000; 283:1967–1975.
Davis BR, Cutler JA, Furberg CD, et al; ALLHAT Collaborative Research Group. Relationship of antihypertensive treatment regimens and change in blood pressure to risk for heart failure in hypertensive patients randomly assigned to doxazosin or chlorthalidone: further analyses from the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial. Ann Intern Med2002; 137:313–320.
Messerli FH. Doxazosin and congestive heart failure (viewpoint). J Am Coll Cardiol2001; 38:1295–1296.
Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med1986; 314:1547–1552.
Mancia G, De Backer G, Dominiczak A, et al; ESH-ESC Task Force on the Management of Arterial Hypertension. 2007 ESH-ESC practice guidelines for the management of arterial hypertension: ESH-ESC Task Force on the Management of Arterial Hypertension. J Hypertens2007; 25:1751–1762.
Chobanian AV, Bakris GL, Black HR, et al; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA2003; 289:2560–2572.
Jamerson K, Weber MA, Bakris GL, et al; for the ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med2008; 359:2417–2428.
Chapman N, Chang CL, Dahlöf B, Sever PS, Wedel H, Poulter NR; ASCOT Investigators. Effect of doxazosin gastrointestinal therapeutic system as third-line antihypertensive therapy on blood pressure and lipids in the Anglo-Scandinavian Cardiac Outcomes Trial. Circulation2008; 118:42–48.
de Alvaro F, Hernandez-Presa MAASOCIA Study. Effect of doxazosin gastrointestinal therapeutic system on patients with uncontrolled hypertension: the ASOCIA Study. J Cardiovasc Pharmacol2006; 47:271–276.
Black HR. Doxazosin as combination therapy for patients with stage 1 and stage 2 hypertension. J Cardiovasc Pharmacol2003; 41:866–869.
Chapman N, Chen C-Y, Fujita T, et al. Time to re-appraise the role of alpha-1 adrenoceptor antagonists in the management of hypertension?J Hypertens2010; 28:1796–1803.
Steers WD, Kirby RS. Clinical ease of using doxazosin in BPH patients with and without hypertension. Prostate Cancer Prostatic Dis2005; 8:152–157.
Guthrie RM, Siegel RL. A multicenter, community-based study of doxazosin in the treatment of concomitant hypertension and symptomatic benign prostatic hyperplasia: the Hypertension and BPH Intervention Trial (HABIT). Clin Ther1999; 21:1732–1748.
MacDonald R, Wilt TJ, Howe RW. Doxazosin for treating lower urinary tract symptoms compatible with benign prostatic obstruction: a systematic review of efficacy and adverse effects. BJU Int2004; 94:1263–1270.
Monoamine oxidase (MAO) inhibitors were the first drugs for treating depression. Introduced in the 1950s, they were used extensively for the next two decades. Their use declined substantially since then because of their reported side effects, their food and drug interactions, and the introduction of new classes of antidepressants.
This trend may be changing. These drugs can be effective in major depressive disorder, and particularly in major depressive disorder with atypical features and in treatment-resistant depression.
New, selective MAO inhibitors are being developed. Moreover, the selegiline transdermal system (Emsam),1,2 introduced in 2006, offers the potential advantage of eliminating the need for burdensome dietary restrictions and has renewed interest in this group of drugs.
In this article, we discuss the history, pharmacology, safety and tolerability of MAO inhibitors, and we summarize recent MAO inhibitor research. Our goal is to familiarize physicians with this class of drugs, including recent updates regarding their safety profile and liberalized dietary recommendations.
DEPRESSION IS COMMON, DIFFICULT
Depression affects 121 million people worldwide.3 According to a study that compared two surveys of 40,000 people each, the prevalence of major depressive disorder in the United States more than doubled (from 3.3% to 7.0%) from 1992 to 2002.4 Another survey, in 2002 and 2003, revealed the lifetime prevalence of major depressive disorder to be 16.6%.5
Treatments for depression have expanded over the past 20 years, with new classes of drugs such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). However, depression has remained a difficult condition to treat. In the National Institute of Mental Health’s Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study,6 the remission rate in patients treated with the SSRI citalopram (Celexa) for up to 14 weeks was 28% using one measure and 33% using another. Diversifying and understanding existing and emerging therapeutic options is important to the effective treatment of this disease.
THE RISE AND FALL OF MAO INHIBITORS
The first antidepressant introduced was an MAO inhibitor, iproniazid, followed shortly thereafter by a tricyclic antidepressant, imipramine (Tofranil). When iproniazid, originally an antituberculosis agent, was promoted for its antidepressant properties in the 1950s, very little was known about its side effects. It was later removed from the market because of hepatotoxicity, but several other MAO inhibitors had surfaced for the treatment of depression—eg, phenelzine (Nardil), isocarboxazid (Marplan), and tranylcypromine (Parnate).
Currently, MAO inhibitors are typically reserved for third- or fourth-line treatment. As a result, even psychiatrists have little experience with these agents. In a 1999 survey of the Michigan Psychiatric Association,7 12% of practicing psychiatrists said they had never prescribed an MAO inhibitor, another 27% had not prescribed one in the prior 3 years, and only 2% said they prescribed them frequently. A decade earlier, about 25% had said they prescribed them often.8
The prescription rate of MAO inhibitors has remained low during the past 10 years. In a Canadian population-based study9 conducted among older adults in a large health care database from January 1997 to April 2007, the yearly incidence of MAO inhibitor prescriptions decreased from a rate of 3.1 per 100,000 to 1.4 per 100,000. Drug interactions, side effects, preference for other treatments, and dietary restrictions were the reasons most often cited for not prescribing these drugs.7
The side effects of MAO inhibitors were recognized by the mid-1960s, when more than 40 cases of tyramine-induced hypertensive crisis were reported (particularly with tranylcypromine).10,11 Many of the reported events happened after the patient ate tyramine-rich foods such as aged cheese (hence, “the cheese reaction”—more on this below) or drank draft beer.10,11 The US Food and Drug Administration (FDA) consequently established dietary restrictions for patients taking MAO inhibitors, but people found the guidelines cumbersome and often switched to newer drugs that did not require a restrictive diet, such as tricyclics and, much later (in the 1980s), SSRIs.
MAO HAS TWO SUBTYPES
MAO is a flavin-containing enzyme critical for regulating neurotransmitter levels by catabolizing endogenous monoamines (eg, norepinephrine, serotonin, and dopamine) and exogenous amines (eg, dietary tyramine). It is found throughout the body but is more highly concentrated in the liver, kidneys, intestinal wall, and brain.
MAO has two subtypes, isoenzyme A (MAO-A) and isoenzyme B (MAO-B), which vary in their distribution. MAO-A is found primarily in the intestinal tract, liver, and peripheral adrenergic neurons (adrenal glands, arterial vessels, and sympathetic nerves) and preferentially metabolizes serotonin and norepinephrine. MAO-B is found mostly in the brain and liver. However, both isotypes are found in all of the areas mentioned. Since 80% of intestinal MAO is MAO-A, this isoenzyme is primarily responsible for degradation of tyramine, and thus inhibition of MAO-A is associated with the cheese reaction.10,11
TYPES OF MAO INHIBITORS
MAO inhibitors can be classified on the basis of whether they are nonselective or selective for either MAO-A or MAO-B, and whether their effect is reversible.
Nonselective MAO inhibitors are phenelzine, isocarboxazid, and tranylcypromine.
Selective MAO inhibitors. Selegiline is selective for MAO-B. Clorgyline is selective for MAO-A, but it is not available in the United States.
A reversible MAO inhibitor is moclobemide (not available in the United States).
Do selectivity and reversibility matter?
Classic MAO inhibitors such as tranylcypromine and phenelzine are neither reversible (binding to the enzyme for the extent of its lifetime of 14–28 days) nor selective for the subtypes. These drugs were used extensively several decades ago to treat atypical depression, anxiety, and phobias. The only selective MAO inhibitor now available in the United States is selegiline, which inhibits MAO-B at low doses but loses its selectivity at dosages greater than 20 mg/day.
Experimental studies suggest that inhibition of more than 70% of MAO-A activity is necessary for the antidepressant effect of selegiline.12 At oral doses that selectively inhibit MAO-B (5–10 mg/day), selegiline does not seem to have potent antidepressant activity, although it does show success as an adjunctive treatment for Parkinson disease and does not necessitate any dietary restriction. Only at higher oral doses (20–60 mg/day), at which MAO-B selectivity is lost, is the antidepressant effect seen. But the higher doses necessitate dietary restrictions. Therefore, patients who are taking the oral selective MAO inhibitor selegiline have to follow the same dietary restrictions as patients taking the nonselective ones.
Reversible inhibitors of MAO-A have the distinction of being easily displaced by ingested tyramine in the gut and thus do not cause the cheese reaction. However, the only reversible agent available in the world market is moclobemide. It is not available in the United States, and appears to be less effective than older, nonselective MAO inhibitors.13
SELEGILINE TRANSDERMAL SYSTEM
The selegiline transdermal system (Emsam) is the first FDA-approved transdermal patch for treatment of major depression. Patients who are using Emsam at its lowest effective dose of 6 mg/24 hours do not need to follow the dietary restrictions that are needed for all oral MAO inhibitors.
Pharmacokinetics of the selegiline patch
With the transdermal patch, selegiline is extensively absorbed through the skin. Plasma levels are maintained over a 24-hour period, allowing once-daily application. Patches are available that deliver 6, 9, or 12 mg per 24 hours. Steady-state plasma levels are reached after about 5 days.
The bioavailability of selegiline is about 75% with the transdermal delivery system vs 4.4% after oral administration, the lower number being due to first-pass metabolism.1 About 90% of selegiline is bound to plasma proteins and quickly penetrates the central nervous system.
This drug is metabolized by cytochrome P450 isoenzymes, including CYP2C9, CYP2B6, and CYP3A4. Its metabolites are l-methamphetamine and n-desmethylselegiline.
Clinical research showed that dosage adjustments were not necessary in specific populations studied, including patients with various stages of renal or hepatic failure.1 Clearance of selegiline was independent of dose, age, sex, renal function, body weight, or concomitant medications.1
Advantages of the patch system
Since selegiline delivered via the patch is not absorbed through the gut, it has little effect on gut MAO-A and therefore is unlikely to lead to tyramine-induced hypertensive crisis. Studies of the selegiline patch show that inhibition of more than 80% of gut MAO-A is necessary to impair metabolism of tyramine in the gut.1 Therefore, the 6-mg patch will not significantly impair tyramine degradation in the gut. In phase III testing of the selegiline patch, no hypertensive crises were reported among 2,656 outpatients without dietary restrictions. However, it is still recommended that patients on the 9-mg and 12-mg patches follow a tyramine-free diet.1
Although there are no data available to suggest that higher dosages are more effective, it is recommended that the dose be titrated in 3-mg increments at intervals of at least 2 weeks until the maximum recommended dosage of 12 mg/24 hours is reached.2
Disadvantage of the selegiline patch: Cost
The selegiline patch is expensive: $692.99 for 1 month’s supply at a dose of 6 mg/24 hours and $638.99 for 1 month’s supply at a dose of 9 or 12 mg/24 hours (verified with a national pharmacy chain at the time of this writing). Insurance coverage for the patch varies, and documentation may be required from the physician. Oral MAO inhibitors are much less expensive.
SAFETY, TOLERABILITY OF MAO INHIBITORS
Side effects of oral agents
Orthostatic hypotension, dizziness, drowsiness, insomnia, and nausea are the most frequently reported side effects of oral MAO inhibitors.14,15 These side effects can generally be managed symptomatically by slowing the titration, dividing the doses, changing the time it is taken, or, in the case of orthostatic hypotension, increasing fluid intake.14 Phenelzine has the strongest association with sedation.14
Weight gain, edema, muscle pain, myoclonus, paresthesias, sexual dysfunction, and, rarely, hepatotoxicity are late side effects.15–18 Paresthesias, an infrequent side effect, are often treated with pyridoxine supplementation.15
Transient hypertensive episodes within 2 hours after ingestion of MAO inhibitors, which were independent of dietary or drug interactions, have been reported.19 The hypertensive episodes are usually self-limited but in rare cases result in hypertensive crisis.19–21
Serotonin syndrome has been reported with MAO inhibitor monotherapy in rare cases.22 Serotonin syndrome is characterized by mental status changes, restlessness, myoclonus, hyperreflexia, diaphoresis, or evidence of autonomic hyperactivity.23 The syndrome is potentially fatal and is treated symptomatically by removing the offending drugs and giving intravenous rehydration.23
Side effects of the selegiline patch
The most common adverse events with the selegiline patch include application-site reaction (24% vs 12% with placebo), headache (18% vs 17%), insomnia, diarrhea, dry mouth, and dyspepsia.24,25 Dose-related orthostatic hypotension was reported (occurring in 9.8% vs 6.7% with placebo) and was most likely to occur in elderly patients.25 It is suggested that insomnia may be lessened by removing the patch before bedtime. Also, rotating the patch application sites and prompt topical treatment of irritation may lessen local effects.24
Observe a washout period when switching between serotonergic drugs
Most MAO inhibitors irreversibly inhibit MAO for the life of the enzyme, and thus the physiologic effects of phenelzine, isocarboxazid, and tranylcypromine last for up to 2 to 3 weeks.26 Although the elimination half-life of typical MAO inhibitors is short (1.5–4 hours),27,28 their physiologic effects are long-lasting.14
Switching from a MAO inhibitor to another serotonergic agent. Concomitant use of MAO inhibitors and other serotonergic drugs is associated with the risk of serotonin syndrome. After stopping an MAO inhibitor, a 14-day washout period is recommended before starting another serotonergic agent.29 Patients should continue to be monitored closely after the washout period, as cases of serotonin syndrome have been reported later.30 A 14-day washout period is also recommended when switching between MAO inhibitors, although more rapid switches have been made safely.31
Switching from another serotonergic agent to an oral MAO inhibitor. Similarly, a 14-day washout period (or five half-lives) is necessary after stopping most of the serotonergic agents mentioned above before beginning treatment with an oral MAO inhibitor. Fluoxetine (Prozac) has a longer half-life and therefore requires a longer washout period, ie, 5 weeks.
Switching from another serotonergic agent to the selegiline patch. When switching to the selegiline patch from another serotonergic drug, the washout period is 1 week after stopping most drugs or 5 weeks after stopping fluoxetine. One must wait 2 weeks after stopping the selegiline patch before starting therapy with any of the other serotonergic drugs.
Drugs to avoid due to interactions
In view of the risk of severe of drug-drug interactions, particularly the risk of serotonin syndrome, the following serotonin-enhancing compounds are contraindicated in patients taking a MAO inhibitor: SSRIs, SNRIs, tricyclic antidepressants, other MAO inhibitors, mirtazapine, and St. John’s wort. Other pharmaceuticals to be avoided include bupropion, meperidine, tramadol, methadone, propoxyphene, pentazocine, dextromethorphan, and cyclobenzaprine (Table 1). Also, there have been numerous reports of serotonin syndrome with the use of the broad-spectrum, MAO-based antibiotic linezolid (Zyvox), by itself or in conjunction with other serotonergic agents.32–35
Several studies suggested a hazardous combination of nonsubcutaneous sumatriptans (5-HT1B/1D agonists) and MAO-B inhibitors, while subcutaneous sumatriptan migraine-abortive treatment and MAO-B inhibitors appear to be safe.36,37
Also, amphetamines, cough-and-cold preparations, and weight-reducing preparations that contain vasoconstrictors (eg, pseudoephedrine, phenylephrine, phenylpropanolamine, and ephedrine) should be avoided, as the risk of hypertensive crisis increases with these products.
Patients on MAO inhibitors should wear a medical alert bracelet in case they need to undergo emergency surgery and are unable to verbally communicate their drug history. They should be instructed to alert all health care providers about their MAO inhibitor use.14
Beware of worsening depression
Physicians, patients, and family members should be advised to observe for worsening depression or “suicidality” during the course of treatment with MAO inhibitors, as with all antidepressants.
Diet can be more lenient than in the past
The dietary restrictions classically advised for patients taking oral MAO inhibitors were established to prevent hypertensive crises associated with tyramine ingestion. However, some of these restrictions were unsubstantiated,38 and evidence from more recent studies suggests that they are unnecessarily strict39 and may lead to resistance by the physician, the patient, or both to using this potentially beneficial therapy.14 There is also a risk that patients will inadvertently discover that a food that was in the “restricted” list caused them no harm upon ingestion and thus will become cavalier about dietary adherence.39
To prevent dietary noncompliance, physicians should conduct ongoing diet surveys and encourage adherence to evidence-based dietary recommendations.40
The FDA and drug-package inserts for oral MAO inhibitors continue to recommend stringent dietary restrictions, including no aged cheeses or meats, soy sauce, soy beans, soy paste, miso soup, Italian green beans (fava beans), snow peas, broad bean pods, sauerkraut, kimchee, concentrated yeast extracts (Marmite), wine, beer (including alcohol-free beer), and many other foods. However, several studies have measured the tyramine content of food and determined that less than 6 mg per serving is generally safe.39,41 The results of these investigations have led to more lenient dietary guidelines.39
Absolute dietary restrictions include39:
Aged cheeses and meats
Banana peels
Broad bean (fava) pods
Spoiled meats
Marmite
Sauerkraut
Soybean products
Draft beers.
Among the many foods determined to be unnecessarily restricted are avocados; bananas; beef or chicken bouillon; chocolate; fresh and mild cheeses, eg, ricotta, cottage cheese, cream cheese, processed cheese slices; fresh meat, poultry, or fish; meat gravy (fresh); monosodium glutamate; peanuts; properly stored pickled or smoked fish (eg, herring); raspberries; and yeast extracts (except Marmite).39
Dietary restrictions should continue for 2 weeks after stopping an MAO inhibitor.
Dietary restrictions for the selegiline patch
Tyramine-containing foods pose less risk with the selegiline patch than with oral MAO inhibitors, and studies42 show that the 6-mg patch does not necessitate dietary restrictions. The accumulating data suggest that the risk of a tyramine-induced event is extremely low with the patch even in doses above 6 mg. But in the meantime, the recommendations for the 9-mg and 12-mg patches remain the same as for the classic oral MAO inhibitors, and tyramine-containing food should be restricted.
EFFICACY OF MAO INHIBITORS IN CLINICAL PRACTICE
Data from numerous studies suggest MAO inhibitors are effective in managing major depressive disorder, and specifically atypical depression,43–48 treatment-resistant major depressive disorder,49,50 and bipolar depression.51,52 Guidelines from the American Psychiatric Association and the British Association for Psychopharmacology suggest that MAO inhibitors be recommended for treatment of major depressive disorder in patients with atypical features and when other antidepressants have failed.53
MAO inhibitors have also been used in the treatment of Parkinson disease, bulimia, anxiety disorders, anorexia nervosa, and body dysmorphic disorder.54
Major depressive disorder
In controlled trials in outpatients with depression who were treated with therapeutic doses of MAO inhibitors, the response rate was 50% to 70%.55 When tranylcypromine was used in severely depressed inpatients, its efficacy was comparable to that of electroconvulsive therapy, imipramine, and amitriptyline.56 Thase et al,57 in a meta-analysis, found that the MAO inhibitors tranylcypromine, phenelzine, and isocarboxazid were equally effective in treating depression.
Atypical depression
Atypical depression is one of the most common subtypes of major depressive disorder. Diagnostic criteria for major depressive disorder with atypical features include mood reactivity and two of the following: weight gain or hyperphagia, hypersomnolence, leaden paralysis, or an enduring pattern of rejection sensitivity.58 An estimated 30% of outpatients with unipolar depression meet these criteria.59
Multiple randomized controlled trials showed that MAO inhibitors were superior to tricyclic antidepressants in treating atypical depression. One study, involving more than 400 patients, determined that atypical depression responded better to phenelzine than to imipramine.43 Another study evaluating 153 critically depressed patients showed significantly greater response with phenelzine than with imipramine or placebo.49 Furthermore, in another double-blind controlled crossover study, 89 mood-reactive, nonmelancholic, chronically depressed outpatients were found to have a striking response to phenelzine after being unresponsive to imipramine.50 Another report48 indicated that in a double-blind, randomized, placebo-controlled trial among 119 patients with atypical depression treated for 6 weeks, the overall response rates were 78% with phenelzine, 50% with imipramine, and 28% with placebo.
A recent meta-analysis of treatment trials in atypical depression revealed a large mean effect size of 0.45 for the superiority of MAO inhibitors over placebo and a medium mean effect size of 0.27 for the superiority of MAO inhibitors over tricyclic antidepressants.60 Additionally, in a randomized, double-blind placebo-controlled trial, patients with comorbid atypical depression and bulimia showed significant improvement in both bulimic and depressive symptoms when given phenelzine vs imipramine or placebo.61
The current data comparing SSRIs and MAO inhibitors in the treatment of atypical depression are limited. The above-mentioned meta-analysis of three such trials (when moclobemide was used in two out of three trials) revealed no significant difference in efficacy.60 However, the authors themselves warned about the limitations of the studies, including low power to detect differences. Parker and Crawford59 compared self-rating of effectiveness of the various previous treatments in patients with depression with and without atypical features using an online survey. The analysis of the responses of 1,934 patients showed no overall difference in treatment response to both drug and non-drug therapies between respondents with and without atypical features, except with SSRIs. The “atypical” group had a significantly lower mean effectiveness score for SSRIs overall, and a lower mean effectiveness rating for two of six SSRIs examined. The authors speculated that even though there was no differential outcome detected in individuals with atypical depression treated with MAO inhibitors, this negative finding may simply have reflected the low prevalence of sample respondents who received MAO inhibitors (which was 4% in the “atypical depression” group of 338).59
Treatment-resistant depression
The ultimate goal in treating major depressive disorder is to achieve complete remission. If complete remission is not achieved, the risk of relapse is high,62,63 as is the risk of more severe future depressive episodes63 and death from any cause.64 Therefore, the ability of clinicians to make appropriate and evidence-based changes in treatment strategy is of high importance.
The use of MAO inhibitors as a third-line or fourth-line choice for treatment-resistant depression is supported by a number of studies.49,50,65–67 MAO inhibitors appear to be especially effective in the subgroup of patients who have treatment-resistant depression with atypical or anergic bipolar features.
Bipolar depression
Anergic bipolar depression is defined as a condition associated with fatigue, psychomotor retardation, and at least one reversed neurovegetative symptom in a patient with bipolar disorder meeting the criteria for a major depressive episode. According to several trials,51,52,68 MAO inhibitors may be more effective than a tricyclic antidepressant in the treatment of anergic bipolar depression. However, more studies are required to determine the role of antidepressants in general and MAO inhibitors in particular in the management of bipolar depression.
Efficacy of the selegiline patch
The efficacy of the selegiline patch in the treatment of depression was examined in four double-blind placebo-controlled studies.69–72 There were three short-term studies (a 6-week study of 177 patients,69 an 8-week study of 265 patients,72 and an 8-week study of 289 patients70) and a fixed-dose 1-year relapse prevention study of 322 patients.71 The inclusion criterion for the short-term studies was diagnosis of a first or a recurrent episode of major depressive disorder in patients with a Hamilton Depression Rating Scale (HDRS) score higher than 20. The HDRS score was used to assess improvement in depressive symptoms. In all studies, patients on active patch had significant improvement in depressive symptoms on the HDRS compared with placebo. In the relapse prevention study,71 patients with major depressive disorder that responded to transdermal selegiline 6 mg within the first 10 weeks were stratified either to continue receiving the selegiline 6-mg patch or to receive placebo. Those continually receiving selegiline experienced a significantly longer time to relapse. At 12 months, the relapse rate was 16.8% with the selegiline patch vs 30.7% with placebo. The patch was reported to be well tolerated, with the most common side effect being application site reaction. The adherence to the treatment was high—84.2% in the active-patch group and 89.6% in the placebo group.71
DO MAO INHIBITORS HAVE A PLACE IN PRIMARY CARE?
MAO inhibitors have secured their place in the history of psychiatry as the first antidepressants. Overall, MAO inhibitors remain underused. However, with the introduction of new and selective MAO inhibitors including the selegiline patch, and with data suggesting efficacy in the management of certain subtypes of depression, we expect that interest in this class of drugs will grow among psychiatrists. Based on the current guidelines for MAO inhibitors to be used as a third- or fourth-line treatment, as well as on research data, it is premature to recommend their more extensive use in a primary care setting. Whether this will change in the future depends on both the research advances and new, safer formulations of MAO inhibitors.
Compton WM, Conway KP, Stinson FS, Grant BF. Changes in the prevalence of major depression and comorbid substance use disorders in the United States between 1991–1992 and 2001–2002. Am J Psychiatry2006; 163:2141–2147.
Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry2005; 62:593–602.
Trivedi MH, Rush AJ, Wisniewski SR, et al; STAR*D Study Team. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry2006; 163:28–40.
Balon R, Mufti R, Arfken CL. A survey of prescribing practices for monoamine oxidase inhibitors. Psychiatr Serv1999; 50:945–947.
Clary C, Mandos LA, Schweizer E. Results of a brief survey on the prescribing practices for monoamine oxidase inhibitor antidepressants. J Clin Psychiatry1990; 51:226–231.
