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Evaluation and Treatment of the Patient with Osteoarthritis
Osteoarthritis (OA) is a chronic and progressive disease in which damage is done to the joint and surrounding tissue. In the United States, OA is found in 6% of people older than 30 years and in 50% of those older than 60 years.1,2 It is the most common cause of disability in the United States and leads to considerable costs due to medical and surgical interventions and frequent absences from work.3-5 OA accounts for 2% of all visits to family physicians and is the 10th leading diagnosis encountered.6 Thus, a family physician can expect to have 2 or 3 patient encounters per week in which OA is one of the diagnoses. With the growing elderly population, this burden is likely to increase.
Pathophysiology
In OA, the smooth surface of hyaline cartilage develops irregularities because of alterations at the cellular level and gross mechanical forces.2 The role of inflammation has been debated in recent years, and its exact role is unknown. As OA progresses, the nearby bone remodels and forms further joint irregularities and osteophytes. These changes lead to narrowing of the joint space, and in some cases, chronic synovitis. Clinically, this causes pain, restricted movement, and periarticular muscle wasting. Treatment is aimed at these symptoms and structural abnormalities. The joints most commonly affected include the knees, hips, cervical and lumbosacral spine, distal interphalangeal (DIP) joints (producing Heberden nodes), proximal interphalangeal (PIP) joints (producing Bouchard nodes), and the first carpometacarpal joints of the hand. It is not known why these changes occur in some people and not in others. Epidemiologic studies and a recent sibling study raise the question of genetic influences in OA of the hip.7,8
Diagnosis
The diagnosis of OA is made on the basis of clinical and radiographic features. Few studies have compared a diagnostic test or strategy with a gold standard. Unfortunately, we do not have any good data about the usefulness of individual history and physical examination elements for diagnosing OA. Radiographs suggesting the diagnosis of OA (joint space narrowing, presence of osteophytes, irregular joint surfaces, sclerosis of subchondral bone, or bony cysts) must be closely correlated with clinical symptoms. According to epidemiologic surveys, only one half of patients with radiographic changes of OA of the knee complain of persistent pain.9 Classification criteria for OA of the knee, hip, and hands have been developed; they are outlined in Tables 1 Table 2 through Table 3.10,13
Although these criteria have limitations, they are becoming the standard for defining these types of OA and have been adapted by the American College of Rheumatology.11-13 Currently, there are no criteria for diagnosing OA of the back. When evaluating a patient with joint pain, other diagnoses must be considered (ie, rheumatoid arthritis, gout, pseudogout, septic arthritis, bursitis, and tendonitis).
Treatment
Most of the treatments of OA address the symptoms rather than the cause of the disease. The short-term goal is to decrease pain; long-term goals are to improve functioning and slow progression of disease. Table 4 provides a summary of treatment options.
Exercise
A systematic review of 12 randomized controlled trials (RCTs) showed beneficial effects of exercise therapy in patients with mild to moderate OA of the knee and, to a lesser extent, the hip.14 Benefits included improvements in pain, self-reported disability, walking performance, and the patient’s global assessment of symptoms. Insufficient evidence was available to recommend one type of exercise program over another. Exercise interventions included aerobic exercises, strength training, range of motion exercises, and fitness walking. Exercise programs were conducted as individuals or groups, supervised or home-based. Although this review was limited by the small number of good studies, recommending exercise for OA may improve patients’ symptoms and add other health benefits.
Physical Therapy
A recent RCT compared 4 weeks of manual physical therapy plus a supervised knee exercise program with sham ultrasound for treatment of OA of the knee.15 By 8 weeks, 6-minute walk distances had improved by 13% in the treatment group compared with no change in the placebo group; osteoarthritis index scores had improved 56% over baseline compared with 15% in the placebo group. One year following therapy 5% of the treated group had undergone knee arthroplasty compared with 20% of the untreated group (number needed to treat = 7). Given these clinically important improvements, physical therapy should be an early choice in the treatment of OA.
A systematic review of transcutaneous electrical nerve stimulation (TENS) for treatment of OA of the knee found that this noninvasive modality offered significant pain relief.16 Both high-frequency and strong burst mode TENS showed significant improvement in pain relief when used for 4 weeks or more. Also, the acupuncture-like TENS improved pain relief, stiffness, and walking time in a 2-week placebo-controlled trial.
Although spa therapy and low-level laser therapy may show some benefit, the true effectiveness cannot be determined, since the trials were small and of poor quality.17,18 No benefit was found in the one well-done RCT for ultrasound.19
Patient Education
Group patient education programs teach patients how to manage their disease. A 4-year longitudinal study using the Arthritis Self-Management Program (6 2-hour sessions), suggests that health education may decrease pain and visits to physicians.20,21 Estimated 4-year savings were $189 per patient.21 Telephone-based interventions have also been studied. A randomized trial of telephone contact for patients with OA found statistically significant differences in pain reduction according to the Arthritis Impact Measurement Scales at a very low cost.22,23 However, these differences may not be clinically significant as the groups differed by less than 1 point on a 10-point scale. Interestingly, educating patients during regularly scheduled appointments had no benefit and even resulted in worsening physical functioning.22 A systematic review of patient education interventions found a nonsignificant trend toward benefit using patient education compared with nonsteroidal anti-inflammatory drugs (NSAIDs).24 Despite the lack of convincing evidence from randomized trials, the possible benefits of educating our patients while using other therapies may outweigh the cost of the time involved, particularly if education can be done in a group setting.
Medication
Acetaminophen (4 g per day) has been shown in randomized trials to reduce pain in OA of the knee by approximately 30%.25,26 This improvement was seen at 4 weeks and at 2 years. Another study found the combination of codeine plus acetaminophen to be significantly better in reducing pain in patients with OA of the hip than acetaminophen alone, although one third of the patients receiving the combination discontinued therapy because of side effects.27 Narcotic analgesics alone have been shown in a randomized trial to be more effective in reducing pain than placebo but have not been adequately tested against acetaminophen or NSAIDs.28
NSAIDs also produce a 30% reduction in pain caused by OA.25,26 Two systematic reviews of OA concluded that there is no reliable evidence suggesting that any NSAID is more efficacious than the others in treating OA of the hip and knee.29,30 A separate meta-analysis found ibuprofen to have the lowest risk of side effects among the nonselective NSAIDs, a finding supported by the Committee on Safety in Medicine.31 For this reason, ibuprofen is recommended as the first-line nonselective NSAID.
Acetaminophen and NSAIDs have been found to be equally efficacious when compared in randomized controlled trials.25,26 According to a meta-analysis, the quality-of-life measures were similar between the 2 groups, despite a greater improvement in both pain at rest and pain on motion in the NSAID-treated patients.31 Interestingly, 2 recent surveys showed that patients with OA prefer NSAIDs to acetaminophen.27 However, based on the results of clinical trials, safety profiles, and cost issues acetaminophen should continue to be used as the first-line agent.27
The selective cyclooxygenase-2 (COX-2) inhibitors are effective in relieving the pain caused by OA.32-35 The COX-2 inhibitors have been shown to minimize fecal blood loss and produce fewer endoscopically proven gastrointestinal erosions/ulcerations than the nonselective inhibitors.36-39 This, however, is disease-oriented evidence and does not help us know about the more important clinical outcomes.
Using the STEPS approach (Safety, Tolerability, Efficacy, Price, Simplicity) to compare COX-2 inhibitors and nonselective NSAIDs is one way to help guide the choice of NSAIDs in the management of OA. A systematic review of a COX-2 inhibitor found the differences in adverse gastrointestinal events including perforations, symptomatic ulcers, and clinically significant bleeding episodes to be small when compared with the older NSAIDs (incidence = 1.3% vs 1.8%).36-39 Thus, 200 patients would have to receive a COX-2 inhibitor instead of a nonselective NSAID for 1 year to prevent 1 clinically significant bleeding episode (number needed to harm = 200). These safety differences seem small. However, the safety benefits of the COX-2 inhibitors increase when patients have multiple risk factors for adverse gastrointestinal events (age Ž65, history of peptic ulcer disease or gastrointestinal bleeding, use of oral glucocorticoids or anticoagulants, and comorbid medical conditions).27 Tolerability can be measured by looking at dropout rates. A meta-analysis found that the percentage of patients withdrawing from studies because of gastrointestinal adverse events was lower with the COX-2 inhibitor than with the nonselective NSAIDs (odds ratio = 0.59; 95% confidence interval, 0.52-0.67).37 Tolerability favors the COX-2 agents. Meta-analyses of trials comparing the efficacy of COX-2 inhibitors and nonselective NSAIDs in the treatment of OA show no differences between them.32-35 The average wholesale price of a month’s supply of a COX-2 inhibitor is approximately $73, and a month’s supply of a generic nonselective NSAID is $15. Nonselective NSAIDs are favored when looking at cost. While the nonselective NSAIDs require multiple dosing throughout the day, the COX-2 inhibitors can be given once daily, thus making the COX-2 inhibitors easier to use for patients. Overall, because of equal efficacy, minimal safety differences, and low cost, the older NSAIDs are recommended for low-risk patients, while the COX-2 inhibitors are recommended for high-risk patients because of increased safety and tolerability. (Of note, the COX-2 inhibitors have not been compared with acetaminophen, which is equally as efficacious as the nonselective NSAIDs and also has minimal side effects.)
Topical NSAIDs are more effective than placebo in treating the pain of OA, according to a systematic review.27 Also, few side effects were noted. A small randomized trial (n=70) of 0.025% capsaicin cream applied topically 4 times daily for 4 weeks reduced pain by 8% compared with placebo in patients with OA of the knee over a 4-week period.19 Further studies are needed to confirm this finding.
Complementary and Alternative Medicine
A recent meta-analysis found that glucosamine produces a modest to large improvement in pain relief and functional outcomes compared with placebo.40 A systematic review of controlled trials found that glucosamine performed equally well or better than NSAIDs.41 Most trials used a dose of 1500 mg glucosamine per day and addressed OA of the knee. The benefits may be overestimated because of the presence of publication bias. Because glucosamine is not regulated by the United States Food and Drug Administration, preparations and effectiveness may vary. However, it is very well tolerated and costs approximately $20 per month. Based on these results, glucosamine should be considered in the treatment of OA.
Although chondroitin has not been as well studied as glucosamine, a meta-analysis found evidence of effectiveness.40 Most studies used 800 to 1200 mg of chondroitin daily for OA of the knee. An added benefit of using both together has not been proved.
Another therapy supported by good-quality evidence is the use of avocado/soybean unsaponifiables. A systematic review of herbal therapy concluded that 300 mg daily of avocado/soybean unsaponifiables can provide long-term symptomatic relief, particularly for patients with chronic stable OA of the hip.42 It may also help patients reduce their intake of NSAIDs.
The most recent systematic review of acupuncture for OA of the knee concluded that real acupuncture is better than sham acupuncture in treating pain but not function.43 Four of the studies in the meta-analysis were of high quality, although none assessed the patient’s rating of global improvement. Acupuncture should be considered in the treatment of OA of the knee.
Less convincing therapies include therapeutic touch and electromagnetic fields. Therapeutic touch aims at manipulating a person’s energy system to bring the body system back into balance. A well-done single-blinded randomized trial compared therapeutic touch with mock therapeutic touch for OA of the knee.44 The treatment group had a statistically significant decrease in pain and improved function compared with the placebo group in most of the outcomes measured. However, the differences were small (0.5- to 1.4-point difference on a 10-point scale) and may not be clinically important. Further studies are needed to demonstrate a clinical impact and to help us know how to incorporate this into our practices. A small study of 27 patients compared pulsed electromagnetic fields (PEMF) and placebo for the treatment of OA of the knee. Although, this double-blind randomized trial showed a 31% reduction in overall pain compared with sham PEMF, larger studies are needed before widespread use of this therapy is warranted.19
Injections
Intra-articular steroids for OA of the knee have been recommended by the American College of Rheumatology when an effusion and local signs of inflammation are present.45 In 3 studies comparing steroid injections to placebo, 2 found that steroids were effective over 1 to 2 weeks, and 1 trial showed no difference. None of the trials showed any long-term benefit of steroid injections.46
A systematic review of injectable biologic agents (glycosaminoglycans, mostly hyaluronic acid) found that in 6 of the 8 randomized trials for OA of the knee they were superior to placebo.46 Treatment regimens varied, making it difficult to determine optimal duration of treatment and route of administration (intramuscular vs intra-articular). A comparison of hyaluronic acid injections with naproxen found that they were equally effective in improving pain relief and function, although the injections had fewer side effects.47 Dextrose in a 10% solution is another biologic agent used intra-articularly; however, a well-designed study found that it was no more effective than placebo for OA of the knee.48 Injectable glycosminoglycans, such as hyaluronic acid, are recommended in the treatment of OA of the knee, although the cost must be considered. The most effective regimen has not been determined.
Surgery
Surgery is reserved for patients with severe disease of the hip or knee that is not controlled by less invasive measures. Total hip arthroplasty has been shown to improve quality of life in patients with advanced hip OA.49 Also, a cost-effectiveness analysis showed that total hip arthroplasty can be cost-effective in improving quality-adjusted life expectancy in the short term and long term.50 Total joint arthroplasty for OA of the knee has shown similar benefits in pain relief and functional improvement.45,46 It is not surprising that OA of the hip and knee is the most common indication for elective total hip and knee arthroplasty in the United States.51
Other Recommendations
On the basis of lower-quality studies, the American College of Rheumatology also recommends the following for individual patients: a weight-loss program, an occupational therapy evaluation, bracing and footwear, joint lavage of the knee, arthroscopic debridement of the knee, and osteotomy of the knee or hip.45,52 The benefits from these interventions have not been well studied. The costs and benefits of these interventions must be weighed before recommending them to individual patients. Most trials have been conducted in patients with OA of the knee or hip. We do not know if applying treatment modalities to other joints (back and hands) will produce similar results. Also, most trials have been placebo controlled, and we do not know whether some treatments would add benefit to the first-line therapy of acetaminophen and NSAIDs.
Prognosis
OA is a chronic progressive disease of the joints that leads to increased pain and decreased functioning. Two longitudinal studies examined the natural course of OA of the knee in 191 patients. They showed that 56% of patients had no change, and 44% worsened over 15 years.53-55 A study of OA of the hip showed similar trends except that a small group (7%) experienced improvement over 10 years.56 We do not know whether current treatment options can improve the long-term prognosis of OA. Epidemiologic studies suggest that increasing age, obesity, family history, occupation, and joint injury are risk factors for OA.6,53 Whether modifying these risk factors will decrease symptoms or slow the course of the disease is not known. The progressive nature of OA makes treatment a challenge for the patient and clinician.
1. Centers for Disease Control and Prevention. Prevalence of disabilities and associated health conditions—United States, 1991-1992. JAMA 1994;272:735-36.
2. Solomon L. Clinical features of osteoarthritis. In: Kelly WN, Harris ED Jr, Ruddy S, Sledge CB, eds. Textbook of rheumatology. 5th ed. Vol 2. Philadelphia, Pa: WB Saunders; 1997;1383-93.
3. Bellamy N, Buchanan WW, Goldsmith CH, Cambell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol 1988;15:1833-40.
4. Badley EM, Rasooly I, Webster GK. Relative importance of musculoskeletal disorders as a cause of chronic health problems, disability and health care utilization: findings from the 1990 Ontario Health Survey. J Rheumatol 1994;21:505-14.
5. Ruddy S. Kelley’s textbook of rheumatology. 6th ed. St. Louis, Mo: W.B Saunders Company; 2001.
6. Stange KC, Zyzanski JS, Jaen CR, et al. Illuminating the ‘black box’: a description of 4454 patient visits to 138 family physicians. J Fam Pract 1998;46:377-89.
7. Hochberg MC. Epidemiology and genetics of osteoarthritis. Curr Opin Rheumatol 1991;3:662-68.
8. Lanyon P, Muir K, Doherty S, Doherty M. Assessment of a genetic contribution to osteoarthritis of the hip: sibling study. BMJ 2000;321:1179-83.
9. Lawrence RD, Everett D, Hochberg MC. Arthritis. In: Huntley R, Cornoni-Huntley J, eds. Health status and well-being of the elderly: national health and nutrition examination-I epidemiologic follow-up survey. Oxford, England: Oxford University Press; 1990.
10. Altman RD. Criteria for classification of clinical osteoarthritis. J Rheumatol 1991;18(suppl):10-12.
11. Altman R, Asch E, Bloch D, et al. Development criteria for the classification and reporting of osteoarthtitis: classification of osteoarthritis of the knee. Arthritis Rheum 1986;29:1039-49.
12. Altman R, Alarcon G, Appelrouth D, et al. The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the hip. Arthritis Rheum 1991;34:505-14.
13. Altman R, Alarcon G, Appelrouth D, et al. The American College of Rheumatology criteria for classification and reporting of osteoarthritis of the hand. Arthritis Rheum 1990;33:1601-10.
14. Van Baar ME, Assendelft WJJ, Dekker J, Oostendorp RAB, Bijlsma JW. Effectiveness of exercise therapy in patients with osteoarthritis of the hip or knee: a systematic review of randomized clinical trials. Arthritis Rheum 1999;42:1361-69.
15. Deyle GD, Henderson NE, Matekel RL, Ryder MG, Garber MB, Allison SC. Effectiveness of manual physical therapy and exercise in osteoarthritis of the knee: a randomized controlled trial. Ann Intern Med 2000;132:173-81.
16. Osiri M, Welch V, Brosseau L, Shea B, McGowan J, Tugwell P, Wells G. Transcutaneous electrical nerve stimulation for knee osteoarthritis. The Cochrane library Oxford, England: Update Software; 2001.
17. Verhagen AP, de Vet HCW, de Bie RA, Kessels AGH, Boers M, Knipschild PG. Balneotherapy for rheumatoid arthritis and osteoarthritis. The Cochrane library Oxford, England: Update Software; 2001.
18. Brosseau L, Welch V, Wells G, et al. Low level laser therapy (classes I, II and III) for treating osteoarthritis. The Cochrane library Oxford, England: Update Software; 2001.
19. Puett DW, Griffin MR. Published trials of nonmedicinal and noninvasive therapies for hip and knee osteoarthritis. Ann Intern Med 1994;121:133-40.
20. Lorig K, Lubeck D, Kraines RG, et al. Outcomes of self-help education for patients with arthritis. Arthritis Rheum 1985;28:680-85.
21. Lorig K, Mazonson PD, Holman HR. Evidence suggesting that health education for self-management in patients with chronic arthritis has sustained health benefits while reducing health care costs. Arthritis and Rheumat 1993;36:439-46.
22. Weinberger M, Tierney WM, Booher P, et al. Can the provision of information to patients with osteoarthritis improve functional status? A RCT. Arthritis Rheum 1989;32:1577-83.
23. Weinberger M, Tierney WM, Cowper PA, et al. Cost-effectiveness of increased telephone contact for patients with osteoarthritis: A RCT. Arthritis Rheum 1993;36:243-46.
24. Superio-Cabuslay E, Ward MM, Lorig KR. Patient education interventions in osteoarthritis and rheumatoid arthritis: a meta-analytic comparison with nonsteroidal anti-inflammatory drug treatment. Arthritis Care Res 1996;9:292-301.
25. Bradley JD, Brandt KD, Katz BP, Kalasinski LA, Ryan SL. Comparison of an inflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the treatment of patients with osteoarthritis of the knee. N Eng J Med 1991;325:87-91.
26. Williams JH, Ward JR, Egger JM, Neuner R, et al. Comparison of naproxen and acetaminophen in a two-year study of treatment of osteoarthritis of the knee. Arthritis Rheum 1993;36:1196-206.
27. American College of Rheumatology. Recommendations for the medical management of osteoarthritis of the hip and knee. Arthritis Rheum 2000;43:1905-15.
28. Roth SH, Fleischmann RM, Burch FX, et al. Around-the-clock, controlled-release oxycodone therapy for osteoarthritis-related pain: placebo-controlled trial and long-term evaluation. Arch Intern Med 2000;160:853-60.
29. Watson MC, Brookes ST, Kirwan JR, Faulkner A. Non-aspirin, non-steroidal anti-inflammatory drugs for treating osteoarthritis of the knee. The Cochrane library Oxford, England: Update Software; 2001.
30. Towheed T, Shea B, Wells G, Hochberg M. Analgesia and non-aspirin, non-steroidal anti-inflammatory drugs for osteoarthritis of the hip. The Cochrane library Oxford, England: Update Software; 2001.
31. Eccles Freemantel N, Mason J. North of England evidence based guideline development project: summary guideline for non-steroidal anti-inflammatory drugs versus basic analgesia in treating the pain of degenerative arthritis. BMJ 1998;317:526-30.
32. Bensen WG, Fiechtner JJ, McMillen JI, et al. Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial. Mayo Clin Proc 1999;74:1095-105.
33. Yocum D, Fleischmann R, Dalgin P, et al. Safety and efficacy of meloxicam in the treatment of osteoarthritis: a 12-week, double-blind, multiple-dose, placebo-controlled trial. Arch Intern Med 2000;160:2947-54.
34. Cannon GW, Caldwell JR, Holt P, et al. Rofecoxib, a specific inhibitor of cyclooxygenase 2, with clinical efficacy comparable with that of diclofenac sodium: results of a one-year, randomized clinical trial in patients with osteoarthritis of the knee and hip. Arthritis Rheum 2000;43:978-87.
35. Saag K, van der Heijde D, Fisher C, et al. Rofecoxib, a new cyclooxygenase 2 inhibitor shows sustained efficacy comparable with other nonsteroidal anti-inflammatory drugs. Arch Intern Med 2000;9:1124-34.
36. Silverstein RE, Faich G, Goldstein JL. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis-the CLASS study: a randomized controlled trial. JAMA 2000;284:1247-55.
37. Schoenfeld P. Gastroitestinal safety profile of meloxicam: a meta-analysis and systematic review of randomized controlled trials. Am J Med 1999;107:48S-54S.
38. Langman MJ, Jensen DM, Watson DJ, et al. Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs. JAMA 1999;282:1929-33.
39. Watson DJ, Harper SE, Zhao PL, et al. Gastrointestinal tolerability of the selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib compared with nonselective cox-1 and cox-2 inhibitors in osteoarthritis. Arch Intern Med 2000;160:2998-3003.
40. McAlindon TE, LaValley MP, Gulin JP, Felson DT. Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA 2000;283:1469-75.
41. Towheed TE, Anastassiades TP, Shea B, Houpt J, Welch V, Hochberg MC. Glucosamine therapy for treating osteoarthritis. The Cochrane library Oxford, England: Update Software; 2001.
42. Little CV, Parsons T. Herbal Therapy for treating osteoarthritis. The Cochrane library, Oxford, England: Updated Software; 2001.
43. Ezzo J, Hadhazy V, Birch S, et al. Acupuncture for osteoarthritis of the knee: a systematic review. Arthritis Rheum 2001;44:819-25.
44. Gordon A, Merenstein JH, D’Amico F, et al. The effects of therapeutic touch on patients with osteoarthritis of the knee. J Fam Pract 1998;47:271-77.
45. Hochberg MC, Altman RD, Brandt KD, Clark BM, et al. Guidelines for the medical management of osteoarthritis: part II, osteoarthritis of the knee. Arthritis Rheum 1995;38:1541-46.
46. Towheed TE, Hochberg MC. A systematic review of randomized controlled trials of pharmacological therapy in osteoarthritis of the knee with an emphasis on trial methodology. Sem Arthritis Rheum 1997;26:755-70.
47. Altman RD, Moskowitz R. Intraarticular sodium hyaluronate (Hyalgan) in the treatment of patients with osteoarthritis of the knee: a randomized clinical trial. Hyalgan Study Group. J Rheumatol 1998;25:2203-12.
48. Reeves KD, Hassanein K. Randomized prospective double-blind placebo-controlled study of dextrose prolotherapy for knee osteoarthritis with or without ACL laxity. Alt Therapies 2000;6:68-80.
49. Towheed TE, Hochberg MC. Health-related quality of life after total hip replacement. Sem Arthritis Rheum 1996;26:483-91.
50. Chang RW, Pellissier JM, Hazen GB. A cost-effectiveness analysis of total hip arthroplasty for osteoarthritis of the hip. JAMA 1996;275:858-65.
51. National Institutes of Health. National Intitutes of Health consensus statement: total hip replacement. Nat Instit Health 1994;12:1-31.
52. Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for the medical management of osteoarthritis: part I osteoarthritis of the hip. Arthritis Rheum 1995;38:1535-40.
53. Felson DT. Osteoarthritis. Rheum Dis Clin N Am 1990;16:499-512.
54. Hernborg JS, Nilsson BE. The natural course of untreated osteoarthritis of the knee. Clin Orthop 1977;123:130-37.
55. Danielsson L, Hernborg J. Clinical and roentgenologic study of knee joints with osteophytes. Clin Orthop 1970;69:302-12.
56. Danielsson L. Incidence and prognosis of coxarthrosis. Acta Orthop Scand 1964;66(suppl):9-87.
Osteoarthritis (OA) is a chronic and progressive disease in which damage is done to the joint and surrounding tissue. In the United States, OA is found in 6% of people older than 30 years and in 50% of those older than 60 years.1,2 It is the most common cause of disability in the United States and leads to considerable costs due to medical and surgical interventions and frequent absences from work.3-5 OA accounts for 2% of all visits to family physicians and is the 10th leading diagnosis encountered.6 Thus, a family physician can expect to have 2 or 3 patient encounters per week in which OA is one of the diagnoses. With the growing elderly population, this burden is likely to increase.
Pathophysiology
In OA, the smooth surface of hyaline cartilage develops irregularities because of alterations at the cellular level and gross mechanical forces.2 The role of inflammation has been debated in recent years, and its exact role is unknown. As OA progresses, the nearby bone remodels and forms further joint irregularities and osteophytes. These changes lead to narrowing of the joint space, and in some cases, chronic synovitis. Clinically, this causes pain, restricted movement, and periarticular muscle wasting. Treatment is aimed at these symptoms and structural abnormalities. The joints most commonly affected include the knees, hips, cervical and lumbosacral spine, distal interphalangeal (DIP) joints (producing Heberden nodes), proximal interphalangeal (PIP) joints (producing Bouchard nodes), and the first carpometacarpal joints of the hand. It is not known why these changes occur in some people and not in others. Epidemiologic studies and a recent sibling study raise the question of genetic influences in OA of the hip.7,8
Diagnosis
The diagnosis of OA is made on the basis of clinical and radiographic features. Few studies have compared a diagnostic test or strategy with a gold standard. Unfortunately, we do not have any good data about the usefulness of individual history and physical examination elements for diagnosing OA. Radiographs suggesting the diagnosis of OA (joint space narrowing, presence of osteophytes, irregular joint surfaces, sclerosis of subchondral bone, or bony cysts) must be closely correlated with clinical symptoms. According to epidemiologic surveys, only one half of patients with radiographic changes of OA of the knee complain of persistent pain.9 Classification criteria for OA of the knee, hip, and hands have been developed; they are outlined in Tables 1 Table 2 through Table 3.10,13
Although these criteria have limitations, they are becoming the standard for defining these types of OA and have been adapted by the American College of Rheumatology.11-13 Currently, there are no criteria for diagnosing OA of the back. When evaluating a patient with joint pain, other diagnoses must be considered (ie, rheumatoid arthritis, gout, pseudogout, septic arthritis, bursitis, and tendonitis).
Treatment
Most of the treatments of OA address the symptoms rather than the cause of the disease. The short-term goal is to decrease pain; long-term goals are to improve functioning and slow progression of disease. Table 4 provides a summary of treatment options.
Exercise
A systematic review of 12 randomized controlled trials (RCTs) showed beneficial effects of exercise therapy in patients with mild to moderate OA of the knee and, to a lesser extent, the hip.14 Benefits included improvements in pain, self-reported disability, walking performance, and the patient’s global assessment of symptoms. Insufficient evidence was available to recommend one type of exercise program over another. Exercise interventions included aerobic exercises, strength training, range of motion exercises, and fitness walking. Exercise programs were conducted as individuals or groups, supervised or home-based. Although this review was limited by the small number of good studies, recommending exercise for OA may improve patients’ symptoms and add other health benefits.
Physical Therapy
A recent RCT compared 4 weeks of manual physical therapy plus a supervised knee exercise program with sham ultrasound for treatment of OA of the knee.15 By 8 weeks, 6-minute walk distances had improved by 13% in the treatment group compared with no change in the placebo group; osteoarthritis index scores had improved 56% over baseline compared with 15% in the placebo group. One year following therapy 5% of the treated group had undergone knee arthroplasty compared with 20% of the untreated group (number needed to treat = 7). Given these clinically important improvements, physical therapy should be an early choice in the treatment of OA.
A systematic review of transcutaneous electrical nerve stimulation (TENS) for treatment of OA of the knee found that this noninvasive modality offered significant pain relief.16 Both high-frequency and strong burst mode TENS showed significant improvement in pain relief when used for 4 weeks or more. Also, the acupuncture-like TENS improved pain relief, stiffness, and walking time in a 2-week placebo-controlled trial.
Although spa therapy and low-level laser therapy may show some benefit, the true effectiveness cannot be determined, since the trials were small and of poor quality.17,18 No benefit was found in the one well-done RCT for ultrasound.19
Patient Education
Group patient education programs teach patients how to manage their disease. A 4-year longitudinal study using the Arthritis Self-Management Program (6 2-hour sessions), suggests that health education may decrease pain and visits to physicians.20,21 Estimated 4-year savings were $189 per patient.21 Telephone-based interventions have also been studied. A randomized trial of telephone contact for patients with OA found statistically significant differences in pain reduction according to the Arthritis Impact Measurement Scales at a very low cost.22,23 However, these differences may not be clinically significant as the groups differed by less than 1 point on a 10-point scale. Interestingly, educating patients during regularly scheduled appointments had no benefit and even resulted in worsening physical functioning.22 A systematic review of patient education interventions found a nonsignificant trend toward benefit using patient education compared with nonsteroidal anti-inflammatory drugs (NSAIDs).24 Despite the lack of convincing evidence from randomized trials, the possible benefits of educating our patients while using other therapies may outweigh the cost of the time involved, particularly if education can be done in a group setting.
Medication
Acetaminophen (4 g per day) has been shown in randomized trials to reduce pain in OA of the knee by approximately 30%.25,26 This improvement was seen at 4 weeks and at 2 years. Another study found the combination of codeine plus acetaminophen to be significantly better in reducing pain in patients with OA of the hip than acetaminophen alone, although one third of the patients receiving the combination discontinued therapy because of side effects.27 Narcotic analgesics alone have been shown in a randomized trial to be more effective in reducing pain than placebo but have not been adequately tested against acetaminophen or NSAIDs.28
NSAIDs also produce a 30% reduction in pain caused by OA.25,26 Two systematic reviews of OA concluded that there is no reliable evidence suggesting that any NSAID is more efficacious than the others in treating OA of the hip and knee.29,30 A separate meta-analysis found ibuprofen to have the lowest risk of side effects among the nonselective NSAIDs, a finding supported by the Committee on Safety in Medicine.31 For this reason, ibuprofen is recommended as the first-line nonselective NSAID.
Acetaminophen and NSAIDs have been found to be equally efficacious when compared in randomized controlled trials.25,26 According to a meta-analysis, the quality-of-life measures were similar between the 2 groups, despite a greater improvement in both pain at rest and pain on motion in the NSAID-treated patients.31 Interestingly, 2 recent surveys showed that patients with OA prefer NSAIDs to acetaminophen.27 However, based on the results of clinical trials, safety profiles, and cost issues acetaminophen should continue to be used as the first-line agent.27
The selective cyclooxygenase-2 (COX-2) inhibitors are effective in relieving the pain caused by OA.32-35 The COX-2 inhibitors have been shown to minimize fecal blood loss and produce fewer endoscopically proven gastrointestinal erosions/ulcerations than the nonselective inhibitors.36-39 This, however, is disease-oriented evidence and does not help us know about the more important clinical outcomes.
Using the STEPS approach (Safety, Tolerability, Efficacy, Price, Simplicity) to compare COX-2 inhibitors and nonselective NSAIDs is one way to help guide the choice of NSAIDs in the management of OA. A systematic review of a COX-2 inhibitor found the differences in adverse gastrointestinal events including perforations, symptomatic ulcers, and clinically significant bleeding episodes to be small when compared with the older NSAIDs (incidence = 1.3% vs 1.8%).36-39 Thus, 200 patients would have to receive a COX-2 inhibitor instead of a nonselective NSAID for 1 year to prevent 1 clinically significant bleeding episode (number needed to harm = 200). These safety differences seem small. However, the safety benefits of the COX-2 inhibitors increase when patients have multiple risk factors for adverse gastrointestinal events (age Ž65, history of peptic ulcer disease or gastrointestinal bleeding, use of oral glucocorticoids or anticoagulants, and comorbid medical conditions).27 Tolerability can be measured by looking at dropout rates. A meta-analysis found that the percentage of patients withdrawing from studies because of gastrointestinal adverse events was lower with the COX-2 inhibitor than with the nonselective NSAIDs (odds ratio = 0.59; 95% confidence interval, 0.52-0.67).37 Tolerability favors the COX-2 agents. Meta-analyses of trials comparing the efficacy of COX-2 inhibitors and nonselective NSAIDs in the treatment of OA show no differences between them.32-35 The average wholesale price of a month’s supply of a COX-2 inhibitor is approximately $73, and a month’s supply of a generic nonselective NSAID is $15. Nonselective NSAIDs are favored when looking at cost. While the nonselective NSAIDs require multiple dosing throughout the day, the COX-2 inhibitors can be given once daily, thus making the COX-2 inhibitors easier to use for patients. Overall, because of equal efficacy, minimal safety differences, and low cost, the older NSAIDs are recommended for low-risk patients, while the COX-2 inhibitors are recommended for high-risk patients because of increased safety and tolerability. (Of note, the COX-2 inhibitors have not been compared with acetaminophen, which is equally as efficacious as the nonselective NSAIDs and also has minimal side effects.)
Topical NSAIDs are more effective than placebo in treating the pain of OA, according to a systematic review.27 Also, few side effects were noted. A small randomized trial (n=70) of 0.025% capsaicin cream applied topically 4 times daily for 4 weeks reduced pain by 8% compared with placebo in patients with OA of the knee over a 4-week period.19 Further studies are needed to confirm this finding.
Complementary and Alternative Medicine
A recent meta-analysis found that glucosamine produces a modest to large improvement in pain relief and functional outcomes compared with placebo.40 A systematic review of controlled trials found that glucosamine performed equally well or better than NSAIDs.41 Most trials used a dose of 1500 mg glucosamine per day and addressed OA of the knee. The benefits may be overestimated because of the presence of publication bias. Because glucosamine is not regulated by the United States Food and Drug Administration, preparations and effectiveness may vary. However, it is very well tolerated and costs approximately $20 per month. Based on these results, glucosamine should be considered in the treatment of OA.
Although chondroitin has not been as well studied as glucosamine, a meta-analysis found evidence of effectiveness.40 Most studies used 800 to 1200 mg of chondroitin daily for OA of the knee. An added benefit of using both together has not been proved.
Another therapy supported by good-quality evidence is the use of avocado/soybean unsaponifiables. A systematic review of herbal therapy concluded that 300 mg daily of avocado/soybean unsaponifiables can provide long-term symptomatic relief, particularly for patients with chronic stable OA of the hip.42 It may also help patients reduce their intake of NSAIDs.
The most recent systematic review of acupuncture for OA of the knee concluded that real acupuncture is better than sham acupuncture in treating pain but not function.43 Four of the studies in the meta-analysis were of high quality, although none assessed the patient’s rating of global improvement. Acupuncture should be considered in the treatment of OA of the knee.
Less convincing therapies include therapeutic touch and electromagnetic fields. Therapeutic touch aims at manipulating a person’s energy system to bring the body system back into balance. A well-done single-blinded randomized trial compared therapeutic touch with mock therapeutic touch for OA of the knee.44 The treatment group had a statistically significant decrease in pain and improved function compared with the placebo group in most of the outcomes measured. However, the differences were small (0.5- to 1.4-point difference on a 10-point scale) and may not be clinically important. Further studies are needed to demonstrate a clinical impact and to help us know how to incorporate this into our practices. A small study of 27 patients compared pulsed electromagnetic fields (PEMF) and placebo for the treatment of OA of the knee. Although, this double-blind randomized trial showed a 31% reduction in overall pain compared with sham PEMF, larger studies are needed before widespread use of this therapy is warranted.19
Injections
Intra-articular steroids for OA of the knee have been recommended by the American College of Rheumatology when an effusion and local signs of inflammation are present.45 In 3 studies comparing steroid injections to placebo, 2 found that steroids were effective over 1 to 2 weeks, and 1 trial showed no difference. None of the trials showed any long-term benefit of steroid injections.46
A systematic review of injectable biologic agents (glycosaminoglycans, mostly hyaluronic acid) found that in 6 of the 8 randomized trials for OA of the knee they were superior to placebo.46 Treatment regimens varied, making it difficult to determine optimal duration of treatment and route of administration (intramuscular vs intra-articular). A comparison of hyaluronic acid injections with naproxen found that they were equally effective in improving pain relief and function, although the injections had fewer side effects.47 Dextrose in a 10% solution is another biologic agent used intra-articularly; however, a well-designed study found that it was no more effective than placebo for OA of the knee.48 Injectable glycosminoglycans, such as hyaluronic acid, are recommended in the treatment of OA of the knee, although the cost must be considered. The most effective regimen has not been determined.
Surgery
Surgery is reserved for patients with severe disease of the hip or knee that is not controlled by less invasive measures. Total hip arthroplasty has been shown to improve quality of life in patients with advanced hip OA.49 Also, a cost-effectiveness analysis showed that total hip arthroplasty can be cost-effective in improving quality-adjusted life expectancy in the short term and long term.50 Total joint arthroplasty for OA of the knee has shown similar benefits in pain relief and functional improvement.45,46 It is not surprising that OA of the hip and knee is the most common indication for elective total hip and knee arthroplasty in the United States.51
Other Recommendations
On the basis of lower-quality studies, the American College of Rheumatology also recommends the following for individual patients: a weight-loss program, an occupational therapy evaluation, bracing and footwear, joint lavage of the knee, arthroscopic debridement of the knee, and osteotomy of the knee or hip.45,52 The benefits from these interventions have not been well studied. The costs and benefits of these interventions must be weighed before recommending them to individual patients. Most trials have been conducted in patients with OA of the knee or hip. We do not know if applying treatment modalities to other joints (back and hands) will produce similar results. Also, most trials have been placebo controlled, and we do not know whether some treatments would add benefit to the first-line therapy of acetaminophen and NSAIDs.
Prognosis
OA is a chronic progressive disease of the joints that leads to increased pain and decreased functioning. Two longitudinal studies examined the natural course of OA of the knee in 191 patients. They showed that 56% of patients had no change, and 44% worsened over 15 years.53-55 A study of OA of the hip showed similar trends except that a small group (7%) experienced improvement over 10 years.56 We do not know whether current treatment options can improve the long-term prognosis of OA. Epidemiologic studies suggest that increasing age, obesity, family history, occupation, and joint injury are risk factors for OA.6,53 Whether modifying these risk factors will decrease symptoms or slow the course of the disease is not known. The progressive nature of OA makes treatment a challenge for the patient and clinician.
Osteoarthritis (OA) is a chronic and progressive disease in which damage is done to the joint and surrounding tissue. In the United States, OA is found in 6% of people older than 30 years and in 50% of those older than 60 years.1,2 It is the most common cause of disability in the United States and leads to considerable costs due to medical and surgical interventions and frequent absences from work.3-5 OA accounts for 2% of all visits to family physicians and is the 10th leading diagnosis encountered.6 Thus, a family physician can expect to have 2 or 3 patient encounters per week in which OA is one of the diagnoses. With the growing elderly population, this burden is likely to increase.
Pathophysiology
In OA, the smooth surface of hyaline cartilage develops irregularities because of alterations at the cellular level and gross mechanical forces.2 The role of inflammation has been debated in recent years, and its exact role is unknown. As OA progresses, the nearby bone remodels and forms further joint irregularities and osteophytes. These changes lead to narrowing of the joint space, and in some cases, chronic synovitis. Clinically, this causes pain, restricted movement, and periarticular muscle wasting. Treatment is aimed at these symptoms and structural abnormalities. The joints most commonly affected include the knees, hips, cervical and lumbosacral spine, distal interphalangeal (DIP) joints (producing Heberden nodes), proximal interphalangeal (PIP) joints (producing Bouchard nodes), and the first carpometacarpal joints of the hand. It is not known why these changes occur in some people and not in others. Epidemiologic studies and a recent sibling study raise the question of genetic influences in OA of the hip.7,8
Diagnosis
The diagnosis of OA is made on the basis of clinical and radiographic features. Few studies have compared a diagnostic test or strategy with a gold standard. Unfortunately, we do not have any good data about the usefulness of individual history and physical examination elements for diagnosing OA. Radiographs suggesting the diagnosis of OA (joint space narrowing, presence of osteophytes, irregular joint surfaces, sclerosis of subchondral bone, or bony cysts) must be closely correlated with clinical symptoms. According to epidemiologic surveys, only one half of patients with radiographic changes of OA of the knee complain of persistent pain.9 Classification criteria for OA of the knee, hip, and hands have been developed; they are outlined in Tables 1 Table 2 through Table 3.10,13
Although these criteria have limitations, they are becoming the standard for defining these types of OA and have been adapted by the American College of Rheumatology.11-13 Currently, there are no criteria for diagnosing OA of the back. When evaluating a patient with joint pain, other diagnoses must be considered (ie, rheumatoid arthritis, gout, pseudogout, septic arthritis, bursitis, and tendonitis).
Treatment
Most of the treatments of OA address the symptoms rather than the cause of the disease. The short-term goal is to decrease pain; long-term goals are to improve functioning and slow progression of disease. Table 4 provides a summary of treatment options.
Exercise
A systematic review of 12 randomized controlled trials (RCTs) showed beneficial effects of exercise therapy in patients with mild to moderate OA of the knee and, to a lesser extent, the hip.14 Benefits included improvements in pain, self-reported disability, walking performance, and the patient’s global assessment of symptoms. Insufficient evidence was available to recommend one type of exercise program over another. Exercise interventions included aerobic exercises, strength training, range of motion exercises, and fitness walking. Exercise programs were conducted as individuals or groups, supervised or home-based. Although this review was limited by the small number of good studies, recommending exercise for OA may improve patients’ symptoms and add other health benefits.
Physical Therapy
A recent RCT compared 4 weeks of manual physical therapy plus a supervised knee exercise program with sham ultrasound for treatment of OA of the knee.15 By 8 weeks, 6-minute walk distances had improved by 13% in the treatment group compared with no change in the placebo group; osteoarthritis index scores had improved 56% over baseline compared with 15% in the placebo group. One year following therapy 5% of the treated group had undergone knee arthroplasty compared with 20% of the untreated group (number needed to treat = 7). Given these clinically important improvements, physical therapy should be an early choice in the treatment of OA.
A systematic review of transcutaneous electrical nerve stimulation (TENS) for treatment of OA of the knee found that this noninvasive modality offered significant pain relief.16 Both high-frequency and strong burst mode TENS showed significant improvement in pain relief when used for 4 weeks or more. Also, the acupuncture-like TENS improved pain relief, stiffness, and walking time in a 2-week placebo-controlled trial.