Shulman KI, Fischer HD, Herrmann N, Huo CY, Anderson GM, Rochon PA. Current prescription patterns and safety profile of irreversible monoamine oxidase inhibitors: a population-based cohort study of older adults. J Clin Psychiatry2009; 70:1681–1686.
Horwitz D, Lovenberg W, Engelman K, Sjoerdsma A. Monoamine oxidase inhibitors, tyramine, and cheese. JAMA1964; 188:1108–1110.
Asatoor AM, Levi AJ, Milne MD. Tranylcypromine and cheese. Lancet1963; 2:733–734.
Gordon MN, Muller CD, Sherman KA, Morgan DG, Azzaro AJ, Wecker L. Oral versus transdermal selegiline: antidepressant-like activity in rats. Pharmacol Biochem Behav1999; 63:501–506.
Lotufu-Neto F, Trivedi M, Thase ME. Meta-analysis of the reversible inhibitors of monoamine oxidase type A moclobemide and brofaromine for the treatment of depression. Neuropsychopharmacology1999; 20:226–247.
Fiedorowicz JG, Swartz KL. The role of monoamine oxidase inhibitors in current psychiatric practice. J Psychiatr Pract2004; 10:239–248.
Evans DL, Davidson J, Raft D. Early and late side effects of phenelzine. J Clin Psychopharmacol1982; 2:208–210.
Fava M. Weight gain and antidepressants. J Clin Psychiatry2000; 61(suppl 11):37–41.
Rabkin J, Quitkin F, Harrison W, Tricamo E, McGrath P. Adverse reactions to monoamine oxidase inhibitors. Part I. A comparative study. J Clin Psychopharmacol1984; 4:270–278.
Gomez-Gil E, Salmeron JM, Mas A. Phenelzine-induced fulminant hepatic failure. Ann Intern Med1996; 124:692–693.
Lavin MR, Mendelwitz A, Kronig MH. Spontaneous hypertensive reactions with monoamine oxidase inhibitors. Biol Psychiatry1993; 34:146–151.
Fisher P. Serotonin syndrome in the elderly after antidepressive monotherapy. J Clin Psychopharmacol1995; 15:440–442.
Sternback H. The serotonin syndrome. Am J Psychiatry1991; 148:705–713.
Thase M. Novel transdermal delivery formulation of the monoamine oxidase inhibitor selegiline nearing release for treatment of depression. J Clin Psychiatry2006; 67:671–672.
Lee KC, Chen JJ. Transdermal selegiline for the treatment of major depressive disorder. Neuropsychiatr Dis Treat2007; 3:527–537.
Cooper AJ. Tyramine and irreversible monoamine oxidase inhibitors in clinical practice. Br J Psychiatry Suppl1989; Oct(6):38–45.
Mallinger AG, Smith E. Pharmacokinetics of monoamine oxidase inhibitors. Psychopharmacol Bull1991; 27:493–502.
Fulton B, Benfield P. Moclobemide. An update of its pharmacological properties and therapeutic use. Drugs1996; 52:450–474.
Marangell LB. Switching antidepressants for treatment-resistant major depression. J Clin Psychiatry2001; 62(suppl 18):12–17.
Gitlin MJ. Venlafaxine, monoamine oxidase inhibitors, and the serotonin syndrome. J Clin Psychopharmacol1997; 17:66–67.
Szuba MP, Hornig-Rohan M, Amsterdam JD. Rapid conversion from one monoamine oxidase inhibitor to another. J Clin Psychiatry1997; 58:307–310.
Lorenz RA, Vandenberg AM, Canepa EA. Serotonergic antidepressants and linezolid: a retrospective chart review and presentation of cases. Int J Psychiatry Med2008; 38:81–90.
Miller DG, Lovell EO. Antibiotic-induced serotonin syndrome. J Emerg Med2008, May1(Epub ahead of print).
Das PK, Wakentin DI, Hewko R, Forrest DL. Serotonin syndrome after concomitant treatment with linezolid and meperidine. Clin Infect Dis2008; 46:264–265.
Packer S, Berman SA. Serotonin syndrome precipitated by the monoamine oxidase inhibitor linezolid. Am J Psychiatry2007; 164:346–347.
Diamond S. The use of sumatriptan in patients on monoamine oxidase inhibitors. Neurology1995; 45:1039–1040.
Fox AW. Subcutaneous sumatriptan pharmacokinetics: delimiting the monoamine oxidase inhibitor effect. Headache2010; 50:249–255.
Gardner DM, Shulman KI, Walker SE, Tailor SA. The making of a user friendly MAOI diet. J Clin Psychiatry1996; 57:99–104.
Sweet RA, Brown EJ, Heimberg RG, et al. Monoamine oxidase inhibitor dietary restrictions: what are we asking patients to give up?J Clin Psychiatry1995; 56:196–201.
Shulman KI, Walker SE. Refining the MAOI diet: tyramine content of pizzas and soy products. J Clin Psychiatry1999; 60:191–193.
Azzaro AJ, Vandenberg CM, Blob LF, et al. Tyramine pressor sensitivity during treatment with the selegiline transdermal system 6 mg/24 h in healthy subjects. J Clin Pharmacol2006; 46:933–944.
Quitkin FM, Stewart JW, McGrath PJ, et al. Columbia atypical depression. A subgroup of depressives with better response to MAOI than to tricyclic antidepressants or placebo. Br J Psychiatry Suppl1993; Sep(21):30–34.
Davidson J, Pelton S. Forms of atypical depression and their response to antidepressant drugs. Psychiatry Res1986; 17:87–95.
Liebowitz MR, Quitkin FM, Stewart JW, et al. Antidepressant specificity in atypical depression. Arch Gen Psychiatry1988; 45:129–137.
Rapaport MH, Thase ME. Translating the evidence on atypical depression into clinical practice. J Clin Psychiatry2007; 68:e11.
Liebowitz MR. Depression with anxiety and atypical depression. J Clin Psychiatry1993; 54(suppl):10–14.
Stewart JW, McGrath PJ, Quitkin FM, et al. Chronic depression: response to placebo, imipramine, and phenelzine. J Clin Psychopharmacol1993; 13:391–396.
McGrath PJ, Stewart JW, Nunes EV, et al. A double-blind crossover trial of imipramine and phenelzine for outpatients with treatment-refractory depression. Am J Psychiatry1993; 150:118–123.
Zarate CA, Tohen M, Baraibar G, Kando JC, Mirin J. Prescribing trends of antidepressants in bipolar depression. J Clin Psychiatry1995; 56:260–264.
Mallinger AG, Frank E, Thase ME, Barwell MM, Diazgranados N, Luckenbaugh DA, Kupfer DJ. Revisiting the effectiveness of standard antidepressants in bipolar disorder: are monoamine oxidase inhibitors superior?Psychopharmacol Bull2009; 42:64–74.
Anderson IM, Nutt DJ, Deakin JF. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 1993 British Association for Psychopharmacology guidelines. British Association for Psychopharmacology. J Psychopharmacol2000; 14:3–20.
Liebowitz MR, Hollander E, Schneier F, et al. Reversible and irreversible monoamine oxidase inhibitors in other psychiatric disorders. Acta Psychiatr Scand Suppl1990; 360:29–34.
Davidson JR, Giller EL, Zisook S, Overall JE. An efficacy study of isocarboxazid and placebo in depression, and its relationship to depressive nosology. Arch Gen Psychiatry1988; 45:120–127.
Razani J, White KL, White J, et al. The safety and efficacy of combined amitriptyline and tranylcypromine antidepressant treatment: a controlled trial. Arch Gen Psychiatry1983; 40:657–661.
Thase ME, Triverdi MH, Rush AJ. MAOIs in the contemporary treatment of depression. Neuropsychopharmacology1995; 12:185–219.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000.
Parker G, Crawford J. Atypical depression: retrospective self-reporting of treatment effectiveness. Acta Psychiatr Scand2009; 120:213–221.
Henkel V, Mergl R, Algaier AK, Kohnen R, Moller HJ, Hergerl U. Treatment of depression with atypical features: a meta-analytic approach. Psychiatry Res2006; 141:89–101.
Rothschild R, Quitkin HM, Quitkin FM, et al. A double-blind placebo-controlled comparison of phenelzine and imipramine in the treatment of bulimia in atypical depressives. Int J Eat Disord1994; 15:1–9.
Judd LL, Paulus MJ, Schettler PJ, et al. Does incomplete recovery from first life-time major depressive episode herald a chronic course of illness?Am J Psychiatry2000; 157:1501–1504.
Murphy JM, Monson RR, Olivier DC, Sobol AM, Leighton AH. Affective disorders and mortality: a general population study. Arch Gen Psychiatry1987; 44:473–480.
Thase ME, Frank E, Mallinger AG, Hamer T, Kupfer DJ. Treatment of imipramine-resistant recurrent depression, III: efficacy of monoamine oxidase inhibitors. J Clin Psychiatry1992; 53:5–11.
Thase ME, Mallinger AG, McKnight D, Himmelhoch JM. Treatment of imipramine-resistant recurrent depression, IV: a double blind crossover study of tranylcypromine for anergic bipolar depression. Am J Psychiatry1992; 149:195–198.
Quitkin FM, McGrath PJ, Stewart JW, et al. Atypical depression, panic attacks, and response to imipramine and phenelzine: a replication. Arch Gen Psychiatry1990; 47:935–941.
Himmelhoch JM, Thase ME, Mallinger AG, Houck P. Tranylcypromine versus imipramine in anergic bipolar depression. Am J Psychiatry1991; 148:910–916.
Bodkin JA, Amsterdam JD. Transdermal selegiline in major depression: a double-blind, placebo-controlled, parallel-group study in outpatients. Am J Psychiatry2002; 159:1869–1875.
Amsterdam JD. A double-blind, placebo-controlled trial of the safety and efficacy of selegiline transdermal system without dietary restrictions in patients with major depressive disorder. J Clin Psychiatry2003; 64:208–214.
Amsterdam JD, Bodkin JA. Selegiline transdermal system in the prevention of relapse of major depressive disorder: a 52-week, double-blind, placebo-substitution, parallel-group clinical trial. J Clin Psychopharmacol2006; 26:579–586.
Feiger AD, Rickels K, Rynn MA, et al. Selegiline transdermal system for the treatment of major depressive disorder: an 8-week, double-blind, placebo-controlled, flexible-dose titration trial. J Clin Psychiatry2006; 67:1354–1361.
Monoamine oxidase (MAO) inhibitors were the first drugs for treating depression. Introduced in the 1950s, they were used extensively for the next two decades. Their use declined substantially since then because of their reported side effects, their food and drug interactions, and the introduction of new classes of antidepressants.
This trend may be changing. These drugs can be effective in major depressive disorder, and particularly in major depressive disorder with atypical features and in treatment-resistant depression.
New, selective MAO inhibitors are being developed. Moreover, the selegiline transdermal system (Emsam),1,2 introduced in 2006, offers the potential advantage of eliminating the need for burdensome dietary restrictions and has renewed interest in this group of drugs.
In this article, we discuss the history, pharmacology, safety and tolerability of MAO inhibitors, and we summarize recent MAO inhibitor research. Our goal is to familiarize physicians with this class of drugs, including recent updates regarding their safety profile and liberalized dietary recommendations.
DEPRESSION IS COMMON, DIFFICULT
Depression affects 121 million people worldwide.3 According to a study that compared two surveys of 40,000 people each, the prevalence of major depressive disorder in the United States more than doubled (from 3.3% to 7.0%) from 1992 to 2002.4 Another survey, in 2002 and 2003, revealed the lifetime prevalence of major depressive disorder to be 16.6%.5
Treatments for depression have expanded over the past 20 years, with new classes of drugs such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). However, depression has remained a difficult condition to treat. In the National Institute of Mental Health’s Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study,6 the remission rate in patients treated with the SSRI citalopram (Celexa) for up to 14 weeks was 28% using one measure and 33% using another. Diversifying and understanding existing and emerging therapeutic options is important to the effective treatment of this disease.
THE RISE AND FALL OF MAO INHIBITORS
The first antidepressant introduced was an MAO inhibitor, iproniazid, followed shortly thereafter by a tricyclic antidepressant, imipramine (Tofranil). When iproniazid, originally an antituberculosis agent, was promoted for its antidepressant properties in the 1950s, very little was known about its side effects. It was later removed from the market because of hepatotoxicity, but several other MAO inhibitors had surfaced for the treatment of depression—eg, phenelzine (Nardil), isocarboxazid (Marplan), and tranylcypromine (Parnate).
Currently, MAO inhibitors are typically reserved for third- or fourth-line treatment. As a result, even psychiatrists have little experience with these agents. In a 1999 survey of the Michigan Psychiatric Association,7 12% of practicing psychiatrists said they had never prescribed an MAO inhibitor, another 27% had not prescribed one in the prior 3 years, and only 2% said they prescribed them frequently. A decade earlier, about 25% had said they prescribed them often.8
The prescription rate of MAO inhibitors has remained low during the past 10 years. In a Canadian population-based study9 conducted among older adults in a large health care database from January 1997 to April 2007, the yearly incidence of MAO inhibitor prescriptions decreased from a rate of 3.1 per 100,000 to 1.4 per 100,000. Drug interactions, side effects, preference for other treatments, and dietary restrictions were the reasons most often cited for not prescribing these drugs.7
The side effects of MAO inhibitors were recognized by the mid-1960s, when more than 40 cases of tyramine-induced hypertensive crisis were reported (particularly with tranylcypromine).10,11 Many of the reported events happened after the patient ate tyramine-rich foods such as aged cheese (hence, “the cheese reaction”—more on this below) or drank draft beer.10,11 The US Food and Drug Administration (FDA) consequently established dietary restrictions for patients taking MAO inhibitors, but people found the guidelines cumbersome and often switched to newer drugs that did not require a restrictive diet, such as tricyclics and, much later (in the 1980s), SSRIs.
MAO HAS TWO SUBTYPES
MAO is a flavin-containing enzyme critical for regulating neurotransmitter levels by catabolizing endogenous monoamines (eg, norepinephrine, serotonin, and dopamine) and exogenous amines (eg, dietary tyramine). It is found throughout the body but is more highly concentrated in the liver, kidneys, intestinal wall, and brain.
MAO has two subtypes, isoenzyme A (MAO-A) and isoenzyme B (MAO-B), which vary in their distribution. MAO-A is found primarily in the intestinal tract, liver, and peripheral adrenergic neurons (adrenal glands, arterial vessels, and sympathetic nerves) and preferentially metabolizes serotonin and norepinephrine. MAO-B is found mostly in the brain and liver. However, both isotypes are found in all of the areas mentioned. Since 80% of intestinal MAO is MAO-A, this isoenzyme is primarily responsible for degradation of tyramine, and thus inhibition of MAO-A is associated with the cheese reaction.10,11
TYPES OF MAO INHIBITORS
MAO inhibitors can be classified on the basis of whether they are nonselective or selective for either MAO-A or MAO-B, and whether their effect is reversible.
Nonselective MAO inhibitors are phenelzine, isocarboxazid, and tranylcypromine.
Selective MAO inhibitors. Selegiline is selective for MAO-B. Clorgyline is selective for MAO-A, but it is not available in the United States.
A reversible MAO inhibitor is moclobemide (not available in the United States).
Do selectivity and reversibility matter?
Classic MAO inhibitors such as tranylcypromine and phenelzine are neither reversible (binding to the enzyme for the extent of its lifetime of 14–28 days) nor selective for the subtypes. These drugs were used extensively several decades ago to treat atypical depression, anxiety, and phobias. The only selective MAO inhibitor now available in the United States is selegiline, which inhibits MAO-B at low doses but loses its selectivity at dosages greater than 20 mg/day.
Experimental studies suggest that inhibition of more than 70% of MAO-A activity is necessary for the antidepressant effect of selegiline.12 At oral doses that selectively inhibit MAO-B (5–10 mg/day), selegiline does not seem to have potent antidepressant activity, although it does show success as an adjunctive treatment for Parkinson disease and does not necessitate any dietary restriction. Only at higher oral doses (20–60 mg/day), at which MAO-B selectivity is lost, is the antidepressant effect seen. But the higher doses necessitate dietary restrictions. Therefore, patients who are taking the oral selective MAO inhibitor selegiline have to follow the same dietary restrictions as patients taking the nonselective ones.
Reversible inhibitors of MAO-A have the distinction of being easily displaced by ingested tyramine in the gut and thus do not cause the cheese reaction. However, the only reversible agent available in the world market is moclobemide. It is not available in the United States, and appears to be less effective than older, nonselective MAO inhibitors.13
SELEGILINE TRANSDERMAL SYSTEM
The selegiline transdermal system (Emsam) is the first FDA-approved transdermal patch for treatment of major depression. Patients who are using Emsam at its lowest effective dose of 6 mg/24 hours do not need to follow the dietary restrictions that are needed for all oral MAO inhibitors.
Pharmacokinetics of the selegiline patch
With the transdermal patch, selegiline is extensively absorbed through the skin. Plasma levels are maintained over a 24-hour period, allowing once-daily application. Patches are available that deliver 6, 9, or 12 mg per 24 hours. Steady-state plasma levels are reached after about 5 days.
The bioavailability of selegiline is about 75% with the transdermal delivery system vs 4.4% after oral administration, the lower number being due to first-pass metabolism.1 About 90% of selegiline is bound to plasma proteins and quickly penetrates the central nervous system.
This drug is metabolized by cytochrome P450 isoenzymes, including CYP2C9, CYP2B6, and CYP3A4. Its metabolites are l-methamphetamine and n-desmethylselegiline.
Clinical research showed that dosage adjustments were not necessary in specific populations studied, including patients with various stages of renal or hepatic failure.1 Clearance of selegiline was independent of dose, age, sex, renal function, body weight, or concomitant medications.1
Advantages of the patch system
Since selegiline delivered via the patch is not absorbed through the gut, it has little effect on gut MAO-A and therefore is unlikely to lead to tyramine-induced hypertensive crisis. Studies of the selegiline patch show that inhibition of more than 80% of gut MAO-A is necessary to impair metabolism of tyramine in the gut.1 Therefore, the 6-mg patch will not significantly impair tyramine degradation in the gut. In phase III testing of the selegiline patch, no hypertensive crises were reported among 2,656 outpatients without dietary restrictions. However, it is still recommended that patients on the 9-mg and 12-mg patches follow a tyramine-free diet.1
Although there are no data available to suggest that higher dosages are more effective, it is recommended that the dose be titrated in 3-mg increments at intervals of at least 2 weeks until the maximum recommended dosage of 12 mg/24 hours is reached.2
Disadvantage of the selegiline patch: Cost
The selegiline patch is expensive: $692.99 for 1 month’s supply at a dose of 6 mg/24 hours and $638.99 for 1 month’s supply at a dose of 9 or 12 mg/24 hours (verified with a national pharmacy chain at the time of this writing). Insurance coverage for the patch varies, and documentation may be required from the physician. Oral MAO inhibitors are much less expensive.
SAFETY, TOLERABILITY OF MAO INHIBITORS
Side effects of oral agents
Orthostatic hypotension, dizziness, drowsiness, insomnia, and nausea are the most frequently reported side effects of oral MAO inhibitors.14,15 These side effects can generally be managed symptomatically by slowing the titration, dividing the doses, changing the time it is taken, or, in the case of orthostatic hypotension, increasing fluid intake.14 Phenelzine has the strongest association with sedation.14
Weight gain, edema, muscle pain, myoclonus, paresthesias, sexual dysfunction, and, rarely, hepatotoxicity are late side effects.15–18 Paresthesias, an infrequent side effect, are often treated with pyridoxine supplementation.15
Transient hypertensive episodes within 2 hours after ingestion of MAO inhibitors, which were independent of dietary or drug interactions, have been reported.19 The hypertensive episodes are usually self-limited but in rare cases result in hypertensive crisis.19–21
Serotonin syndrome has been reported with MAO inhibitor monotherapy in rare cases.22 Serotonin syndrome is characterized by mental status changes, restlessness, myoclonus, hyperreflexia, diaphoresis, or evidence of autonomic hyperactivity.23 The syndrome is potentially fatal and is treated symptomatically by removing the offending drugs and giving intravenous rehydration.23
Side effects of the selegiline patch
The most common adverse events with the selegiline patch include application-site reaction (24% vs 12% with placebo), headache (18% vs 17%), insomnia, diarrhea, dry mouth, and dyspepsia.24,25 Dose-related orthostatic hypotension was reported (occurring in 9.8% vs 6.7% with placebo) and was most likely to occur in elderly patients.25 It is suggested that insomnia may be lessened by removing the patch before bedtime. Also, rotating the patch application sites and prompt topical treatment of irritation may lessen local effects.24
Observe a washout period when switching between serotonergic drugs
Most MAO inhibitors irreversibly inhibit MAO for the life of the enzyme, and thus the physiologic effects of phenelzine, isocarboxazid, and tranylcypromine last for up to 2 to 3 weeks.26 Although the elimination half-life of typical MAO inhibitors is short (1.5–4 hours),27,28 their physiologic effects are long-lasting.14
Switching from a MAO inhibitor to another serotonergic agent. Concomitant use of MAO inhibitors and other serotonergic drugs is associated with the risk of serotonin syndrome. After stopping an MAO inhibitor, a 14-day washout period is recommended before starting another serotonergic agent.29 Patients should continue to be monitored closely after the washout period, as cases of serotonin syndrome have been reported later.30 A 14-day washout period is also recommended when switching between MAO inhibitors, although more rapid switches have been made safely.31
Switching from another serotonergic agent to an oral MAO inhibitor. Similarly, a 14-day washout period (or five half-lives) is necessary after stopping most of the serotonergic agents mentioned above before beginning treatment with an oral MAO inhibitor. Fluoxetine (Prozac) has a longer half-life and therefore requires a longer washout period, ie, 5 weeks.
Switching from another serotonergic agent to the selegiline patch. When switching to the selegiline patch from another serotonergic drug, the washout period is 1 week after stopping most drugs or 5 weeks after stopping fluoxetine. One must wait 2 weeks after stopping the selegiline patch before starting therapy with any of the other serotonergic drugs.
Drugs to avoid due to interactions
In view of the risk of severe of drug-drug interactions, particularly the risk of serotonin syndrome, the following serotonin-enhancing compounds are contraindicated in patients taking a MAO inhibitor: SSRIs, SNRIs, tricyclic antidepressants, other MAO inhibitors, mirtazapine, and St. John’s wort. Other pharmaceuticals to be avoided include bupropion, meperidine, tramadol, methadone, propoxyphene, pentazocine, dextromethorphan, and cyclobenzaprine (Table 1). Also, there have been numerous reports of serotonin syndrome with the use of the broad-spectrum, MAO-based antibiotic linezolid (Zyvox), by itself or in conjunction with other serotonergic agents.32–35
Several studies suggested a hazardous combination of nonsubcutaneous sumatriptans (5-HT1B/1D agonists) and MAO-B inhibitors, while subcutaneous sumatriptan migraine-abortive treatment and MAO-B inhibitors appear to be safe.36,37
Also, amphetamines, cough-and-cold preparations, and weight-reducing preparations that contain vasoconstrictors (eg, pseudoephedrine, phenylephrine, phenylpropanolamine, and ephedrine) should be avoided, as the risk of hypertensive crisis increases with these products.
Patients on MAO inhibitors should wear a medical alert bracelet in case they need to undergo emergency surgery and are unable to verbally communicate their drug history. They should be instructed to alert all health care providers about their MAO inhibitor use.14
Beware of worsening depression
Physicians, patients, and family members should be advised to observe for worsening depression or “suicidality” during the course of treatment with MAO inhibitors, as with all antidepressants.
Diet can be more lenient than in the past
The dietary restrictions classically advised for patients taking oral MAO inhibitors were established to prevent hypertensive crises associated with tyramine ingestion. However, some of these restrictions were unsubstantiated,38 and evidence from more recent studies suggests that they are unnecessarily strict39 and may lead to resistance by the physician, the patient, or both to using this potentially beneficial therapy.14 There is also a risk that patients will inadvertently discover that a food that was in the “restricted” list caused them no harm upon ingestion and thus will become cavalier about dietary adherence.39
To prevent dietary noncompliance, physicians should conduct ongoing diet surveys and encourage adherence to evidence-based dietary recommendations.40
The FDA and drug-package inserts for oral MAO inhibitors continue to recommend stringent dietary restrictions, including no aged cheeses or meats, soy sauce, soy beans, soy paste, miso soup, Italian green beans (fava beans), snow peas, broad bean pods, sauerkraut, kimchee, concentrated yeast extracts (Marmite), wine, beer (including alcohol-free beer), and many other foods. However, several studies have measured the tyramine content of food and determined that less than 6 mg per serving is generally safe.39,41 The results of these investigations have led to more lenient dietary guidelines.39
Absolute dietary restrictions include39:
Aged cheeses and meats
Banana peels
Broad bean (fava) pods
Spoiled meats
Marmite
Sauerkraut
Soybean products
Draft beers.
Among the many foods determined to be unnecessarily restricted are avocados; bananas; beef or chicken bouillon; chocolate; fresh and mild cheeses, eg, ricotta, cottage cheese, cream cheese, processed cheese slices; fresh meat, poultry, or fish; meat gravy (fresh); monosodium glutamate; peanuts; properly stored pickled or smoked fish (eg, herring); raspberries; and yeast extracts (except Marmite).39
Dietary restrictions should continue for 2 weeks after stopping an MAO inhibitor.