Although spa therapy and low-level laser therapy may show some benefit, the true effectiveness cannot be determined, since the trials were small and of poor quality.17,18 No benefit was found in the one well-done RCT for ultrasound.19
Patient Education
Group patient education programs teach patients how to manage their disease. A 4-year longitudinal study using the Arthritis Self-Management Program (6 2-hour sessions), suggests that health education may decrease pain and visits to physicians.20,21 Estimated 4-year savings were $189 per patient.21 Telephone-based interventions have also been studied. A randomized trial of telephone contact for patients with OA found statistically significant differences in pain reduction according to the Arthritis Impact Measurement Scales at a very low cost.22,23 However, these differences may not be clinically significant as the groups differed by less than 1 point on a 10-point scale. Interestingly, educating patients during regularly scheduled appointments had no benefit and even resulted in worsening physical functioning.22 A systematic review of patient education interventions found a nonsignificant trend toward benefit using patient education compared with nonsteroidal anti-inflammatory drugs (NSAIDs).24 Despite the lack of convincing evidence from randomized trials, the possible benefits of educating our patients while using other therapies may outweigh the cost of the time involved, particularly if education can be done in a group setting.
Medication
Acetaminophen (4 g per day) has been shown in randomized trials to reduce pain in OA of the knee by approximately 30%.25,26 This improvement was seen at 4 weeks and at 2 years. Another study found the combination of codeine plus acetaminophen to be significantly better in reducing pain in patients with OA of the hip than acetaminophen alone, although one third of the patients receiving the combination discontinued therapy because of side effects.27 Narcotic analgesics alone have been shown in a randomized trial to be more effective in reducing pain than placebo but have not been adequately tested against acetaminophen or NSAIDs.28
NSAIDs also produce a 30% reduction in pain caused by OA.25,26 Two systematic reviews of OA concluded that there is no reliable evidence suggesting that any NSAID is more efficacious than the others in treating OA of the hip and knee.29,30 A separate meta-analysis found ibuprofen to have the lowest risk of side effects among the nonselective NSAIDs, a finding supported by the Committee on Safety in Medicine.31 For this reason, ibuprofen is recommended as the first-line nonselective NSAID.
Acetaminophen and NSAIDs have been found to be equally efficacious when compared in randomized controlled trials.25,26 According to a meta-analysis, the quality-of-life measures were similar between the 2 groups, despite a greater improvement in both pain at rest and pain on motion in the NSAID-treated patients.31 Interestingly, 2 recent surveys showed that patients with OA prefer NSAIDs to acetaminophen.27 However, based on the results of clinical trials, safety profiles, and cost issues acetaminophen should continue to be used as the first-line agent.27
The selective cyclooxygenase-2 (COX-2) inhibitors are effective in relieving the pain caused by OA.32-35 The COX-2 inhibitors have been shown to minimize fecal blood loss and produce fewer endoscopically proven gastrointestinal erosions/ulcerations than the nonselective inhibitors.36-39 This, however, is disease-oriented evidence and does not help us know about the more important clinical outcomes.
Using the STEPS approach (Safety, Tolerability, Efficacy, Price, Simplicity) to compare COX-2 inhibitors and nonselective NSAIDs is one way to help guide the choice of NSAIDs in the management of OA. A systematic review of a COX-2 inhibitor found the differences in adverse gastrointestinal events including perforations, symptomatic ulcers, and clinically significant bleeding episodes to be small when compared with the older NSAIDs (incidence = 1.3% vs 1.8%).36-39 Thus, 200 patients would have to receive a COX-2 inhibitor instead of a nonselective NSAID for 1 year to prevent 1 clinically significant bleeding episode (number needed to harm = 200). These safety differences seem small. However, the safety benefits of the COX-2 inhibitors increase when patients have multiple risk factors for adverse gastrointestinal events (age Ž65, history of peptic ulcer disease or gastrointestinal bleeding, use of oral glucocorticoids or anticoagulants, and comorbid medical conditions).27 Tolerability can be measured by looking at dropout rates. A meta-analysis found that the percentage of patients withdrawing from studies because of gastrointestinal adverse events was lower with the COX-2 inhibitor than with the nonselective NSAIDs (odds ratio = 0.59; 95% confidence interval, 0.52-0.67).37 Tolerability favors the COX-2 agents. Meta-analyses of trials comparing the efficacy of COX-2 inhibitors and nonselective NSAIDs in the treatment of OA show no differences between them.32-35 The average wholesale price of a month’s supply of a COX-2 inhibitor is approximately $73, and a month’s supply of a generic nonselective NSAID is $15. Nonselective NSAIDs are favored when looking at cost. While the nonselective NSAIDs require multiple dosing throughout the day, the COX-2 inhibitors can be given once daily, thus making the COX-2 inhibitors easier to use for patients. Overall, because of equal efficacy, minimal safety differences, and low cost, the older NSAIDs are recommended for low-risk patients, while the COX-2 inhibitors are recommended for high-risk patients because of increased safety and tolerability. (Of note, the COX-2 inhibitors have not been compared with acetaminophen, which is equally as efficacious as the nonselective NSAIDs and also has minimal side effects.)
Topical NSAIDs are more effective than placebo in treating the pain of OA, according to a systematic review.27 Also, few side effects were noted. A small randomized trial (n=70) of 0.025% capsaicin cream applied topically 4 times daily for 4 weeks reduced pain by 8% compared with placebo in patients with OA of the knee over a 4-week period.19 Further studies are needed to confirm this finding.
Complementary and Alternative Medicine
A recent meta-analysis found that glucosamine produces a modest to large improvement in pain relief and functional outcomes compared with placebo.40 A systematic review of controlled trials found that glucosamine performed equally well or better than NSAIDs.41 Most trials used a dose of 1500 mg glucosamine per day and addressed OA of the knee. The benefits may be overestimated because of the presence of publication bias. Because glucosamine is not regulated by the United States Food and Drug Administration, preparations and effectiveness may vary. However, it is very well tolerated and costs approximately $20 per month. Based on these results, glucosamine should be considered in the treatment of OA.
Although chondroitin has not been as well studied as glucosamine, a meta-analysis found evidence of effectiveness.40 Most studies used 800 to 1200 mg of chondroitin daily for OA of the knee. An added benefit of using both together has not been proved.
Another therapy supported by good-quality evidence is the use of avocado/soybean unsaponifiables. A systematic review of herbal therapy concluded that 300 mg daily of avocado/soybean unsaponifiables can provide long-term symptomatic relief, particularly for patients with chronic stable OA of the hip.42 It may also help patients reduce their intake of NSAIDs.
The most recent systematic review of acupuncture for OA of the knee concluded that real acupuncture is better than sham acupuncture in treating pain but not function.43 Four of the studies in the meta-analysis were of high quality, although none assessed the patient’s rating of global improvement. Acupuncture should be considered in the treatment of OA of the knee.
Less convincing therapies include therapeutic touch and electromagnetic fields. Therapeutic touch aims at manipulating a person’s energy system to bring the body system back into balance. A well-done single-blinded randomized trial compared therapeutic touch with mock therapeutic touch for OA of the knee.44 The treatment group had a statistically significant decrease in pain and improved function compared with the placebo group in most of the outcomes measured. However, the differences were small (0.5- to 1.4-point difference on a 10-point scale) and may not be clinically important. Further studies are needed to demonstrate a clinical impact and to help us know how to incorporate this into our practices. A small study of 27 patients compared pulsed electromagnetic fields (PEMF) and placebo for the treatment of OA of the knee. Although, this double-blind randomized trial showed a 31% reduction in overall pain compared with sham PEMF, larger studies are needed before widespread use of this therapy is warranted.19
Injections
Intra-articular steroids for OA of the knee have been recommended by the American College of Rheumatology when an effusion and local signs of inflammation are present.45 In 3 studies comparing steroid injections to placebo, 2 found that steroids were effective over 1 to 2 weeks, and 1 trial showed no difference. None of the trials showed any long-term benefit of steroid injections.46
A systematic review of injectable biologic agents (glycosaminoglycans, mostly hyaluronic acid) found that in 6 of the 8 randomized trials for OA of the knee they were superior to placebo.46 Treatment regimens varied, making it difficult to determine optimal duration of treatment and route of administration (intramuscular vs intra-articular). A comparison of hyaluronic acid injections with naproxen found that they were equally effective in improving pain relief and function, although the injections had fewer side effects.47 Dextrose in a 10% solution is another biologic agent used intra-articularly; however, a well-designed study found that it was no more effective than placebo for OA of the knee.48 Injectable glycosminoglycans, such as hyaluronic acid, are recommended in the treatment of OA of the knee, although the cost must be considered. The most effective regimen has not been determined.
Surgery
Surgery is reserved for patients with severe disease of the hip or knee that is not controlled by less invasive measures. Total hip arthroplasty has been shown to improve quality of life in patients with advanced hip OA.49 Also, a cost-effectiveness analysis showed that total hip arthroplasty can be cost-effective in improving quality-adjusted life expectancy in the short term and long term.50 Total joint arthroplasty for OA of the knee has shown similar benefits in pain relief and functional improvement.45,46 It is not surprising that OA of the hip and knee is the most common indication for elective total hip and knee arthroplasty in the United States.51
Other Recommendations
On the basis of lower-quality studies, the American College of Rheumatology also recommends the following for individual patients: a weight-loss program, an occupational therapy evaluation, bracing and footwear, joint lavage of the knee, arthroscopic debridement of the knee, and osteotomy of the knee or hip.45,52 The benefits from these interventions have not been well studied. The costs and benefits of these interventions must be weighed before recommending them to individual patients. Most trials have been conducted in patients with OA of the knee or hip. We do not know if applying treatment modalities to other joints (back and hands) will produce similar results. Also, most trials have been placebo controlled, and we do not know whether some treatments would add benefit to the first-line therapy of acetaminophen and NSAIDs.
Prognosis
OA is a chronic progressive disease of the joints that leads to increased pain and decreased functioning. Two longitudinal studies examined the natural course of OA of the knee in 191 patients. They showed that 56% of patients had no change, and 44% worsened over 15 years.53-55 A study of OA of the hip showed similar trends except that a small group (7%) experienced improvement over 10 years.56 We do not know whether current treatment options can improve the long-term prognosis of OA. Epidemiologic studies suggest that increasing age, obesity, family history, occupation, and joint injury are risk factors for OA.6,53 Whether modifying these risk factors will decrease symptoms or slow the course of the disease is not known. The progressive nature of OA makes treatment a challenge for the patient and clinician.
1. Centers for Disease Control and Prevention. Prevalence of disabilities and associated health conditions—United States, 1991-1992. JAMA 1994;272:735-36.
2. Solomon L. Clinical features of osteoarthritis. In: Kelly WN, Harris ED Jr, Ruddy S, Sledge CB, eds. Textbook of rheumatology. 5th ed. Vol 2. Philadelphia, Pa: WB Saunders; 1997;1383-93.
3. Bellamy N, Buchanan WW, Goldsmith CH, Cambell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol 1988;15:1833-40.
4. Badley EM, Rasooly I, Webster GK. Relative importance of musculoskeletal disorders as a cause of chronic health problems, disability and health care utilization: findings from the 1990 Ontario Health Survey. J Rheumatol 1994;21:505-14.
5. Ruddy S. Kelley’s textbook of rheumatology. 6th ed. St. Louis, Mo: W.B Saunders Company; 2001.
6. Stange KC, Zyzanski JS, Jaen CR, et al. Illuminating the ‘black box’: a description of 4454 patient visits to 138 family physicians. J Fam Pract 1998;46:377-89.
7. Hochberg MC. Epidemiology and genetics of osteoarthritis. Curr Opin Rheumatol 1991;3:662-68.
8. Lanyon P, Muir K, Doherty S, Doherty M. Assessment of a genetic contribution to osteoarthritis of the hip: sibling study. BMJ 2000;321:1179-83.
9. Lawrence RD, Everett D, Hochberg MC. Arthritis. In: Huntley R, Cornoni-Huntley J, eds. Health status and well-being of the elderly: national health and nutrition examination-I epidemiologic follow-up survey. Oxford, England: Oxford University Press; 1990.
10. Altman RD. Criteria for classification of clinical osteoarthritis. J Rheumatol 1991;18(suppl):10-12.
11. Altman R, Asch E, Bloch D, et al. Development criteria for the classification and reporting of osteoarthtitis: classification of osteoarthritis of the knee. Arthritis Rheum 1986;29:1039-49.
12. Altman R, Alarcon G, Appelrouth D, et al. The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the hip. Arthritis Rheum 1991;34:505-14.
13. Altman R, Alarcon G, Appelrouth D, et al. The American College of Rheumatology criteria for classification and reporting of osteoarthritis of the hand. Arthritis Rheum 1990;33:1601-10.
14. Van Baar ME, Assendelft WJJ, Dekker J, Oostendorp RAB, Bijlsma JW. Effectiveness of exercise therapy in patients with osteoarthritis of the hip or knee: a systematic review of randomized clinical trials. Arthritis Rheum 1999;42:1361-69.
15. Deyle GD, Henderson NE, Matekel RL, Ryder MG, Garber MB, Allison SC. Effectiveness of manual physical therapy and exercise in osteoarthritis of the knee: a randomized controlled trial. Ann Intern Med 2000;132:173-81.
16. Osiri M, Welch V, Brosseau L, Shea B, McGowan J, Tugwell P, Wells G. Transcutaneous electrical nerve stimulation for knee osteoarthritis. The Cochrane library Oxford, England: Update Software; 2001.
17. Verhagen AP, de Vet HCW, de Bie RA, Kessels AGH, Boers M, Knipschild PG. Balneotherapy for rheumatoid arthritis and osteoarthritis. The Cochrane library Oxford, England: Update Software; 2001.
18. Brosseau L, Welch V, Wells G, et al. Low level laser therapy (classes I, II and III) for treating osteoarthritis. The Cochrane library Oxford, England: Update Software; 2001.
19. Puett DW, Griffin MR. Published trials of nonmedicinal and noninvasive therapies for hip and knee osteoarthritis. Ann Intern Med 1994;121:133-40.
20. Lorig K, Lubeck D, Kraines RG, et al. Outcomes of self-help education for patients with arthritis. Arthritis Rheum 1985;28:680-85.
21. Lorig K, Mazonson PD, Holman HR. Evidence suggesting that health education for self-management in patients with chronic arthritis has sustained health benefits while reducing health care costs. Arthritis and Rheumat 1993;36:439-46.
22. Weinberger M, Tierney WM, Booher P, et al. Can the provision of information to patients with osteoarthritis improve functional status? A RCT. Arthritis Rheum 1989;32:1577-83.
23. Weinberger M, Tierney WM, Cowper PA, et al. Cost-effectiveness of increased telephone contact for patients with osteoarthritis: A RCT. Arthritis Rheum 1993;36:243-46.
24. Superio-Cabuslay E, Ward MM, Lorig KR. Patient education interventions in osteoarthritis and rheumatoid arthritis: a meta-analytic comparison with nonsteroidal anti-inflammatory drug treatment. Arthritis Care Res 1996;9:292-301.
25. Bradley JD, Brandt KD, Katz BP, Kalasinski LA, Ryan SL. Comparison of an inflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the treatment of patients with osteoarthritis of the knee. N Eng J Med 1991;325:87-91.
26. Williams JH, Ward JR, Egger JM, Neuner R, et al. Comparison of naproxen and acetaminophen in a two-year study of treatment of osteoarthritis of the knee. Arthritis Rheum 1993;36:1196-206.
27. American College of Rheumatology. Recommendations for the medical management of osteoarthritis of the hip and knee. Arthritis Rheum 2000;43:1905-15.
28. Roth SH, Fleischmann RM, Burch FX, et al. Around-the-clock, controlled-release oxycodone therapy for osteoarthritis-related pain: placebo-controlled trial and long-term evaluation. Arch Intern Med 2000;160:853-60.
29. Watson MC, Brookes ST, Kirwan JR, Faulkner A. Non-aspirin, non-steroidal anti-inflammatory drugs for treating osteoarthritis of the knee. The Cochrane library Oxford, England: Update Software; 2001.
30. Towheed T, Shea B, Wells G, Hochberg M. Analgesia and non-aspirin, non-steroidal anti-inflammatory drugs for osteoarthritis of the hip. The Cochrane library Oxford, England: Update Software; 2001.
31. Eccles Freemantel N, Mason J. North of England evidence based guideline development project: summary guideline for non-steroidal anti-inflammatory drugs versus basic analgesia in treating the pain of degenerative arthritis. BMJ 1998;317:526-30.
32. Bensen WG, Fiechtner JJ, McMillen JI, et al. Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial. Mayo Clin Proc 1999;74:1095-105.
33. Yocum D, Fleischmann R, Dalgin P, et al. Safety and efficacy of meloxicam in the treatment of osteoarthritis: a 12-week, double-blind, multiple-dose, placebo-controlled trial. Arch Intern Med 2000;160:2947-54.
34. Cannon GW, Caldwell JR, Holt P, et al. Rofecoxib, a specific inhibitor of cyclooxygenase 2, with clinical efficacy comparable with that of diclofenac sodium: results of a one-year, randomized clinical trial in patients with osteoarthritis of the knee and hip. Arthritis Rheum 2000;43:978-87.
35. Saag K, van der Heijde D, Fisher C, et al. Rofecoxib, a new cyclooxygenase 2 inhibitor shows sustained efficacy comparable with other nonsteroidal anti-inflammatory drugs. Arch Intern Med 2000;9:1124-34.
36. Silverstein RE, Faich G, Goldstein JL. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis-the CLASS study: a randomized controlled trial. JAMA 2000;284:1247-55.
37. Schoenfeld P. Gastroitestinal safety profile of meloxicam: a meta-analysis and systematic review of randomized controlled trials. Am J Med 1999;107:48S-54S.
38. Langman MJ, Jensen DM, Watson DJ, et al. Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs. JAMA 1999;282:1929-33.
39. Watson DJ, Harper SE, Zhao PL, et al. Gastrointestinal tolerability of the selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib compared with nonselective cox-1 and cox-2 inhibitors in osteoarthritis. Arch Intern Med 2000;160:2998-3003.
40. McAlindon TE, LaValley MP, Gulin JP, Felson DT. Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA 2000;283:1469-75.
41. Towheed TE, Anastassiades TP, Shea B, Houpt J, Welch V, Hochberg MC. Glucosamine therapy for treating osteoarthritis. The Cochrane library Oxford, England: Update Software; 2001.
42. Little CV, Parsons T. Herbal Therapy for treating osteoarthritis. The Cochrane library, Oxford, England: Updated Software; 2001.
43. Ezzo J, Hadhazy V, Birch S, et al. Acupuncture for osteoarthritis of the knee: a systematic review. Arthritis Rheum 2001;44:819-25.
44. Gordon A, Merenstein JH, D’Amico F, et al. The effects of therapeutic touch on patients with osteoarthritis of the knee. J Fam Pract 1998;47:271-77.
45. Hochberg MC, Altman RD, Brandt KD, Clark BM, et al. Guidelines for the medical management of osteoarthritis: part II, osteoarthritis of the knee. Arthritis Rheum 1995;38:1541-46.
46. Towheed TE, Hochberg MC. A systematic review of randomized controlled trials of pharmacological therapy in osteoarthritis of the knee with an emphasis on trial methodology. Sem Arthritis Rheum 1997;26:755-70.
47. Altman RD, Moskowitz R. Intraarticular sodium hyaluronate (Hyalgan) in the treatment of patients with osteoarthritis of the knee: a randomized clinical trial. Hyalgan Study Group. J Rheumatol 1998;25:2203-12.
48. Reeves KD, Hassanein K. Randomized prospective double-blind placebo-controlled study of dextrose prolotherapy for knee osteoarthritis with or without ACL laxity. Alt Therapies 2000;6:68-80.
49. Towheed TE, Hochberg MC. Health-related quality of life after total hip replacement. Sem Arthritis Rheum 1996;26:483-91.
50. Chang RW, Pellissier JM, Hazen GB. A cost-effectiveness analysis of total hip arthroplasty for osteoarthritis of the hip. JAMA 1996;275:858-65.
51. National Institutes of Health. National Intitutes of Health consensus statement: total hip replacement. Nat Instit Health 1994;12:1-31.
52. Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for the medical management of osteoarthritis: part I osteoarthritis of the hip. Arthritis Rheum 1995;38:1535-40.
53. Felson DT. Osteoarthritis. Rheum Dis Clin N Am 1990;16:499-512.
54. Hernborg JS, Nilsson BE. The natural course of untreated osteoarthritis of the knee. Clin Orthop 1977;123:130-37.
55. Danielsson L, Hernborg J. Clinical and roentgenologic study of knee joints with osteophytes. Clin Orthop 1970;69:302-12.
56. Danielsson L. Incidence and prognosis of coxarthrosis. Acta Orthop Scand 1964;66(suppl):9-87.
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33. Yocum D, Fleischmann R, Dalgin P, et al. Safety and efficacy of meloxicam in the treatment of osteoarthritis: a 12-week, double-blind, multiple-dose, placebo-controlled trial. Arch Intern Med 2000;160:2947-54.
34. Cannon GW, Caldwell JR, Holt P, et al. Rofecoxib, a specific inhibitor of cyclooxygenase 2, with clinical efficacy comparable with that of diclofenac sodium: results of a one-year, randomized clinical trial in patients with osteoarthritis of the knee and hip. Arthritis Rheum 2000;43:978-87.
35. Saag K, van der Heijde D, Fisher C, et al. Rofecoxib, a new cyclooxygenase 2 inhibitor shows sustained efficacy comparable with other nonsteroidal anti-inflammatory drugs. Arch Intern Med 2000;9:1124-34.
36. Silverstein RE, Faich G, Goldstein JL. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis-the CLASS study: a randomized controlled trial. JAMA 2000;284:1247-55.
37. Schoenfeld P. Gastroitestinal safety profile of meloxicam: a meta-analysis and systematic review of randomized controlled trials. Am J Med 1999;107:48S-54S.
38. Langman MJ, Jensen DM, Watson DJ, et al. Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs. JAMA 1999;282:1929-33.
39. Watson DJ, Harper SE, Zhao PL, et al. Gastrointestinal tolerability of the selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib compared with nonselective cox-1 and cox-2 inhibitors in osteoarthritis. Arch Intern Med 2000;160:2998-3003.
40. McAlindon TE, LaValley MP, Gulin JP, Felson DT. Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA 2000;283:1469-75.
41. Towheed TE, Anastassiades TP, Shea B, Houpt J, Welch V, Hochberg MC. Glucosamine therapy for treating osteoarthritis. The Cochrane library Oxford, England: Update Software; 2001.