Dietary restrictions for the selegiline patch
Tyramine-containing foods pose less risk with the selegiline patch than with oral MAO inhibitors, and studies42 show that the 6-mg patch does not necessitate dietary restrictions. The accumulating data suggest that the risk of a tyramine-induced event is extremely low with the patch even in doses above 6 mg. But in the meantime, the recommendations for the 9-mg and 12-mg patches remain the same as for the classic oral MAO inhibitors, and tyramine-containing food should be restricted.
EFFICACY OF MAO INHIBITORS IN CLINICAL PRACTICE
Data from numerous studies suggest MAO inhibitors are effective in managing major depressive disorder, and specifically atypical depression,43–48 treatment-resistant major depressive disorder,49,50 and bipolar depression.51,52 Guidelines from the American Psychiatric Association and the British Association for Psychopharmacology suggest that MAO inhibitors be recommended for treatment of major depressive disorder in patients with atypical features and when other antidepressants have failed.53
MAO inhibitors have also been used in the treatment of Parkinson disease, bulimia, anxiety disorders, anorexia nervosa, and body dysmorphic disorder.54
Major depressive disorder
In controlled trials in outpatients with depression who were treated with therapeutic doses of MAO inhibitors, the response rate was 50% to 70%.55 When tranylcypromine was used in severely depressed inpatients, its efficacy was comparable to that of electroconvulsive therapy, imipramine, and amitriptyline.56 Thase et al,57 in a meta-analysis, found that the MAO inhibitors tranylcypromine, phenelzine, and isocarboxazid were equally effective in treating depression.
Atypical depression
Atypical depression is one of the most common subtypes of major depressive disorder. Diagnostic criteria for major depressive disorder with atypical features include mood reactivity and two of the following: weight gain or hyperphagia, hypersomnolence, leaden paralysis, or an enduring pattern of rejection sensitivity.58 An estimated 30% of outpatients with unipolar depression meet these criteria.59
Multiple randomized controlled trials showed that MAO inhibitors were superior to tricyclic antidepressants in treating atypical depression. One study, involving more than 400 patients, determined that atypical depression responded better to phenelzine than to imipramine.43 Another study evaluating 153 critically depressed patients showed significantly greater response with phenelzine than with imipramine or placebo.49 Furthermore, in another double-blind controlled crossover study, 89 mood-reactive, nonmelancholic, chronically depressed outpatients were found to have a striking response to phenelzine after being unresponsive to imipramine.50 Another report48 indicated that in a double-blind, randomized, placebo-controlled trial among 119 patients with atypical depression treated for 6 weeks, the overall response rates were 78% with phenelzine, 50% with imipramine, and 28% with placebo.
A recent meta-analysis of treatment trials in atypical depression revealed a large mean effect size of 0.45 for the superiority of MAO inhibitors over placebo and a medium mean effect size of 0.27 for the superiority of MAO inhibitors over tricyclic antidepressants.60 Additionally, in a randomized, double-blind placebo-controlled trial, patients with comorbid atypical depression and bulimia showed significant improvement in both bulimic and depressive symptoms when given phenelzine vs imipramine or placebo.61
The current data comparing SSRIs and MAO inhibitors in the treatment of atypical depression are limited. The above-mentioned meta-analysis of three such trials (when moclobemide was used in two out of three trials) revealed no significant difference in efficacy.60 However, the authors themselves warned about the limitations of the studies, including low power to detect differences. Parker and Crawford59 compared self-rating of effectiveness of the various previous treatments in patients with depression with and without atypical features using an online survey. The analysis of the responses of 1,934 patients showed no overall difference in treatment response to both drug and non-drug therapies between respondents with and without atypical features, except with SSRIs. The “atypical” group had a significantly lower mean effectiveness score for SSRIs overall, and a lower mean effectiveness rating for two of six SSRIs examined. The authors speculated that even though there was no differential outcome detected in individuals with atypical depression treated with MAO inhibitors, this negative finding may simply have reflected the low prevalence of sample respondents who received MAO inhibitors (which was 4% in the “atypical depression” group of 338).59
Treatment-resistant depression
The ultimate goal in treating major depressive disorder is to achieve complete remission. If complete remission is not achieved, the risk of relapse is high,62,63 as is the risk of more severe future depressive episodes63 and death from any cause.64 Therefore, the ability of clinicians to make appropriate and evidence-based changes in treatment strategy is of high importance.
The use of MAO inhibitors as a third-line or fourth-line choice for treatment-resistant depression is supported by a number of studies.49,50,65–67 MAO inhibitors appear to be especially effective in the subgroup of patients who have treatment-resistant depression with atypical or anergic bipolar features.
Bipolar depression
Anergic bipolar depression is defined as a condition associated with fatigue, psychomotor retardation, and at least one reversed neurovegetative symptom in a patient with bipolar disorder meeting the criteria for a major depressive episode. According to several trials,51,52,68 MAO inhibitors may be more effective than a tricyclic antidepressant in the treatment of anergic bipolar depression. However, more studies are required to determine the role of antidepressants in general and MAO inhibitors in particular in the management of bipolar depression.
Efficacy of the selegiline patch
The efficacy of the selegiline patch in the treatment of depression was examined in four double-blind placebo-controlled studies.69–72 There were three short-term studies (a 6-week study of 177 patients,69 an 8-week study of 265 patients,72 and an 8-week study of 289 patients70) and a fixed-dose 1-year relapse prevention study of 322 patients.71 The inclusion criterion for the short-term studies was diagnosis of a first or a recurrent episode of major depressive disorder in patients with a Hamilton Depression Rating Scale (HDRS) score higher than 20. The HDRS score was used to assess improvement in depressive symptoms. In all studies, patients on active patch had significant improvement in depressive symptoms on the HDRS compared with placebo. In the relapse prevention study,71 patients with major depressive disorder that responded to transdermal selegiline 6 mg within the first 10 weeks were stratified either to continue receiving the selegiline 6-mg patch or to receive placebo. Those continually receiving selegiline experienced a significantly longer time to relapse. At 12 months, the relapse rate was 16.8% with the selegiline patch vs 30.7% with placebo. The patch was reported to be well tolerated, with the most common side effect being application site reaction. The adherence to the treatment was high—84.2% in the active-patch group and 89.6% in the placebo group.71
DO MAO INHIBITORS HAVE A PLACE IN PRIMARY CARE?
MAO inhibitors have secured their place in the history of psychiatry as the first antidepressants. Overall, MAO inhibitors remain underused. However, with the introduction of new and selective MAO inhibitors including the selegiline patch, and with data suggesting efficacy in the management of certain subtypes of depression, we expect that interest in this class of drugs will grow among psychiatrists. Based on the current guidelines for MAO inhibitors to be used as a third- or fourth-line treatment, as well as on research data, it is premature to recommend their more extensive use in a primary care setting. Whether this will change in the future depends on both the research advances and new, safer formulations of MAO inhibitors.
Monoamine oxidase (MAO) inhibitors were the first drugs for treating depression. Introduced in the 1950s, they were used extensively for the next two decades. Their use declined substantially since then because of their reported side effects, their food and drug interactions, and the introduction of new classes of antidepressants.
This trend may be changing. These drugs can be effective in major depressive disorder, and particularly in major depressive disorder with atypical features and in treatment-resistant depression.
New, selective MAO inhibitors are being developed. Moreover, the selegiline transdermal system (Emsam),1,2 introduced in 2006, offers the potential advantage of eliminating the need for burdensome dietary restrictions and has renewed interest in this group of drugs.
In this article, we discuss the history, pharmacology, safety and tolerability of MAO inhibitors, and we summarize recent MAO inhibitor research. Our goal is to familiarize physicians with this class of drugs, including recent updates regarding their safety profile and liberalized dietary recommendations.
DEPRESSION IS COMMON, DIFFICULT
Depression affects 121 million people worldwide.3 According to a study that compared two surveys of 40,000 people each, the prevalence of major depressive disorder in the United States more than doubled (from 3.3% to 7.0%) from 1992 to 2002.4 Another survey, in 2002 and 2003, revealed the lifetime prevalence of major depressive disorder to be 16.6%.5
Treatments for depression have expanded over the past 20 years, with new classes of drugs such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). However, depression has remained a difficult condition to treat. In the National Institute of Mental Health’s Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study,6 the remission rate in patients treated with the SSRI citalopram (Celexa) for up to 14 weeks was 28% using one measure and 33% using another. Diversifying and understanding existing and emerging therapeutic options is important to the effective treatment of this disease.
THE RISE AND FALL OF MAO INHIBITORS
The first antidepressant introduced was an MAO inhibitor, iproniazid, followed shortly thereafter by a tricyclic antidepressant, imipramine (Tofranil). When iproniazid, originally an antituberculosis agent, was promoted for its antidepressant properties in the 1950s, very little was known about its side effects. It was later removed from the market because of hepatotoxicity, but several other MAO inhibitors had surfaced for the treatment of depression—eg, phenelzine (Nardil), isocarboxazid (Marplan), and tranylcypromine (Parnate).
Currently, MAO inhibitors are typically reserved for third- or fourth-line treatment. As a result, even psychiatrists have little experience with these agents. In a 1999 survey of the Michigan Psychiatric Association,7 12% of practicing psychiatrists said they had never prescribed an MAO inhibitor, another 27% had not prescribed one in the prior 3 years, and only 2% said they prescribed them frequently. A decade earlier, about 25% had said they prescribed them often.8
The prescription rate of MAO inhibitors has remained low during the past 10 years. In a Canadian population-based study9 conducted among older adults in a large health care database from January 1997 to April 2007, the yearly incidence of MAO inhibitor prescriptions decreased from a rate of 3.1 per 100,000 to 1.4 per 100,000. Drug interactions, side effects, preference for other treatments, and dietary restrictions were the reasons most often cited for not prescribing these drugs.7
The side effects of MAO inhibitors were recognized by the mid-1960s, when more than 40 cases of tyramine-induced hypertensive crisis were reported (particularly with tranylcypromine).10,11 Many of the reported events happened after the patient ate tyramine-rich foods such as aged cheese (hence, “the cheese reaction”—more on this below) or drank draft beer.10,11 The US Food and Drug Administration (FDA) consequently established dietary restrictions for patients taking MAO inhibitors, but people found the guidelines cumbersome and often switched to newer drugs that did not require a restrictive diet, such as tricyclics and, much later (in the 1980s), SSRIs.
MAO HAS TWO SUBTYPES
MAO is a flavin-containing enzyme critical for regulating neurotransmitter levels by catabolizing endogenous monoamines (eg, norepinephrine, serotonin, and dopamine) and exogenous amines (eg, dietary tyramine). It is found throughout the body but is more highly concentrated in the liver, kidneys, intestinal wall, and brain.
MAO has two subtypes, isoenzyme A (MAO-A) and isoenzyme B (MAO-B), which vary in their distribution. MAO-A is found primarily in the intestinal tract, liver, and peripheral adrenergic neurons (adrenal glands, arterial vessels, and sympathetic nerves) and preferentially metabolizes serotonin and norepinephrine. MAO-B is found mostly in the brain and liver. However, both isotypes are found in all of the areas mentioned. Since 80% of intestinal MAO is MAO-A, this isoenzyme is primarily responsible for degradation of tyramine, and thus inhibition of MAO-A is associated with the cheese reaction.10,11
TYPES OF MAO INHIBITORS
MAO inhibitors can be classified on the basis of whether they are nonselective or selective for either MAO-A or MAO-B, and whether their effect is reversible.
Nonselective MAO inhibitors are phenelzine, isocarboxazid, and tranylcypromine.
Selective MAO inhibitors. Selegiline is selective for MAO-B. Clorgyline is selective for MAO-A, but it is not available in the United States.
A reversible MAO inhibitor is moclobemide (not available in the United States).
Do selectivity and reversibility matter?
Classic MAO inhibitors such as tranylcypromine and phenelzine are neither reversible (binding to the enzyme for the extent of its lifetime of 14–28 days) nor selective for the subtypes. These drugs were used extensively several decades ago to treat atypical depression, anxiety, and phobias. The only selective MAO inhibitor now available in the United States is selegiline, which inhibits MAO-B at low doses but loses its selectivity at dosages greater than 20 mg/day.
Experimental studies suggest that inhibition of more than 70% of MAO-A activity is necessary for the antidepressant effect of selegiline.12 At oral doses that selectively inhibit MAO-B (5–10 mg/day), selegiline does not seem to have potent antidepressant activity, although it does show success as an adjunctive treatment for Parkinson disease and does not necessitate any dietary restriction. Only at higher oral doses (20–60 mg/day), at which MAO-B selectivity is lost, is the antidepressant effect seen. But the higher doses necessitate dietary restrictions. Therefore, patients who are taking the oral selective MAO inhibitor selegiline have to follow the same dietary restrictions as patients taking the nonselective ones.
Reversible inhibitors of MAO-A have the distinction of being easily displaced by ingested tyramine in the gut and thus do not cause the cheese reaction. However, the only reversible agent available in the world market is moclobemide. It is not available in the United States, and appears to be less effective than older, nonselective MAO inhibitors.13
SELEGILINE TRANSDERMAL SYSTEM
The selegiline transdermal system (Emsam) is the first FDA-approved transdermal patch for treatment of major depression. Patients who are using Emsam at its lowest effective dose of 6 mg/24 hours do not need to follow the dietary restrictions that are needed for all oral MAO inhibitors.
Pharmacokinetics of the selegiline patch
With the transdermal patch, selegiline is extensively absorbed through the skin. Plasma levels are maintained over a 24-hour period, allowing once-daily application. Patches are available that deliver 6, 9, or 12 mg per 24 hours. Steady-state plasma levels are reached after about 5 days.
The bioavailability of selegiline is about 75% with the transdermal delivery system vs 4.4% after oral administration, the lower number being due to first-pass metabolism.1 About 90% of selegiline is bound to plasma proteins and quickly penetrates the central nervous system.
This drug is metabolized by cytochrome P450 isoenzymes, including CYP2C9, CYP2B6, and CYP3A4. Its metabolites are l-methamphetamine and n-desmethylselegiline.
Clinical research showed that dosage adjustments were not necessary in specific populations studied, including patients with various stages of renal or hepatic failure.1 Clearance of selegiline was independent of dose, age, sex, renal function, body weight, or concomitant medications.1
Advantages of the patch system
Since selegiline delivered via the patch is not absorbed through the gut, it has little effect on gut MAO-A and therefore is unlikely to lead to tyramine-induced hypertensive crisis. Studies of the selegiline patch show that inhibition of more than 80% of gut MAO-A is necessary to impair metabolism of tyramine in the gut.1 Therefore, the 6-mg patch will not significantly impair tyramine degradation in the gut. In phase III testing of the selegiline patch, no hypertensive crises were reported among 2,656 outpatients without dietary restrictions. However, it is still recommended that patients on the 9-mg and 12-mg patches follow a tyramine-free diet.1
Although there are no data available to suggest that higher dosages are more effective, it is recommended that the dose be titrated in 3-mg increments at intervals of at least 2 weeks until the maximum recommended dosage of 12 mg/24 hours is reached.2
Disadvantage of the selegiline patch: Cost
The selegiline patch is expensive: $692.99 for 1 month’s supply at a dose of 6 mg/24 hours and $638.99 for 1 month’s supply at a dose of 9 or 12 mg/24 hours (verified with a national pharmacy chain at the time of this writing). Insurance coverage for the patch varies, and documentation may be required from the physician. Oral MAO inhibitors are much less expensive.
SAFETY, TOLERABILITY OF MAO INHIBITORS
Side effects of oral agents
Orthostatic hypotension, dizziness, drowsiness, insomnia, and nausea are the most frequently reported side effects of oral MAO inhibitors.14,15 These side effects can generally be managed symptomatically by slowing the titration, dividing the doses, changing the time it is taken, or, in the case of orthostatic hypotension, increasing fluid intake.14 Phenelzine has the strongest association with sedation.14
Weight gain, edema, muscle pain, myoclonus, paresthesias, sexual dysfunction, and, rarely, hepatotoxicity are late side effects.15–18 Paresthesias, an infrequent side effect, are often treated with pyridoxine supplementation.15
Transient hypertensive episodes within 2 hours after ingestion of MAO inhibitors, which were independent of dietary or drug interactions, have been reported.19 The hypertensive episodes are usually self-limited but in rare cases result in hypertensive crisis.19–21
Serotonin syndrome has been reported with MAO inhibitor monotherapy in rare cases.22 Serotonin syndrome is characterized by mental status changes, restlessness, myoclonus, hyperreflexia, diaphoresis, or evidence of autonomic hyperactivity.23 The syndrome is potentially fatal and is treated symptomatically by removing the offending drugs and giving intravenous rehydration.23
Side effects of the selegiline patch
The most common adverse events with the selegiline patch include application-site reaction (24% vs 12% with placebo), headache (18% vs 17%), insomnia, diarrhea, dry mouth, and dyspepsia.24,25 Dose-related orthostatic hypotension was reported (occurring in 9.8% vs 6.7% with placebo) and was most likely to occur in elderly patients.25 It is suggested that insomnia may be lessened by removing the patch before bedtime. Also, rotating the patch application sites and prompt topical treatment of irritation may lessen local effects.24
Observe a washout period when switching between serotonergic drugs
Most MAO inhibitors irreversibly inhibit MAO for the life of the enzyme, and thus the physiologic effects of phenelzine, isocarboxazid, and tranylcypromine last for up to 2 to 3 weeks.26 Although the elimination half-life of typical MAO inhibitors is short (1.5–4 hours),27,28 their physiologic effects are long-lasting.14
Switching from a MAO inhibitor to another serotonergic agent. Concomitant use of MAO inhibitors and other serotonergic drugs is associated with the risk of serotonin syndrome. After stopping an MAO inhibitor, a 14-day washout period is recommended before starting another serotonergic agent.29 Patients should continue to be monitored closely after the washout period, as cases of serotonin syndrome have been reported later.30 A 14-day washout period is also recommended when switching between MAO inhibitors, although more rapid switches have been made safely.31
Switching from another serotonergic agent to an oral MAO inhibitor. Similarly, a 14-day washout period (or five half-lives) is necessary after stopping most of the serotonergic agents mentioned above before beginning treatment with an oral MAO inhibitor. Fluoxetine (Prozac) has a longer half-life and therefore requires a longer washout period, ie, 5 weeks.
Switching from another serotonergic agent to the selegiline patch. When switching to the selegiline patch from another serotonergic drug, the washout period is 1 week after stopping most drugs or 5 weeks after stopping fluoxetine. One must wait 2 weeks after stopping the selegiline patch before starting therapy with any of the other serotonergic drugs.
Drugs to avoid due to interactions
In view of the risk of severe of drug-drug interactions, particularly the risk of serotonin syndrome, the following serotonin-enhancing compounds are contraindicated in patients taking a MAO inhibitor: SSRIs, SNRIs, tricyclic antidepressants, other MAO inhibitors, mirtazapine, and St. John’s wort. Other pharmaceuticals to be avoided include bupropion, meperidine, tramadol, methadone, propoxyphene, pentazocine, dextromethorphan, and cyclobenzaprine (Table 1). Also, there have been numerous reports of serotonin syndrome with the use of the broad-spectrum, MAO-based antibiotic linezolid (Zyvox), by itself or in conjunction with other serotonergic agents.32–35
Several studies suggested a hazardous combination of nonsubcutaneous sumatriptans (5-HT1B/1D agonists) and MAO-B inhibitors, while subcutaneous sumatriptan migraine-abortive treatment and MAO-B inhibitors appear to be safe.36,37
Also, amphetamines, cough-and-cold preparations, and weight-reducing preparations that contain vasoconstrictors (eg, pseudoephedrine, phenylephrine, phenylpropanolamine, and ephedrine) should be avoided, as the risk of hypertensive crisis increases with these products.
Patients on MAO inhibitors should wear a medical alert bracelet in case they need to undergo emergency surgery and are unable to verbally communicate their drug history. They should be instructed to alert all health care providers about their MAO inhibitor use.14
Beware of worsening depression
Physicians, patients, and family members should be advised to observe for worsening depression or “suicidality” during the course of treatment with MAO inhibitors, as with all antidepressants.
Diet can be more lenient than in the past
The dietary restrictions classically advised for patients taking oral MAO inhibitors were established to prevent hypertensive crises associated with tyramine ingestion. However, some of these restrictions were unsubstantiated,38 and evidence from more recent studies suggests that they are unnecessarily strict39 and may lead to resistance by the physician, the patient, or both to using this potentially beneficial therapy.14 There is also a risk that patients will inadvertently discover that a food that was in the “restricted” list caused them no harm upon ingestion and thus will become cavalier about dietary adherence.39
To prevent dietary noncompliance, physicians should conduct ongoing diet surveys and encourage adherence to evidence-based dietary recommendations.40
The FDA and drug-package inserts for oral MAO inhibitors continue to recommend stringent dietary restrictions, including no aged cheeses or meats, soy sauce, soy beans, soy paste, miso soup, Italian green beans (fava beans), snow peas, broad bean pods, sauerkraut, kimchee, concentrated yeast extracts (Marmite), wine, beer (including alcohol-free beer), and many other foods. However, several studies have measured the tyramine content of food and determined that less than 6 mg per serving is generally safe.39,41 The results of these investigations have led to more lenient dietary guidelines.39
Absolute dietary restrictions include39:
Aged cheeses and meats
Banana peels
Broad bean (fava) pods
Spoiled meats
Marmite
Sauerkraut
Soybean products
Draft beers.
Among the many foods determined to be unnecessarily restricted are avocados; bananas; beef or chicken bouillon; chocolate; fresh and mild cheeses, eg, ricotta, cottage cheese, cream cheese, processed cheese slices; fresh meat, poultry, or fish; meat gravy (fresh); monosodium glutamate; peanuts; properly stored pickled or smoked fish (eg, herring); raspberries; and yeast extracts (except Marmite).39
Dietary restrictions should continue for 2 weeks after stopping an MAO inhibitor.
Dietary restrictions for the selegiline patch
Tyramine-containing foods pose less risk with the selegiline patch than with oral MAO inhibitors, and studies42 show that the 6-mg patch does not necessitate dietary restrictions. The accumulating data suggest that the risk of a tyramine-induced event is extremely low with the patch even in doses above 6 mg. But in the meantime, the recommendations for the 9-mg and 12-mg patches remain the same as for the classic oral MAO inhibitors, and tyramine-containing food should be restricted.
EFFICACY OF MAO INHIBITORS IN CLINICAL PRACTICE
Data from numerous studies suggest MAO inhibitors are effective in managing major depressive disorder, and specifically atypical depression,43–48 treatment-resistant major depressive disorder,49,50 and bipolar depression.51,52 Guidelines from the American Psychiatric Association and the British Association for Psychopharmacology suggest that MAO inhibitors be recommended for treatment of major depressive disorder in patients with atypical features and when other antidepressants have failed.53
MAO inhibitors have also been used in the treatment of Parkinson disease, bulimia, anxiety disorders, anorexia nervosa, and body dysmorphic disorder.54
Major depressive disorder
In controlled trials in outpatients with depression who were treated with therapeutic doses of MAO inhibitors, the response rate was 50% to 70%.55 When tranylcypromine was used in severely depressed inpatients, its efficacy was comparable to that of electroconvulsive therapy, imipramine, and amitriptyline.56 Thase et al,57 in a meta-analysis, found that the MAO inhibitors tranylcypromine, phenelzine, and isocarboxazid were equally effective in treating depression.
Atypical depression
Atypical depression is one of the most common subtypes of major depressive disorder. Diagnostic criteria for major depressive disorder with atypical features include mood reactivity and two of the following: weight gain or hyperphagia, hypersomnolence, leaden paralysis, or an enduring pattern of rejection sensitivity.58 An estimated 30% of outpatients with unipolar depression meet these criteria.59
Multiple randomized controlled trials showed that MAO inhibitors were superior to tricyclic antidepressants in treating atypical depression. One study, involving more than 400 patients, determined that atypical depression responded better to phenelzine than to imipramine.43 Another study evaluating 153 critically depressed patients showed significantly greater response with phenelzine than with imipramine or placebo.49 Furthermore, in another double-blind controlled crossover study, 89 mood-reactive, nonmelancholic, chronically depressed outpatients were found to have a striking response to phenelzine after being unresponsive to imipramine.50 Another report48 indicated that in a double-blind, randomized, placebo-controlled trial among 119 patients with atypical depression treated for 6 weeks, the overall response rates were 78% with phenelzine, 50% with imipramine, and 28% with placebo.
A recent meta-analysis of treatment trials in atypical depression revealed a large mean effect size of 0.45 for the superiority of MAO inhibitors over placebo and a medium mean effect size of 0.27 for the superiority of MAO inhibitors over tricyclic antidepressants.60 Additionally, in a randomized, double-blind placebo-controlled trial, patients with comorbid atypical depression and bulimia showed significant improvement in both bulimic and depressive symptoms when given phenelzine vs imipramine or placebo.61
The current data comparing SSRIs and MAO inhibitors in the treatment of atypical depression are limited. The above-mentioned meta-analysis of three such trials (when moclobemide was used in two out of three trials) revealed no significant difference in efficacy.60 However, the authors themselves warned about the limitations of the studies, including low power to detect differences. Parker and Crawford59 compared self-rating of effectiveness of the various previous treatments in patients with depression with and without atypical features using an online survey. The analysis of the responses of 1,934 patients showed no overall difference in treatment response to both drug and non-drug therapies between respondents with and without atypical features, except with SSRIs. The “atypical” group had a significantly lower mean effectiveness score for SSRIs overall, and a lower mean effectiveness rating for two of six SSRIs examined. The authors speculated that even though there was no differential outcome detected in individuals with atypical depression treated with MAO inhibitors, this negative finding may simply have reflected the low prevalence of sample respondents who received MAO inhibitors (which was 4% in the “atypical depression” group of 338).59
Treatment-resistant depression
The ultimate goal in treating major depressive disorder is to achieve complete remission. If complete remission is not achieved, the risk of relapse is high,62,63 as is the risk of more severe future depressive episodes63 and death from any cause.64 Therefore, the ability of clinicians to make appropriate and evidence-based changes in treatment strategy is of high importance.
The use of MAO inhibitors as a third-line or fourth-line choice for treatment-resistant depression is supported by a number of studies.49,50,65–67 MAO inhibitors appear to be especially effective in the subgroup of patients who have treatment-resistant depression with atypical or anergic bipolar features.
Bipolar depression
Anergic bipolar depression is defined as a condition associated with fatigue, psychomotor retardation, and at least one reversed neurovegetative symptom in a patient with bipolar disorder meeting the criteria for a major depressive episode. According to several trials,51,52,68 MAO inhibitors may be more effective than a tricyclic antidepressant in the treatment of anergic bipolar depression. However, more studies are required to determine the role of antidepressants in general and MAO inhibitors in particular in the management of bipolar depression.
Efficacy of the selegiline patch
The efficacy of the selegiline patch in the treatment of depression was examined in four double-blind placebo-controlled studies.69–72 There were three short-term studies (a 6-week study of 177 patients,69 an 8-week study of 265 patients,72 and an 8-week study of 289 patients70) and a fixed-dose 1-year relapse prevention study of 322 patients.71 The inclusion criterion for the short-term studies was diagnosis of a first or a recurrent episode of major depressive disorder in patients with a Hamilton Depression Rating Scale (HDRS) score higher than 20. The HDRS score was used to assess improvement in depressive symptoms. In all studies, patients on active patch had significant improvement in depressive symptoms on the HDRS compared with placebo. In the relapse prevention study,71 patients with major depressive disorder that responded to transdermal selegiline 6 mg within the first 10 weeks were stratified either to continue receiving the selegiline 6-mg patch or to receive placebo. Those continually receiving selegiline experienced a significantly longer time to relapse. At 12 months, the relapse rate was 16.8% with the selegiline patch vs 30.7% with placebo. The patch was reported to be well tolerated, with the most common side effect being application site reaction. The adherence to the treatment was high—84.2% in the active-patch group and 89.6% in the placebo group.71
DO MAO INHIBITORS HAVE A PLACE IN PRIMARY CARE?
MAO inhibitors have secured their place in the history of psychiatry as the first antidepressants. Overall, MAO inhibitors remain underused. However, with the introduction of new and selective MAO inhibitors including the selegiline patch, and with data suggesting efficacy in the management of certain subtypes of depression, we expect that interest in this class of drugs will grow among psychiatrists. Based on the current guidelines for MAO inhibitors to be used as a third- or fourth-line treatment, as well as on research data, it is premature to recommend their more extensive use in a primary care setting. Whether this will change in the future depends on both the research advances and new, safer formulations of MAO inhibitors.
Compton WM, Conway KP, Stinson FS, Grant BF. Changes in the prevalence of major depression and comorbid substance use disorders in the United States between 1991–1992 and 2001–2002. Am J Psychiatry2006; 163:2141–2147.
Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry2005; 62:593–602.
Trivedi MH, Rush AJ, Wisniewski SR, et al; STAR*D Study Team. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry2006; 163:28–40.
Balon R, Mufti R, Arfken CL. A survey of prescribing practices for monoamine oxidase inhibitors. Psychiatr Serv1999; 50:945–947.
Clary C, Mandos LA, Schweizer E. Results of a brief survey on the prescribing practices for monoamine oxidase inhibitor antidepressants. J Clin Psychiatry1990; 51:226–231.
Shulman KI, Fischer HD, Herrmann N, Huo CY, Anderson GM, Rochon PA. Current prescription patterns and safety profile of irreversible monoamine oxidase inhibitors: a population-based cohort study of older adults. J Clin Psychiatry2009; 70:1681–1686.
Horwitz D, Lovenberg W, Engelman K, Sjoerdsma A. Monoamine oxidase inhibitors, tyramine, and cheese. JAMA1964; 188:1108–1110.
Asatoor AM, Levi AJ, Milne MD. Tranylcypromine and cheese. Lancet1963; 2:733–734.
Gordon MN, Muller CD, Sherman KA, Morgan DG, Azzaro AJ, Wecker L. Oral versus transdermal selegiline: antidepressant-like activity in rats. Pharmacol Biochem Behav1999; 63:501–506.
Lotufu-Neto F, Trivedi M, Thase ME. Meta-analysis of the reversible inhibitors of monoamine oxidase type A moclobemide and brofaromine for the treatment of depression. Neuropsychopharmacology1999; 20:226–247.
Fiedorowicz JG, Swartz KL. The role of monoamine oxidase inhibitors in current psychiatric practice. J Psychiatr Pract2004; 10:239–248.
Evans DL, Davidson J, Raft D. Early and late side effects of phenelzine. J Clin Psychopharmacol1982; 2:208–210.
Fava M. Weight gain and antidepressants. J Clin Psychiatry2000; 61(suppl 11):37–41.
Rabkin J, Quitkin F, Harrison W, Tricamo E, McGrath P. Adverse reactions to monoamine oxidase inhibitors. Part I. A comparative study. J Clin Psychopharmacol1984; 4:270–278.
Gomez-Gil E, Salmeron JM, Mas A. Phenelzine-induced fulminant hepatic failure. Ann Intern Med1996; 124:692–693.
Lavin MR, Mendelwitz A, Kronig MH. Spontaneous hypertensive reactions with monoamine oxidase inhibitors. Biol Psychiatry1993; 34:146–151.
Fisher P. Serotonin syndrome in the elderly after antidepressive monotherapy. J Clin Psychopharmacol1995; 15:440–442.
Sternback H. The serotonin syndrome. Am J Psychiatry1991; 148:705–713.
Thase M. Novel transdermal delivery formulation of the monoamine oxidase inhibitor selegiline nearing release for treatment of depression. J Clin Psychiatry2006; 67:671–672.
Lee KC, Chen JJ. Transdermal selegiline for the treatment of major depressive disorder. Neuropsychiatr Dis Treat2007; 3:527–537.
Cooper AJ. Tyramine and irreversible monoamine oxidase inhibitors in clinical practice. Br J Psychiatry Suppl1989; Oct(6):38–45.
Mallinger AG, Smith E. Pharmacokinetics of monoamine oxidase inhibitors. Psychopharmacol Bull1991; 27:493–502.
Fulton B, Benfield P. Moclobemide. An update of its pharmacological properties and therapeutic use. Drugs1996; 52:450–474.
Marangell LB. Switching antidepressants for treatment-resistant major depression. J Clin Psychiatry2001; 62(suppl 18):12–17.
Gitlin MJ. Venlafaxine, monoamine oxidase inhibitors, and the serotonin syndrome. J Clin Psychopharmacol1997; 17:66–67.
Szuba MP, Hornig-Rohan M, Amsterdam JD. Rapid conversion from one monoamine oxidase inhibitor to another. J Clin Psychiatry1997; 58:307–310.
Lorenz RA, Vandenberg AM, Canepa EA. Serotonergic antidepressants and linezolid: a retrospective chart review and presentation of cases. Int J Psychiatry Med2008; 38:81–90.
Miller DG, Lovell EO. Antibiotic-induced serotonin syndrome. J Emerg Med2008, May1(Epub ahead of print).
Das PK, Wakentin DI, Hewko R, Forrest DL. Serotonin syndrome after concomitant treatment with linezolid and meperidine. Clin Infect Dis2008; 46:264–265.
Packer S, Berman SA. Serotonin syndrome precipitated by the monoamine oxidase inhibitor linezolid. Am J Psychiatry2007; 164:346–347.
Diamond S. The use of sumatriptan in patients on monoamine oxidase inhibitors. Neurology1995; 45:1039–1040.
Fox AW. Subcutaneous sumatriptan pharmacokinetics: delimiting the monoamine oxidase inhibitor effect. Headache2010; 50:249–255.
Gardner DM, Shulman KI, Walker SE, Tailor SA. The making of a user friendly MAOI diet. J Clin Psychiatry1996; 57:99–104.
Sweet RA, Brown EJ, Heimberg RG, et al. Monoamine oxidase inhibitor dietary restrictions: what are we asking patients to give up?J Clin Psychiatry1995; 56:196–201.
Shulman KI, Walker SE. Refining the MAOI diet: tyramine content of pizzas and soy products. J Clin Psychiatry1999; 60:191–193.
Azzaro AJ, Vandenberg CM, Blob LF, et al. Tyramine pressor sensitivity during treatment with the selegiline transdermal system 6 mg/24 h in healthy subjects. J Clin Pharmacol2006; 46:933–944.
Quitkin FM, Stewart JW, McGrath PJ, et al. Columbia atypical depression. A subgroup of depressives with better response to MAOI than to tricyclic antidepressants or placebo. Br J Psychiatry Suppl1993; Sep(21):30–34.
Davidson J, Pelton S. Forms of atypical depression and their response to antidepressant drugs. Psychiatry Res1986; 17:87–95.
Liebowitz MR, Quitkin FM, Stewart JW, et al. Antidepressant specificity in atypical depression. Arch Gen Psychiatry1988; 45:129–137.
Rapaport MH, Thase ME. Translating the evidence on atypical depression into clinical practice. J Clin Psychiatry2007; 68:e11.
Liebowitz MR. Depression with anxiety and atypical depression. J Clin Psychiatry1993; 54(suppl):10–14.
Stewart JW, McGrath PJ, Quitkin FM, et al. Chronic depression: response to placebo, imipramine, and phenelzine. J Clin Psychopharmacol1993; 13:391–396.
McGrath PJ, Stewart JW, Nunes EV, et al. A double-blind crossover trial of imipramine and phenelzine for outpatients with treatment-refractory depression. Am J Psychiatry1993; 150:118–123.
Zarate CA, Tohen M, Baraibar G, Kando JC, Mirin J. Prescribing trends of antidepressants in bipolar depression. J Clin Psychiatry1995; 56:260–264.
Mallinger AG, Frank E, Thase ME, Barwell MM, Diazgranados N, Luckenbaugh DA, Kupfer DJ. Revisiting the effectiveness of standard antidepressants in bipolar disorder: are monoamine oxidase inhibitors superior?Psychopharmacol Bull2009; 42:64–74.
Anderson IM, Nutt DJ, Deakin JF. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 1993 British Association for Psychopharmacology guidelines. British Association for Psychopharmacology. J Psychopharmacol2000; 14:3–20.
Liebowitz MR, Hollander E, Schneier F, et al. Reversible and irreversible monoamine oxidase inhibitors in other psychiatric disorders. Acta Psychiatr Scand Suppl1990; 360:29–34.
Davidson JR, Giller EL, Zisook S, Overall JE. An efficacy study of isocarboxazid and placebo in depression, and its relationship to depressive nosology. Arch Gen Psychiatry1988; 45:120–127.
Razani J, White KL, White J, et al. The safety and efficacy of combined amitriptyline and tranylcypromine antidepressant treatment: a controlled trial. Arch Gen Psychiatry1983; 40:657–661.
Thase ME, Triverdi MH, Rush AJ. MAOIs in the contemporary treatment of depression. Neuropsychopharmacology1995; 12:185–219.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000.
Parker G, Crawford J. Atypical depression: retrospective self-reporting of treatment effectiveness. Acta Psychiatr Scand2009; 120:213–221.
Henkel V, Mergl R, Algaier AK, Kohnen R, Moller HJ, Hergerl U. Treatment of depression with atypical features: a meta-analytic approach. Psychiatry Res2006; 141:89–101.
Rothschild R, Quitkin HM, Quitkin FM, et al. A double-blind placebo-controlled comparison of phenelzine and imipramine in the treatment of bulimia in atypical depressives. Int J Eat Disord1994; 15:1–9.
Judd LL, Paulus MJ, Schettler PJ, et al. Does incomplete recovery from first life-time major depressive episode herald a chronic course of illness?Am J Psychiatry2000; 157:1501–1504.
Murphy JM, Monson RR, Olivier DC, Sobol AM, Leighton AH. Affective disorders and mortality: a general population study. Arch Gen Psychiatry1987; 44:473–480.
Thase ME, Frank E, Mallinger AG, Hamer T, Kupfer DJ. Treatment of imipramine-resistant recurrent depression, III: efficacy of monoamine oxidase inhibitors. J Clin Psychiatry1992; 53:5–11.
Thase ME, Mallinger AG, McKnight D, Himmelhoch JM. Treatment of imipramine-resistant recurrent depression, IV: a double blind crossover study of tranylcypromine for anergic bipolar depression. Am J Psychiatry1992; 149:195–198.
Quitkin FM, McGrath PJ, Stewart JW, et al. Atypical depression, panic attacks, and response to imipramine and phenelzine: a replication. Arch Gen Psychiatry1990; 47:935–941.
Himmelhoch JM, Thase ME, Mallinger AG, Houck P. Tranylcypromine versus imipramine in anergic bipolar depression. Am J Psychiatry1991; 148:910–916.
Bodkin JA, Amsterdam JD. Transdermal selegiline in major depression: a double-blind, placebo-controlled, parallel-group study in outpatients. Am J Psychiatry2002; 159:1869–1875.
Amsterdam JD. A double-blind, placebo-controlled trial of the safety and efficacy of selegiline transdermal system without dietary restrictions in patients with major depressive disorder. J Clin Psychiatry2003; 64:208–214.
Amsterdam JD, Bodkin JA. Selegiline transdermal system in the prevention of relapse of major depressive disorder: a 52-week, double-blind, placebo-substitution, parallel-group clinical trial. J Clin Psychopharmacol2006; 26:579–586.
Feiger AD, Rickels K, Rynn MA, et al. Selegiline transdermal system for the treatment of major depressive disorder: an 8-week, double-blind, placebo-controlled, flexible-dose titration trial. J Clin Psychiatry2006; 67:1354–1361.
Compton WM, Conway KP, Stinson FS, Grant BF. Changes in the prevalence of major depression and comorbid substance use disorders in the United States between 1991–1992 and 2001–2002. Am J Psychiatry2006; 163:2141–2147.
Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry2005; 62:593–602.
Trivedi MH, Rush AJ, Wisniewski SR, et al; STAR*D Study Team. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry2006; 163:28–40.
Balon R, Mufti R, Arfken CL. A survey of prescribing practices for monoamine oxidase inhibitors. Psychiatr Serv1999; 50:945–947.
Clary C, Mandos LA, Schweizer E. Results of a brief survey on the prescribing practices for monoamine oxidase inhibitor antidepressants. J Clin Psychiatry1990; 51:226–231.
Shulman KI, Fischer HD, Herrmann N, Huo CY, Anderson GM, Rochon PA. Current prescription patterns and safety profile of irreversible monoamine oxidase inhibitors: a population-based cohort study of older adults. J Clin Psychiatry2009; 70:1681–1686.
Horwitz D, Lovenberg W, Engelman K, Sjoerdsma A. Monoamine oxidase inhibitors, tyramine, and cheese. JAMA1964; 188:1108–1110.
Asatoor AM, Levi AJ, Milne MD. Tranylcypromine and cheese. Lancet1963; 2:733–734.
Gordon MN, Muller CD, Sherman KA, Morgan DG, Azzaro AJ, Wecker L. Oral versus transdermal selegiline: antidepressant-like activity in rats. Pharmacol Biochem Behav1999; 63:501–506.
Lotufu-Neto F, Trivedi M, Thase ME. Meta-analysis of the reversible inhibitors of monoamine oxidase type A moclobemide and brofaromine for the treatment of depression. Neuropsychopharmacology1999; 20:226–247.
Fiedorowicz JG, Swartz KL. The role of monoamine oxidase inhibitors in current psychiatric practice. J Psychiatr Pract2004; 10:239–248.
Evans DL, Davidson J, Raft D. Early and late side effects of phenelzine. J Clin Psychopharmacol1982; 2:208–210.
Fava M. Weight gain and antidepressants. J Clin Psychiatry2000; 61(suppl 11):37–41.
Rabkin J, Quitkin F, Harrison W, Tricamo E, McGrath P. Adverse reactions to monoamine oxidase inhibitors. Part I. A comparative study. J Clin Psychopharmacol1984; 4:270–278.
Gomez-Gil E, Salmeron JM, Mas A. Phenelzine-induced fulminant hepatic failure. Ann Intern Med1996; 124:692–693.
Lavin MR, Mendelwitz A, Kronig MH. Spontaneous hypertensive reactions with monoamine oxidase inhibitors. Biol Psychiatry1993; 34:146–151.
Fisher P. Serotonin syndrome in the elderly after antidepressive monotherapy. J Clin Psychopharmacol1995; 15:440–442.
Sternback H. The serotonin syndrome. Am J Psychiatry1991; 148:705–713.
Thase M. Novel transdermal delivery formulation of the monoamine oxidase inhibitor selegiline nearing release for treatment of depression. J Clin Psychiatry2006; 67:671–672.
Lee KC, Chen JJ. Transdermal selegiline for the treatment of major depressive disorder. Neuropsychiatr Dis Treat2007; 3:527–537.
Cooper AJ. Tyramine and irreversible monoamine oxidase inhibitors in clinical practice. Br J Psychiatry Suppl1989; Oct(6):38–45.
Mallinger AG, Smith E. Pharmacokinetics of monoamine oxidase inhibitors. Psychopharmacol Bull1991; 27:493–502.
Fulton B, Benfield P. Moclobemide. An update of its pharmacological properties and therapeutic use. Drugs1996; 52:450–474.
Marangell LB. Switching antidepressants for treatment-resistant major depression. J Clin Psychiatry2001; 62(suppl 18):12–17.
Gitlin MJ. Venlafaxine, monoamine oxidase inhibitors, and the serotonin syndrome. J Clin Psychopharmacol1997; 17:66–67.
Szuba MP, Hornig-Rohan M, Amsterdam JD. Rapid conversion from one monoamine oxidase inhibitor to another. J Clin Psychiatry1997; 58:307–310.
Lorenz RA, Vandenberg AM, Canepa EA. Serotonergic antidepressants and linezolid: a retrospective chart review and presentation of cases. Int J Psychiatry Med2008; 38:81–90.
Miller DG, Lovell EO. Antibiotic-induced serotonin syndrome. J Emerg Med2008, May1(Epub ahead of print).
Das PK, Wakentin DI, Hewko R, Forrest DL. Serotonin syndrome after concomitant treatment with linezolid and meperidine. Clin Infect Dis2008; 46:264–265.
Packer S, Berman SA. Serotonin syndrome precipitated by the monoamine oxidase inhibitor linezolid. Am J Psychiatry2007; 164:346–347.
Diamond S. The use of sumatriptan in patients on monoamine oxidase inhibitors. Neurology1995; 45:1039–1040.
Fox AW. Subcutaneous sumatriptan pharmacokinetics: delimiting the monoamine oxidase inhibitor effect. Headache2010; 50:249–255.
Gardner DM, Shulman KI, Walker SE, Tailor SA. The making of a user friendly MAOI diet. J Clin Psychiatry1996; 57:99–104.
Sweet RA, Brown EJ, Heimberg RG, et al. Monoamine oxidase inhibitor dietary restrictions: what are we asking patients to give up?J Clin Psychiatry1995; 56:196–201.
Shulman KI, Walker SE. Refining the MAOI diet: tyramine content of pizzas and soy products. J Clin Psychiatry1999; 60:191–193.
Azzaro AJ, Vandenberg CM, Blob LF, et al. Tyramine pressor sensitivity during treatment with the selegiline transdermal system 6 mg/24 h in healthy subjects. J Clin Pharmacol2006; 46:933–944.
Quitkin FM, Stewart JW, McGrath PJ, et al. Columbia atypical depression. A subgroup of depressives with better response to MAOI than to tricyclic antidepressants or placebo. Br J Psychiatry Suppl1993; Sep(21):30–34.
Davidson J, Pelton S. Forms of atypical depression and their response to antidepressant drugs. Psychiatry Res1986; 17:87–95.
Liebowitz MR, Quitkin FM, Stewart JW, et al. Antidepressant specificity in atypical depression. Arch Gen Psychiatry1988; 45:129–137.
Rapaport MH, Thase ME. Translating the evidence on atypical depression into clinical practice. J Clin Psychiatry2007; 68:e11.
Liebowitz MR. Depression with anxiety and atypical depression. J Clin Psychiatry1993; 54(suppl):10–14.
Stewart JW, McGrath PJ, Quitkin FM, et al. Chronic depression: response to placebo, imipramine, and phenelzine. J Clin Psychopharmacol1993; 13:391–396.
McGrath PJ, Stewart JW, Nunes EV, et al. A double-blind crossover trial of imipramine and phenelzine for outpatients with treatment-refractory depression. Am J Psychiatry1993; 150:118–123.
Zarate CA, Tohen M, Baraibar G, Kando JC, Mirin J. Prescribing trends of antidepressants in bipolar depression. J Clin Psychiatry1995; 56:260–264.
Mallinger AG, Frank E, Thase ME, Barwell MM, Diazgranados N, Luckenbaugh DA, Kupfer DJ. Revisiting the effectiveness of standard antidepressants in bipolar disorder: are monoamine oxidase inhibitors superior?Psychopharmacol Bull2009; 42:64–74.
Anderson IM, Nutt DJ, Deakin JF. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 1993 British Association for Psychopharmacology guidelines. British Association for Psychopharmacology. J Psychopharmacol2000; 14:3–20.
Liebowitz MR, Hollander E, Schneier F, et al. Reversible and irreversible monoamine oxidase inhibitors in other psychiatric disorders. Acta Psychiatr Scand Suppl1990; 360:29–34.
Davidson JR, Giller EL, Zisook S, Overall JE. An efficacy study of isocarboxazid and placebo in depression, and its relationship to depressive nosology. Arch Gen Psychiatry1988; 45:120–127.
Razani J, White KL, White J, et al. The safety and efficacy of combined amitriptyline and tranylcypromine antidepressant treatment: a controlled trial. Arch Gen Psychiatry1983; 40:657–661.
Thase ME, Triverdi MH, Rush AJ. MAOIs in the contemporary treatment of depression. Neuropsychopharmacology1995; 12:185–219.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000.
Parker G, Crawford J. Atypical depression: retrospective self-reporting of treatment effectiveness. Acta Psychiatr Scand2009; 120:213–221.
Henkel V, Mergl R, Algaier AK, Kohnen R, Moller HJ, Hergerl U. Treatment of depression with atypical features: a meta-analytic approach. Psychiatry Res2006; 141:89–101.
Rothschild R, Quitkin HM, Quitkin FM, et al. A double-blind placebo-controlled comparison of phenelzine and imipramine in the treatment of bulimia in atypical depressives. Int J Eat Disord1994; 15:1–9.
Judd LL, Paulus MJ, Schettler PJ, et al. Does incomplete recovery from first life-time major depressive episode herald a chronic course of illness?Am J Psychiatry2000; 157:1501–1504.
Murphy JM, Monson RR, Olivier DC, Sobol AM, Leighton AH. Affective disorders and mortality: a general population study. Arch Gen Psychiatry1987; 44:473–480.
Thase ME, Frank E, Mallinger AG, Hamer T, Kupfer DJ. Treatment of imipramine-resistant recurrent depression, III: efficacy of monoamine oxidase inhibitors. J Clin Psychiatry1992; 53:5–11.
Thase ME, Mallinger AG, McKnight D, Himmelhoch JM. Treatment of imipramine-resistant recurrent depression, IV: a double blind crossover study of tranylcypromine for anergic bipolar depression. Am J Psychiatry1992; 149:195–198.
Quitkin FM, McGrath PJ, Stewart JW, et al. Atypical depression, panic attacks, and response to imipramine and phenelzine: a replication. Arch Gen Psychiatry1990; 47:935–941.
Himmelhoch JM, Thase ME, Mallinger AG, Houck P. Tranylcypromine versus imipramine in anergic bipolar depression. Am J Psychiatry1991; 148:910–916.
Bodkin JA, Amsterdam JD. Transdermal selegiline in major depression: a double-blind, placebo-controlled, parallel-group study in outpatients. Am J Psychiatry2002; 159:1869–1875.
Amsterdam JD. A double-blind, placebo-controlled trial of the safety and efficacy of selegiline transdermal system without dietary restrictions in patients with major depressive disorder. J Clin Psychiatry2003; 64:208–214.