42. Little CV, Parsons T. Herbal Therapy for treating osteoarthritis. The Cochrane library, Oxford, England: Updated Software; 2001.
43. Ezzo J, Hadhazy V, Birch S, et al. Acupuncture for osteoarthritis of the knee: a systematic review. Arthritis Rheum 2001;44:819-25.
44. Gordon A, Merenstein JH, D’Amico F, et al. The effects of therapeutic touch on patients with osteoarthritis of the knee. J Fam Pract 1998;47:271-77.
45. Hochberg MC, Altman RD, Brandt KD, Clark BM, et al. Guidelines for the medical management of osteoarthritis: part II, osteoarthritis of the knee. Arthritis Rheum 1995;38:1541-46.
46. Towheed TE, Hochberg MC. A systematic review of randomized controlled trials of pharmacological therapy in osteoarthritis of the knee with an emphasis on trial methodology. Sem Arthritis Rheum 1997;26:755-70.
47. Altman RD, Moskowitz R. Intraarticular sodium hyaluronate (Hyalgan) in the treatment of patients with osteoarthritis of the knee: a randomized clinical trial. Hyalgan Study Group. J Rheumatol 1998;25:2203-12.
48. Reeves KD, Hassanein K. Randomized prospective double-blind placebo-controlled study of dextrose prolotherapy for knee osteoarthritis with or without ACL laxity. Alt Therapies 2000;6:68-80.
49. Towheed TE, Hochberg MC. Health-related quality of life after total hip replacement. Sem Arthritis Rheum 1996;26:483-91.
50. Chang RW, Pellissier JM, Hazen GB. A cost-effectiveness analysis of total hip arthroplasty for osteoarthritis of the hip. JAMA 1996;275:858-65.
51. National Institutes of Health. National Intitutes of Health consensus statement: total hip replacement. Nat Instit Health 1994;12:1-31.
52. Hochberg MC, Altman RD, Brandt KD, et al. Guidelines for the medical management of osteoarthritis: part I osteoarthritis of the hip. Arthritis Rheum 1995;38:1535-40.
53. Felson DT. Osteoarthritis. Rheum Dis Clin N Am 1990;16:499-512.
54. Hernborg JS, Nilsson BE. The natural course of untreated osteoarthritis of the knee. Clin Orthop 1977;123:130-37.
55. Danielsson L, Hernborg J. Clinical and roentgenologic study of knee joints with osteophytes. Clin Orthop 1970;69:302-12.
56. Danielsson L. Incidence and prognosis of coxarthrosis. Acta Orthop Scand 1964;66(suppl):9-87.
The Diagnosis of Essential and Secondary Hypertension in Adults
Hypertension is arbitrarily defined as a diastolic blood pressure (DBP) of 90 mm Hg or higher, a systolic blood pressure (SBP) equal to or higher than 140 mm Hg, or both, on 3 separate occasions. It affects 24% of the population of the United States and is common among black (28%), white (24%), and Hispanic (14%) Americans. The prevalence of hypertension increases with age and is more than 70% among people 65 years and older. Among principal diagnoses given by family physicians for outpatient visits, only acute respiratory tract infection (7%) is more common than hypertension (6%). The annual direct medical cost of caring for hypertension exceeds $10 billion.
This article will discuss the pathophysiology and diagnosis of hypertension from an evidence-based perspective. An upcoming Applied Evidence article will cover treatment of hypertension and prognosis.
Pathophysiology
Idiopathic, or essential, hypertension accounts for more than 95% of cases and appears to be caused by a complex interaction between genetic predisposition and environmental factors. The predisposition to essential hypertension is polygenic in origin and may find full expression when combined with environmental factors, such as obesity, low physical activity levels, high stress levels, high alcohol consumption, high dietary sodium, and low dietary potassium, calcium, and magnesium. The complex interaction of genetics and environment may affect sodium, catecholamines, the renin-angiotensin system, insulin, and cell membrane function, causing elevation of the blood pressure.
The more common identifiable causes of hypertension include chronic renal disease (2%-5%), renovascular disease—including renal artery atherosclerosis and fibromuscular dysplasia—(0.2%-0.7%), Cushing syndrome (0.1%-0.6%), pheochromocytoma (0.04%-0.1%), and primary hyperaldosteronism (0.01%-0.3%). Although obesity, excessive alcohol consumption, oral contraceptive therapy, and sleep apnea may cause hypertension, they are not typically included as identifiable causes of hypertension. The prevalence of the latter conditions as identifiable causes of hypertension remains to be defined.
Diagnosis
The presence of hypertension must be confirmed by blood pressure measurements obtained with proper technique. The blood pressure of all patients 18 years and older should be measured at each health care visit because of the high prevalence of hypertension. Patients should be encouraged to abstain from nicotine and caffeine for at least 30 minutes before the measurement of the blood pressure. Measurement should be made with a mercury sphygmomanometer or a recently calibrated aneroid device. The bladder of the blood pressure cuff should encircle 80% of the arm. The pressure should be taken after at least 5 minutes of rest with the patient sitting, back supported, and arm bared and supported at heart level. The first sound heard (phase 1) is the SBP, and the last sound heard (phase 5) is the DBP. Two readings separated by 2 minutes should be averaged. Hypertension is present when an accurately measured blood pressure is high on 3 separate occasions.
A major consensus report, the Sixth Report of the Joint National Committee on Prevention Detection, Evaluation, and Treatment of High Blood Pressure,11 designates 6 categories of blood pressure:
- Optimal—SBP less than 120 mm; DBP less than 80 mm
- Normal—SBP less than 130 mm; DBP less than 85 mm
- High normal—SBP is 130 to 139 mm; DBP is 85 to 89 mm
- Stage 1 hypertension—SBP is 140 to 159 mm; DBP is 90 to 99 mm
- Stage 2 hypertension—SBP is 160 to 179 mm; DBP is 100 to 109 mm
- Stage 3 hypertension—SBP is 180 mm or higher; DBP is 110 mm or higher
It is important to note that the recommended diagnostic evaluation is based on a consensus and should not be considered evidence-based. A complete history, physical examination, and limited diagnostic testing (urinalysis, complete blood count, potassium, sodium, fasting glucose, creatinine, total cholesterol, high-density cholesterol, and electrocardiogram) are recommended once the presence of hypertension has been confirmed. This evaluation has 3 purposes:
- Identify other cardiovascular risk factors. Most patients with hypertension have multiple cardiovascular risk factors at the time of initial evaluation. Risk factors include smoking, hyperlipidemia, diabetes, age older than 60 years, sex (men or postmenopausal women), and family history of cardiovascular disease in a female relative before age 65 years or a male relative before 55 years.
- Identify end-organ damage. Evidence of end-organ damage includes left ventricular hypertrophy, angina, previous myocardial infarction, previous angioplasty or coronary revascularization, heart failure, stroke or transient ischemic attack, nephropathy, peripheral arterial disease, and retinopathy.
- Identify secondary causes of hypertension. Estimating the pretest probability of a secondary (identifiable) cause of hypertension is problematic, because referral bias is a major problem in hypertension prevalence studies; patients are typically included in these studies only after being referred to a study center by their primary care physician for resistant or difficult to control hypertension. On the basis of the best available estimates, it would be reasonable to assume that patients presenting to primary care physicians have a 5% probability of an identifiable cause of hypertension.
The diagnostic evaluation serves to identify other cardiovascular risk factors and end-organ damage in patients with high-normal blood pressure or hypertension. This information is used to identify 3 risk groups: Group A includes patients with no other cardiovascular risk factor, cardiovascular disease, or evidence of end-organ damage; group B includes patients who do not have cardiovascular disease or end-organ damage but have 1 or more of the major risk factors other than diabetes mellitus; and group C includes patients who have cardiovascular disease, other end-organ damage, or diabetes mellitus. The risk associated with hypertension and the intensity of recommended treatment increases progressively as a person moves from risk group A through risk group C.
The diagnostic evaluation may also reveal patients who are more likely to have an identifiable cause of hypertension. The probability of an identifiable cause of hypertension is increased by the onset of hypertension outside the normal age for essential hypertension (30-55 years), sudden onset or worsening of hypertension, stage 3 hypertension, and blood pressure that responds poorly to treatment. Elevated creatinine levels suggest hypertension caused by renal parenchymal disease. Abdominal or flank bruits, hypokalemia, or a significant rise in the serum creatinine level after an angiotensin-converting enzyme inhibitor is started suggests renovascular hypertension. Osteoporosis, truncal obesity, moon face, purple striae, muscle weakness, easy bruising, hirsutism, hyperglycemia, hypokalemia, and hyperlipidemia suggest Cushing syndrome. Labile hypertension, orthostatic hypotension, headache, palpitations, pallor, and diaphoresis suggests pheochromocytoma. Isolated hypokalemia may be caused by hyperaldosteronism.
Unfortunately, the accuracy of the history, physical examination, and preliminary diagnostic testing for patients presenting with hypertension has not been adequately studied. Therefore, estimating the pretest probability of a secondary cause of hypertension in a patient with specific clinical characteristics must be considered crude at best. The best available evidence is shown in Table 1.
Diagnostic Strategy
Patients whose initial history, physical, and laboratory evaluation suggest the possibility of a secondary cause of hypertension should undergo additional testing. The search for the secondary cause of hypertension should focus on chronic renal disease, renovascular hypertension, pheochromocytoma, Cushing syndrome, and primary aldosteronism, depending on the clinical scenario Table 2.
Chronic renal disease will be evident from the blood urea nitrogen, creatinine, and the urinalysis results. The diagnostic approach to other causes of hypertension is more complicated.
Although renal artery stenosis is suggested by the presence of an abdominal or flank bruit, it is an insensitive test (sensitivity=65%; specificity=90%). It is useful when positive (positive likelihood ratio=6.5) but does not rule out renal artery stenosis when negative (negative likelihood ratio=0.4). A clinical decision rule has been developed and validated that integrates several findings from the history and physical examination. Software to implement this decision rule in clinical practice, using Palm or PocketPC hand-held computers, is available at no charge from the JFP Web site at PC download.
Duplex sonography is very accurate (sensitivity=98%; specificity=98%) when the study is adequate but is often nondiagnostic in obese patients. For these patients, magnetic resonance angiography (MRA) is better (sensitivity=93%; specificity=95%). Captopril renal scanning (CRS) is less sensitive and less specific than either sonography or MRA. Renal artery stenosis is confirmed by the highly accurate but more invasive reference standard test of conventional angiography.
Pheochromocytoma is rare even in the presence of suggestive symptoms (headache, palpitations, and excessive and inappropriate perspiration), but failure to identify this disease can have disastrous consequences. Therefore, patients who have suggestive signs and symptoms should be screened for pheochromocytoma. However, the standard for screening pheochromocytoma remains controversial. A 24-hour urinary metanephrine (cutoff point of >3.70 nmol/day ) is highly sensitive and specific when done well, but urine collection is inconvenient and may be incomplete. Plasma metanephrines (metanephrine >0.66 nmol/L or normetanephrine >0.30 nmol/L) are easy to obtain, 100% sensitive, and may represent a good screening test for pheochromocytoma. Because they have limited specificity (85%), a positive plasma metanephrine should be confirmed by the 24-hour urinary metanephrine-to-creatinine ratio (cutoff point of >0.354; specificity=98%) before proceeding to anatomical localization of the tumor.
Two imaging studies are commonly used to localize pheochromocytomas. Metaiodobenzylguanidine (MIBG) scintigraphy is more specific but less sensitive than computed tomography (CT). Relying on CT to guide surgery is less likely to miss tumors than MIBG scintigraphy (CT sensitivity = 100% vs MIBG=88%) but is more likely to result in unnecessary surgery because of the lower specificity (CT specificity = 50%; MIBG=89%).
The 24-hour urinary free cortisol (cutoff point >90 mg/day; sensitivity=100%; specificity=98%) is a useful screening test for Cushing syndrome. It is very sensitive, but false-positives may be seen in patients with depression and polycystic ovarian syndrome. The single-dose (1 mg) overnight dexamethasone suppression test is equally sensitive but is a little less specific than the 24-hour urinary cortisol. However, this test is relatively simple for patients. The patient takes 1 mg of dexamethasone at midnight, and the plasma cortisol level is drawn in the morning (cutoff point >100 nmol). The combined dexamethasone and corticotropin-releasing hormone (CRH) suppression test, which has both a sensitivity and a specificity of almost 100%, can be used to confirm the diagnosis of Cushing syndrome. However, it is a little more complicated for the patient. The patient takes 0.5 mg of dexamethasone at noon on the first day and repeats this dose every 6 hours for a total of 8 doses (ending at 6 am on the third day). Two hours after the last dose the patient is given an intravenous bolus of CRH (1 μg/kg), and 15 minutes later a plasma cortisol is drawn. A cortisol level greater than 38 nmol is the cutoff point for this test.
The coexistence of hypertension and spontaneous or diuretic-induced hypokalemia is strongly suggestive of primary aldosteronism. However, it is important to remember that many (if not most) patients with primary aldosteronism do not have hypokalemia. In the past, screening for primary aldosteronism was accomplished by measuring urinary aldosterone levels after oral or intravenous salt loading. The sensitivity of these tests is 90% to 95%, and they carry a risk of precipitous elevation of blood pressure due to volume expansion or hypokalemia. Measuring the plasma renin and aldosterone levels can be used to test for hyperaldosteronism. Various cut points and ratios have been suggested, but the plasma aldosterone-to-renin ratio (cutoff point >25) is currently the most useful screening test for hyperaldosteronism. For this test the patient is asked to rise at 6 am and remain ambulatory for 2 hours, at which time the plasma aldosterone and renin levels are drawn. Beta-blockers and dihydropyridine calcium channel blockers must be stopped for 2 weeks, and spironolactone and loop diuretics must be stopped for 6 weeks before the test. Primary aldosteronism can be confirmed by the fludrocortisone suppression test.
Acknowledgments
Special thanks to Kathleen Dosh, MS; Greg Tan, MD; and Mark Povich, DO, for help during the initial editing of this paper.
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34. Jacques W, Lenders M, Keiser H, Goldstein D. Plasma metanephrines in the diagnosis of pheochromocytoma. Ann Intern Med 1995;123:101-09.
35. Heron E, Chatellier G, Billaud E, Foos E. The urinary metanephrine-to-creatinine ratio for the diagnosis of pheochromocytoma. Ann Intern Med 1996;125:300-03.
36. Mengden T, Habmann P, Mullen J, Vetter W. Urinary free cortisol versus 17-hydroxysteroids: a comparative study of their diagnostic value in Cushing’s syndrome. Clin Invest 1992;70:545-48.
37. Montwill J, Igoe D, McKenna T. The overnight dexamethasone test is the procedure of choice in screening for Cushing’s syndrome. Steroids 1994;59:296-98.
38. Weinberger M, Fineberg N. The diagnosis of primary aldosteronism and separation of two major subtypes. Arch Intern Med 1993;153:2125-29.
Hypertension is arbitrarily defined as a diastolic blood pressure (DBP) of 90 mm Hg or higher, a systolic blood pressure (SBP) equal to or higher than 140 mm Hg, or both, on 3 separate occasions. It affects 24% of the population of the United States and is common among black (28%), white (24%), and Hispanic (14%) Americans. The prevalence of hypertension increases with age and is more than 70% among people 65 years and older. Among principal diagnoses given by family physicians for outpatient visits, only acute respiratory tract infection (7%) is more common than hypertension (6%). The annual direct medical cost of caring for hypertension exceeds $10 billion.
This article will discuss the pathophysiology and diagnosis of hypertension from an evidence-based perspective. An upcoming Applied Evidence article will cover treatment of hypertension and prognosis.
Pathophysiology
Idiopathic, or essential, hypertension accounts for more than 95% of cases and appears to be caused by a complex interaction between genetic predisposition and environmental factors. The predisposition to essential hypertension is polygenic in origin and may find full expression when combined with environmental factors, such as obesity, low physical activity levels, high stress levels, high alcohol consumption, high dietary sodium, and low dietary potassium, calcium, and magnesium. The complex interaction of genetics and environment may affect sodium, catecholamines, the renin-angiotensin system, insulin, and cell membrane function, causing elevation of the blood pressure.
The more common identifiable causes of hypertension include chronic renal disease (2%-5%), renovascular disease—including renal artery atherosclerosis and fibromuscular dysplasia—(0.2%-0.7%), Cushing syndrome (0.1%-0.6%), pheochromocytoma (0.04%-0.1%), and primary hyperaldosteronism (0.01%-0.3%). Although obesity, excessive alcohol consumption, oral contraceptive therapy, and sleep apnea may cause hypertension, they are not typically included as identifiable causes of hypertension. The prevalence of the latter conditions as identifiable causes of hypertension remains to be defined.
Diagnosis
The presence of hypertension must be confirmed by blood pressure measurements obtained with proper technique. The blood pressure of all patients 18 years and older should be measured at each health care visit because of the high prevalence of hypertension. Patients should be encouraged to abstain from nicotine and caffeine for at least 30 minutes before the measurement of the blood pressure. Measurement should be made with a mercury sphygmomanometer or a recently calibrated aneroid device. The bladder of the blood pressure cuff should encircle 80% of the arm. The pressure should be taken after at least 5 minutes of rest with the patient sitting, back supported, and arm bared and supported at heart level. The first sound heard (phase 1) is the SBP, and the last sound heard (phase 5) is the DBP. Two readings separated by 2 minutes should be averaged. Hypertension is present when an accurately measured blood pressure is high on 3 separate occasions.
A major consensus report, the Sixth Report of the Joint National Committee on Prevention Detection, Evaluation, and Treatment of High Blood Pressure,11 designates 6 categories of blood pressure:
- Optimal—SBP less than 120 mm; DBP less than 80 mm
- Normal—SBP less than 130 mm; DBP less than 85 mm
- High normal—SBP is 130 to 139 mm; DBP is 85 to 89 mm
- Stage 1 hypertension—SBP is 140 to 159 mm; DBP is 90 to 99 mm
- Stage 2 hypertension—SBP is 160 to 179 mm; DBP is 100 to 109 mm
- Stage 3 hypertension—SBP is 180 mm or higher; DBP is 110 mm or higher
It is important to note that the recommended diagnostic evaluation is based on a consensus and should not be considered evidence-based. A complete history, physical examination, and limited diagnostic testing (urinalysis, complete blood count, potassium, sodium, fasting glucose, creatinine, total cholesterol, high-density cholesterol, and electrocardiogram) are recommended once the presence of hypertension has been confirmed. This evaluation has 3 purposes:
- Identify other cardiovascular risk factors. Most patients with hypertension have multiple cardiovascular risk factors at the time of initial evaluation. Risk factors include smoking, hyperlipidemia, diabetes, age older than 60 years, sex (men or postmenopausal women), and family history of cardiovascular disease in a female relative before age 65 years or a male relative before 55 years.
- Identify end-organ damage. Evidence of end-organ damage includes left ventricular hypertrophy, angina, previous myocardial infarction, previous angioplasty or coronary revascularization, heart failure, stroke or transient ischemic attack, nephropathy, peripheral arterial disease, and retinopathy.
- Identify secondary causes of hypertension. Estimating the pretest probability of a secondary (identifiable) cause of hypertension is problematic, because referral bias is a major problem in hypertension prevalence studies; patients are typically included in these studies only after being referred to a study center by their primary care physician for resistant or difficult to control hypertension. On the basis of the best available estimates, it would be reasonable to assume that patients presenting to primary care physicians have a 5% probability of an identifiable cause of hypertension.
The diagnostic evaluation serves to identify other cardiovascular risk factors and end-organ damage in patients with high-normal blood pressure or hypertension. This information is used to identify 3 risk groups: Group A includes patients with no other cardiovascular risk factor, cardiovascular disease, or evidence of end-organ damage; group B includes patients who do not have cardiovascular disease or end-organ damage but have 1 or more of the major risk factors other than diabetes mellitus; and group C includes patients who have cardiovascular disease, other end-organ damage, or diabetes mellitus. The risk associated with hypertension and the intensity of recommended treatment increases progressively as a person moves from risk group A through risk group C.
The diagnostic evaluation may also reveal patients who are more likely to have an identifiable cause of hypertension. The probability of an identifiable cause of hypertension is increased by the onset of hypertension outside the normal age for essential hypertension (30-55 years), sudden onset or worsening of hypertension, stage 3 hypertension, and blood pressure that responds poorly to treatment. Elevated creatinine levels suggest hypertension caused by renal parenchymal disease. Abdominal or flank bruits, hypokalemia, or a significant rise in the serum creatinine level after an angiotensin-converting enzyme inhibitor is started suggests renovascular hypertension. Osteoporosis, truncal obesity, moon face, purple striae, muscle weakness, easy bruising, hirsutism, hyperglycemia, hypokalemia, and hyperlipidemia suggest Cushing syndrome. Labile hypertension, orthostatic hypotension, headache, palpitations, pallor, and diaphoresis suggests pheochromocytoma. Isolated hypokalemia may be caused by hyperaldosteronism.
Unfortunately, the accuracy of the history, physical examination, and preliminary diagnostic testing for patients presenting with hypertension has not been adequately studied. Therefore, estimating the pretest probability of a secondary cause of hypertension in a patient with specific clinical characteristics must be considered crude at best. The best available evidence is shown in Table 1.
Diagnostic Strategy
Patients whose initial history, physical, and laboratory evaluation suggest the possibility of a secondary cause of hypertension should undergo additional testing. The search for the secondary cause of hypertension should focus on chronic renal disease, renovascular hypertension, pheochromocytoma, Cushing syndrome, and primary aldosteronism, depending on the clinical scenario Table 2.
Chronic renal disease will be evident from the blood urea nitrogen, creatinine, and the urinalysis results. The diagnostic approach to other causes of hypertension is more complicated.
Although renal artery stenosis is suggested by the presence of an abdominal or flank bruit, it is an insensitive test (sensitivity=65%; specificity=90%). It is useful when positive (positive likelihood ratio=6.5) but does not rule out renal artery stenosis when negative (negative likelihood ratio=0.4). A clinical decision rule has been developed and validated that integrates several findings from the history and physical examination. Software to implement this decision rule in clinical practice, using Palm or PocketPC hand-held computers, is available at no charge from the JFP Web site at PC download.
Duplex sonography is very accurate (sensitivity=98%; specificity=98%) when the study is adequate but is often nondiagnostic in obese patients. For these patients, magnetic resonance angiography (MRA) is better (sensitivity=93%; specificity=95%). Captopril renal scanning (CRS) is less sensitive and less specific than either sonography or MRA. Renal artery stenosis is confirmed by the highly accurate but more invasive reference standard test of conventional angiography.
Pheochromocytoma is rare even in the presence of suggestive symptoms (headache, palpitations, and excessive and inappropriate perspiration), but failure to identify this disease can have disastrous consequences. Therefore, patients who have suggestive signs and symptoms should be screened for pheochromocytoma. However, the standard for screening pheochromocytoma remains controversial. A 24-hour urinary metanephrine (cutoff point of >3.70 nmol/day ) is highly sensitive and specific when done well, but urine collection is inconvenient and may be incomplete. Plasma metanephrines (metanephrine >0.66 nmol/L or normetanephrine >0.30 nmol/L) are easy to obtain, 100% sensitive, and may represent a good screening test for pheochromocytoma. Because they have limited specificity (85%), a positive plasma metanephrine should be confirmed by the 24-hour urinary metanephrine-to-creatinine ratio (cutoff point of >0.354; specificity=98%) before proceeding to anatomical localization of the tumor.
Two imaging studies are commonly used to localize pheochromocytomas. Metaiodobenzylguanidine (MIBG) scintigraphy is more specific but less sensitive than computed tomography (CT). Relying on CT to guide surgery is less likely to miss tumors than MIBG scintigraphy (CT sensitivity = 100% vs MIBG=88%) but is more likely to result in unnecessary surgery because of the lower specificity (CT specificity = 50%; MIBG=89%).
The 24-hour urinary free cortisol (cutoff point >90 mg/day; sensitivity=100%; specificity=98%) is a useful screening test for Cushing syndrome. It is very sensitive, but false-positives may be seen in patients with depression and polycystic ovarian syndrome. The single-dose (1 mg) overnight dexamethasone suppression test is equally sensitive but is a little less specific than the 24-hour urinary cortisol. However, this test is relatively simple for patients. The patient takes 1 mg of dexamethasone at midnight, and the plasma cortisol level is drawn in the morning (cutoff point >100 nmol). The combined dexamethasone and corticotropin-releasing hormone (CRH) suppression test, which has both a sensitivity and a specificity of almost 100%, can be used to confirm the diagnosis of Cushing syndrome. However, it is a little more complicated for the patient. The patient takes 0.5 mg of dexamethasone at noon on the first day and repeats this dose every 6 hours for a total of 8 doses (ending at 6 am on the third day). Two hours after the last dose the patient is given an intravenous bolus of CRH (1 μg/kg), and 15 minutes later a plasma cortisol is drawn. A cortisol level greater than 38 nmol is the cutoff point for this test.
The coexistence of hypertension and spontaneous or diuretic-induced hypokalemia is strongly suggestive of primary aldosteronism. However, it is important to remember that many (if not most) patients with primary aldosteronism do not have hypokalemia. In the past, screening for primary aldosteronism was accomplished by measuring urinary aldosterone levels after oral or intravenous salt loading. The sensitivity of these tests is 90% to 95%, and they carry a risk of precipitous elevation of blood pressure due to volume expansion or hypokalemia. Measuring the plasma renin and aldosterone levels can be used to test for hyperaldosteronism. Various cut points and ratios have been suggested, but the plasma aldosterone-to-renin ratio (cutoff point >25) is currently the most useful screening test for hyperaldosteronism. For this test the patient is asked to rise at 6 am and remain ambulatory for 2 hours, at which time the plasma aldosterone and renin levels are drawn. Beta-blockers and dihydropyridine calcium channel blockers must be stopped for 2 weeks, and spironolactone and loop diuretics must be stopped for 6 weeks before the test. Primary aldosteronism can be confirmed by the fludrocortisone suppression test.
Acknowledgments
Special thanks to Kathleen Dosh, MS; Greg Tan, MD; and Mark Povich, DO, for help during the initial editing of this paper.
Hypertension is arbitrarily defined as a diastolic blood pressure (DBP) of 90 mm Hg or higher, a systolic blood pressure (SBP) equal to or higher than 140 mm Hg, or both, on 3 separate occasions. It affects 24% of the population of the United States and is common among black (28%), white (24%), and Hispanic (14%) Americans. The prevalence of hypertension increases with age and is more than 70% among people 65 years and older. Among principal diagnoses given by family physicians for outpatient visits, only acute respiratory tract infection (7%) is more common than hypertension (6%). The annual direct medical cost of caring for hypertension exceeds $10 billion.
This article will discuss the pathophysiology and diagnosis of hypertension from an evidence-based perspective. An upcoming Applied Evidence article will cover treatment of hypertension and prognosis.
Pathophysiology
Idiopathic, or essential, hypertension accounts for more than 95% of cases and appears to be caused by a complex interaction between genetic predisposition and environmental factors. The predisposition to essential hypertension is polygenic in origin and may find full expression when combined with environmental factors, such as obesity, low physical activity levels, high stress levels, high alcohol consumption, high dietary sodium, and low dietary potassium, calcium, and magnesium. The complex interaction of genetics and environment may affect sodium, catecholamines, the renin-angiotensin system, insulin, and cell membrane function, causing elevation of the blood pressure.
The more common identifiable causes of hypertension include chronic renal disease (2%-5%), renovascular disease—including renal artery atherosclerosis and fibromuscular dysplasia—(0.2%-0.7%), Cushing syndrome (0.1%-0.6%), pheochromocytoma (0.04%-0.1%), and primary hyperaldosteronism (0.01%-0.3%). Although obesity, excessive alcohol consumption, oral contraceptive therapy, and sleep apnea may cause hypertension, they are not typically included as identifiable causes of hypertension. The prevalence of the latter conditions as identifiable causes of hypertension remains to be defined.
Diagnosis
The presence of hypertension must be confirmed by blood pressure measurements obtained with proper technique. The blood pressure of all patients 18 years and older should be measured at each health care visit because of the high prevalence of hypertension. Patients should be encouraged to abstain from nicotine and caffeine for at least 30 minutes before the measurement of the blood pressure. Measurement should be made with a mercury sphygmomanometer or a recently calibrated aneroid device. The bladder of the blood pressure cuff should encircle 80% of the arm. The pressure should be taken after at least 5 minutes of rest with the patient sitting, back supported, and arm bared and supported at heart level. The first sound heard (phase 1) is the SBP, and the last sound heard (phase 5) is the DBP. Two readings separated by 2 minutes should be averaged. Hypertension is present when an accurately measured blood pressure is high on 3 separate occasions.
A major consensus report, the Sixth Report of the Joint National Committee on Prevention Detection, Evaluation, and Treatment of High Blood Pressure,11 designates 6 categories of blood pressure:
- Optimal—SBP less than 120 mm; DBP less than 80 mm
- Normal—SBP less than 130 mm; DBP less than 85 mm
- High normal—SBP is 130 to 139 mm; DBP is 85 to 89 mm
- Stage 1 hypertension—SBP is 140 to 159 mm; DBP is 90 to 99 mm
- Stage 2 hypertension—SBP is 160 to 179 mm; DBP is 100 to 109 mm
- Stage 3 hypertension—SBP is 180 mm or higher; DBP is 110 mm or higher
It is important to note that the recommended diagnostic evaluation is based on a consensus and should not be considered evidence-based. A complete history, physical examination, and limited diagnostic testing (urinalysis, complete blood count, potassium, sodium, fasting glucose, creatinine, total cholesterol, high-density cholesterol, and electrocardiogram) are recommended once the presence of hypertension has been confirmed. This evaluation has 3 purposes:
- Identify other cardiovascular risk factors. Most patients with hypertension have multiple cardiovascular risk factors at the time of initial evaluation. Risk factors include smoking, hyperlipidemia, diabetes, age older than 60 years, sex (men or postmenopausal women), and family history of cardiovascular disease in a female relative before age 65 years or a male relative before 55 years.
- Identify end-organ damage. Evidence of end-organ damage includes left ventricular hypertrophy, angina, previous myocardial infarction, previous angioplasty or coronary revascularization, heart failure, stroke or transient ischemic attack, nephropathy, peripheral arterial disease, and retinopathy.
- Identify secondary causes of hypertension. Estimating the pretest probability of a secondary (identifiable) cause of hypertension is problematic, because referral bias is a major problem in hypertension prevalence studies; patients are typically included in these studies only after being referred to a study center by their primary care physician for resistant or difficult to control hypertension. On the basis of the best available estimates, it would be reasonable to assume that patients presenting to primary care physicians have a 5% probability of an identifiable cause of hypertension.
The diagnostic evaluation serves to identify other cardiovascular risk factors and end-organ damage in patients with high-normal blood pressure or hypertension. This information is used to identify 3 risk groups: Group A includes patients with no other cardiovascular risk factor, cardiovascular disease, or evidence of end-organ damage; group B includes patients who do not have cardiovascular disease or end-organ damage but have 1 or more of the major risk factors other than diabetes mellitus; and group C includes patients who have cardiovascular disease, other end-organ damage, or diabetes mellitus. The risk associated with hypertension and the intensity of recommended treatment increases progressively as a person moves from risk group A through risk group C.
The diagnostic evaluation may also reveal patients who are more likely to have an identifiable cause of hypertension. The probability of an identifiable cause of hypertension is increased by the onset of hypertension outside the normal age for essential hypertension (30-55 years), sudden onset or worsening of hypertension, stage 3 hypertension, and blood pressure that responds poorly to treatment. Elevated creatinine levels suggest hypertension caused by renal parenchymal disease. Abdominal or flank bruits, hypokalemia, or a significant rise in the serum creatinine level after an angiotensin-converting enzyme inhibitor is started suggests renovascular hypertension. Osteoporosis, truncal obesity, moon face, purple striae, muscle weakness, easy bruising, hirsutism, hyperglycemia, hypokalemia, and hyperlipidemia suggest Cushing syndrome. Labile hypertension, orthostatic hypotension, headache, palpitations, pallor, and diaphoresis suggests pheochromocytoma. Isolated hypokalemia may be caused by hyperaldosteronism.
Unfortunately, the accuracy of the history, physical examination, and preliminary diagnostic testing for patients presenting with hypertension has not been adequately studied. Therefore, estimating the pretest probability of a secondary cause of hypertension in a patient with specific clinical characteristics must be considered crude at best. The best available evidence is shown in Table 1.
Diagnostic Strategy
Patients whose initial history, physical, and laboratory evaluation suggest the possibility of a secondary cause of hypertension should undergo additional testing. The search for the secondary cause of hypertension should focus on chronic renal disease, renovascular hypertension, pheochromocytoma, Cushing syndrome, and primary aldosteronism, depending on the clinical scenario Table 2.
Chronic renal disease will be evident from the blood urea nitrogen, creatinine, and the urinalysis results. The diagnostic approach to other causes of hypertension is more complicated.
Although renal artery stenosis is suggested by the presence of an abdominal or flank bruit, it is an insensitive test (sensitivity=65%; specificity=90%). It is useful when positive (positive likelihood ratio=6.5) but does not rule out renal artery stenosis when negative (negative likelihood ratio=0.4). A clinical decision rule has been developed and validated that integrates several findings from the history and physical examination. Software to implement this decision rule in clinical practice, using Palm or PocketPC hand-held computers, is available at no charge from the JFP Web site at PC download.
Duplex sonography is very accurate (sensitivity=98%; specificity=98%) when the study is adequate but is often nondiagnostic in obese patients. For these patients, magnetic resonance angiography (MRA) is better (sensitivity=93%; specificity=95%). Captopril renal scanning (CRS) is less sensitive and less specific than either sonography or MRA. Renal artery stenosis is confirmed by the highly accurate but more invasive reference standard test of conventional angiography.
Pheochromocytoma is rare even in the presence of suggestive symptoms (headache, palpitations, and excessive and inappropriate perspiration), but failure to identify this disease can have disastrous consequences. Therefore, patients who have suggestive signs and symptoms should be screened for pheochromocytoma. However, the standard for screening pheochromocytoma remains controversial. A 24-hour urinary metanephrine (cutoff point of >3.70 nmol/day ) is highly sensitive and specific when done well, but urine collection is inconvenient and may be incomplete. Plasma metanephrines (metanephrine >0.66 nmol/L or normetanephrine >0.30 nmol/L) are easy to obtain, 100% sensitive, and may represent a good screening test for pheochromocytoma. Because they have limited specificity (85%), a positive plasma metanephrine should be confirmed by the 24-hour urinary metanephrine-to-creatinine ratio (cutoff point of >0.354; specificity=98%) before proceeding to anatomical localization of the tumor.
Two imaging studies are commonly used to localize pheochromocytomas. Metaiodobenzylguanidine (MIBG) scintigraphy is more specific but less sensitive than computed tomography (CT). Relying on CT to guide surgery is less likely to miss tumors than MIBG scintigraphy (CT sensitivity = 100% vs MIBG=88%) but is more likely to result in unnecessary surgery because of the lower specificity (CT specificity = 50%; MIBG=89%).
The 24-hour urinary free cortisol (cutoff point >90 mg/day; sensitivity=100%; specificity=98%) is a useful screening test for Cushing syndrome. It is very sensitive, but false-positives may be seen in patients with depression and polycystic ovarian syndrome. The single-dose (1 mg) overnight dexamethasone suppression test is equally sensitive but is a little less specific than the 24-hour urinary cortisol. However, this test is relatively simple for patients. The patient takes 1 mg of dexamethasone at midnight, and the plasma cortisol level is drawn in the morning (cutoff point >100 nmol). The combined dexamethasone and corticotropin-releasing hormone (CRH) suppression test, which has both a sensitivity and a specificity of almost 100%, can be used to confirm the diagnosis of Cushing syndrome. However, it is a little more complicated for the patient. The patient takes 0.5 mg of dexamethasone at noon on the first day and repeats this dose every 6 hours for a total of 8 doses (ending at 6 am on the third day). Two hours after the last dose the patient is given an intravenous bolus of CRH (1 μg/kg), and 15 minutes later a plasma cortisol is drawn. A cortisol level greater than 38 nmol is the cutoff point for this test.
The coexistence of hypertension and spontaneous or diuretic-induced hypokalemia is strongly suggestive of primary aldosteronism. However, it is important to remember that many (if not most) patients with primary aldosteronism do not have hypokalemia. In the past, screening for primary aldosteronism was accomplished by measuring urinary aldosterone levels after oral or intravenous salt loading. The sensitivity of these tests is 90% to 95%, and they carry a risk of precipitous elevation of blood pressure due to volume expansion or hypokalemia. Measuring the plasma renin and aldosterone levels can be used to test for hyperaldosteronism. Various cut points and ratios have been suggested, but the plasma aldosterone-to-renin ratio (cutoff point >25) is currently the most useful screening test for hyperaldosteronism. For this test the patient is asked to rise at 6 am and remain ambulatory for 2 hours, at which time the plasma aldosterone and renin levels are drawn. Beta-blockers and dihydropyridine calcium channel blockers must be stopped for 2 weeks, and spironolactone and loop diuretics must be stopped for 6 weeks before the test. Primary aldosteronism can be confirmed by the fludrocortisone suppression test.
Acknowledgments
Special thanks to Kathleen Dosh, MS; Greg Tan, MD; and Mark Povich, DO, for help during the initial editing of this paper.
1. Burt V, Whelton P, Rocella E, Brown C, Cutler J. Prevalence of hypertension in the US population: results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension 1995;25:305-13.
2. Barker W, Mullooly J, Linton K. Trends in hypertension prevalence, treatment, and control: in a well-defined older population. Hypertension 1998;31:552-59.
3. Schappert S, Nelson C. National Ambulatory Medical Care Survey: 1995-96 summary. Vital Health Stat 1999;142:1-122.
4. Stason W. Opportunities to improve cost-effectiveness of treatment of hypertension. Hypertension 1991;18:1161-66.
5. Lander E, Schork N. Genetic dissection of complex traits. Science 1994;265:2037-48.
6. Stevens V, Obarzanek E, Cook N, Lee I-M. Long-term weight loss and changes in blood pressure: results of the trials of hypertension prevention, phase II. Ann Intern Med 2001;134:1-11.
7. Moore R, Levine D, Southard J, Entwisle G, Shapiro S. Alcohol consumption and blood pressure in the 1982 Maryland Hypertension Survey. Am J Hypertens 1990;3:1-7.
8. Chasan-Taber L, Willett W, Manson J, et al. Prospective study of oral contraceptives and hypertension among women in the United States. Circulation 1996;94:483-89.
9. Nieto F, Young T, Lind B, et al. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study: Sleep Heart Health Study. JAMA 2000;283:1829-36.
10. Reeves R. Does this patient have hypertension? How to measure blood pressure. JAMA 1995;273:1211-18.
11. Joint National Committee on Prevention. Evaluation and Treatment of High Blood Pressure. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Arch Intern Med 1997;157:2413-46.
12. Fuster V, Pearson T. 27th Bethesda conference: matching the intensity of risk factor management with the hazard for coronary disease events. September 14-15, 1995. J Am Coll Cardiol 1996;27:957-1047.
13. Rudnick K, Sackett D, Hirst S, Holmes C. Hypertension in a family practice. Can Med Assoc J 1977;117:492-97.
14. Sinclair A, Isles C, Brown I, Cameron H, Murray G, Robertson J. Secondary hypertension in a blood pressure clinic. Arch Intern Med 1987;147:1289-93.
15. Anderson G, Blakeman N, Streeten D. The effect of age on prevalence of secondary forms of hypertension in 4429 consecutively referred patients. J Hypertens 1994;12:609-15.
16. Tucker R, Labarthe D. Frequency of surgical treatment for hypertension in adults at the Mayo Clinic from 1973 through 1975. Mayo Clin Proc 1977;52:549-55.
17. Gifford R. Evaluation of the hypertensive patient. Chest 1973;64:336-40.
18. Krjnen P, Jaarsveld B, Steyerberg E, Schalekamp M. A clinical prediction rule for renal artery stenosis. Ann Intern Med 1998;129:705-11.
19. Berglund AS, Hulthen UL, Manhem P, Thorsson O, Wollmer P, Tornquist C. Metaiodobenzylguanidine (MIBG) scintigraphy and computed tomography (CT) in clinical practice: primary and secondary evaluation for localization of phaeochromocytomas. J Intern Med 2001;249:247-51.
20. Yanovski J, Cutler G, Chrousos G, Nieman L. Corticotropin-releasing hormone stimulation following low-dose dexamethasone administration: a new test to distinguish Cushing’s syndrome from pseudo-Cushing’s states. JAMA 1993;269:2232-38.
21. Blumenfeld J, Sealey J, Schussel Y, Vaughan E. Diagnosis and treatment of primary aldosteronism. Ann Intern Med 1994;121:877-85.
22. Fardella C, Lorena M, Gomez-Sanchez C, Cortes J. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metabol 2000;85:1863-67.
23. Streeten D, Tomycz N, Anderson G. Reliability of screening methods for the diagnosis of primary aldosteronism. Am J Med 1979;67:403-13.
24. Bravo E, Tarazi R, Dustan H, Fouad F. The changing clinical spectrum of primary aldosteronism. Am J Med 1983;74:641-51.
25. Gordon R. Primary aldosteronism. J Endocrinol Invest 1995;18:495-511.
26. Anderson G, Blakeman N, Streeten D. Prediction of renovascular hypertension. Am J Hypertens 1988;1:301-04.
27. Manger W, Gifford R. Clinical and experimental pheochromocytoma. Cambridge, Mass: Blackwell Science; 1996.
28. Nugent C, Warner H, Dunn J, Tyler F. Probability theory in the diagnosis of Cushing’s syndrome. J Clin Endocrinol Metabol 1964;24:621-27.
29. Fishman L, Kuchel O, Liddle G, Michelakis A. Incidence of primary hyperaldosteronism in uncomplicated ‘essential’ hypertension. JAMA 1968;205:85-90.
30. Fenton S, Lyttle J, Pantridge J. Diagnosis and results of surgery in renovascular hypertension. Lancet 1966;2:117-21.
31. de Haan M, Kouwenhoven M, Thelissen G, Koster D. Renovascular disease in patients with hypertension: detection with systolic and diastolic gating in three-dimensional, phase-contrast MR angiography. Radiology 1996;198:449-56.
32. Olin J, Piedmonte M, Young J, DeAnna S. The utility of duplex ultrasound screening of renal arteries for diagnosing significant renal artery stenosis. Ann Intern Med 1995;122:833-38.
33. Setaro J, Chen C, Hoffer P, Black H. Captopril renography in the diagnosis of renal artery stenosis and the prediction of improvement with revascularization: the Yale Vascular Center experience. Am J Hypertens 1991;4:698S-705S.
34. Jacques W, Lenders M, Keiser H, Goldstein D. Plasma metanephrines in the diagnosis of pheochromocytoma. Ann Intern Med 1995;123:101-09.
35. Heron E, Chatellier G, Billaud E, Foos E. The urinary metanephrine-to-creatinine ratio for the diagnosis of pheochromocytoma. Ann Intern Med 1996;125:300-03.
36. Mengden T, Habmann P, Mullen J, Vetter W. Urinary free cortisol versus 17-hydroxysteroids: a comparative study of their diagnostic value in Cushing’s syndrome. Clin Invest 1992;70:545-48.
37. Montwill J, Igoe D, McKenna T. The overnight dexamethasone test is the procedure of choice in screening for Cushing’s syndrome. Steroids 1994;59:296-98.
38. Weinberger M, Fineberg N. The diagnosis of primary aldosteronism and separation of two major subtypes. Arch Intern Med 1993;153:2125-29.
1. Burt V, Whelton P, Rocella E, Brown C, Cutler J. Prevalence of hypertension in the US population: results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension 1995;25:305-13.