Amsterdam JD, Bodkin JA. Selegiline transdermal system in the prevention of relapse of major depressive disorder: a 52-week, double-blind, placebo-substitution, parallel-group clinical trial. J Clin Psychopharmacol2006; 26:579–586.
Feiger AD, Rickels K, Rynn MA, et al. Selegiline transdermal system for the treatment of major depressive disorder: an 8-week, double-blind, placebo-controlled, flexible-dose titration trial. J Clin Psychiatry2006; 67:1354–1361.
Data from multiple studies suggest the efficacy of MAO inhibitors in the management of major depressive disorder and, in particular, major depressive disorder with atypical features and in treatment-resistant depression.
When using oral MAO inhibitors, patients must follow a low-tyramine diet to avoid the “cheese reaction,” ie, tyramine-induced hypertensive crisis. However, recent studies suggest that traditional dietary advice may be unnecessarily restrictive.
The selegiline transdermal system (Emsam) is the first approved transdermal patch for treatment of major depression. Unlike oral MAO inhibitors, the patch can be used without the dietary restrictions at its lowest effective dose of 6 mg/24 hours. Because of its transdermal delivery, it has the advantage of not inhibiting the metabolism of dietary tyramine by MAO subtype A in the gut, while providing antidepressant effect in the brain. The patch may be a promising alternative to existing strategies for the management of major depressive disorder.
For patients with carotid artery stenosis, percutaneous intervention with stenting is as good as surgery (carotid endarterectomy). This was the major finding of the recently completed Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)1—with some qualifications.
CREST is the latest in a series of clinical trials of treatment of carotid stenosis that have generated reams of numbers and much debate. The topic of surgery vs percutaneous intervention is a moving target, as techniques evolve and improve. We believe the CREST results are valuable and should help inform decisions about treatment in the “real world.”
In this article, we offer a critical review of CREST, with a careful evaluation of its methods, results, and conclusions.
AN EVOLVING FIELD
Despite improvements in diagnosis and management, stroke remains one of the leading causes of morbidity and death in the United States, with an annual incidence of 780,000 cases and 270,000 deaths.2,3
Figure 1. Carotid endarterectomy has long been an established treatment in selected patients with symptomatic carotid artery stenosis of 50% or greater or asymptomatic stenosis of 60% or greater. However, percutaneous carotid artery angioplasty with stenting and placement of an embolic protection device is gaining ground as a reasonable, safe, less invasive alternative.From 10% to 30% of ischemic strokes are due to emboli from the carotid arteries.4–6 Carotid endarterectomy is an established treatment in selected patients with symptomatic carotid stenosis of 50% or greater or asymptomatic stenosis of 60% or greater.7,8 However, percutaneous techniques such as carotid artery angioplasty with stenting have improved, making them a viable, less invasive option (Figure 1).
Randomized trials of stenting have had mixed results, leading the Centers for Medicare and Medicaid Services (CMS) to adopt strict reimbursement policies. Currently, CMS reimburses for stenting only in symptomatic cases with at least 50% carotid artery stenosis. It also reimburses for stenting in asymptomatic cases in patients at high risk with 80% or greater stenosis, but only if the patients are enrolled in ongoing clinical trials or registries.
CREST compared stenting with endarterectomy and provided important insights into each approach.1
BEFORE CREST
Endarterectomy is superior to medical therapy for symptomatic stenosis
First described in 1953, carotid endarterectomy became the most widely used invasive treatment for significant carotid stenosis.9 Several studies have described patient subsets that benefit from this procedure.
NASCET (the North American Symptomatic Carotid Endarterectomy Trial)10 assigned 2,226 patients with symptomatic stenosis (transient ischemic attack or stroke within the past 180 days) to medical management or endarterectomy.
Surgery was associated with a 65% lower rate of ipsilateral cerebral events in patients with 70% or greater stenosis.10 Surgery was also found to be superior in patients with moderate disease (50% to 69% stenosis), but the difference only approached statistical significance. In patients with stenosis of less than 50%, the outcomes were similar with endarterectomy and medical management.11
ECST (the European Carotid Surgery Trial)12 included a similar population of 3,024 patients. Those with high-grade disease (stenosis ≥ 80%) had significantly better outcomes with endarterectomy, but in those with stenosis less than 70%, surgery was no better than drug therapy.
Comment. NASCET and ECST taught us that endarterectomy is clearly superior to medical therapy in patients with severe symptomatic carotid disease. However, both trials excluded patients at high surgical risk, eg, those with severe coronary artery disease, kidney disease, or heart failure. Additionally, medical management was not aggressive by today’s standards in terms of control of blood pressure and hyperlipidemia, and this could have skewed the results in favor of carotid endarterectomy.
The case for carotid endarterectomy for asymptomatic stenosis
Endarterectomy has also been compared with drug therapy for asymp tomatic carotid artery stenosis in several trials.13–15
ACAS (the Asymptomatic Carotid Atherosclerosis Study)15 assigned 1,662 patients who had no symptoms and had at least 60% carotid artery stenosis to endarterectomy or to medical management, and found a relative risk reduction of 53% in favor of surgery.15
The Veterans Affairs Cooperative Study Group14 corroborated these results in 444 patients with asymptomatic stenosis of greater than 50%. Endarterectomy was associated with a 61% lower risk of transient ischemic attack, transient monocular blindness, or stroke compared with medical therapy. However, there was no statistically significant difference in rates of stroke or death at 30 days.14
ACST (the Asymptomatic Carotid Surgery Trial),13 the largest study to compare carotid endarterectomy with drug therapy for asymptomatic stenosis, randomized 3,120 patients to surgery or drug therapy. The net 5-year risk of stroke was 6.4% with endarterectomy vs 11.8% with drug therapy (P < .0001). The rate of fatal stroke was also lower with endarterectomy: 2.1% vs 4.2% (P = .006).13
Comment. The results of these and other studies of endarterectomy vs medical therapy may not be applicable to current practice, since medical therapy has evolved and the risks with current drug therapy are likely much lower than seen in these trials, some of which began 2 decades ago. Another problem with interpreting these trials is that they excluded surgically “high-risk” patients, which limits the generalizability of the findings to this particular patient population.
The American Heart Association and the American Stroke Association have, on the basis of these trials, recommended carotid endarterectomy in patients with7,8,16:
Ipsilateral, symptomatic carotid artery stenosis of 70% to 99% (class I, level of evidence A)
Symptomatic stenosis of 50% to 69%, depending on patient-specific factors such as age, sex, and comorbidities
High-grade asymptomatic carotid stenosis, if the patients are carefully selected and the surgery is performed by surgeons with procedural morbidity and mortality rates of less than 3% (class I, level of evidence A).
In all cases, treatment should be individualized according to the patient’s comorbid conditions and preferences, with a thorough discussion of risks and benefits (Table 1).7,8,16
The case for percutaneous intervention
While carotid endarterectomy is proven to be more efficacious than medical management in certain patient subsets, studies favoring surgery over medical therapy have been criticized because they excluded patients with significant comorbidities. In addition, surgery has been associated with significant cardiovascular events, wound complications, and cranial nerve damage, and it requires general anesthesia in most cases.12,17–19 These and other factors spurred the development of less invasive, percutaneous approaches for patients with substantial comorbidities.
So far, several trials have investigated carotid angioplasty with or without stents and with or without devices to capture distal emboli. This interest set the stage for CREST.20,21
Initial attempts at angioplasty without distal protection were not very successful. A meta-analysis of nonrandomized trials that included 714 patients from the initial 13 studies of angioplasty (with or without stenting) and 6,970 patients from 20 studies of carotid endarterectomy found angioplasty to be possibly associated with higher rates of stroke within 30 days of the procedure.20
With improvements in technology, routine use of embolic protection devices, more experience, and better selection of patients, the outcome of carotid stenting has improved. In fact, a meta-analysis comparing stenting without an embolic protection device (26 trials with 2,357 patients) vs stenting with an embolic protection device (11 trials with 839 patients) showed that embolic protection led to significantly better outcomes with fewer strokes—outcomes arguably similar to those of carotid endarterectomy.21
SAPPHIRE (the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy trial)22 was the only completed US trial until CREST that compared carotid artery stenting with distal protection against surgery. It included 334 high-risk patients with either symptomatic stenosis of 50% or greater or asymptomatic stenosis of 80% or greater.
The results suggested that the outcomes with stenting with embolic protection were in fact similar to those of endarterectomy, with possibly fewer complications.23 The benefit persisted up to 2 years.22
The US Food and Drug Administration (FDA), on the basis of these data, approved the use of stenting with distal protection for high-risk patients, and the CMS reimburses for symptomatic stenosis of 50% or greater and for asymptomatic stenosis of 80% or greater as long as the patient is enrolled in a registry.
SPACE (the Stent-Protected Angioplasty Versus Carotid Endarterectomy in Symptomatic Patients trial),24 conducted in Germany, included 1,214 patients with symptomatic stenosis of at least 50%. Results were similar in terms of the combined primary end point of stroke or death at 30 days. However, the results were not similar enough to prove that stenting is not inferior to surgery, according to preset study criteria.
EVA-3S (the Endarterectomy Versus Stenting in Patients With Symptomatic Severe Carotid Stenosis trial),25 in France, evaluated 527 patients with symptomatic carotid disease (stenosis ≥ 60%), but was terminated early due to significantly higher rates of death or stroke at 30 days in the stenting group.
Comment. SPACE and EVA-3S have been widely criticized for not mandating the use of an embolic protection device (used in 27% of cases in SPACE and in 91.9% of cases in EVA-3S). Questions were also raised about the experience level of the operators who performed the carotid stenting: up to 39% of the primary operators involved in stent placement were trainees.26 Also, myocardial infarction (MI), an important complication of carotid endarterectomy, was not included in the primary end point.
ICSS (the International Carotid Stenting Study)27 compared stenting with endarterectomy in 1,713 patients with symptomatic carotid stenosis of greater than 50%. The primary end point was the rate of fatal or disabling stroke at 3 years.
An interim safety analysis at 120 days of follow-up showed the primary end point had occurred in 4.0% of stenting cases vs 3.2% of endarterectomy cases, a difference that was not statistically significant (hazard ratio [HR] 1.28, 95% confidence interval [CI] 0.77–2.11). However, the risk of any stroke was higher with stenting, with a rate of 7.7% vs 4.1% in the surgical group—a statistically significant difference (HR 1.92, 95% CI 1.27–2.89).
In a substudy of ICSS,28 the investigators corroborated these findings, using magnetic resonance imaging to evaluate for new ischemic brain lesions periprocedurally. They found more new ischemic brain lesions in patients who underwent stenting than in patients who underwent surgery—a statistically significant finding.
Comment. ICSS had limitations: eg, it included only patients with symptoms, and the training for the stenting procedure was not standardized. Furthermore, the use of embolic protection devices was not mandated in stenting procedures.
Because of the controversial and incongruous findings of the above trials, there has been much anticipation for further large, appropriately conducted, randomized controlled trials such as CREST.
CREST STUDY DESIGN
CREST was a prospective, multicenter randomized controlled trial with blinded end point adjudication. Assignment to stenting or surgery occurred in a one-to-one fashion, and patients were stratified by medical center and symptomatic status.
Conducted at 108 sites in the United States and nine sites in Canada, CREST was supported by a grant from the National Institutes of Health and by the manufacturer of the catheter and stent delivery and embolic protection systems. The manufacturer’s representative held a nonvoting position on the executive committee and reviewed the manuscript of the results before submission.
CREST included patients with or without symptoms
CREST was initially designed to compare carotid artery stenting vs carotid endarterectomy in patients with symptoms, but enrollment was later extended to patients without symptoms.
Patients with symptoms were included if they had stenosis of at least 50% on angiography, at least 70% on ultrasonography, or at least 70% on computed tomographic angiography or magnetic resonance angiography if stenosis on ultrasonography was 50% to 69%. Carotid artery stenosis was considered symptomatic if the patient had a transient ischemic attack, amaurosis fugax, or minor disabling stroke in the hemisphere supplied by the target vessel within 180 days of randomization.
Patients without symptoms were eligible if they had at least 60% stenosis on angiography, at least 70% stenosis on ultrasonography, or at least 80% stenosis on computed tomographic angiography or magnetic resonance angiography if the stenosis was 50% to 69% on ultrasonography.
Other eligibility criteria included favorable anatomy and clinical stability for both stenting and surgical procedures.
Exclusion criteria were evolving stroke, history of major stroke, chronic or paroxysmal atrial fibrillation on anticoagulation therapy, MI within the previous 30 days, and unstable angina.
Patients received antiplatelet agents
Patients undergoing stenting received aspirin and clopidogrel (Plavix) before and up to 30 days after the procedure. Continuation of antiplatelet therapy was recommended beyond 1 month.
Patients undergoing endarterectomy received aspirin before surgery and continued to receive aspirin for at least 1 year.
Alternatives to aspirin in both groups were ticlopidine (Ticlid), clopidogrel, or aspirin with extended-release dipyridamole (Aggrenox).
End points: Stroke, MI, death
The primary end point was a composite of periprocedural clinical stroke (any type), MI, or death, and of ipsilateral stroke up to 4 years after the procedure. Secondary analyses were also planned for evaluation of treatment modification by age, symptom status, and sex.
Stroke was defined as any acute neurologic ischemic event lasting at least 24 hours with focal signs and symptoms.
Two separate definitions were applied to distinguish major stroke from nonmajor stroke. Major stroke was defined as a National Institutes of Health Stroke Scale (NIHSS) score greater than 9 or records suggesting that the event was a disabling stroke if admitted to another facility. Nonmajor stroke included an event that did not fit these criteria. The stroke review process was initiated with a significant neurologic event, a positive transient ischemia attack or stroke questionnaire, or a two-point or greater increase in the NIHSS score.
MI was defined as a combination of an elevation of cardiac enzymes to at least twice the laboratory upper limit of normal, as well as clinical signs suggesting MI or electrocardiographic evidence of ischemia.29
Stroke was adjudicated by two independent neurologists, and MI was adjudicated by two independent cardiologists blinded to treatment group assignment.
The Rankin scale, the transient ischemic attack and stroke questionnaire, and the Medical Outcomes Survey were also used to assess for disability and quality of life in long-term follow-up.
Intention-to-treat analysis
Intention-to-treat survival analysis was used along with time-to-event statistical modeling with adjustment for major baseline covariates. Differences in outcomes were assessed, and a noninferiority analysis was performed. Kaplan-Meier estimates were constructed of the proportion of patients remaining free of the composite end point at 30 days, 6 months, 1 year, and annually thereafter, and of the associated confidence intervals. The hazard ratios between groups were estimated after adjustment for important covariates.
Most patients enrolled were available for analysis
From December 2000 to July 2008, 2,522 patients were enrolled; 1,271 were assigned to stenting, and 1,251 were assigned to surgery. After randomization, 2.8% of the patients assigned to stenting withdrew consent, 5.7% underwent surgery, and 2.6% were lost to follow-up. Of those assigned to surgery, 5.1% withdrew consent, 1.0% underwent stenting, and 3.8% were lost to follow-up.
A ‘conventional-risk’ patient population
The trial sought to include a “conventional-risk” patient population to make the study more applicable to real-world practice. The mean age was 69 years in both groups. Of the 2,522 patients enrolled:
35% were women
47% had asymptomatic carotid disease
86% had carotid stenosis of 70% or greater
86% had hypertension
30% had diabetes mellitus
83% had hyperlipidemia
26% were current smokers
42% had a history of cardiovascular disease
21% had undergone coronary artery bypass grafting surgery.
The only statistically significant difference in measured baseline variables between the two treatment groups was a slightly higher rate of dyslipidemia in the group undergoing surgery.
The interventionalists and surgeons were highly experienced
Operators performing stenting underwent a lead-in phase of training, with close supervision and scrutiny before eligibility. Of patients undergoing stenting, 96.1% also received an embolic protection device. Antiplatelet therapy was continued in 99% of the patients.
The surgeons performing endarterectomy were experienced and had documented low complication rates. General anesthesia was used in 90% of surgical patients. Shunts were used during surgery in 57%, and patches were used in 62%. After endarterectomy, 91% of the patients received antiplatelet therapy.
CREST STUDY RESULTS: STENTING WAS AS GOOD AS SURGERY
Periprocedural outcomes
Stroke, MI, or death: 5.2% with stenting vs 4.5% with surgery, HR 1.18, 95% CI 0.82–1.68, P = .38
Stroke: 4.1% vs 2.3%, HR 1.79, 95% CI 1.14–2.82, P = .01
Major ipsilateral stroke: 0.9% vs 0.3%, HR 2.67, 95% CI 0.85–8.40, P = .09.
MI: 1.1% vs 2.3%, HR 0.50, 95% CI 0.26–0.94, P = .03
Cranial nerve palsy: 0.3% vs 4.8%, HR 0.07, 95% CI 0.02–0.18, P < .0001 (Table 2).
Outcomes at 4 years
Brott TG, et al; CREST Investigators. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010; 363:11–23. Copyright 2010, Massachusetts Medical Society. All rights reserved.
Figure 2. Kaplan-Meier analysis of the primary outcome (stroke, myocardial infarction, or death during the periprocedural period or any ipsilateral stroke within 4 years after randomization) for patients undergoing carotid artery stenting or carotid endarterectomy.The primary end point (periprocedural stroke, MI, or death, or ipsilateral stroke within 4 years after the procedure): 7.2% with stenting vs 6.8% with surgery, HR 1.11, 95% CI 0.81–1.51, P = .51. A Kaplan-Meier analysis showed similar findings with statistically similar outcomes (Figure 2).
Ipsilateral stroke: 2.0% vs 2.4%, HR 0.94, 95% CI 0.50–1.76, P = .85.
The primary outcome was analyzed for interactions of baseline variables, and no effect was detected for symptomatic status or sex. There was a suggestion of an interaction with age, with older patients (over age 70) benefiting more from endarterectomy.
Quality-of-life indices showed that both major and minor strokes were likely to produce long-term physical limitations, with minor stroke associated with worse mental and physical health at 1 year. The effect of periprocedural MI on long-term physical and mental health was less certain. The increased incidence of cranial nerve palsy noted with endarterectomy has been found before and has had no effect on quality of life.
WHAT DO THE CREST FINDINGS MEAN?
CREST is the largest trial to date to compare stenting and surgery. It is an important addition to the literature, not only because of its size, but also because it focused on a real-world patient population. For this reason, its results are more applicable to patients seen in primary care clinics, ie, with peripheral vascular disease, coronary artery disease, diabetes mellitus, hypertension, and smoking.
As noted, previous studies of endarterectomy had strict inclusion and exclusion criteria, which selected against patients at high surgical risk. Therefore, the CREST findings are of greater relevance when comparing stenting and endarterectomy.
Periprocedural and long-term neurologic outcomes
CREST showed similar findings for the composite end point of periprocedural stroke, death, or MI (ie, within 30 days of the procedure) and long-term stroke, establishing similar outcomes in patients undergoing stenting and surgery.
However, an analysis of the individual components of the composite end point showed significant differences between the two treatments. The risk of ipsilateral periprocedural stroke was higher with stenting; these events were defined as nonmajor by NIHSS criteria. The risk of contralateral stroke was similar and low with each treatment.
While the increased risk of periprocedural ipsilateral stroke was not synonymous with an increased risk of major stroke, post hoc analysis showed that any stroke was associated with decreased physical and mental health at 1 year. Therefore, patients who had even a minor stroke did worse from a physical and mental standpoint, a finding that argues for the superiority of surgery in selected patients at risk of periprocedural stroke.
If periprocedural stroke is excluded, the risk of long-term ipsilateral stroke was similar for each treatment, and extremely low (2% for stenting, 2.4% for surgery). Despite this, given the importance of periprocedural minor and major stroke, better predictive models are needed to identify patients at risk of procedural neurologic events. These prediction models will allow better patient selection.
The CREST data and medical therapy
The rates of stroke in this trial were similar to those observed with current medical treatment (approximately 1% per year), especially for patients with asymptomatic disease. Such findings introduce fresh controversy in the necessity of performing either procedure for this patient subset and may lead to further studies evaluating current medical therapy vs intervention.
Periprocedural myocardial infarction
Vascular surgery has long been associated with high cardiovascular risk, especially an increased risk of periprocedural MI.30 Findings from CREST provide further evidence of the risk of MI with endarterectomy in a real-world patient population. Given the evidence of a strong correlation between periprocedural cardiac enzyme elevations and adverse outcomes, the increased incidence of periprocedural MI is worrisome.31 As with risk assessment for periprocedural stroke, better predictive models are needed for patients at risk of cardiovascular events during endarterectomy.
Procedural complications
Carotid endarterectomy entails incisions in the neck with disruption of tissue planes, as opposed to catheter entry site wounds with stenting. The more invasive nature of endarterectomy thus carries a higher risk of wound complications. In fact, in the NASCET trial, the risk of wound complications was 9.3%.10,19 In CREST, surgery carried a higher risk of wound complications compared with stenting (42 vs 0 cases), although stenting involved more periprocedural transfusions, presumably due to retroperitoneal bleeding in four patients.
Use of general anesthesia is also associated with adverse outcomes.17,18 In CREST, 90% of endarterectomy procedures required general anesthesia, whereas none of the stenting procedures required this.
Cranial nerve palsy is an often overlooked but real complication after these procedures. Cranial nerve palsies can lead to vocal, swallowing, and sensory problems that can have a transient or permanent impact on quality of life. In CREST, as in EVA-3S, SAPPHIRE, and ICSS, this risk was substantially higher with surgery,23,25,27 although the long-term consequences of these palsies were not found to affect quality of life at 1 year of follow-up.
HOW CREST FINDINGS COMPARE WITH PREVIOUS STUDIES
Patients in CREST enjoyed overall better outcomes than in previous studies. In earlier trials of surgery vs medical therapy, the rates of adverse outcomes were higher than in CREST. In NASCET, the risk of ipsilateral stroke was 9% with surgery, with 2.5% being fatal or disabling strokes.10 In the ECST, rates of major stroke or death with endarterectomy were 7.0% within 30 days of surgery and 37.0% at a mean follow-up of 6.1 years.12
In earlier studies of surgery vs stenting, outcomes at 30 days were also substantially worse than those in CREST. In the EVA-3S trial, the 30-day incidence of stroke or death was 3.9% after surgery and 9.6% after stenting. These findings were similar at 6 months in EVA-3S, with a 6.1% rate of adverse events after surgery and 11.7% after stenting.25 In the SAPPHIRE trial, the cumulative incidence of stroke and death at 1 year was 21.4% for surgery and 13.6% for stenting.23
Overall, the CREST results show better outcomes than in previous trials. This may be due to improvements in technical aspects of the interventions and to more aggressive drug therapy. Also, because of the high number of patients enrolled in CREST, surgeons and interventionalists were required to meet eligibility criteria, which could have contributed to the improved outcomes.32
CREST was also unique in that stenting was done with an embolic protection device whenever possible, and this also likely had an impact on outcomes.
The CREST data suggest that interventions for carotid artery stenosis should only be performed by rigorously trained, experienced personnel at high-volume centers, as this provided lower event rates compared with previous studies. Additional data should also help identify those at risk of periprocedural stroke and MI, thereby helping to match the patient to the most appropriate procedure. The pros and cons of surgery and stenting are shown in Table 3.1,10,23,25,27
CREST vs ICSS
CREST and ICSS, published within a few months of each other, seem to have arrived at entirely different conclusions. As both studies are well-designed randomized controlled trials, these distinct results have yielded much controversy. However, closer scrutiny sheds light as to why the results may be different.
While ICSS focused only on patients with symptoms, CREST also included those without symptoms. The difference in patient populations is itself enough to account for the different outcomes.
Also, the interim analysis of ICSS was at 120 days, which makes periprocedural events a more dominant factor in outcomes, whereas these events likely do not last into the long term, as was the case in CREST. Analysis of the ICSS data at a later follow-up date may show results more similar to those of CREST.
The design of ICSS was also different than CREST. In ICSS, the use of an embolic protection device in stenting was not mandated, and the study lacked a lead-in phase of intensive training for those performing stenting. Furthermore, MI was adjudicated only when clinically recognized, which is different than the more rigorous method used in CREST.
Yet despite these differences, CREST and ICSS shed light on a controversial area of carotid stenosis management, and both studies boasted low rates of periprocedural complications. Clinicians should keep in mind the inclusion criteria and the technical specificities of these trials in order to explain to patients the risks and benefits of stenting and surgery, and to arrive at a decision together.
Limitations
The results of CREST should also be reviewed carefully due to a number of limitations. The study began in 2000 with symptomatic patients only, and began enrolling asymptomatic patients in 2005, so that the methodology of the study was changed midway. However, the investigators performed a subgroup analysis to distinguish between outcomes of the symptomatic and the asymptomatic groups and found no statistical interaction for the primary end point based on symptom status.
Despite careful patient selection, many of the predictors of adverse outcomes with stenting, such as lesion length, level of calcification, and lesion location, were not accounted for in the earlier days of enrollment. This may have had an impact on the incidence of stroke in patients enrolled in the early years of the trial. We await the analysis of predictors of perioperative stroke from CREST.
TAKE-HOME POINTS AND FUTURE DIRECTIONS
The CREST findings show that outcomes with stenting are similar to those with surgery in both the short term and the long term, and that the choice of management should be individualized. Each patient’s risk of MI and stroke should be considered based on a variety of factors, including the severity of coronary artery disease, the length of the carotid lesion, the level of calcification, the location of the lesion, and aortic atheroma. The treatment should be selected after also taking into account the patient’s preference and the available expertise, and only after a comprehensive discussion with the patient.
References
Brott TG, Hobson RW, Howard G, et al; CREST Investigators. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med2010; 363:11–23.
Thom T, Haase N, Rosamond W, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation2006; 113:e85–e151.
Rosamond WD, Folsom AR, Chambless LE, et al. Stroke incidence and survival among middle-aged adults: 9-year follow-up of the Atherosclerosis Risk in Communities (ARIC) cohort. Stroke1999; 30:736–743.
Chaturvedi S, Bruno A, Feasby T, et al; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Carotid endarterectomy—an evidence-based review: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology2005; 65:794–801.
Howell GM, Makaroun MS, Chaer RA. Current management of extracranial carotid occlusive disease. J Am Coll Surg2009; 208:442–453.
Barnett HJ, Gunton RW, Eliasziw M, et al. Causes and severity of ischemic stroke in patients with internal carotid artery stenosis. JAMA2000; 283:1429–1436.
Biller J, Feinberg WM, Castaldo JE, et al. Guidelines for carotid endarterectomy: a statement for healthcare professionals from a Special Writing Group of the Stroke Council, American Heart Association. Circulation1998; 97:501–509.
Goldstein LB, Adams R, Alberts MJ, et al; American Heart Association; American Stroke Association Stroke Council. Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation2006; 113:e873–e923.
Strully KJ, Hurwitt ES, Blankenberg HW. Thrombo-endarterectomy for thrombosis of the internal carotid artery in the neck. J Neurosurg1953; 10:474–482.
Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med1991; 325:445–453.
Barnett HJ, Taylor DW, Eliasziw M, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med1998; 339:1415–1425.
Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet1998; 351:1379–1387.
Halliday A, Mansfield A, Marro J, et al; MRC Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial. Lancet2004; 363:1491–1502.
Hobson RW, Weiss DG, Fields WS, et al. Efficacy of carotid endarterectomy for asymptomatic carotid stenosis. The Veterans Affairs Cooperative Study Group. N Engl J Med1993; 328:221–227.
Endarterectomy for asymptomatic carotid artery stenosis. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. JAMA1995; 273:1421–1428.
Sacco RL, Adams R, Albers G, et al; American Heart Association/American Stroke Association Council on Stroke; Council on Cardiovascular Radiology and Intervention; American Academy of Neurology. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline. Circulation2006; 113:e409–e449.
Watts K, Lin PH, Bush RL, et al. The impact of anesthetic modality on the outcome of carotid endarterectomy. Am J Surg2004; 188:741–747.
Weber CF, Friedl H, Hueppe M, et al. Impact of general versus local anesthesia on early postoperative cognitive dysfunction following carotid endarterectomy: GALA Study Subgroup Analysis. World J Surg2009; 33:1526–1532.
Ferguson GG, Eliasziw M, Barr HW, et al. The North American Symptomatic Carotid Endarterectomy Trial: surgical results in 1415 patients. Stroke1999; 30:1751–1758.
Golledge J, Mitchell A, Greenhalgh RM, Davies AH. Systematic comparison of the early outcome of angioplasty and endarterectomy for symptomatic carotid artery disease. Stroke2000; 31:1439–1443.
Kastrup A, Gröschel K, Krapf H, Brehm BR, Dichgans J, Schulz JB. Early outcome of carotid angioplasty and stenting with and without cerebral protection devices: a systematic review of the literature. Stroke2003; 34:813–819.
Gurm HS, Yadav JS, Fayad P, et al; SAPPHIRE Investigators. Long-term results of carotid stenting versus endarterectomy in high-risk patients. N Engl J Med2008; 358:1572–1579.
Yadav JS, Wholey MH, Kuntz RE, et al; Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy Investigators. Protected carotid-artery stenting versus endarterectomy in high-risk patients. N Engl J Med2004; 351:1493–1501.
Eckstein HH, Ringleb P, Allenberg JR, et al. Results of the Stent-Protected Angioplasty versus Carotid Endarterectomy (SPACE) study to treat symptomatic stenoses at 2 years: a multinational, prospective, randomised trial. Lancet Neurol2008; 7:893–902.
Mas JL, Chatellier G, Beyssen B, et al; EVA-3S Investigators. Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis. N Engl J Med2006; 355:1660–1771.
Roffi M, Sievert H, Gray WA, et al. Carotid artery stenting versus surgery: adequate comparisons?Lancet Neurol2010; 9:339–341.
International Carotid Stenting Study Investigators; Ederle J, Dobson J, Featherstone RL, et al. Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial. Lancet2010; 375:985–997.
Bonati LH, Jongen LM, Haller S, et al; ICSS-MRI study group. New ischaemic brain lesions on MRI after stenting or endarterectomy for symptomatic carotid stenosis: a sub-study of the International Carotid Stenting Study (ICSS). Lancet Neurol2010; 9:353–362.
Sheffet AJ, Roubin G, Howard G, et al. Design of the Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST). Int J Stroke2010; 5:40–46.
Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery) developed in collaboration with the American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, and Society for Vascular Surgery. J Am Coll Cardiol2007; 50:e159–e241.
Bhatt DL, Topol EJ. Does creatinine kinase-MB elevation after percutaneous coronary intervention predict outcomes in 2005? Periprocedural cardiac enzyme elevation predicts adverse outcomes. Circulation2005; 112:906–915.
Hobson RW, Howard VJ, Roubin GS, et al; CREST. Credentialing of surgeons as interventionalists for carotid artery stenting: experience from the lead-in phase of CREST. J Vasc Surg2004; 40:952–957.
Olcay Aksoy, MD Department of Cardiovascular Medicine, Cleveland Clinic
Samir R. Kapadia, MD Department of Cardiovascular Medicine, Cleveland Clinic
Christopher Bajzer, MD Department of Cardiovascular Medicine, Cleveland Clinic
Wayne M. Clark, MD Department of Neurology, Oregon Health & Science University, Portland; Investigator, Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)
Mehdi H. Shishehbor, DO, MPH, PhD Department of Cardiovascular Medicine, Cleveland Clinic
Address: Mehdi H. Shishehbor, DO, MPH, Heart & Vascular Institute, J3-5, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]
Dr. Shishehbor has disclosed teaching and speaking for Abbott Vascular.
Olcay Aksoy, MD Department of Cardiovascular Medicine, Cleveland Clinic
Samir R. Kapadia, MD Department of Cardiovascular Medicine, Cleveland Clinic
Christopher Bajzer, MD Department of Cardiovascular Medicine, Cleveland Clinic
Wayne M. Clark, MD Department of Neurology, Oregon Health & Science University, Portland; Investigator, Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)
Mehdi H. Shishehbor, DO, MPH, PhD Department of Cardiovascular Medicine, Cleveland Clinic
Address: Mehdi H. Shishehbor, DO, MPH, Heart & Vascular Institute, J3-5, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]
Dr. Shishehbor has disclosed teaching and speaking for Abbott Vascular.
Author and Disclosure Information
Olcay Aksoy, MD Department of Cardiovascular Medicine, Cleveland Clinic
Samir R. Kapadia, MD Department of Cardiovascular Medicine, Cleveland Clinic
Christopher Bajzer, MD Department of Cardiovascular Medicine, Cleveland Clinic
Wayne M. Clark, MD Department of Neurology, Oregon Health & Science University, Portland; Investigator, Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)
Mehdi H. Shishehbor, DO, MPH, PhD Department of Cardiovascular Medicine, Cleveland Clinic
Address: Mehdi H. Shishehbor, DO, MPH, Heart & Vascular Institute, J3-5, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]
Dr. Shishehbor has disclosed teaching and speaking for Abbott Vascular.
For patients with carotid artery stenosis, percutaneous intervention with stenting is as good as surgery (carotid endarterectomy). This was the major finding of the recently completed Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)1—with some qualifications.
CREST is the latest in a series of clinical trials of treatment of carotid stenosis that have generated reams of numbers and much debate. The topic of surgery vs percutaneous intervention is a moving target, as techniques evolve and improve. We believe the CREST results are valuable and should help inform decisions about treatment in the “real world.”
In this article, we offer a critical review of CREST, with a careful evaluation of its methods, results, and conclusions.
AN EVOLVING FIELD
Despite improvements in diagnosis and management, stroke remains one of the leading causes of morbidity and death in the United States, with an annual incidence of 780,000 cases and 270,000 deaths.2,3
Figure 1. Carotid endarterectomy has long been an established treatment in selected patients with symptomatic carotid artery stenosis of 50% or greater or asymptomatic stenosis of 60% or greater. However, percutaneous carotid artery angioplasty with stenting and placement of an embolic protection device is gaining ground as a reasonable, safe, less invasive alternative.From 10% to 30% of ischemic strokes are due to emboli from the carotid arteries.4–6 Carotid endarterectomy is an established treatment in selected patients with symptomatic carotid stenosis of 50% or greater or asymptomatic stenosis of 60% or greater.7,8 However, percutaneous techniques such as carotid artery angioplasty with stenting have improved, making them a viable, less invasive option (Figure 1).
Randomized trials of stenting have had mixed results, leading the Centers for Medicare and Medicaid Services (CMS) to adopt strict reimbursement policies. Currently, CMS reimburses for stenting only in symptomatic cases with at least 50% carotid artery stenosis. It also reimburses for stenting in asymptomatic cases in patients at high risk with 80% or greater stenosis, but only if the patients are enrolled in ongoing clinical trials or registries.
CREST compared stenting with endarterectomy and provided important insights into each approach.1
BEFORE CREST
Endarterectomy is superior to medical therapy for symptomatic stenosis
First described in 1953, carotid endarterectomy became the most widely used invasive treatment for significant carotid stenosis.9 Several studies have described patient subsets that benefit from this procedure.
NASCET (the North American Symptomatic Carotid Endarterectomy Trial)10 assigned 2,226 patients with symptomatic stenosis (transient ischemic attack or stroke within the past 180 days) to medical management or endarterectomy.
Surgery was associated with a 65% lower rate of ipsilateral cerebral events in patients with 70% or greater stenosis.10 Surgery was also found to be superior in patients with moderate disease (50% to 69% stenosis), but the difference only approached statistical significance. In patients with stenosis of less than 50%, the outcomes were similar with endarterectomy and medical management.11
ECST (the European Carotid Surgery Trial)12 included a similar population of 3,024 patients. Those with high-grade disease (stenosis ≥ 80%) had significantly better outcomes with endarterectomy, but in those with stenosis less than 70%, surgery was no better than drug therapy.
Comment. NASCET and ECST taught us that endarterectomy is clearly superior to medical therapy in patients with severe symptomatic carotid disease. However, both trials excluded patients at high surgical risk, eg, those with severe coronary artery disease, kidney disease, or heart failure. Additionally, medical management was not aggressive by today’s standards in terms of control of blood pressure and hyperlipidemia, and this could have skewed the results in favor of carotid endarterectomy.
The case for carotid endarterectomy for asymptomatic stenosis
Endarterectomy has also been compared with drug therapy for asymp tomatic carotid artery stenosis in several trials.13–15
ACAS (the Asymptomatic Carotid Atherosclerosis Study)15 assigned 1,662 patients who had no symptoms and had at least 60% carotid artery stenosis to endarterectomy or to medical management, and found a relative risk reduction of 53% in favor of surgery.15
The Veterans Affairs Cooperative Study Group14 corroborated these results in 444 patients with asymptomatic stenosis of greater than 50%. Endarterectomy was associated with a 61% lower risk of transient ischemic attack, transient monocular blindness, or stroke compared with medical therapy. However, there was no statistically significant difference in rates of stroke or death at 30 days.14
ACST (the Asymptomatic Carotid Surgery Trial),13 the largest study to compare carotid endarterectomy with drug therapy for asymptomatic stenosis, randomized 3,120 patients to surgery or drug therapy. The net 5-year risk of stroke was 6.4% with endarterectomy vs 11.8% with drug therapy (P < .0001). The rate of fatal stroke was also lower with endarterectomy: 2.1% vs 4.2% (P = .006).13
Comment. The results of these and other studies of endarterectomy vs medical therapy may not be applicable to current practice, since medical therapy has evolved and the risks with current drug therapy are likely much lower than seen in these trials, some of which began 2 decades ago. Another problem with interpreting these trials is that they excluded surgically “high-risk” patients, which limits the generalizability of the findings to this particular patient population.
The American Heart Association and the American Stroke Association have, on the basis of these trials, recommended carotid endarterectomy in patients with7,8,16:
Ipsilateral, symptomatic carotid artery stenosis of 70% to 99% (class I, level of evidence A)
Symptomatic stenosis of 50% to 69%, depending on patient-specific factors such as age, sex, and comorbidities
High-grade asymptomatic carotid stenosis, if the patients are carefully selected and the surgery is performed by surgeons with procedural morbidity and mortality rates of less than 3% (class I, level of evidence A).
In all cases, treatment should be individualized according to the patient’s comorbid conditions and preferences, with a thorough discussion of risks and benefits (Table 1).7,8,16
The case for percutaneous intervention
While carotid endarterectomy is proven to be more efficacious than medical management in certain patient subsets, studies favoring surgery over medical therapy have been criticized because they excluded patients with significant comorbidities. In addition, surgery has been associated with significant cardiovascular events, wound complications, and cranial nerve damage, and it requires general anesthesia in most cases.12,17–19 These and other factors spurred the development of less invasive, percutaneous approaches for patients with substantial comorbidities.
So far, several trials have investigated carotid angioplasty with or without stents and with or without devices to capture distal emboli. This interest set the stage for CREST.20,21
Initial attempts at angioplasty without distal protection were not very successful. A meta-analysis of nonrandomized trials that included 714 patients from the initial 13 studies of angioplasty (with or without stenting) and 6,970 patients from 20 studies of carotid endarterectomy found angioplasty to be possibly associated with higher rates of stroke within 30 days of the procedure.20
With improvements in technology, routine use of embolic protection devices, more experience, and better selection of patients, the outcome of carotid stenting has improved. In fact, a meta-analysis comparing stenting without an embolic protection device (26 trials with 2,357 patients) vs stenting with an embolic protection device (11 trials with 839 patients) showed that embolic protection led to significantly better outcomes with fewer strokes—outcomes arguably similar to those of carotid endarterectomy.21
SAPPHIRE (the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy trial)22 was the only completed US trial until CREST that compared carotid artery stenting with distal protection against surgery. It included 334 high-risk patients with either symptomatic stenosis of 50% or greater or asymptomatic stenosis of 80% or greater.
The results suggested that the outcomes with stenting with embolic protection were in fact similar to those of endarterectomy, with possibly fewer complications.23 The benefit persisted up to 2 years.22
The US Food and Drug Administration (FDA), on the basis of these data, approved the use of stenting with distal protection for high-risk patients, and the CMS reimburses for symptomatic stenosis of 50% or greater and for asymptomatic stenosis of 80% or greater as long as the patient is enrolled in a registry.
SPACE (the Stent-Protected Angioplasty Versus Carotid Endarterectomy in Symptomatic Patients trial),24 conducted in Germany, included 1,214 patients with symptomatic stenosis of at least 50%. Results were similar in terms of the combined primary end point of stroke or death at 30 days. However, the results were not similar enough to prove that stenting is not inferior to surgery, according to preset study criteria.
EVA-3S (the Endarterectomy Versus Stenting in Patients With Symptomatic Severe Carotid Stenosis trial),25 in France, evaluated 527 patients with symptomatic carotid disease (stenosis ≥ 60%), but was terminated early due to significantly higher rates of death or stroke at 30 days in the stenting group.
Comment. SPACE and EVA-3S have been widely criticized for not mandating the use of an embolic protection device (used in 27% of cases in SPACE and in 91.9% of cases in EVA-3S). Questions were also raised about the experience level of the operators who performed the carotid stenting: up to 39% of the primary operators involved in stent placement were trainees.26 Also, myocardial infarction (MI), an important complication of carotid endarterectomy, was not included in the primary end point.
ICSS (the International Carotid Stenting Study)27 compared stenting with endarterectomy in 1,713 patients with symptomatic carotid stenosis of greater than 50%. The primary end point was the rate of fatal or disabling stroke at 3 years.
An interim safety analysis at 120 days of follow-up showed the primary end point had occurred in 4.0% of stenting cases vs 3.2% of endarterectomy cases, a difference that was not statistically significant (hazard ratio [HR] 1.28, 95% confidence interval [CI] 0.77–2.11). However, the risk of any stroke was higher with stenting, with a rate of 7.7% vs 4.1% in the surgical group—a statistically significant difference (HR 1.92, 95% CI 1.27–2.89).
In a substudy of ICSS,28 the investigators corroborated these findings, using magnetic resonance imaging to evaluate for new ischemic brain lesions periprocedurally. They found more new ischemic brain lesions in patients who underwent stenting than in patients who underwent surgery—a statistically significant finding.
Comment. ICSS had limitations: eg, it included only patients with symptoms, and the training for the stenting procedure was not standardized. Furthermore, the use of embolic protection devices was not mandated in stenting procedures.
Because of the controversial and incongruous findings of the above trials, there has been much anticipation for further large, appropriately conducted, randomized controlled trials such as CREST.
CREST STUDY DESIGN
CREST was a prospective, multicenter randomized controlled trial with blinded end point adjudication. Assignment to stenting or surgery occurred in a one-to-one fashion, and patients were stratified by medical center and symptomatic status.
Conducted at 108 sites in the United States and nine sites in Canada, CREST was supported by a grant from the National Institutes of Health and by the manufacturer of the catheter and stent delivery and embolic protection systems. The manufacturer’s representative held a nonvoting position on the executive committee and reviewed the manuscript of the results before submission.
CREST included patients with or without symptoms
CREST was initially designed to compare carotid artery stenting vs carotid endarterectomy in patients with symptoms, but enrollment was later extended to patients without symptoms.
Patients with symptoms were included if they had stenosis of at least 50% on angiography, at least 70% on ultrasonography, or at least 70% on computed tomographic angiography or magnetic resonance angiography if stenosis on ultrasonography was 50% to 69%. Carotid artery stenosis was considered symptomatic if the patient had a transient ischemic attack, amaurosis fugax, or minor disabling stroke in the hemisphere supplied by the target vessel within 180 days of randomization.
Patients without symptoms were eligible if they had at least 60% stenosis on angiography, at least 70% stenosis on ultrasonography, or at least 80% stenosis on computed tomographic angiography or magnetic resonance angiography if the stenosis was 50% to 69% on ultrasonography.
Other eligibility criteria included favorable anatomy and clinical stability for both stenting and surgical procedures.
Exclusion criteria were evolving stroke, history of major stroke, chronic or paroxysmal atrial fibrillation on anticoagulation therapy, MI within the previous 30 days, and unstable angina.
Patients received antiplatelet agents
Patients undergoing stenting received aspirin and clopidogrel (Plavix) before and up to 30 days after the procedure. Continuation of antiplatelet therapy was recommended beyond 1 month.
Patients undergoing endarterectomy received aspirin before surgery and continued to receive aspirin for at least 1 year.
Alternatives to aspirin in both groups were ticlopidine (Ticlid), clopidogrel, or aspirin with extended-release dipyridamole (Aggrenox).
End points: Stroke, MI, death
The primary end point was a composite of periprocedural clinical stroke (any type), MI, or death, and of ipsilateral stroke up to 4 years after the procedure. Secondary analyses were also planned for evaluation of treatment modification by age, symptom status, and sex.
Stroke was defined as any acute neurologic ischemic event lasting at least 24 hours with focal signs and symptoms.
Two separate definitions were applied to distinguish major stroke from nonmajor stroke. Major stroke was defined as a National Institutes of Health Stroke Scale (NIHSS) score greater than 9 or records suggesting that the event was a disabling stroke if admitted to another facility. Nonmajor stroke included an event that did not fit these criteria. The stroke review process was initiated with a significant neurologic event, a positive transient ischemia attack or stroke questionnaire, or a two-point or greater increase in the NIHSS score.
MI was defined as a combination of an elevation of cardiac enzymes to at least twice the laboratory upper limit of normal, as well as clinical signs suggesting MI or electrocardiographic evidence of ischemia.29
Stroke was adjudicated by two independent neurologists, and MI was adjudicated by two independent cardiologists blinded to treatment group assignment.
The Rankin scale, the transient ischemic attack and stroke questionnaire, and the Medical Outcomes Survey were also used to assess for disability and quality of life in long-term follow-up.
Intention-to-treat analysis
Intention-to-treat survival analysis was used along with time-to-event statistical modeling with adjustment for major baseline covariates. Differences in outcomes were assessed, and a noninferiority analysis was performed. Kaplan-Meier estimates were constructed of the proportion of patients remaining free of the composite end point at 30 days, 6 months, 1 year, and annually thereafter, and of the associated confidence intervals. The hazard ratios between groups were estimated after adjustment for important covariates.
Most patients enrolled were available for analysis
From December 2000 to July 2008, 2,522 patients were enrolled; 1,271 were assigned to stenting, and 1,251 were assigned to surgery. After randomization, 2.8% of the patients assigned to stenting withdrew consent, 5.7% underwent surgery, and 2.6% were lost to follow-up. Of those assigned to surgery, 5.1% withdrew consent, 1.0% underwent stenting, and 3.8% were lost to follow-up.
A ‘conventional-risk’ patient population
The trial sought to include a “conventional-risk” patient population to make the study more applicable to real-world practice. The mean age was 69 years in both groups. Of the 2,522 patients enrolled:
35% were women
47% had asymptomatic carotid disease
86% had carotid stenosis of 70% or greater
86% had hypertension
30% had diabetes mellitus
83% had hyperlipidemia
26% were current smokers
42% had a history of cardiovascular disease
21% had undergone coronary artery bypass grafting surgery.
The only statistically significant difference in measured baseline variables between the two treatment groups was a slightly higher rate of dyslipidemia in the group undergoing surgery.
The interventionalists and surgeons were highly experienced
Operators performing stenting underwent a lead-in phase of training, with close supervision and scrutiny before eligibility. Of patients undergoing stenting, 96.1% also received an embolic protection device. Antiplatelet therapy was continued in 99% of the patients.
The surgeons performing endarterectomy were experienced and had documented low complication rates. General anesthesia was used in 90% of surgical patients. Shunts were used during surgery in 57%, and patches were used in 62%. After endarterectomy, 91% of the patients received antiplatelet therapy.
CREST STUDY RESULTS: STENTING WAS AS GOOD AS SURGERY
Periprocedural outcomes
Stroke, MI, or death: 5.2% with stenting vs 4.5% with surgery, HR 1.18, 95% CI 0.82–1.68, P = .38
Stroke: 4.1% vs 2.3%, HR 1.79, 95% CI 1.14–2.82, P = .01
Major ipsilateral stroke: 0.9% vs 0.3%, HR 2.67, 95% CI 0.85–8.40, P = .09.
MI: 1.1% vs 2.3%, HR 0.50, 95% CI 0.26–0.94, P = .03
Cranial nerve palsy: 0.3% vs 4.8%, HR 0.07, 95% CI 0.02–0.18, P < .0001 (Table 2).
Outcomes at 4 years
Brott TG, et al; CREST Investigators. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010; 363:11–23. Copyright 2010, Massachusetts Medical Society. All rights reserved.
Figure 2. Kaplan-Meier analysis of the primary outcome (stroke, myocardial infarction, or death during the periprocedural period or any ipsilateral stroke within 4 years after randomization) for patients undergoing carotid artery stenting or carotid endarterectomy.The primary end point (periprocedural stroke, MI, or death, or ipsilateral stroke within 4 years after the procedure): 7.2% with stenting vs 6.8% with surgery, HR 1.11, 95% CI 0.81–1.51, P = .51. A Kaplan-Meier analysis showed similar findings with statistically similar outcomes (Figure 2).
Ipsilateral stroke: 2.0% vs 2.4%, HR 0.94, 95% CI 0.50–1.76, P = .85.
The primary outcome was analyzed for interactions of baseline variables, and no effect was detected for symptomatic status or sex. There was a suggestion of an interaction with age, with older patients (over age 70) benefiting more from endarterectomy.
Quality-of-life indices showed that both major and minor strokes were likely to produce long-term physical limitations, with minor stroke associated with worse mental and physical health at 1 year. The effect of periprocedural MI on long-term physical and mental health was less certain. The increased incidence of cranial nerve palsy noted with endarterectomy has been found before and has had no effect on quality of life.
WHAT DO THE CREST FINDINGS MEAN?
CREST is the largest trial to date to compare stenting and surgery. It is an important addition to the literature, not only because of its size, but also because it focused on a real-world patient population. For this reason, its results are more applicable to patients seen in primary care clinics, ie, with peripheral vascular disease, coronary artery disease, diabetes mellitus, hypertension, and smoking.
As noted, previous studies of endarterectomy had strict inclusion and exclusion criteria, which selected against patients at high surgical risk. Therefore, the CREST findings are of greater relevance when comparing stenting and endarterectomy.