2. Barker W, Mullooly J, Linton K. Trends in hypertension prevalence, treatment, and control: in a well-defined older population. Hypertension 1998;31:552-59.
3. Schappert S, Nelson C. National Ambulatory Medical Care Survey: 1995-96 summary. Vital Health Stat 1999;142:1-122.
4. Stason W. Opportunities to improve cost-effectiveness of treatment of hypertension. Hypertension 1991;18:1161-66.
5. Lander E, Schork N. Genetic dissection of complex traits. Science 1994;265:2037-48.
6. Stevens V, Obarzanek E, Cook N, Lee I-M. Long-term weight loss and changes in blood pressure: results of the trials of hypertension prevention, phase II. Ann Intern Med 2001;134:1-11.
7. Moore R, Levine D, Southard J, Entwisle G, Shapiro S. Alcohol consumption and blood pressure in the 1982 Maryland Hypertension Survey. Am J Hypertens 1990;3:1-7.
8. Chasan-Taber L, Willett W, Manson J, et al. Prospective study of oral contraceptives and hypertension among women in the United States. Circulation 1996;94:483-89.
9. Nieto F, Young T, Lind B, et al. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study: Sleep Heart Health Study. JAMA 2000;283:1829-36.
10. Reeves R. Does this patient have hypertension? How to measure blood pressure. JAMA 1995;273:1211-18.
11. Joint National Committee on Prevention. Evaluation and Treatment of High Blood Pressure. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Arch Intern Med 1997;157:2413-46.
12. Fuster V, Pearson T. 27th Bethesda conference: matching the intensity of risk factor management with the hazard for coronary disease events. September 14-15, 1995. J Am Coll Cardiol 1996;27:957-1047.
13. Rudnick K, Sackett D, Hirst S, Holmes C. Hypertension in a family practice. Can Med Assoc J 1977;117:492-97.
14. Sinclair A, Isles C, Brown I, Cameron H, Murray G, Robertson J. Secondary hypertension in a blood pressure clinic. Arch Intern Med 1987;147:1289-93.
15. Anderson G, Blakeman N, Streeten D. The effect of age on prevalence of secondary forms of hypertension in 4429 consecutively referred patients. J Hypertens 1994;12:609-15.
16. Tucker R, Labarthe D. Frequency of surgical treatment for hypertension in adults at the Mayo Clinic from 1973 through 1975. Mayo Clin Proc 1977;52:549-55.
17. Gifford R. Evaluation of the hypertensive patient. Chest 1973;64:336-40.
18. Krjnen P, Jaarsveld B, Steyerberg E, Schalekamp M. A clinical prediction rule for renal artery stenosis. Ann Intern Med 1998;129:705-11.
19. Berglund AS, Hulthen UL, Manhem P, Thorsson O, Wollmer P, Tornquist C. Metaiodobenzylguanidine (MIBG) scintigraphy and computed tomography (CT) in clinical practice: primary and secondary evaluation for localization of phaeochromocytomas. J Intern Med 2001;249:247-51.
20. Yanovski J, Cutler G, Chrousos G, Nieman L. Corticotropin-releasing hormone stimulation following low-dose dexamethasone administration: a new test to distinguish Cushing’s syndrome from pseudo-Cushing’s states. JAMA 1993;269:2232-38.
21. Blumenfeld J, Sealey J, Schussel Y, Vaughan E. Diagnosis and treatment of primary aldosteronism. Ann Intern Med 1994;121:877-85.
22. Fardella C, Lorena M, Gomez-Sanchez C, Cortes J. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metabol 2000;85:1863-67.
23. Streeten D, Tomycz N, Anderson G. Reliability of screening methods for the diagnosis of primary aldosteronism. Am J Med 1979;67:403-13.
24. Bravo E, Tarazi R, Dustan H, Fouad F. The changing clinical spectrum of primary aldosteronism. Am J Med 1983;74:641-51.
25. Gordon R. Primary aldosteronism. J Endocrinol Invest 1995;18:495-511.
26. Anderson G, Blakeman N, Streeten D. Prediction of renovascular hypertension. Am J Hypertens 1988;1:301-04.
27. Manger W, Gifford R. Clinical and experimental pheochromocytoma. Cambridge, Mass: Blackwell Science; 1996.
28. Nugent C, Warner H, Dunn J, Tyler F. Probability theory in the diagnosis of Cushing’s syndrome. J Clin Endocrinol Metabol 1964;24:621-27.
29. Fishman L, Kuchel O, Liddle G, Michelakis A. Incidence of primary hyperaldosteronism in uncomplicated ‘essential’ hypertension. JAMA 1968;205:85-90.
30. Fenton S, Lyttle J, Pantridge J. Diagnosis and results of surgery in renovascular hypertension. Lancet 1966;2:117-21.
31. de Haan M, Kouwenhoven M, Thelissen G, Koster D. Renovascular disease in patients with hypertension: detection with systolic and diastolic gating in three-dimensional, phase-contrast MR angiography. Radiology 1996;198:449-56.
32. Olin J, Piedmonte M, Young J, DeAnna S. The utility of duplex ultrasound screening of renal arteries for diagnosing significant renal artery stenosis. Ann Intern Med 1995;122:833-38.
33. Setaro J, Chen C, Hoffer P, Black H. Captopril renography in the diagnosis of renal artery stenosis and the prediction of improvement with revascularization: the Yale Vascular Center experience. Am J Hypertens 1991;4:698S-705S.
34. Jacques W, Lenders M, Keiser H, Goldstein D. Plasma metanephrines in the diagnosis of pheochromocytoma. Ann Intern Med 1995;123:101-09.
35. Heron E, Chatellier G, Billaud E, Foos E. The urinary metanephrine-to-creatinine ratio for the diagnosis of pheochromocytoma. Ann Intern Med 1996;125:300-03.
36. Mengden T, Habmann P, Mullen J, Vetter W. Urinary free cortisol versus 17-hydroxysteroids: a comparative study of their diagnostic value in Cushing’s syndrome. Clin Invest 1992;70:545-48.
37. Montwill J, Igoe D, McKenna T. The overnight dexamethasone test is the procedure of choice in screening for Cushing’s syndrome. Steroids 1994;59:296-98.
38. Weinberger M, Fineberg N. The diagnosis of primary aldosteronism and separation of two major subtypes. Arch Intern Med 1993;153:2125-29.
Treatment of Peptic Ulcer Disease and Nonulcer Dyspepsia
In the June 2001 issue of The Journal of Family Practice, the diagnostic approach to the patient with dyspepsia was presented.1 In that analysis, gastroesophageal reflux disease (GERD), gastric ulcers, and duodenal ulcers emerged as the most common identifiable causes of dyspepsia. However, most patients with dyspepsia do not have one of these conditions, and are considered to have functional or nonulcer dyspepsia. The diagnosis and management of adults with GERD was recently described in detail.2 Therefore, this paper reviews the treatment of undifferentiated dyspepsia, gastric ulcer caused by nonsteroidal anti-inflammatory drugs (NSAIDs), peptic ulcer disease not associated with NSAID use, and nonulcer dyspepsia (dyspepsia in a patient who has no evidence of ulcer or GERD on endoscopy). An algorithm for the management of the patient with known ulcer disease is shown in the Figure 1. (J Fam Pract 2001; 50:614-619)
Undifferentiated dyspepsia
In primary care, the typical patient presenting with dyspepsia will not have had endoscopy. Therefore, the presence of an underlying lesion will be unknown, a situation known as undifferentiated dyspepsia. As described by Smucny,2 randomized trials and economic analyses have demonstrated the cost-effectiveness of a test-and-treat strategy3,4 in which patients with dyspepsia are tested for Helicobacter pylori and treated with eradication therapy if positive. This strategy would reserve endoscopy for those patients with alarm signs Table1 or those who have persistent symptoms despite appropriate empiric therapy. Certainly a physician must weigh the potential for complications during endoscopy with the risks of adverse reactions to eradication therapy, including the development of antimicrobial resistant organisms. All patients with dyspepsia should be counseled to avoid factors that exacerbate their symptoms or disrupt the integrity of the mucosal lining of the stomach, such as NSAID use and cigarette smoking. Both of these have been identified as risk factors for the development of peptic ulcers and delayed ulcer healing.5,6
NSAID-related gastric ulcers
NSAIDs are associated with a 5- to 7-fold increased risk of gastric ulceration in the first 3 months of use. In a meta-analysis of observational studies of gastrointestinal bleeding risk due to various NSAIDs, a 4-fold increased risk associated with NSAID-use persisted throughout therapy and fell to baseline within 2 months of discontinuation of the NSAID.7 This study demonstrated a clear dose-response relationship; the difference between NSAIDs, however, was minimal.
Table 2 summarizes treatments for NSAID-related gastric ulcers. Misoprostol is an effective prophylaxis against ulcers when used with NSAIDs, but is associated with diarrhea, even at lower than optimal doses.8 Standard doses of H2-receptor agonists (H2RAs) are ineffective at preventing NSAID-related gastric ulcers, but double doses of H2RAs (eg, ranitidine 300 mg twice daily) and standard doses of proton-pump inhibitors (PPIs; eg, omeprazole 20 mg 4 times per day) are effective prophylactic agents for the duration of NSAID use according to the results of endoscopic studies. New COX-2 specific anti-inflammatory agents are associated with a significantly lower risk of ulcers as seen by endoscopy (4.7% with rofecoxib vs 27.7% with ibuprofen).9 The benefit in terms of actual adverse clinical outcomes and ulcer complications, however, is much smaller; the risk of symptomatic ulcer, perforation, symptomatic ulcer, and clinically significant bleeding was 1.3% for rofecoxib (Vioxx) and 1.8% with ibuprofen, diclofenac, or nabumetone taken for 1 year (P <.05).10 Thus, one would have to treat 200 patients for 1 year to prevent 1 adverse outcome. Similarly, the annual risk of bleeding, perforation, or gastric outlet obstruction was lower with celecoxib (Celebrex) than with naproxen, diclofenac, or ibuprofen (0.2% vs. 1.68%; P <.002; number needed to treat=60).11 COX-2 inhibitors have not been studied as an alternative therapy in patients with a history of NSAID-induced ulcers. While no trial data are available, a consensus-based recommendation has been made for dyspeptic patients with no alarm symptoms who are regular NSAID-users: The first step in management is to stop the NSAID use if possible, and determine if the symptoms improve.12 If symptoms persist after NSAID use is discontinued, the patient should be managed as others with undifferentiated dyspepsia.
Non–NSAID-related duodenal and gastric ulcers
Helicobacter pylori is now well recognized as a major risk factor for the development of peptic ulcer disease. Although most H pylori–infected patients do not develop an ulcer, as many as 95% of patients with duodenal ulcers and 80% of those with gastric ulcers are infected. These rates may be lower in the United States because of greater use of NSAIDs and a lower rate of H pylori infection than in other parts of the world.13 Successful eradication of the organism following treatment heals ulcers and reduces the risk of recurrence from 67% to 6% for patients with duodenal ulcers, and from 59% to 4% for patients with gastric ulcers.14 A meta-analysis of North American randomized controlled trials of H pylori eradication for duodenal ulcer found that one ulcer recurrence (by endoscopy) would be prevented for every 2.8 patients successfully treated.15
However, a multi-drug regimen and an adequate length of treatment are required for eradication. Because antimicrobial resistance and incomplete treatment are major reasons for treatment failure,16,17 convenience and tolerability become important considerations in choosing a treatment plan.
Effective H pylori treatment regimens include a combination of two antibiotics and acid suppression therapy, with or without a bismuth compound, taken for 10 to 14 days. Choosing a combination that can be taken in two daily doses may be easier for patients, although this option is also more costly.Table 3 provides a practical list of selected effective drug combinations used for treating H pylori infection. Triple therapies with reported eradication rates approaching 90% or more are included, though resistant strains may continue to emerge. Single and dual therapies, though FDA-approved for treatment of H pylori, have unacceptably low cure rates and are not recommended. PPI quadruple therapy or a regimen including furazolidone (a monoamine oxidase inhibitor) may serve as second-line treatment for eradication of initial failures and in case of metronidazole resistance.18,19 Studies using ranitidine bismuth citrate in place of PPIs have also shown comparable results.
Patient education regarding the need for effective eradication therapy and to encourage adherence to the drug regimen is critical. Patients should have adequate follow-up, since further diagnostic testing may be needed to ensure eradication of the H pylori organism, particularly in the case of treatment failure or relapse. Because eradication usually cures peptic ulcer disease, chronic acid suppression therapy should not be needed in most patients who have cleared the H pylori infection and who are not taking NSAIDs. Among primary care patients with a history of peptic ulcer disease taking chronic acid suppressive therapy, 78% of those treated for H pylori were able to discontinue their therapy.21
Persistent or recurrent ulcers in patients treated for H pylori are strongly associated with persistent or recurrent infection.22 Because symptom relief is not always correlated with eradication, testing for cure following eradication therapy should be considered, particularly in high-risk patients, such as those with a history of bleeding or perforation.13 However, no randomized studies have been done to assess the outcomes associated with the decision to test for cure. If desired, noninvasive tests (eg stool antigen test or urea breath test) may be used for patients who become symptom-free following eradication therapy or for patients with persistent symptoms and a previously documented duodenal ulcer. Acid suppressive therapy with a PPI can result in false negative results, so this should be withheld for at least 2 weeks prior to testing for persistent infection.23 Because of the risk of cancer associated with gastric ulcers, endoscopic documentation of gastric ulcer healing might be preferable to noninvasive testing, particularly in high-risk patients. In either case, patients with persistent or recurrent symptoms following eradication should have endoscopy to document ulcer healing and to obtain biopsies if necessary.
Nonulcer Dyspepsia
The pathophysiology of nonulcer dyspepsia (NUD) is not definitively known, though factors implicated include gastric acid secretion, gastro-duodenal dysmotility, visceral hypersensitivity, stress, and psychological factors.24 A relationship with H pylori has not been established, though there is some evidence of an association.25
Studies of drug treatments for NUD are limited by small samples, short duration of follow-up and the use of unvalidated outcome measures.26 A recent meta-analysis found no significant benefit from the use of antacids or sucralfate for NUD, defined as dyspeptic symptoms with negative endoscopic or barium studies, excluding other organic (eg pancreato-biliary disease, oesophagitis) and drug-induced (NSAIDs) disease. The same study reported statistically significant benefits with the prokinetic drug cisapride, but there was evidence of a publication bias in these comparisons, making interpretation difficult (“positive” studies were more likely to be published than “negative” trials). Cisapride was also recently taken off the market, so is no longer available as a treatment option. No placebo-controlled studies of metoclopramide were identified in this systematic review.
Antisecretory treatments were more effective than placebo in the treatment of NUD, with a number needed to treat of 6 for H2-RAs and 11 for PPIs (ie, for every 11 patients who received a PPI instead of placebo, one benefited).24 Thus, PPIs were actually less effective than H2-RAs in this meta-analysis of placebo-controlled trials. Long-term use of antisecretory therapy may be associated with hypergastrinemia, increased gastrointestinal bacterial counts, and altered absorption of nutrients, though the clinical significance of this is unclear.27 For patients who do not respond to acid-suppressive therapy it might be necessary to entertain alternative diagnoses, and if no explanation for the symptoms can be identified, consider counseling or pain management strategies to help the patient cope with the discomfort. Studies of the use of antidepressants, though small and of questionable quality, consistently show improvement in symptoms of patients with functional gastrointestinal disorders, including NUD and irritable bowel syndrome.28 Treatment recommendations for NUD are shown inTable 4.
To date there is no convincing evidence that empiric eradication of H pylori in patients with NUD improves symptoms. One recent meta-analysis of randomized controlled trials revealed no improvement with H pylori eradication for the symptoms of NUD,29 while 2 others25,30 showed a modest but statistically significant benefit, with 1 patient cured for every 19 treated (number needed to treat = 19).
Prognosis
Without treatment, peptic ulcer disease can lead to serious complications such as gastrointestinal bleeding and cancer. Acid suppression achieves ulcer healing rates of approximately 90%, but is associated with a 10% recurrence rate even with long-term treatment.22 Successful eradication of H pylori in the absence of NSAID use cures ulcer disease in 95% of cases; the recurrence rate is 33% to 41% if eradication is not achieved.14 Reinfection is rare once eradication has been accomplished, with a rate of about 1% per year,31 though rates can be much higher in endemic areas.32 Persistent infection requires re-treatment, ideally with a regimen not previously used, in case of antimicrobial resistance. Persistent gastric ulcers can harbor malignancy and therefore, evaluation with endoscopy might be prudent. H pylori itself is associated with a 2- to 6-fold increase in risk of gastric cancer.33 Widespread screening or treatment to prevent cancer has not been recommended to date. A cost-benefit analysis suggests that the development and distribution of a vaccination for H pylori would be highly cost-effective,34 but such a vaccine is not available as yet.
The prognosis of NUD is more discouraging. NUD is a chronic relapsing and remitting disorder, and treatment responses difficult to measure. For example, one systematic review of the literature found 56% of patients experienced an improvement in symptom scores when given placebo (range 5% - 90%). As with other functional gastrointestinal disorders, underlying psychosocial and lifestyle factors may be involved and must be addressed. Further research is needed in this area, particularly in the primary care setting.
Each Applied Evidence review article considers a common presenting complaint or disease and summarizes the best available evidence for clinicians. The collected reviews are published online at www.jfponline.com. Explanations of the Levels of Evidence can be found at http://cebm.jr2.ox.ac.uk/docs/levels.html.
1. Smucny J. Evaluation of the patient with dyspepsia. J Fam Pract 2001;50:583-542.
2. Flynn CA. Evaluation and treatment of adults with gastro-esophageal reflux disease. J Fam Pract 2001;50:57-63.
3. Jones R, Tate C, Sladen G, Weston-Baker J. A trial of test-and-treat strategy for Helicobacter pylori positive dyspeptic patients in general practice. Intern J Clin Pract 1999;53:413-16.
4. Ebell MH, Warbasse L, Brenner C. Evaluation of the dyspeptic patient: a cost utility study. J Fam Pract 1997;44:545-55.
5. Kurata J, Nogawa A. Meta-analysis of risk factors for peptic ulcer: nonsteroidal antiinflammatory drugs, Helicobacter pylori, and smoking. J Clin Gastroenterol 1997;24:2-17.
6. Graham DY. Nonsteriodal anti-inflammatory druge, Helicobacter pylori, and ulcers: where we stand. Am J Gastroenterol 1996;91:2080-86.
7. Hernandez-Diaz S, Rodriguez LA. Association between nonsteroidal anti-inflammatory drugs and upper gastrointestinal tract bleeding/perforation: an overview of epidemiologic studies published in the 1990s. Arch Intern Med 2000;160:2093-99.
8. Rostom A, Wells G, Tugwell P, Welch V, Dube C, McGowan J. Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database of Systematic Reviews 2001; Issue 1.
9. Laine L, Harper S, Simon T, et al. A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2-specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis. Rofecoxib Osteoarthritis Endoscopy Study Group. Gastroenterology 1999;117:776-83.
10. Langman MJ, Jensen DM, Watson DJ, et al. Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs. JAMA 1999;282:1929-933.
11. Goldstein JL, Silverstein FE, Agrawal NM, et al. Reduced risk of upper gastrointestinal ulcer complications with celecoxib, a novel COX-2 inhibitor. Am J Gastroenterol 2000;95:1681-690.
12. Veldhuyzen van Zanten SJ, Flook N, et al. An evidence-based approach to the management of uninvestigated dyspepsia in the era of Helicobacter pylori. Can Med Assoc J 2000;162(suppl 12):S3-S23.
13. Peterson WL, Fendrick AM, Cave DR, Peura DA, Garabedian-Raffalo S, Laine L. Helicobacter pylori-related disease: guidelines for testing and treatment. Arch Intern Med 2000;160:1285-291.
14. Hopkins RJ, Girardi LS, Turney EA. Relationship between Helicobacter pylori eradication and reduced duodenal and gastric ulcer recurrence: a review. Gastroenterology 1996;110:1244-252.
15. Laine L, Hopkins RJ, Girardi L. Has the impact of Helicobacter pylori therapy on ulcer recurrence in the Unites States been overstated? A meta-analysis of rigourously designed trials. Amer J Gastroenterol 1998;93:1409-415.
16. Megraud F. Resistance of Helicobacter pylori to antibiotics: the main limitation of current proton-pump inhibitor triple therapy. Eur J Gastroenterol Hepatol 1999;11(suppl 2):S35-S37.
17. Graham DY, Lew GM, Malaty HM, et al. Factors influencing the eradication of Helicobacter pylori with triple therapy. Gastroenterology 1992;102:493-96.
18. Rene W.M., van der Hulst RWM, Keller JJ, Rauws EA, Tytgat G. Treatment of Helicobacter pylori infection: a review of the world literature. Helicobacter 1996;1:6-18.
19. Graham D Y. Highlights from 100th Annual Meeting of the American Gastroenterological Association and Digestive Disease Week. Helicobacter Today 1999;6:1-24.
20. Laine L, Estrada R, Trujillo M, Emami S. Randomized comparison of ranitidine bismuth citrate-based triple therapies for Helicobacter pylori. Am J Gastroenterol 1997;92:2213-215.
21. De Wit NJ, Quartero AO, Numans ME. Helicobacter pylori treatment instead of maintenance therapy for peptic ulcer disease: the effectiveness of case-finding in general practice. Aliment Pharmacol Ther 1999;13:1317-321.
22. Wong BC, Lam SK, Lai KC, et al. Triple therapy for Helicobacter pylori eradication is more effective than long-term maintenance antisecretory treatment in the prevention of recurrence of duodenal ulcer: a prospective long-term follow-up study. Aliment Pharmacol Ther 1999;13:303-09.
23. Laine L, Estrada R, Trujillo M, Knigge K, Fennerty MB. Effect of proton-pump inhibitor therapy on diagnostic testing for Helicobacter pylori. Ann Intern Med 1998;129:547-50.
24. Soo S, Moayyedi P, Deeks J, Delaney B, Innes M, Forman D. Pharmacological interventions for nonulcer dyspepsia. Cochrane Database of Systematic Reviews 2001; Issue 1.
25. Jaakkimainen RL, Boyle E, Tudiver F. Is Helicobacter pylori associated with non-ulcer dyspepsia and will eradication improve symptoms? A meta-analysis [see comments]. BMJ 1999;319:1040-44.
26. Veldhuyzen van Zanten SJ, Cleary C, et al. Drug treatment of functional dyspepsia: a systematic analysis of trial methodology with recommendations for design of future trials. Amer J Gastroenterol 1996;91:660-73.
27. Laine L, Ahnen D, McClain C, Solcia E, Walsh JH. Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther 2000;14:651-68.
28. Jackson JL, O’Malley PG, Tomkins G, Balden E, Santoro J, Kroenke K. Treatment of functional gastrointestinal disorders with antidepressant medications: a meta-analysis. Amer J Med 2000;108:65-72.
29. Laine L, Schoenfeld P, Fennerty MB. Therapy for Helicobacter pylori in patients with nonulcer dyspepsia: a meta-analysis of randomized, controlled trials. Ann Intern Med 2001;134:361-69.
30. Moayyedi P, Soo S, Deeks J, et al. Eradication of Helicobacter pylori for non-ulcer dyspepsia. Cochrane Database of Systematic Reviews 2001; Issue 1.
31. Mohammed Z, Abu-Mahfouz MD, Prasad VM, Santogade P, Cutler AF. Helicobacter pylori recurrence after successful eradication: 5-year follow-up in the United States. Am J Gastroenterol 1997;11:2025-28.
32. Kepekci Y, Kadayifci A. Does the eradication of Helicobacter pylori cure duodenal ulcer disease in communities with a high prevalence rate? Comparison with long-term acid suppression. Int J Clin Pract 1999;53:505-8.
33. Scheiman JM, Cutler AF. Helicobacter pylori and gastric cancer. Am J Med 1999;106:222-26.
34. Rupnow MF, Owens DK, Shachter R, Parsonnet J. Helicobacter pylori vaccine development and use: a cost-effectiveness analysis using the Institute of Medicine Methodology. Helicobacter 1999;4:272-80.
35. Laine L, Estrada R, Fukanaga K, Neil G. Randomized comparison of differing periods of twice-a-day triple therapy for the eradication of Helicobacter pylori. Aliment Pharmacol Ther 1996;10:1029-33.
36. Yousfi MM, El-Zimaity HMT, Al-assi MT, Cole RA, Genta RM, Graham DY. Metronidazole, omeprazole and clarithromycin: an effective combination therapy for Helicobacter pylori infection. Aliment Pharmacol Ther 1995;9:209-12.
37. de Boer WA, Driessen W, Jansz A, Tytgat G. Effect of acid suppression on efficacy of treatment for Helicobacter pylori infection. Lancet 95 A.D.;345:817-820.
38. Hansen JM, Bytzer P, Schaffalitzky de Muckadell OB. Placebo-controlled trial of cisapride and nizatidine in unselected patients with functional dyspepsia. Am J Gastroenterol 1998;93:368-74.
In the June 2001 issue of The Journal of Family Practice, the diagnostic approach to the patient with dyspepsia was presented.1 In that analysis, gastroesophageal reflux disease (GERD), gastric ulcers, and duodenal ulcers emerged as the most common identifiable causes of dyspepsia. However, most patients with dyspepsia do not have one of these conditions, and are considered to have functional or nonulcer dyspepsia. The diagnosis and management of adults with GERD was recently described in detail.2 Therefore, this paper reviews the treatment of undifferentiated dyspepsia, gastric ulcer caused by nonsteroidal anti-inflammatory drugs (NSAIDs), peptic ulcer disease not associated with NSAID use, and nonulcer dyspepsia (dyspepsia in a patient who has no evidence of ulcer or GERD on endoscopy). An algorithm for the management of the patient with known ulcer disease is shown in the Figure 1. (J Fam Pract 2001; 50:614-619)
Undifferentiated dyspepsia
In primary care, the typical patient presenting with dyspepsia will not have had endoscopy. Therefore, the presence of an underlying lesion will be unknown, a situation known as undifferentiated dyspepsia. As described by Smucny,2 randomized trials and economic analyses have demonstrated the cost-effectiveness of a test-and-treat strategy3,4 in which patients with dyspepsia are tested for Helicobacter pylori and treated with eradication therapy if positive. This strategy would reserve endoscopy for those patients with alarm signs Table1 or those who have persistent symptoms despite appropriate empiric therapy. Certainly a physician must weigh the potential for complications during endoscopy with the risks of adverse reactions to eradication therapy, including the development of antimicrobial resistant organisms. All patients with dyspepsia should be counseled to avoid factors that exacerbate their symptoms or disrupt the integrity of the mucosal lining of the stomach, such as NSAID use and cigarette smoking. Both of these have been identified as risk factors for the development of peptic ulcers and delayed ulcer healing.5,6
NSAID-related gastric ulcers
NSAIDs are associated with a 5- to 7-fold increased risk of gastric ulceration in the first 3 months of use. In a meta-analysis of observational studies of gastrointestinal bleeding risk due to various NSAIDs, a 4-fold increased risk associated with NSAID-use persisted throughout therapy and fell to baseline within 2 months of discontinuation of the NSAID.7 This study demonstrated a clear dose-response relationship; the difference between NSAIDs, however, was minimal.
Table 2 summarizes treatments for NSAID-related gastric ulcers. Misoprostol is an effective prophylaxis against ulcers when used with NSAIDs, but is associated with diarrhea, even at lower than optimal doses.8 Standard doses of H2-receptor agonists (H2RAs) are ineffective at preventing NSAID-related gastric ulcers, but double doses of H2RAs (eg, ranitidine 300 mg twice daily) and standard doses of proton-pump inhibitors (PPIs; eg, omeprazole 20 mg 4 times per day) are effective prophylactic agents for the duration of NSAID use according to the results of endoscopic studies. New COX-2 specific anti-inflammatory agents are associated with a significantly lower risk of ulcers as seen by endoscopy (4.7% with rofecoxib vs 27.7% with ibuprofen).9 The benefit in terms of actual adverse clinical outcomes and ulcer complications, however, is much smaller; the risk of symptomatic ulcer, perforation, symptomatic ulcer, and clinically significant bleeding was 1.3% for rofecoxib (Vioxx) and 1.8% with ibuprofen, diclofenac, or nabumetone taken for 1 year (P <.05).10 Thus, one would have to treat 200 patients for 1 year to prevent 1 adverse outcome. Similarly, the annual risk of bleeding, perforation, or gastric outlet obstruction was lower with celecoxib (Celebrex) than with naproxen, diclofenac, or ibuprofen (0.2% vs. 1.68%; P <.002; number needed to treat=60).11 COX-2 inhibitors have not been studied as an alternative therapy in patients with a history of NSAID-induced ulcers. While no trial data are available, a consensus-based recommendation has been made for dyspeptic patients with no alarm symptoms who are regular NSAID-users: The first step in management is to stop the NSAID use if possible, and determine if the symptoms improve.12 If symptoms persist after NSAID use is discontinued, the patient should be managed as others with undifferentiated dyspepsia.
Non–NSAID-related duodenal and gastric ulcers
Helicobacter pylori is now well recognized as a major risk factor for the development of peptic ulcer disease. Although most H pylori–infected patients do not develop an ulcer, as many as 95% of patients with duodenal ulcers and 80% of those with gastric ulcers are infected. These rates may be lower in the United States because of greater use of NSAIDs and a lower rate of H pylori infection than in other parts of the world.13 Successful eradication of the organism following treatment heals ulcers and reduces the risk of recurrence from 67% to 6% for patients with duodenal ulcers, and from 59% to 4% for patients with gastric ulcers.14 A meta-analysis of North American randomized controlled trials of H pylori eradication for duodenal ulcer found that one ulcer recurrence (by endoscopy) would be prevented for every 2.8 patients successfully treated.15
However, a multi-drug regimen and an adequate length of treatment are required for eradication. Because antimicrobial resistance and incomplete treatment are major reasons for treatment failure,16,17 convenience and tolerability become important considerations in choosing a treatment plan.
Effective H pylori treatment regimens include a combination of two antibiotics and acid suppression therapy, with or without a bismuth compound, taken for 10 to 14 days. Choosing a combination that can be taken in two daily doses may be easier for patients, although this option is also more costly.Table 3 provides a practical list of selected effective drug combinations used for treating H pylori infection. Triple therapies with reported eradication rates approaching 90% or more are included, though resistant strains may continue to emerge. Single and dual therapies, though FDA-approved for treatment of H pylori, have unacceptably low cure rates and are not recommended. PPI quadruple therapy or a regimen including furazolidone (a monoamine oxidase inhibitor) may serve as second-line treatment for eradication of initial failures and in case of metronidazole resistance.18,19 Studies using ranitidine bismuth citrate in place of PPIs have also shown comparable results.
Patient education regarding the need for effective eradication therapy and to encourage adherence to the drug regimen is critical. Patients should have adequate follow-up, since further diagnostic testing may be needed to ensure eradication of the H pylori organism, particularly in the case of treatment failure or relapse. Because eradication usually cures peptic ulcer disease, chronic acid suppression therapy should not be needed in most patients who have cleared the H pylori infection and who are not taking NSAIDs. Among primary care patients with a history of peptic ulcer disease taking chronic acid suppressive therapy, 78% of those treated for H pylori were able to discontinue their therapy.21
Persistent or recurrent ulcers in patients treated for H pylori are strongly associated with persistent or recurrent infection.22 Because symptom relief is not always correlated with eradication, testing for cure following eradication therapy should be considered, particularly in high-risk patients, such as those with a history of bleeding or perforation.13 However, no randomized studies have been done to assess the outcomes associated with the decision to test for cure. If desired, noninvasive tests (eg stool antigen test or urea breath test) may be used for patients who become symptom-free following eradication therapy or for patients with persistent symptoms and a previously documented duodenal ulcer. Acid suppressive therapy with a PPI can result in false negative results, so this should be withheld for at least 2 weeks prior to testing for persistent infection.23 Because of the risk of cancer associated with gastric ulcers, endoscopic documentation of gastric ulcer healing might be preferable to noninvasive testing, particularly in high-risk patients. In either case, patients with persistent or recurrent symptoms following eradication should have endoscopy to document ulcer healing and to obtain biopsies if necessary.
Nonulcer Dyspepsia
The pathophysiology of nonulcer dyspepsia (NUD) is not definitively known, though factors implicated include gastric acid secretion, gastro-duodenal dysmotility, visceral hypersensitivity, stress, and psychological factors.24 A relationship with H pylori has not been established, though there is some evidence of an association.25
Studies of drug treatments for NUD are limited by small samples, short duration of follow-up and the use of unvalidated outcome measures.26 A recent meta-analysis found no significant benefit from the use of antacids or sucralfate for NUD, defined as dyspeptic symptoms with negative endoscopic or barium studies, excluding other organic (eg pancreato-biliary disease, oesophagitis) and drug-induced (NSAIDs) disease. The same study reported statistically significant benefits with the prokinetic drug cisapride, but there was evidence of a publication bias in these comparisons, making interpretation difficult (“positive” studies were more likely to be published than “negative” trials). Cisapride was also recently taken off the market, so is no longer available as a treatment option. No placebo-controlled studies of metoclopramide were identified in this systematic review.
Antisecretory treatments were more effective than placebo in the treatment of NUD, with a number needed to treat of 6 for H2-RAs and 11 for PPIs (ie, for every 11 patients who received a PPI instead of placebo, one benefited).24 Thus, PPIs were actually less effective than H2-RAs in this meta-analysis of placebo-controlled trials. Long-term use of antisecretory therapy may be associated with hypergastrinemia, increased gastrointestinal bacterial counts, and altered absorption of nutrients, though the clinical significance of this is unclear.27 For patients who do not respond to acid-suppressive therapy it might be necessary to entertain alternative diagnoses, and if no explanation for the symptoms can be identified, consider counseling or pain management strategies to help the patient cope with the discomfort. Studies of the use of antidepressants, though small and of questionable quality, consistently show improvement in symptoms of patients with functional gastrointestinal disorders, including NUD and irritable bowel syndrome.28 Treatment recommendations for NUD are shown inTable 4.
To date there is no convincing evidence that empiric eradication of H pylori in patients with NUD improves symptoms. One recent meta-analysis of randomized controlled trials revealed no improvement with H pylori eradication for the symptoms of NUD,29 while 2 others25,30 showed a modest but statistically significant benefit, with 1 patient cured for every 19 treated (number needed to treat = 19).
Prognosis
Without treatment, peptic ulcer disease can lead to serious complications such as gastrointestinal bleeding and cancer. Acid suppression achieves ulcer healing rates of approximately 90%, but is associated with a 10% recurrence rate even with long-term treatment.22 Successful eradication of H pylori in the absence of NSAID use cures ulcer disease in 95% of cases; the recurrence rate is 33% to 41% if eradication is not achieved.14 Reinfection is rare once eradication has been accomplished, with a rate of about 1% per year,31 though rates can be much higher in endemic areas.32 Persistent infection requires re-treatment, ideally with a regimen not previously used, in case of antimicrobial resistance. Persistent gastric ulcers can harbor malignancy and therefore, evaluation with endoscopy might be prudent. H pylori itself is associated with a 2- to 6-fold increase in risk of gastric cancer.33 Widespread screening or treatment to prevent cancer has not been recommended to date. A cost-benefit analysis suggests that the development and distribution of a vaccination for H pylori would be highly cost-effective,34 but such a vaccine is not available as yet.
The prognosis of NUD is more discouraging. NUD is a chronic relapsing and remitting disorder, and treatment responses difficult to measure. For example, one systematic review of the literature found 56% of patients experienced an improvement in symptom scores when given placebo (range 5% - 90%). As with other functional gastrointestinal disorders, underlying psychosocial and lifestyle factors may be involved and must be addressed. Further research is needed in this area, particularly in the primary care setting.
Each Applied Evidence review article considers a common presenting complaint or disease and summarizes the best available evidence for clinicians. The collected reviews are published online at www.jfponline.com. Explanations of the Levels of Evidence can be found at http://cebm.jr2.ox.ac.uk/docs/levels.html.
In the June 2001 issue of The Journal of Family Practice, the diagnostic approach to the patient with dyspepsia was presented.1 In that analysis, gastroesophageal reflux disease (GERD), gastric ulcers, and duodenal ulcers emerged as the most common identifiable causes of dyspepsia. However, most patients with dyspepsia do not have one of these conditions, and are considered to have functional or nonulcer dyspepsia. The diagnosis and management of adults with GERD was recently described in detail.2 Therefore, this paper reviews the treatment of undifferentiated dyspepsia, gastric ulcer caused by nonsteroidal anti-inflammatory drugs (NSAIDs), peptic ulcer disease not associated with NSAID use, and nonulcer dyspepsia (dyspepsia in a patient who has no evidence of ulcer or GERD on endoscopy). An algorithm for the management of the patient with known ulcer disease is shown in the Figure 1. (J Fam Pract 2001; 50:614-619)
Undifferentiated dyspepsia
In primary care, the typical patient presenting with dyspepsia will not have had endoscopy. Therefore, the presence of an underlying lesion will be unknown, a situation known as undifferentiated dyspepsia. As described by Smucny,2 randomized trials and economic analyses have demonstrated the cost-effectiveness of a test-and-treat strategy3,4 in which patients with dyspepsia are tested for Helicobacter pylori and treated with eradication therapy if positive. This strategy would reserve endoscopy for those patients with alarm signs Table1 or those who have persistent symptoms despite appropriate empiric therapy. Certainly a physician must weigh the potential for complications during endoscopy with the risks of adverse reactions to eradication therapy, including the development of antimicrobial resistant organisms. All patients with dyspepsia should be counseled to avoid factors that exacerbate their symptoms or disrupt the integrity of the mucosal lining of the stomach, such as NSAID use and cigarette smoking. Both of these have been identified as risk factors for the development of peptic ulcers and delayed ulcer healing.5,6
NSAID-related gastric ulcers
NSAIDs are associated with a 5- to 7-fold increased risk of gastric ulceration in the first 3 months of use. In a meta-analysis of observational studies of gastrointestinal bleeding risk due to various NSAIDs, a 4-fold increased risk associated with NSAID-use persisted throughout therapy and fell to baseline within 2 months of discontinuation of the NSAID.7 This study demonstrated a clear dose-response relationship; the difference between NSAIDs, however, was minimal.
Table 2 summarizes treatments for NSAID-related gastric ulcers. Misoprostol is an effective prophylaxis against ulcers when used with NSAIDs, but is associated with diarrhea, even at lower than optimal doses.8 Standard doses of H2-receptor agonists (H2RAs) are ineffective at preventing NSAID-related gastric ulcers, but double doses of H2RAs (eg, ranitidine 300 mg twice daily) and standard doses of proton-pump inhibitors (PPIs; eg, omeprazole 20 mg 4 times per day) are effective prophylactic agents for the duration of NSAID use according to the results of endoscopic studies. New COX-2 specific anti-inflammatory agents are associated with a significantly lower risk of ulcers as seen by endoscopy (4.7% with rofecoxib vs 27.7% with ibuprofen).9 The benefit in terms of actual adverse clinical outcomes and ulcer complications, however, is much smaller; the risk of symptomatic ulcer, perforation, symptomatic ulcer, and clinically significant bleeding was 1.3% for rofecoxib (Vioxx) and 1.8% with ibuprofen, diclofenac, or nabumetone taken for 1 year (P <.05).10 Thus, one would have to treat 200 patients for 1 year to prevent 1 adverse outcome. Similarly, the annual risk of bleeding, perforation, or gastric outlet obstruction was lower with celecoxib (Celebrex) than with naproxen, diclofenac, or ibuprofen (0.2% vs. 1.68%; P <.002; number needed to treat=60).11 COX-2 inhibitors have not been studied as an alternative therapy in patients with a history of NSAID-induced ulcers. While no trial data are available, a consensus-based recommendation has been made for dyspeptic patients with no alarm symptoms who are regular NSAID-users: The first step in management is to stop the NSAID use if possible, and determine if the symptoms improve.12 If symptoms persist after NSAID use is discontinued, the patient should be managed as others with undifferentiated dyspepsia.
Non–NSAID-related duodenal and gastric ulcers
Helicobacter pylori is now well recognized as a major risk factor for the development of peptic ulcer disease. Although most H pylori–infected patients do not develop an ulcer, as many as 95% of patients with duodenal ulcers and 80% of those with gastric ulcers are infected. These rates may be lower in the United States because of greater use of NSAIDs and a lower rate of H pylori infection than in other parts of the world.13 Successful eradication of the organism following treatment heals ulcers and reduces the risk of recurrence from 67% to 6% for patients with duodenal ulcers, and from 59% to 4% for patients with gastric ulcers.14 A meta-analysis of North American randomized controlled trials of H pylori eradication for duodenal ulcer found that one ulcer recurrence (by endoscopy) would be prevented for every 2.8 patients successfully treated.15
However, a multi-drug regimen and an adequate length of treatment are required for eradication. Because antimicrobial resistance and incomplete treatment are major reasons for treatment failure,16,17 convenience and tolerability become important considerations in choosing a treatment plan.
Effective H pylori treatment regimens include a combination of two antibiotics and acid suppression therapy, with or without a bismuth compound, taken for 10 to 14 days. Choosing a combination that can be taken in two daily doses may be easier for patients, although this option is also more costly.Table 3 provides a practical list of selected effective drug combinations used for treating H pylori infection. Triple therapies with reported eradication rates approaching 90% or more are included, though resistant strains may continue to emerge. Single and dual therapies, though FDA-approved for treatment of H pylori, have unacceptably low cure rates and are not recommended. PPI quadruple therapy or a regimen including furazolidone (a monoamine oxidase inhibitor) may serve as second-line treatment for eradication of initial failures and in case of metronidazole resistance.18,19 Studies using ranitidine bismuth citrate in place of PPIs have also shown comparable results.
Patient education regarding the need for effective eradication therapy and to encourage adherence to the drug regimen is critical. Patients should have adequate follow-up, since further diagnostic testing may be needed to ensure eradication of the H pylori organism, particularly in the case of treatment failure or relapse. Because eradication usually cures peptic ulcer disease, chronic acid suppression therapy should not be needed in most patients who have cleared the H pylori infection and who are not taking NSAIDs. Among primary care patients with a history of peptic ulcer disease taking chronic acid suppressive therapy, 78% of those treated for H pylori were able to discontinue their therapy.21
Persistent or recurrent ulcers in patients treated for H pylori are strongly associated with persistent or recurrent infection.22 Because symptom relief is not always correlated with eradication, testing for cure following eradication therapy should be considered, particularly in high-risk patients, such as those with a history of bleeding or perforation.13 However, no randomized studies have been done to assess the outcomes associated with the decision to test for cure. If desired, noninvasive tests (eg stool antigen test or urea breath test) may be used for patients who become symptom-free following eradication therapy or for patients with persistent symptoms and a previously documented duodenal ulcer. Acid suppressive therapy with a PPI can result in false negative results, so this should be withheld for at least 2 weeks prior to testing for persistent infection.23 Because of the risk of cancer associated with gastric ulcers, endoscopic documentation of gastric ulcer healing might be preferable to noninvasive testing, particularly in high-risk patients. In either case, patients with persistent or recurrent symptoms following eradication should have endoscopy to document ulcer healing and to obtain biopsies if necessary.
Nonulcer Dyspepsia
The pathophysiology of nonulcer dyspepsia (NUD) is not definitively known, though factors implicated include gastric acid secretion, gastro-duodenal dysmotility, visceral hypersensitivity, stress, and psychological factors.24 A relationship with H pylori has not been established, though there is some evidence of an association.25
Studies of drug treatments for NUD are limited by small samples, short duration of follow-up and the use of unvalidated outcome measures.26 A recent meta-analysis found no significant benefit from the use of antacids or sucralfate for NUD, defined as dyspeptic symptoms with negative endoscopic or barium studies, excluding other organic (eg pancreato-biliary disease, oesophagitis) and drug-induced (NSAIDs) disease. The same study reported statistically significant benefits with the prokinetic drug cisapride, but there was evidence of a publication bias in these comparisons, making interpretation difficult (“positive” studies were more likely to be published than “negative” trials). Cisapride was also recently taken off the market, so is no longer available as a treatment option. No placebo-controlled studies of metoclopramide were identified in this systematic review.