Periprocedural and long-term neurologic outcomes
CREST showed similar findings for the composite end point of periprocedural stroke, death, or MI (ie, within 30 days of the procedure) and long-term stroke, establishing similar outcomes in patients undergoing stenting and surgery.
However, an analysis of the individual components of the composite end point showed significant differences between the two treatments. The risk of ipsilateral periprocedural stroke was higher with stenting; these events were defined as nonmajor by NIHSS criteria. The risk of contralateral stroke was similar and low with each treatment.
While the increased risk of periprocedural ipsilateral stroke was not synonymous with an increased risk of major stroke, post hoc analysis showed that any stroke was associated with decreased physical and mental health at 1 year. Therefore, patients who had even a minor stroke did worse from a physical and mental standpoint, a finding that argues for the superiority of surgery in selected patients at risk of periprocedural stroke.
If periprocedural stroke is excluded, the risk of long-term ipsilateral stroke was similar for each treatment, and extremely low (2% for stenting, 2.4% for surgery). Despite this, given the importance of periprocedural minor and major stroke, better predictive models are needed to identify patients at risk of procedural neurologic events. These prediction models will allow better patient selection.
The CREST data and medical therapy
The rates of stroke in this trial were similar to those observed with current medical treatment (approximately 1% per year), especially for patients with asymptomatic disease. Such findings introduce fresh controversy in the necessity of performing either procedure for this patient subset and may lead to further studies evaluating current medical therapy vs intervention.
Periprocedural myocardial infarction
Vascular surgery has long been associated with high cardiovascular risk, especially an increased risk of periprocedural MI.30 Findings from CREST provide further evidence of the risk of MI with endarterectomy in a real-world patient population. Given the evidence of a strong correlation between periprocedural cardiac enzyme elevations and adverse outcomes, the increased incidence of periprocedural MI is worrisome.31 As with risk assessment for periprocedural stroke, better predictive models are needed for patients at risk of cardiovascular events during endarterectomy.
Procedural complications
Carotid endarterectomy entails incisions in the neck with disruption of tissue planes, as opposed to catheter entry site wounds with stenting. The more invasive nature of endarterectomy thus carries a higher risk of wound complications. In fact, in the NASCET trial, the risk of wound complications was 9.3%.10,19 In CREST, surgery carried a higher risk of wound complications compared with stenting (42 vs 0 cases), although stenting involved more periprocedural transfusions, presumably due to retroperitoneal bleeding in four patients.
Use of general anesthesia is also associated with adverse outcomes.17,18 In CREST, 90% of endarterectomy procedures required general anesthesia, whereas none of the stenting procedures required this.
Cranial nerve palsy is an often overlooked but real complication after these procedures. Cranial nerve palsies can lead to vocal, swallowing, and sensory problems that can have a transient or permanent impact on quality of life. In CREST, as in EVA-3S, SAPPHIRE, and ICSS, this risk was substantially higher with surgery,23,25,27 although the long-term consequences of these palsies were not found to affect quality of life at 1 year of follow-up.
HOW CREST FINDINGS COMPARE WITH PREVIOUS STUDIES
Patients in CREST enjoyed overall better outcomes than in previous studies. In earlier trials of surgery vs medical therapy, the rates of adverse outcomes were higher than in CREST. In NASCET, the risk of ipsilateral stroke was 9% with surgery, with 2.5% being fatal or disabling strokes.10 In the ECST, rates of major stroke or death with endarterectomy were 7.0% within 30 days of surgery and 37.0% at a mean follow-up of 6.1 years.12
In earlier studies of surgery vs stenting, outcomes at 30 days were also substantially worse than those in CREST. In the EVA-3S trial, the 30-day incidence of stroke or death was 3.9% after surgery and 9.6% after stenting. These findings were similar at 6 months in EVA-3S, with a 6.1% rate of adverse events after surgery and 11.7% after stenting.25 In the SAPPHIRE trial, the cumulative incidence of stroke and death at 1 year was 21.4% for surgery and 13.6% for stenting.23
Overall, the CREST results show better outcomes than in previous trials. This may be due to improvements in technical aspects of the interventions and to more aggressive drug therapy. Also, because of the high number of patients enrolled in CREST, surgeons and interventionalists were required to meet eligibility criteria, which could have contributed to the improved outcomes.32
CREST was also unique in that stenting was done with an embolic protection device whenever possible, and this also likely had an impact on outcomes.
The CREST data suggest that interventions for carotid artery stenosis should only be performed by rigorously trained, experienced personnel at high-volume centers, as this provided lower event rates compared with previous studies. Additional data should also help identify those at risk of periprocedural stroke and MI, thereby helping to match the patient to the most appropriate procedure. The pros and cons of surgery and stenting are shown in Table 3.1,10,23,25,27
CREST vs ICSS
CREST and ICSS, published within a few months of each other, seem to have arrived at entirely different conclusions. As both studies are well-designed randomized controlled trials, these distinct results have yielded much controversy. However, closer scrutiny sheds light as to why the results may be different.
While ICSS focused only on patients with symptoms, CREST also included those without symptoms. The difference in patient populations is itself enough to account for the different outcomes.
Also, the interim analysis of ICSS was at 120 days, which makes periprocedural events a more dominant factor in outcomes, whereas these events likely do not last into the long term, as was the case in CREST. Analysis of the ICSS data at a later follow-up date may show results more similar to those of CREST.
The design of ICSS was also different than CREST. In ICSS, the use of an embolic protection device in stenting was not mandated, and the study lacked a lead-in phase of intensive training for those performing stenting. Furthermore, MI was adjudicated only when clinically recognized, which is different than the more rigorous method used in CREST.
Yet despite these differences, CREST and ICSS shed light on a controversial area of carotid stenosis management, and both studies boasted low rates of periprocedural complications. Clinicians should keep in mind the inclusion criteria and the technical specificities of these trials in order to explain to patients the risks and benefits of stenting and surgery, and to arrive at a decision together.
Limitations
The results of CREST should also be reviewed carefully due to a number of limitations. The study began in 2000 with symptomatic patients only, and began enrolling asymptomatic patients in 2005, so that the methodology of the study was changed midway. However, the investigators performed a subgroup analysis to distinguish between outcomes of the symptomatic and the asymptomatic groups and found no statistical interaction for the primary end point based on symptom status.
Despite careful patient selection, many of the predictors of adverse outcomes with stenting, such as lesion length, level of calcification, and lesion location, were not accounted for in the earlier days of enrollment. This may have had an impact on the incidence of stroke in patients enrolled in the early years of the trial. We await the analysis of predictors of perioperative stroke from CREST.
TAKE-HOME POINTS AND FUTURE DIRECTIONS
The CREST findings show that outcomes with stenting are similar to those with surgery in both the short term and the long term, and that the choice of management should be individualized. Each patient’s risk of MI and stroke should be considered based on a variety of factors, including the severity of coronary artery disease, the length of the carotid lesion, the level of calcification, the location of the lesion, and aortic atheroma. The treatment should be selected after also taking into account the patient’s preference and the available expertise, and only after a comprehensive discussion with the patient.
For patients with carotid artery stenosis, percutaneous intervention with stenting is as good as surgery (carotid endarterectomy). This was the major finding of the recently completed Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)1—with some qualifications.
CREST is the latest in a series of clinical trials of treatment of carotid stenosis that have generated reams of numbers and much debate. The topic of surgery vs percutaneous intervention is a moving target, as techniques evolve and improve. We believe the CREST results are valuable and should help inform decisions about treatment in the “real world.”
In this article, we offer a critical review of CREST, with a careful evaluation of its methods, results, and conclusions.
AN EVOLVING FIELD
Despite improvements in diagnosis and management, stroke remains one of the leading causes of morbidity and death in the United States, with an annual incidence of 780,000 cases and 270,000 deaths.2,3
Figure 1. Carotid endarterectomy has long been an established treatment in selected patients with symptomatic carotid artery stenosis of 50% or greater or asymptomatic stenosis of 60% or greater. However, percutaneous carotid artery angioplasty with stenting and placement of an embolic protection device is gaining ground as a reasonable, safe, less invasive alternative.From 10% to 30% of ischemic strokes are due to emboli from the carotid arteries.4–6 Carotid endarterectomy is an established treatment in selected patients with symptomatic carotid stenosis of 50% or greater or asymptomatic stenosis of 60% or greater.7,8 However, percutaneous techniques such as carotid artery angioplasty with stenting have improved, making them a viable, less invasive option (Figure 1).
Randomized trials of stenting have had mixed results, leading the Centers for Medicare and Medicaid Services (CMS) to adopt strict reimbursement policies. Currently, CMS reimburses for stenting only in symptomatic cases with at least 50% carotid artery stenosis. It also reimburses for stenting in asymptomatic cases in patients at high risk with 80% or greater stenosis, but only if the patients are enrolled in ongoing clinical trials or registries.
CREST compared stenting with endarterectomy and provided important insights into each approach.1
BEFORE CREST
Endarterectomy is superior to medical therapy for symptomatic stenosis
First described in 1953, carotid endarterectomy became the most widely used invasive treatment for significant carotid stenosis.9 Several studies have described patient subsets that benefit from this procedure.
NASCET (the North American Symptomatic Carotid Endarterectomy Trial)10 assigned 2,226 patients with symptomatic stenosis (transient ischemic attack or stroke within the past 180 days) to medical management or endarterectomy.
Surgery was associated with a 65% lower rate of ipsilateral cerebral events in patients with 70% or greater stenosis.10 Surgery was also found to be superior in patients with moderate disease (50% to 69% stenosis), but the difference only approached statistical significance. In patients with stenosis of less than 50%, the outcomes were similar with endarterectomy and medical management.11
ECST (the European Carotid Surgery Trial)12 included a similar population of 3,024 patients. Those with high-grade disease (stenosis ≥ 80%) had significantly better outcomes with endarterectomy, but in those with stenosis less than 70%, surgery was no better than drug therapy.
Comment. NASCET and ECST taught us that endarterectomy is clearly superior to medical therapy in patients with severe symptomatic carotid disease. However, both trials excluded patients at high surgical risk, eg, those with severe coronary artery disease, kidney disease, or heart failure. Additionally, medical management was not aggressive by today’s standards in terms of control of blood pressure and hyperlipidemia, and this could have skewed the results in favor of carotid endarterectomy.
The case for carotid endarterectomy for asymptomatic stenosis
Endarterectomy has also been compared with drug therapy for asymp tomatic carotid artery stenosis in several trials.13–15
ACAS (the Asymptomatic Carotid Atherosclerosis Study)15 assigned 1,662 patients who had no symptoms and had at least 60% carotid artery stenosis to endarterectomy or to medical management, and found a relative risk reduction of 53% in favor of surgery.15
The Veterans Affairs Cooperative Study Group14 corroborated these results in 444 patients with asymptomatic stenosis of greater than 50%. Endarterectomy was associated with a 61% lower risk of transient ischemic attack, transient monocular blindness, or stroke compared with medical therapy. However, there was no statistically significant difference in rates of stroke or death at 30 days.14
ACST (the Asymptomatic Carotid Surgery Trial),13 the largest study to compare carotid endarterectomy with drug therapy for asymptomatic stenosis, randomized 3,120 patients to surgery or drug therapy. The net 5-year risk of stroke was 6.4% with endarterectomy vs 11.8% with drug therapy (P < .0001). The rate of fatal stroke was also lower with endarterectomy: 2.1% vs 4.2% (P = .006).13
Comment. The results of these and other studies of endarterectomy vs medical therapy may not be applicable to current practice, since medical therapy has evolved and the risks with current drug therapy are likely much lower than seen in these trials, some of which began 2 decades ago. Another problem with interpreting these trials is that they excluded surgically “high-risk” patients, which limits the generalizability of the findings to this particular patient population.
The American Heart Association and the American Stroke Association have, on the basis of these trials, recommended carotid endarterectomy in patients with7,8,16:
Ipsilateral, symptomatic carotid artery stenosis of 70% to 99% (class I, level of evidence A)
Symptomatic stenosis of 50% to 69%, depending on patient-specific factors such as age, sex, and comorbidities
High-grade asymptomatic carotid stenosis, if the patients are carefully selected and the surgery is performed by surgeons with procedural morbidity and mortality rates of less than 3% (class I, level of evidence A).
In all cases, treatment should be individualized according to the patient’s comorbid conditions and preferences, with a thorough discussion of risks and benefits (Table 1).7,8,16
The case for percutaneous intervention
While carotid endarterectomy is proven to be more efficacious than medical management in certain patient subsets, studies favoring surgery over medical therapy have been criticized because they excluded patients with significant comorbidities. In addition, surgery has been associated with significant cardiovascular events, wound complications, and cranial nerve damage, and it requires general anesthesia in most cases.12,17–19 These and other factors spurred the development of less invasive, percutaneous approaches for patients with substantial comorbidities.
So far, several trials have investigated carotid angioplasty with or without stents and with or without devices to capture distal emboli. This interest set the stage for CREST.20,21
Initial attempts at angioplasty without distal protection were not very successful. A meta-analysis of nonrandomized trials that included 714 patients from the initial 13 studies of angioplasty (with or without stenting) and 6,970 patients from 20 studies of carotid endarterectomy found angioplasty to be possibly associated with higher rates of stroke within 30 days of the procedure.20
With improvements in technology, routine use of embolic protection devices, more experience, and better selection of patients, the outcome of carotid stenting has improved. In fact, a meta-analysis comparing stenting without an embolic protection device (26 trials with 2,357 patients) vs stenting with an embolic protection device (11 trials with 839 patients) showed that embolic protection led to significantly better outcomes with fewer strokes—outcomes arguably similar to those of carotid endarterectomy.21
SAPPHIRE (the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy trial)22 was the only completed US trial until CREST that compared carotid artery stenting with distal protection against surgery. It included 334 high-risk patients with either symptomatic stenosis of 50% or greater or asymptomatic stenosis of 80% or greater.
The results suggested that the outcomes with stenting with embolic protection were in fact similar to those of endarterectomy, with possibly fewer complications.23 The benefit persisted up to 2 years.22
The US Food and Drug Administration (FDA), on the basis of these data, approved the use of stenting with distal protection for high-risk patients, and the CMS reimburses for symptomatic stenosis of 50% or greater and for asymptomatic stenosis of 80% or greater as long as the patient is enrolled in a registry.
SPACE (the Stent-Protected Angioplasty Versus Carotid Endarterectomy in Symptomatic Patients trial),24 conducted in Germany, included 1,214 patients with symptomatic stenosis of at least 50%. Results were similar in terms of the combined primary end point of stroke or death at 30 days. However, the results were not similar enough to prove that stenting is not inferior to surgery, according to preset study criteria.
EVA-3S (the Endarterectomy Versus Stenting in Patients With Symptomatic Severe Carotid Stenosis trial),25 in France, evaluated 527 patients with symptomatic carotid disease (stenosis ≥ 60%), but was terminated early due to significantly higher rates of death or stroke at 30 days in the stenting group.
Comment. SPACE and EVA-3S have been widely criticized for not mandating the use of an embolic protection device (used in 27% of cases in SPACE and in 91.9% of cases in EVA-3S). Questions were also raised about the experience level of the operators who performed the carotid stenting: up to 39% of the primary operators involved in stent placement were trainees.26 Also, myocardial infarction (MI), an important complication of carotid endarterectomy, was not included in the primary end point.
ICSS (the International Carotid Stenting Study)27 compared stenting with endarterectomy in 1,713 patients with symptomatic carotid stenosis of greater than 50%. The primary end point was the rate of fatal or disabling stroke at 3 years.
An interim safety analysis at 120 days of follow-up showed the primary end point had occurred in 4.0% of stenting cases vs 3.2% of endarterectomy cases, a difference that was not statistically significant (hazard ratio [HR] 1.28, 95% confidence interval [CI] 0.77–2.11). However, the risk of any stroke was higher with stenting, with a rate of 7.7% vs 4.1% in the surgical group—a statistically significant difference (HR 1.92, 95% CI 1.27–2.89).
In a substudy of ICSS,28 the investigators corroborated these findings, using magnetic resonance imaging to evaluate for new ischemic brain lesions periprocedurally. They found more new ischemic brain lesions in patients who underwent stenting than in patients who underwent surgery—a statistically significant finding.
Comment. ICSS had limitations: eg, it included only patients with symptoms, and the training for the stenting procedure was not standardized. Furthermore, the use of embolic protection devices was not mandated in stenting procedures.
Because of the controversial and incongruous findings of the above trials, there has been much anticipation for further large, appropriately conducted, randomized controlled trials such as CREST.
CREST STUDY DESIGN
CREST was a prospective, multicenter randomized controlled trial with blinded end point adjudication. Assignment to stenting or surgery occurred in a one-to-one fashion, and patients were stratified by medical center and symptomatic status.
Conducted at 108 sites in the United States and nine sites in Canada, CREST was supported by a grant from the National Institutes of Health and by the manufacturer of the catheter and stent delivery and embolic protection systems. The manufacturer’s representative held a nonvoting position on the executive committee and reviewed the manuscript of the results before submission.
CREST included patients with or without symptoms
CREST was initially designed to compare carotid artery stenting vs carotid endarterectomy in patients with symptoms, but enrollment was later extended to patients without symptoms.
Patients with symptoms were included if they had stenosis of at least 50% on angiography, at least 70% on ultrasonography, or at least 70% on computed tomographic angiography or magnetic resonance angiography if stenosis on ultrasonography was 50% to 69%. Carotid artery stenosis was considered symptomatic if the patient had a transient ischemic attack, amaurosis fugax, or minor disabling stroke in the hemisphere supplied by the target vessel within 180 days of randomization.
Patients without symptoms were eligible if they had at least 60% stenosis on angiography, at least 70% stenosis on ultrasonography, or at least 80% stenosis on computed tomographic angiography or magnetic resonance angiography if the stenosis was 50% to 69% on ultrasonography.
Other eligibility criteria included favorable anatomy and clinical stability for both stenting and surgical procedures.
Exclusion criteria were evolving stroke, history of major stroke, chronic or paroxysmal atrial fibrillation on anticoagulation therapy, MI within the previous 30 days, and unstable angina.
Patients received antiplatelet agents
Patients undergoing stenting received aspirin and clopidogrel (Plavix) before and up to 30 days after the procedure. Continuation of antiplatelet therapy was recommended beyond 1 month.
Patients undergoing endarterectomy received aspirin before surgery and continued to receive aspirin for at least 1 year.
Alternatives to aspirin in both groups were ticlopidine (Ticlid), clopidogrel, or aspirin with extended-release dipyridamole (Aggrenox).
End points: Stroke, MI, death
The primary end point was a composite of periprocedural clinical stroke (any type), MI, or death, and of ipsilateral stroke up to 4 years after the procedure. Secondary analyses were also planned for evaluation of treatment modification by age, symptom status, and sex.
Stroke was defined as any acute neurologic ischemic event lasting at least 24 hours with focal signs and symptoms.
Two separate definitions were applied to distinguish major stroke from nonmajor stroke. Major stroke was defined as a National Institutes of Health Stroke Scale (NIHSS) score greater than 9 or records suggesting that the event was a disabling stroke if admitted to another facility. Nonmajor stroke included an event that did not fit these criteria. The stroke review process was initiated with a significant neurologic event, a positive transient ischemia attack or stroke questionnaire, or a two-point or greater increase in the NIHSS score.
MI was defined as a combination of an elevation of cardiac enzymes to at least twice the laboratory upper limit of normal, as well as clinical signs suggesting MI or electrocardiographic evidence of ischemia.29
Stroke was adjudicated by two independent neurologists, and MI was adjudicated by two independent cardiologists blinded to treatment group assignment.
The Rankin scale, the transient ischemic attack and stroke questionnaire, and the Medical Outcomes Survey were also used to assess for disability and quality of life in long-term follow-up.
Intention-to-treat analysis
Intention-to-treat survival analysis was used along with time-to-event statistical modeling with adjustment for major baseline covariates. Differences in outcomes were assessed, and a noninferiority analysis was performed. Kaplan-Meier estimates were constructed of the proportion of patients remaining free of the composite end point at 30 days, 6 months, 1 year, and annually thereafter, and of the associated confidence intervals. The hazard ratios between groups were estimated after adjustment for important covariates.
Most patients enrolled were available for analysis
From December 2000 to July 2008, 2,522 patients were enrolled; 1,271 were assigned to stenting, and 1,251 were assigned to surgery. After randomization, 2.8% of the patients assigned to stenting withdrew consent, 5.7% underwent surgery, and 2.6% were lost to follow-up. Of those assigned to surgery, 5.1% withdrew consent, 1.0% underwent stenting, and 3.8% were lost to follow-up.
A ‘conventional-risk’ patient population
The trial sought to include a “conventional-risk” patient population to make the study more applicable to real-world practice. The mean age was 69 years in both groups. Of the 2,522 patients enrolled:
35% were women
47% had asymptomatic carotid disease
86% had carotid stenosis of 70% or greater
86% had hypertension
30% had diabetes mellitus
83% had hyperlipidemia
26% were current smokers
42% had a history of cardiovascular disease
21% had undergone coronary artery bypass grafting surgery.
The only statistically significant difference in measured baseline variables between the two treatment groups was a slightly higher rate of dyslipidemia in the group undergoing surgery.
The interventionalists and surgeons were highly experienced
Operators performing stenting underwent a lead-in phase of training, with close supervision and scrutiny before eligibility. Of patients undergoing stenting, 96.1% also received an embolic protection device. Antiplatelet therapy was continued in 99% of the patients.
The surgeons performing endarterectomy were experienced and had documented low complication rates. General anesthesia was used in 90% of surgical patients. Shunts were used during surgery in 57%, and patches were used in 62%. After endarterectomy, 91% of the patients received antiplatelet therapy.
CREST STUDY RESULTS: STENTING WAS AS GOOD AS SURGERY
Periprocedural outcomes
Stroke, MI, or death: 5.2% with stenting vs 4.5% with surgery, HR 1.18, 95% CI 0.82–1.68, P = .38
Stroke: 4.1% vs 2.3%, HR 1.79, 95% CI 1.14–2.82, P = .01
Major ipsilateral stroke: 0.9% vs 0.3%, HR 2.67, 95% CI 0.85–8.40, P = .09.
MI: 1.1% vs 2.3%, HR 0.50, 95% CI 0.26–0.94, P = .03
Cranial nerve palsy: 0.3% vs 4.8%, HR 0.07, 95% CI 0.02–0.18, P < .0001 (Table 2).
Outcomes at 4 years
Brott TG, et al; CREST Investigators. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010; 363:11–23. Copyright 2010, Massachusetts Medical Society. All rights reserved.
Figure 2. Kaplan-Meier analysis of the primary outcome (stroke, myocardial infarction, or death during the periprocedural period or any ipsilateral stroke within 4 years after randomization) for patients undergoing carotid artery stenting or carotid endarterectomy.The primary end point (periprocedural stroke, MI, or death, or ipsilateral stroke within 4 years after the procedure): 7.2% with stenting vs 6.8% with surgery, HR 1.11, 95% CI 0.81–1.51, P = .51. A Kaplan-Meier analysis showed similar findings with statistically similar outcomes (Figure 2).
Ipsilateral stroke: 2.0% vs 2.4%, HR 0.94, 95% CI 0.50–1.76, P = .85.
The primary outcome was analyzed for interactions of baseline variables, and no effect was detected for symptomatic status or sex. There was a suggestion of an interaction with age, with older patients (over age 70) benefiting more from endarterectomy.
Quality-of-life indices showed that both major and minor strokes were likely to produce long-term physical limitations, with minor stroke associated with worse mental and physical health at 1 year. The effect of periprocedural MI on long-term physical and mental health was less certain. The increased incidence of cranial nerve palsy noted with endarterectomy has been found before and has had no effect on quality of life.
WHAT DO THE CREST FINDINGS MEAN?
CREST is the largest trial to date to compare stenting and surgery. It is an important addition to the literature, not only because of its size, but also because it focused on a real-world patient population. For this reason, its results are more applicable to patients seen in primary care clinics, ie, with peripheral vascular disease, coronary artery disease, diabetes mellitus, hypertension, and smoking.
As noted, previous studies of endarterectomy had strict inclusion and exclusion criteria, which selected against patients at high surgical risk. Therefore, the CREST findings are of greater relevance when comparing stenting and endarterectomy.
Periprocedural and long-term neurologic outcomes
CREST showed similar findings for the composite end point of periprocedural stroke, death, or MI (ie, within 30 days of the procedure) and long-term stroke, establishing similar outcomes in patients undergoing stenting and surgery.
However, an analysis of the individual components of the composite end point showed significant differences between the two treatments. The risk of ipsilateral periprocedural stroke was higher with stenting; these events were defined as nonmajor by NIHSS criteria. The risk of contralateral stroke was similar and low with each treatment.
While the increased risk of periprocedural ipsilateral stroke was not synonymous with an increased risk of major stroke, post hoc analysis showed that any stroke was associated with decreased physical and mental health at 1 year. Therefore, patients who had even a minor stroke did worse from a physical and mental standpoint, a finding that argues for the superiority of surgery in selected patients at risk of periprocedural stroke.
If periprocedural stroke is excluded, the risk of long-term ipsilateral stroke was similar for each treatment, and extremely low (2% for stenting, 2.4% for surgery). Despite this, given the importance of periprocedural minor and major stroke, better predictive models are needed to identify patients at risk of procedural neurologic events. These prediction models will allow better patient selection.
The CREST data and medical therapy
The rates of stroke in this trial were similar to those observed with current medical treatment (approximately 1% per year), especially for patients with asymptomatic disease. Such findings introduce fresh controversy in the necessity of performing either procedure for this patient subset and may lead to further studies evaluating current medical therapy vs intervention.
Periprocedural myocardial infarction
Vascular surgery has long been associated with high cardiovascular risk, especially an increased risk of periprocedural MI.30 Findings from CREST provide further evidence of the risk of MI with endarterectomy in a real-world patient population. Given the evidence of a strong correlation between periprocedural cardiac enzyme elevations and adverse outcomes, the increased incidence of periprocedural MI is worrisome.31 As with risk assessment for periprocedural stroke, better predictive models are needed for patients at risk of cardiovascular events during endarterectomy.
Procedural complications
Carotid endarterectomy entails incisions in the neck with disruption of tissue planes, as opposed to catheter entry site wounds with stenting. The more invasive nature of endarterectomy thus carries a higher risk of wound complications. In fact, in the NASCET trial, the risk of wound complications was 9.3%.10,19 In CREST, surgery carried a higher risk of wound complications compared with stenting (42 vs 0 cases), although stenting involved more periprocedural transfusions, presumably due to retroperitoneal bleeding in four patients.
Use of general anesthesia is also associated with adverse outcomes.17,18 In CREST, 90% of endarterectomy procedures required general anesthesia, whereas none of the stenting procedures required this.
Cranial nerve palsy is an often overlooked but real complication after these procedures. Cranial nerve palsies can lead to vocal, swallowing, and sensory problems that can have a transient or permanent impact on quality of life. In CREST, as in EVA-3S, SAPPHIRE, and ICSS, this risk was substantially higher with surgery,23,25,27 although the long-term consequences of these palsies were not found to affect quality of life at 1 year of follow-up.
HOW CREST FINDINGS COMPARE WITH PREVIOUS STUDIES
Patients in CREST enjoyed overall better outcomes than in previous studies. In earlier trials of surgery vs medical therapy, the rates of adverse outcomes were higher than in CREST. In NASCET, the risk of ipsilateral stroke was 9% with surgery, with 2.5% being fatal or disabling strokes.10 In the ECST, rates of major stroke or death with endarterectomy were 7.0% within 30 days of surgery and 37.0% at a mean follow-up of 6.1 years.12
In earlier studies of surgery vs stenting, outcomes at 30 days were also substantially worse than those in CREST. In the EVA-3S trial, the 30-day incidence of stroke or death was 3.9% after surgery and 9.6% after stenting. These findings were similar at 6 months in EVA-3S, with a 6.1% rate of adverse events after surgery and 11.7% after stenting.25 In the SAPPHIRE trial, the cumulative incidence of stroke and death at 1 year was 21.4% for surgery and 13.6% for stenting.23
Overall, the CREST results show better outcomes than in previous trials. This may be due to improvements in technical aspects of the interventions and to more aggressive drug therapy. Also, because of the high number of patients enrolled in CREST, surgeons and interventionalists were required to meet eligibility criteria, which could have contributed to the improved outcomes.32
CREST was also unique in that stenting was done with an embolic protection device whenever possible, and this also likely had an impact on outcomes.
The CREST data suggest that interventions for carotid artery stenosis should only be performed by rigorously trained, experienced personnel at high-volume centers, as this provided lower event rates compared with previous studies. Additional data should also help identify those at risk of periprocedural stroke and MI, thereby helping to match the patient to the most appropriate procedure. The pros and cons of surgery and stenting are shown in Table 3.1,10,23,25,27
CREST vs ICSS
CREST and ICSS, published within a few months of each other, seem to have arrived at entirely different conclusions. As both studies are well-designed randomized controlled trials, these distinct results have yielded much controversy. However, closer scrutiny sheds light as to why the results may be different.
While ICSS focused only on patients with symptoms, CREST also included those without symptoms. The difference in patient populations is itself enough to account for the different outcomes.
Also, the interim analysis of ICSS was at 120 days, which makes periprocedural events a more dominant factor in outcomes, whereas these events likely do not last into the long term, as was the case in CREST. Analysis of the ICSS data at a later follow-up date may show results more similar to those of CREST.
The design of ICSS was also different than CREST. In ICSS, the use of an embolic protection device in stenting was not mandated, and the study lacked a lead-in phase of intensive training for those performing stenting. Furthermore, MI was adjudicated only when clinically recognized, which is different than the more rigorous method used in CREST.
Yet despite these differences, CREST and ICSS shed light on a controversial area of carotid stenosis management, and both studies boasted low rates of periprocedural complications. Clinicians should keep in mind the inclusion criteria and the technical specificities of these trials in order to explain to patients the risks and benefits of stenting and surgery, and to arrive at a decision together.
Limitations
The results of CREST should also be reviewed carefully due to a number of limitations. The study began in 2000 with symptomatic patients only, and began enrolling asymptomatic patients in 2005, so that the methodology of the study was changed midway. However, the investigators performed a subgroup analysis to distinguish between outcomes of the symptomatic and the asymptomatic groups and found no statistical interaction for the primary end point based on symptom status.
Despite careful patient selection, many of the predictors of adverse outcomes with stenting, such as lesion length, level of calcification, and lesion location, were not accounted for in the earlier days of enrollment. This may have had an impact on the incidence of stroke in patients enrolled in the early years of the trial. We await the analysis of predictors of perioperative stroke from CREST.
TAKE-HOME POINTS AND FUTURE DIRECTIONS
The CREST findings show that outcomes with stenting are similar to those with surgery in both the short term and the long term, and that the choice of management should be individualized. Each patient’s risk of MI and stroke should be considered based on a variety of factors, including the severity of coronary artery disease, the length of the carotid lesion, the level of calcification, the location of the lesion, and aortic atheroma. The treatment should be selected after also taking into account the patient’s preference and the available expertise, and only after a comprehensive discussion with the patient.
References
Brott TG, Hobson RW, Howard G, et al; CREST Investigators. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med2010; 363:11–23.
Thom T, Haase N, Rosamond W, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation2006; 113:e85–e151.
Rosamond WD, Folsom AR, Chambless LE, et al. Stroke incidence and survival among middle-aged adults: 9-year follow-up of the Atherosclerosis Risk in Communities (ARIC) cohort. Stroke1999; 30:736–743.
Chaturvedi S, Bruno A, Feasby T, et al; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Carotid endarterectomy—an evidence-based review: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology2005; 65:794–801.
Howell GM, Makaroun MS, Chaer RA. Current management of extracranial carotid occlusive disease. J Am Coll Surg2009; 208:442–453.
Barnett HJ, Gunton RW, Eliasziw M, et al. Causes and severity of ischemic stroke in patients with internal carotid artery stenosis. JAMA2000; 283:1429–1436.
Biller J, Feinberg WM, Castaldo JE, et al. Guidelines for carotid endarterectomy: a statement for healthcare professionals from a Special Writing Group of the Stroke Council, American Heart Association. Circulation1998; 97:501–509.
Goldstein LB, Adams R, Alberts MJ, et al; American Heart Association; American Stroke Association Stroke Council. Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation2006; 113:e873–e923.
Strully KJ, Hurwitt ES, Blankenberg HW. Thrombo-endarterectomy for thrombosis of the internal carotid artery in the neck. J Neurosurg1953; 10:474–482.
Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med1991; 325:445–453.
Barnett HJ, Taylor DW, Eliasziw M, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med1998; 339:1415–1425.
Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet1998; 351:1379–1387.
Halliday A, Mansfield A, Marro J, et al; MRC Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial. Lancet2004; 363:1491–1502.
Hobson RW, Weiss DG, Fields WS, et al. Efficacy of carotid endarterectomy for asymptomatic carotid stenosis. The Veterans Affairs Cooperative Study Group. N Engl J Med1993; 328:221–227.
Endarterectomy for asymptomatic carotid artery stenosis. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. JAMA1995; 273:1421–1428.
Sacco RL, Adams R, Albers G, et al; American Heart Association/American Stroke Association Council on Stroke; Council on Cardiovascular Radiology and Intervention; American Academy of Neurology. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline. Circulation2006; 113:e409–e449.
Watts K, Lin PH, Bush RL, et al. The impact of anesthetic modality on the outcome of carotid endarterectomy. Am J Surg2004; 188:741–747.
Weber CF, Friedl H, Hueppe M, et al. Impact of general versus local anesthesia on early postoperative cognitive dysfunction following carotid endarterectomy: GALA Study Subgroup Analysis. World J Surg2009; 33:1526–1532.
Ferguson GG, Eliasziw M, Barr HW, et al. The North American Symptomatic Carotid Endarterectomy Trial: surgical results in 1415 patients. Stroke1999; 30:1751–1758.
Golledge J, Mitchell A, Greenhalgh RM, Davies AH. Systematic comparison of the early outcome of angioplasty and endarterectomy for symptomatic carotid artery disease. Stroke2000; 31:1439–1443.
Kastrup A, Gröschel K, Krapf H, Brehm BR, Dichgans J, Schulz JB. Early outcome of carotid angioplasty and stenting with and without cerebral protection devices: a systematic review of the literature. Stroke2003; 34:813–819.
Gurm HS, Yadav JS, Fayad P, et al; SAPPHIRE Investigators. Long-term results of carotid stenting versus endarterectomy in high-risk patients. N Engl J Med2008; 358:1572–1579.
Yadav JS, Wholey MH, Kuntz RE, et al; Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy Investigators. Protected carotid-artery stenting versus endarterectomy in high-risk patients. N Engl J Med2004; 351:1493–1501.
Eckstein HH, Ringleb P, Allenberg JR, et al. Results of the Stent-Protected Angioplasty versus Carotid Endarterectomy (SPACE) study to treat symptomatic stenoses at 2 years: a multinational, prospective, randomised trial. Lancet Neurol2008; 7:893–902.
Mas JL, Chatellier G, Beyssen B, et al; EVA-3S Investigators. Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis. N Engl J Med2006; 355:1660–1771.
Roffi M, Sievert H, Gray WA, et al. Carotid artery stenting versus surgery: adequate comparisons?Lancet Neurol2010; 9:339–341.
International Carotid Stenting Study Investigators; Ederle J, Dobson J, Featherstone RL, et al. Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial. Lancet2010; 375:985–997.
Bonati LH, Jongen LM, Haller S, et al; ICSS-MRI study group. New ischaemic brain lesions on MRI after stenting or endarterectomy for symptomatic carotid stenosis: a sub-study of the International Carotid Stenting Study (ICSS). Lancet Neurol2010; 9:353–362.
Sheffet AJ, Roubin G, Howard G, et al. Design of the Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST). Int J Stroke2010; 5:40–46.
Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery) developed in collaboration with the American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, and Society for Vascular Surgery. J Am Coll Cardiol2007; 50:e159–e241.
Bhatt DL, Topol EJ. Does creatinine kinase-MB elevation after percutaneous coronary intervention predict outcomes in 2005? Periprocedural cardiac enzyme elevation predicts adverse outcomes. Circulation2005; 112:906–915.
Hobson RW, Howard VJ, Roubin GS, et al; CREST. Credentialing of surgeons as interventionalists for carotid artery stenting: experience from the lead-in phase of CREST. J Vasc Surg2004; 40:952–957.
References
Brott TG, Hobson RW, Howard G, et al; CREST Investigators. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med2010; 363:11–23.
Thom T, Haase N, Rosamond W, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation2006; 113:e85–e151.
Rosamond WD, Folsom AR, Chambless LE, et al. Stroke incidence and survival among middle-aged adults: 9-year follow-up of the Atherosclerosis Risk in Communities (ARIC) cohort. Stroke1999; 30:736–743.
Chaturvedi S, Bruno A, Feasby T, et al; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Carotid endarterectomy—an evidence-based review: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology2005; 65:794–801.
Howell GM, Makaroun MS, Chaer RA. Current management of extracranial carotid occlusive disease. J Am Coll Surg2009; 208:442–453.
Barnett HJ, Gunton RW, Eliasziw M, et al. Causes and severity of ischemic stroke in patients with internal carotid artery stenosis. JAMA2000; 283:1429–1436.
Biller J, Feinberg WM, Castaldo JE, et al. Guidelines for carotid endarterectomy: a statement for healthcare professionals from a Special Writing Group of the Stroke Council, American Heart Association. Circulation1998; 97:501–509.
Goldstein LB, Adams R, Alberts MJ, et al; American Heart Association; American Stroke Association Stroke Council. Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation2006; 113:e873–e923.
Strully KJ, Hurwitt ES, Blankenberg HW. Thrombo-endarterectomy for thrombosis of the internal carotid artery in the neck. J Neurosurg1953; 10:474–482.
Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med1991; 325:445–453.
Barnett HJ, Taylor DW, Eliasziw M, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med1998; 339:1415–1425.
Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet1998; 351:1379–1387.
Halliday A, Mansfield A, Marro J, et al; MRC Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial. Lancet2004; 363:1491–1502.
Hobson RW, Weiss DG, Fields WS, et al. Efficacy of carotid endarterectomy for asymptomatic carotid stenosis. The Veterans Affairs Cooperative Study Group. N Engl J Med1993; 328:221–227.
Endarterectomy for asymptomatic carotid artery stenosis. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. JAMA1995; 273:1421–1428.
Sacco RL, Adams R, Albers G, et al; American Heart Association/American Stroke Association Council on Stroke; Council on Cardiovascular Radiology and Intervention; American Academy of Neurology. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline. Circulation2006; 113:e409–e449.
Watts K, Lin PH, Bush RL, et al. The impact of anesthetic modality on the outcome of carotid endarterectomy. Am J Surg2004; 188:741–747.
Weber CF, Friedl H, Hueppe M, et al. Impact of general versus local anesthesia on early postoperative cognitive dysfunction following carotid endarterectomy: GALA Study Subgroup Analysis. World J Surg2009; 33:1526–1532.
Ferguson GG, Eliasziw M, Barr HW, et al. The North American Symptomatic Carotid Endarterectomy Trial: surgical results in 1415 patients. Stroke1999; 30:1751–1758.
Golledge J, Mitchell A, Greenhalgh RM, Davies AH. Systematic comparison of the early outcome of angioplasty and endarterectomy for symptomatic carotid artery disease. Stroke2000; 31:1439–1443.
Kastrup A, Gröschel K, Krapf H, Brehm BR, Dichgans J, Schulz JB. Early outcome of carotid angioplasty and stenting with and without cerebral protection devices: a systematic review of the literature. Stroke2003; 34:813–819.
Gurm HS, Yadav JS, Fayad P, et al; SAPPHIRE Investigators. Long-term results of carotid stenting versus endarterectomy in high-risk patients. N Engl J Med2008; 358:1572–1579.
Yadav JS, Wholey MH, Kuntz RE, et al; Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy Investigators. Protected carotid-artery stenting versus endarterectomy in high-risk patients. N Engl J Med2004; 351:1493–1501.
Eckstein HH, Ringleb P, Allenberg JR, et al. Results of the Stent-Protected Angioplasty versus Carotid Endarterectomy (SPACE) study to treat symptomatic stenoses at 2 years: a multinational, prospective, randomised trial. Lancet Neurol2008; 7:893–902.
Mas JL, Chatellier G, Beyssen B, et al; EVA-3S Investigators. Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis. N Engl J Med2006; 355:1660–1771.
Roffi M, Sievert H, Gray WA, et al. Carotid artery stenting versus surgery: adequate comparisons?Lancet Neurol2010; 9:339–341.
International Carotid Stenting Study Investigators; Ederle J, Dobson J, Featherstone RL, et al. Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial. Lancet2010; 375:985–997.
Bonati LH, Jongen LM, Haller S, et al; ICSS-MRI study group. New ischaemic brain lesions on MRI after stenting or endarterectomy for symptomatic carotid stenosis: a sub-study of the International Carotid Stenting Study (ICSS). Lancet Neurol2010; 9:353–362.
Sheffet AJ, Roubin G, Howard G, et al. Design of the Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST). Int J Stroke2010; 5:40–46.
Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery) developed in collaboration with the American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, and Society for Vascular Surgery. J Am Coll Cardiol2007; 50:e159–e241.
Bhatt DL, Topol EJ. Does creatinine kinase-MB elevation after percutaneous coronary intervention predict outcomes in 2005? Periprocedural cardiac enzyme elevation predicts adverse outcomes. Circulation2005; 112:906–915.
Hobson RW, Howard VJ, Roubin GS, et al; CREST. Credentialing of surgeons as interventionalists for carotid artery stenting: experience from the lead-in phase of CREST. J Vasc Surg2004; 40:952–957.
In CREST, stenting and surgery had similar combined rates of stroke, MI, and death when performed by highly qualified interventionalists and surgeons in carefully selected patients.
The risk of periprocedural stroke was higher with stenting; most of those strokes were nonmajor. Both major and nonmajor strokes were associated with decreased quality of life in long-term follow-up.
Endarterectomy was associated with higher rates of periprocedural MI than stenting.
Endarterectomy carried a significantly higher rate of cranial nerve damage than stenting.
mammogram, Duke University, University of North Carolina, Personally Relevant Information on Screening Mammography, PRISM, remindermammogram, Duke University, University of North Carolina, Personally Relevant Information on Screening Mammography, PRISM, reminder
mammogram, Duke University, University of North Carolina, Personally Relevant Information on Screening Mammography, PRISM, remindermammogram, Duke University, University of North Carolina, Personally Relevant Information on Screening Mammography, PRISM, reminder
Legacy Keywords
mammogram, Duke University, University of North Carolina, Personally Relevant Information on Screening Mammography, PRISM, remindermammogram, Duke University, University of North Carolina, Personally Relevant Information on Screening Mammography, PRISM, reminder
fMRI findings may enable researchers to further the understanding of the neural systems underlying autism.
With use of fMRI, researchers have identified a pattern of brain activity that may characterize a child’s genetic vulnerability to develop autism spectrum disorder (ASD), according to a study in the November 15 online Proceedings of the National Academy of Sciences.
The investigators administered an fMRI scan to a group of children, ages 4 to 17, who viewed coherent and scrambled point-light animations of biologic motion in a blocked design. Twenty-five children had ASD, 20 were unaffected siblings of children with ASD, and 17 were typically developing children. By comparing the activation to biologic motion versus that of scrambled motion in the subjects, the investigators observed three types of neural signatures, noted Martha D. Kaiser, PhD, of the Yale School of Medicine in New Haven, Connecticut, and colleagues.
The first type, state activity, is related to the state of having ASD that characterizes the nature of disruption in brain circuitry. The second, trait activity, reflects shared areas of dysfunction in unaffected siblings and children with ASD, thereby providing a possible neuroendophenotype to help efforts in linking genomic complexity and disorder heterogeneity, according to Dr. Kaiser. The third neural signature, compensatory activity, is unique to unaffected siblings, suggesting a neural system-level mechanism by which they may compensate for an increased genetic risk for developing ASD.
“The distinct brain responses to biologic motion exhibited by typically developing children and unaffected siblings are striking given the identical behavioral profile of these two groups,” the researchers reported. “These findings offer far-reaching implications for our understanding of the neural systems underlying autism.
“This fMRI study features the youngest groups of children with and without ASD studied to date, offering a substantial contribution to characterizing early developmental stages of disruptions in the neural systems associated with ASD,” Dr. Kaiser and colleagues concluded. “These disruptions in brain function may arise from various genetic and molecular etiologies and are further transformed across development by the experiences and activity of the individual in the world. Notably, the presence of state, trait, and compensatory activity, elicited by the viewing of socially relevant biologic motion, emphasizes the importance of brain mechanisms in social perception as well as the dysfunction of these mechanisms in this neurodevelopmental disorder.”
—Colby Stong
References
Suggested Reading Kaiser MD, Hudac CM, Shultz S, et al. Neural signatures of autism. Proc Natl Acad Sci USA. 2010 Nov 15; [Epub ahead of print].
Neurology Reviews, Autism, autism spectrum disorder, Proceedings of the National Academy of Sciences, Martha D. KaiserNeurology Reviews, Autism, autism spectrum disorder, Proceedings of the National Academy of Sciences, Martha D. Kaiser
fMRI findings may enable researchers to further the understanding of the neural systems underlying autism.
With use of fMRI, researchers have identified a pattern of brain activity that may characterize a child’s genetic vulnerability to develop autism spectrum disorder (ASD), according to a study in the November 15 online Proceedings of the National Academy of Sciences.
The investigators administered an fMRI scan to a group of children, ages 4 to 17, who viewed coherent and scrambled point-light animations of biologic motion in a blocked design. Twenty-five children had ASD, 20 were unaffected siblings of children with ASD, and 17 were typically developing children. By comparing the activation to biologic motion versus that of scrambled motion in the subjects, the investigators observed three types of neural signatures, noted Martha D. Kaiser, PhD, of the Yale School of Medicine in New Haven, Connecticut, and colleagues.
The first type, state activity, is related to the state of having ASD that characterizes the nature of disruption in brain circuitry. The second, trait activity, reflects shared areas of dysfunction in unaffected siblings and children with ASD, thereby providing a possible neuroendophenotype to help efforts in linking genomic complexity and disorder heterogeneity, according to Dr. Kaiser. The third neural signature, compensatory activity, is unique to unaffected siblings, suggesting a neural system-level mechanism by which they may compensate for an increased genetic risk for developing ASD.
“The distinct brain responses to biologic motion exhibited by typically developing children and unaffected siblings are striking given the identical behavioral profile of these two groups,” the researchers reported. “These findings offer far-reaching implications for our understanding of the neural systems underlying autism.
“This fMRI study features the youngest groups of children with and without ASD studied to date, offering a substantial contribution to characterizing early developmental stages of disruptions in the neural systems associated with ASD,” Dr. Kaiser and colleagues concluded. “These disruptions in brain function may arise from various genetic and molecular etiologies and are further transformed across development by the experiences and activity of the individual in the world. Notably, the presence of state, trait, and compensatory activity, elicited by the viewing of socially relevant biologic motion, emphasizes the importance of brain mechanisms in social perception as well as the dysfunction of these mechanisms in this neurodevelopmental disorder.”
—Colby Stong
fMRI findings may enable researchers to further the understanding of the neural systems underlying autism.
With use of fMRI, researchers have identified a pattern of brain activity that may characterize a child’s genetic vulnerability to develop autism spectrum disorder (ASD), according to a study in the November 15 online Proceedings of the National Academy of Sciences.
The investigators administered an fMRI scan to a group of children, ages 4 to 17, who viewed coherent and scrambled point-light animations of biologic motion in a blocked design. Twenty-five children had ASD, 20 were unaffected siblings of children with ASD, and 17 were typically developing children. By comparing the activation to biologic motion versus that of scrambled motion in the subjects, the investigators observed three types of neural signatures, noted Martha D. Kaiser, PhD, of the Yale School of Medicine in New Haven, Connecticut, and colleagues.
The first type, state activity, is related to the state of having ASD that characterizes the nature of disruption in brain circuitry. The second, trait activity, reflects shared areas of dysfunction in unaffected siblings and children with ASD, thereby providing a possible neuroendophenotype to help efforts in linking genomic complexity and disorder heterogeneity, according to Dr. Kaiser. The third neural signature, compensatory activity, is unique to unaffected siblings, suggesting a neural system-level mechanism by which they may compensate for an increased genetic risk for developing ASD.
“The distinct brain responses to biologic motion exhibited by typically developing children and unaffected siblings are striking given the identical behavioral profile of these two groups,” the researchers reported. “These findings offer far-reaching implications for our understanding of the neural systems underlying autism.
“This fMRI study features the youngest groups of children with and without ASD studied to date, offering a substantial contribution to characterizing early developmental stages of disruptions in the neural systems associated with ASD,” Dr. Kaiser and colleagues concluded. “These disruptions in brain function may arise from various genetic and molecular etiologies and are further transformed across development by the experiences and activity of the individual in the world. Notably, the presence of state, trait, and compensatory activity, elicited by the viewing of socially relevant biologic motion, emphasizes the importance of brain mechanisms in social perception as well as the dysfunction of these mechanisms in this neurodevelopmental disorder.”
—Colby Stong
References
Suggested Reading Kaiser MD, Hudac CM, Shultz S, et al. Neural signatures of autism. Proc Natl Acad Sci USA. 2010 Nov 15; [Epub ahead of print].
References
Suggested Reading Kaiser MD, Hudac CM, Shultz S, et al. Neural signatures of autism. Proc Natl Acad Sci USA. 2010 Nov 15; [Epub ahead of print].
Neurology Reviews, Autism, autism spectrum disorder, Proceedings of the National Academy of Sciences, Martha D. KaiserNeurology Reviews, Autism, autism spectrum disorder, Proceedings of the National Academy of Sciences, Martha D. Kaiser
Legacy Keywords
Neurology Reviews, Autism, autism spectrum disorder, Proceedings of the National Academy of Sciences, Martha D. KaiserNeurology Reviews, Autism, autism spectrum disorder, Proceedings of the National Academy of Sciences, Martha D. Kaiser
Brott TG, et al; CREST Investigators. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010; 363:11–23. Copyright 2010, Massachusetts Medical Society. All rights reserved.