Antisecretory treatments were more effective than placebo in the treatment of NUD, with a number needed to treat of 6 for H2-RAs and 11 for PPIs (ie, for every 11 patients who received a PPI instead of placebo, one benefited).24 Thus, PPIs were actually less effective than H2-RAs in this meta-analysis of placebo-controlled trials. Long-term use of antisecretory therapy may be associated with hypergastrinemia, increased gastrointestinal bacterial counts, and altered absorption of nutrients, though the clinical significance of this is unclear.27 For patients who do not respond to acid-suppressive therapy it might be necessary to entertain alternative diagnoses, and if no explanation for the symptoms can be identified, consider counseling or pain management strategies to help the patient cope with the discomfort. Studies of the use of antidepressants, though small and of questionable quality, consistently show improvement in symptoms of patients with functional gastrointestinal disorders, including NUD and irritable bowel syndrome.28 Treatment recommendations for NUD are shown inTable 4.
To date there is no convincing evidence that empiric eradication of H pylori in patients with NUD improves symptoms. One recent meta-analysis of randomized controlled trials revealed no improvement with H pylori eradication for the symptoms of NUD,29 while 2 others25,30 showed a modest but statistically significant benefit, with 1 patient cured for every 19 treated (number needed to treat = 19).
Prognosis
Without treatment, peptic ulcer disease can lead to serious complications such as gastrointestinal bleeding and cancer. Acid suppression achieves ulcer healing rates of approximately 90%, but is associated with a 10% recurrence rate even with long-term treatment.22 Successful eradication of H pylori in the absence of NSAID use cures ulcer disease in 95% of cases; the recurrence rate is 33% to 41% if eradication is not achieved.14 Reinfection is rare once eradication has been accomplished, with a rate of about 1% per year,31 though rates can be much higher in endemic areas.32 Persistent infection requires re-treatment, ideally with a regimen not previously used, in case of antimicrobial resistance. Persistent gastric ulcers can harbor malignancy and therefore, evaluation with endoscopy might be prudent. H pylori itself is associated with a 2- to 6-fold increase in risk of gastric cancer.33 Widespread screening or treatment to prevent cancer has not been recommended to date. A cost-benefit analysis suggests that the development and distribution of a vaccination for H pylori would be highly cost-effective,34 but such a vaccine is not available as yet.
The prognosis of NUD is more discouraging. NUD is a chronic relapsing and remitting disorder, and treatment responses difficult to measure. For example, one systematic review of the literature found 56% of patients experienced an improvement in symptom scores when given placebo (range 5% - 90%). As with other functional gastrointestinal disorders, underlying psychosocial and lifestyle factors may be involved and must be addressed. Further research is needed in this area, particularly in the primary care setting.
Each Applied Evidence review article considers a common presenting complaint or disease and summarizes the best available evidence for clinicians. The collected reviews are published online at www.jfponline.com. Explanations of the Levels of Evidence can be found at http://cebm.jr2.ox.ac.uk/docs/levels.html.
1. Smucny J. Evaluation of the patient with dyspepsia. J Fam Pract 2001;50:583-542.
2. Flynn CA. Evaluation and treatment of adults with gastro-esophageal reflux disease. J Fam Pract 2001;50:57-63.
3. Jones R, Tate C, Sladen G, Weston-Baker J. A trial of test-and-treat strategy for Helicobacter pylori positive dyspeptic patients in general practice. Intern J Clin Pract 1999;53:413-16.
4. Ebell MH, Warbasse L, Brenner C. Evaluation of the dyspeptic patient: a cost utility study. J Fam Pract 1997;44:545-55.
5. Kurata J, Nogawa A. Meta-analysis of risk factors for peptic ulcer: nonsteroidal antiinflammatory drugs, Helicobacter pylori, and smoking. J Clin Gastroenterol 1997;24:2-17.
6. Graham DY. Nonsteriodal anti-inflammatory druge, Helicobacter pylori, and ulcers: where we stand. Am J Gastroenterol 1996;91:2080-86.
7. Hernandez-Diaz S, Rodriguez LA. Association between nonsteroidal anti-inflammatory drugs and upper gastrointestinal tract bleeding/perforation: an overview of epidemiologic studies published in the 1990s. Arch Intern Med 2000;160:2093-99.
8. Rostom A, Wells G, Tugwell P, Welch V, Dube C, McGowan J. Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database of Systematic Reviews 2001; Issue 1.
9. Laine L, Harper S, Simon T, et al. A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2-specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis. Rofecoxib Osteoarthritis Endoscopy Study Group. Gastroenterology 1999;117:776-83.
10. Langman MJ, Jensen DM, Watson DJ, et al. Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs. JAMA 1999;282:1929-933.
11. Goldstein JL, Silverstein FE, Agrawal NM, et al. Reduced risk of upper gastrointestinal ulcer complications with celecoxib, a novel COX-2 inhibitor. Am J Gastroenterol 2000;95:1681-690.
12. Veldhuyzen van Zanten SJ, Flook N, et al. An evidence-based approach to the management of uninvestigated dyspepsia in the era of Helicobacter pylori. Can Med Assoc J 2000;162(suppl 12):S3-S23.
13. Peterson WL, Fendrick AM, Cave DR, Peura DA, Garabedian-Raffalo S, Laine L. Helicobacter pylori-related disease: guidelines for testing and treatment. Arch Intern Med 2000;160:1285-291.
14. Hopkins RJ, Girardi LS, Turney EA. Relationship between Helicobacter pylori eradication and reduced duodenal and gastric ulcer recurrence: a review. Gastroenterology 1996;110:1244-252.
15. Laine L, Hopkins RJ, Girardi L. Has the impact of Helicobacter pylori therapy on ulcer recurrence in the Unites States been overstated? A meta-analysis of rigourously designed trials. Amer J Gastroenterol 1998;93:1409-415.
16. Megraud F. Resistance of Helicobacter pylori to antibiotics: the main limitation of current proton-pump inhibitor triple therapy. Eur J Gastroenterol Hepatol 1999;11(suppl 2):S35-S37.
17. Graham DY, Lew GM, Malaty HM, et al. Factors influencing the eradication of Helicobacter pylori with triple therapy. Gastroenterology 1992;102:493-96.
18. Rene W.M., van der Hulst RWM, Keller JJ, Rauws EA, Tytgat G. Treatment of Helicobacter pylori infection: a review of the world literature. Helicobacter 1996;1:6-18.
19. Graham D Y. Highlights from 100th Annual Meeting of the American Gastroenterological Association and Digestive Disease Week. Helicobacter Today 1999;6:1-24.
20. Laine L, Estrada R, Trujillo M, Emami S. Randomized comparison of ranitidine bismuth citrate-based triple therapies for Helicobacter pylori. Am J Gastroenterol 1997;92:2213-215.
21. De Wit NJ, Quartero AO, Numans ME. Helicobacter pylori treatment instead of maintenance therapy for peptic ulcer disease: the effectiveness of case-finding in general practice. Aliment Pharmacol Ther 1999;13:1317-321.
22. Wong BC, Lam SK, Lai KC, et al. Triple therapy for Helicobacter pylori eradication is more effective than long-term maintenance antisecretory treatment in the prevention of recurrence of duodenal ulcer: a prospective long-term follow-up study. Aliment Pharmacol Ther 1999;13:303-09.
23. Laine L, Estrada R, Trujillo M, Knigge K, Fennerty MB. Effect of proton-pump inhibitor therapy on diagnostic testing for Helicobacter pylori. Ann Intern Med 1998;129:547-50.
24. Soo S, Moayyedi P, Deeks J, Delaney B, Innes M, Forman D. Pharmacological interventions for nonulcer dyspepsia. Cochrane Database of Systematic Reviews 2001; Issue 1.
25. Jaakkimainen RL, Boyle E, Tudiver F. Is Helicobacter pylori associated with non-ulcer dyspepsia and will eradication improve symptoms? A meta-analysis [see comments]. BMJ 1999;319:1040-44.
26. Veldhuyzen van Zanten SJ, Cleary C, et al. Drug treatment of functional dyspepsia: a systematic analysis of trial methodology with recommendations for design of future trials. Amer J Gastroenterol 1996;91:660-73.
27. Laine L, Ahnen D, McClain C, Solcia E, Walsh JH. Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther 2000;14:651-68.
28. Jackson JL, O’Malley PG, Tomkins G, Balden E, Santoro J, Kroenke K. Treatment of functional gastrointestinal disorders with antidepressant medications: a meta-analysis. Amer J Med 2000;108:65-72.
29. Laine L, Schoenfeld P, Fennerty MB. Therapy for Helicobacter pylori in patients with nonulcer dyspepsia: a meta-analysis of randomized, controlled trials. Ann Intern Med 2001;134:361-69.
30. Moayyedi P, Soo S, Deeks J, et al. Eradication of Helicobacter pylori for non-ulcer dyspepsia. Cochrane Database of Systematic Reviews 2001; Issue 1.
31. Mohammed Z, Abu-Mahfouz MD, Prasad VM, Santogade P, Cutler AF. Helicobacter pylori recurrence after successful eradication: 5-year follow-up in the United States. Am J Gastroenterol 1997;11:2025-28.
32. Kepekci Y, Kadayifci A. Does the eradication of Helicobacter pylori cure duodenal ulcer disease in communities with a high prevalence rate? Comparison with long-term acid suppression. Int J Clin Pract 1999;53:505-8.
33. Scheiman JM, Cutler AF. Helicobacter pylori and gastric cancer. Am J Med 1999;106:222-26.
34. Rupnow MF, Owens DK, Shachter R, Parsonnet J. Helicobacter pylori vaccine development and use: a cost-effectiveness analysis using the Institute of Medicine Methodology. Helicobacter 1999;4:272-80.
35. Laine L, Estrada R, Fukanaga K, Neil G. Randomized comparison of differing periods of twice-a-day triple therapy for the eradication of Helicobacter pylori. Aliment Pharmacol Ther 1996;10:1029-33.
36. Yousfi MM, El-Zimaity HMT, Al-assi MT, Cole RA, Genta RM, Graham DY. Metronidazole, omeprazole and clarithromycin: an effective combination therapy for Helicobacter pylori infection. Aliment Pharmacol Ther 1995;9:209-12.
37. de Boer WA, Driessen W, Jansz A, Tytgat G. Effect of acid suppression on efficacy of treatment for Helicobacter pylori infection. Lancet 95 A.D.;345:817-820.
38. Hansen JM, Bytzer P, Schaffalitzky de Muckadell OB. Placebo-controlled trial of cisapride and nizatidine in unselected patients with functional dyspepsia. Am J Gastroenterol 1998;93:368-74.
1. Smucny J. Evaluation of the patient with dyspepsia. J Fam Pract 2001;50:583-542.
2. Flynn CA. Evaluation and treatment of adults with gastro-esophageal reflux disease. J Fam Pract 2001;50:57-63.
3. Jones R, Tate C, Sladen G, Weston-Baker J. A trial of test-and-treat strategy for Helicobacter pylori positive dyspeptic patients in general practice. Intern J Clin Pract 1999;53:413-16.
4. Ebell MH, Warbasse L, Brenner C. Evaluation of the dyspeptic patient: a cost utility study. J Fam Pract 1997;44:545-55.
5. Kurata J, Nogawa A. Meta-analysis of risk factors for peptic ulcer: nonsteroidal antiinflammatory drugs, Helicobacter pylori, and smoking. J Clin Gastroenterol 1997;24:2-17.
6. Graham DY. Nonsteriodal anti-inflammatory druge, Helicobacter pylori, and ulcers: where we stand. Am J Gastroenterol 1996;91:2080-86.
7. Hernandez-Diaz S, Rodriguez LA. Association between nonsteroidal anti-inflammatory drugs and upper gastrointestinal tract bleeding/perforation: an overview of epidemiologic studies published in the 1990s. Arch Intern Med 2000;160:2093-99.
8. Rostom A, Wells G, Tugwell P, Welch V, Dube C, McGowan J. Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database of Systematic Reviews 2001; Issue 1.
9. Laine L, Harper S, Simon T, et al. A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2-specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis. Rofecoxib Osteoarthritis Endoscopy Study Group. Gastroenterology 1999;117:776-83.
10. Langman MJ, Jensen DM, Watson DJ, et al. Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs. JAMA 1999;282:1929-933.
11. Goldstein JL, Silverstein FE, Agrawal NM, et al. Reduced risk of upper gastrointestinal ulcer complications with celecoxib, a novel COX-2 inhibitor. Am J Gastroenterol 2000;95:1681-690.
12. Veldhuyzen van Zanten SJ, Flook N, et al. An evidence-based approach to the management of uninvestigated dyspepsia in the era of Helicobacter pylori. Can Med Assoc J 2000;162(suppl 12):S3-S23.
13. Peterson WL, Fendrick AM, Cave DR, Peura DA, Garabedian-Raffalo S, Laine L. Helicobacter pylori-related disease: guidelines for testing and treatment. Arch Intern Med 2000;160:1285-291.
14. Hopkins RJ, Girardi LS, Turney EA. Relationship between Helicobacter pylori eradication and reduced duodenal and gastric ulcer recurrence: a review. Gastroenterology 1996;110:1244-252.
15. Laine L, Hopkins RJ, Girardi L. Has the impact of Helicobacter pylori therapy on ulcer recurrence in the Unites States been overstated? A meta-analysis of rigourously designed trials. Amer J Gastroenterol 1998;93:1409-415.
16. Megraud F. Resistance of Helicobacter pylori to antibiotics: the main limitation of current proton-pump inhibitor triple therapy. Eur J Gastroenterol Hepatol 1999;11(suppl 2):S35-S37.
17. Graham DY, Lew GM, Malaty HM, et al. Factors influencing the eradication of Helicobacter pylori with triple therapy. Gastroenterology 1992;102:493-96.
18. Rene W.M., van der Hulst RWM, Keller JJ, Rauws EA, Tytgat G. Treatment of Helicobacter pylori infection: a review of the world literature. Helicobacter 1996;1:6-18.
19. Graham D Y. Highlights from 100th Annual Meeting of the American Gastroenterological Association and Digestive Disease Week. Helicobacter Today 1999;6:1-24.
20. Laine L, Estrada R, Trujillo M, Emami S. Randomized comparison of ranitidine bismuth citrate-based triple therapies for Helicobacter pylori. Am J Gastroenterol 1997;92:2213-215.
21. De Wit NJ, Quartero AO, Numans ME. Helicobacter pylori treatment instead of maintenance therapy for peptic ulcer disease: the effectiveness of case-finding in general practice. Aliment Pharmacol Ther 1999;13:1317-321.
22. Wong BC, Lam SK, Lai KC, et al. Triple therapy for Helicobacter pylori eradication is more effective than long-term maintenance antisecretory treatment in the prevention of recurrence of duodenal ulcer: a prospective long-term follow-up study. Aliment Pharmacol Ther 1999;13:303-09.
23. Laine L, Estrada R, Trujillo M, Knigge K, Fennerty MB. Effect of proton-pump inhibitor therapy on diagnostic testing for Helicobacter pylori. Ann Intern Med 1998;129:547-50.
24. Soo S, Moayyedi P, Deeks J, Delaney B, Innes M, Forman D. Pharmacological interventions for nonulcer dyspepsia. Cochrane Database of Systematic Reviews 2001; Issue 1.
25. Jaakkimainen RL, Boyle E, Tudiver F. Is Helicobacter pylori associated with non-ulcer dyspepsia and will eradication improve symptoms? A meta-analysis [see comments]. BMJ 1999;319:1040-44.
26. Veldhuyzen van Zanten SJ, Cleary C, et al. Drug treatment of functional dyspepsia: a systematic analysis of trial methodology with recommendations for design of future trials. Amer J Gastroenterol 1996;91:660-73.
27. Laine L, Ahnen D, McClain C, Solcia E, Walsh JH. Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther 2000;14:651-68.
28. Jackson JL, O’Malley PG, Tomkins G, Balden E, Santoro J, Kroenke K. Treatment of functional gastrointestinal disorders with antidepressant medications: a meta-analysis. Amer J Med 2000;108:65-72.
29. Laine L, Schoenfeld P, Fennerty MB. Therapy for Helicobacter pylori in patients with nonulcer dyspepsia: a meta-analysis of randomized, controlled trials. Ann Intern Med 2001;134:361-69.
30. Moayyedi P, Soo S, Deeks J, et al. Eradication of Helicobacter pylori for non-ulcer dyspepsia. Cochrane Database of Systematic Reviews 2001; Issue 1.
31. Mohammed Z, Abu-Mahfouz MD, Prasad VM, Santogade P, Cutler AF. Helicobacter pylori recurrence after successful eradication: 5-year follow-up in the United States. Am J Gastroenterol 1997;11:2025-28.
32. Kepekci Y, Kadayifci A. Does the eradication of Helicobacter pylori cure duodenal ulcer disease in communities with a high prevalence rate? Comparison with long-term acid suppression. Int J Clin Pract 1999;53:505-8.
33. Scheiman JM, Cutler AF. Helicobacter pylori and gastric cancer. Am J Med 1999;106:222-26.
34. Rupnow MF, Owens DK, Shachter R, Parsonnet J. Helicobacter pylori vaccine development and use: a cost-effectiveness analysis using the Institute of Medicine Methodology. Helicobacter 1999;4:272-80.
35. Laine L, Estrada R, Fukanaga K, Neil G. Randomized comparison of differing periods of twice-a-day triple therapy for the eradication of Helicobacter pylori. Aliment Pharmacol Ther 1996;10:1029-33.
36. Yousfi MM, El-Zimaity HMT, Al-assi MT, Cole RA, Genta RM, Graham DY. Metronidazole, omeprazole and clarithromycin: an effective combination therapy for Helicobacter pylori infection. Aliment Pharmacol Ther 1995;9:209-12.
37. de Boer WA, Driessen W, Jansz A, Tytgat G. Effect of acid suppression on efficacy of treatment for Helicobacter pylori infection. Lancet 95 A.D.;345:817-820.
38. Hansen JM, Bytzer P, Schaffalitzky de Muckadell OB. Placebo-controlled trial of cisapride and nizatidine in unselected patients with functional dyspepsia. Am J Gastroenterol 1998;93:368-74.
Evaluation of the Patient with Dyspepsia
An international consensus conference has defined dyspepsia as chronic or recurrent pain or discomfort that is centered in the upper abdomen.1 This discomfort includes such symptoms as early satiety, fullness, bloating, and nausea. Up to 50% of people in community surveys in the United States and Europe report having dyspepsia.2 Although only a minority of people with dyspepsia seek care,3,4 this complaint still accounts for 2% to 3% of visits to family physicians.5 Patients with dyspepsia report lower quality of life than asymptomatic people; in one report, they had a quality of life similar to patients with angina.6 This review discusses the evaluation of dyspepsia and will be followed next month by a review of the treatment of dyspepsia.
Differential diagnosis
Information about the differential diagnosis of this condition largely comes from studies in which patients with dyspepsia were referred for upper endoscopy Table 1.7 The most common identifiable conditions were esophagitis, gastric ulcer, and duodenal ulcer. Most patients in these studies did not have any abnormalities on endoscopy and were considered to have functional dyspepsia. The pathophysiology of functional dyspepsia is not well understood and is likely to be multifactorial. Gastroduodenal dysmotility, increased gastric acid secretion, increased visceral sensation to distention and/or gastric acid, psychological distress, and environmental factors such as smoking and Helicobacter pylori infection all may play a role.8
When dyspeptic patients undergo more extensive evaluations and/or are followed up for longer periods of time, a large variety of other conditions have been identified. These include gastroesophageal reflux without esophagitis, lactose intolerance, cholelithiasis, gastroparesis, chronic pancreatitis, pancreatic cancer, celiac disease, giardiasis, and ischemic heart disease.9-11 However, it is not always clear that these diagnoses are completely responsible for a patient’s dyspeptic symptoms. Finally, a variety of medications or other ingestions (such as alcohol) can lead to dyspepsia.12
Using the history and physical examination
The history and physical examination are important in detecting red flags for potentially fatal conditions, such as cancer or complicated ulcers. Alarm symptoms include dysphagia, gastrointestinal bleeding, acute abdominal pain, jaundice, or an abdominal mass. The presence of 1 or more of these symptoms should trigger a consultation with a surgeon or a gastroenterologist and possible endoscopy.
A patient’s age is of some help in diagnosis; older patients are more likely to have identifiable causes for dyspepsia than those who are younger.7,9 This is particularly true for gastric cancer, which is rare in people younger than 45 years in Europe and North America. In 1 study that identified all cases of gastric cancer in a population of 280,500, only 25 of 319 gastric cancers occurred in patients younger than 55 years. Of these patients, 24 of 25 had symptoms or signs of gastric cancer: weight loss (14), dysphagia (8), anemia (7), gastrointestinal bleed (3), previous gastric surgery (3), palpable mass (3), gastrointestinal perforation (1), and cerebral metastases (1).13 Historical and demographic factors that are more likely to be seen in patients with ulcers than in those with functional dyspepsia are male sex, smoking, and nonsteroidal anti-inflammatory drug (NSAID) use.14
Table 2 shows the results of 3 large prospective studies of patients with dyspepsia who were referred for endoscopy.12,15,16 Although certain symptoms are more likely to occur in some conditions than in others, no single item from the history and physical examination clearly establishes a diagnosis. Compared with patients with normal endoscopic examinations, those with ulcers are more likely to have relief of pain with food or antacids; those with gastric cancer are more likely to have lost weight; and those with esophagitis are more likely to have heartburn and pain relief with antacids. Symptoms such as nausea, distinct localization of pain, and nocturnal pain overlap to a large degree among patients with different diagnoses and are therefore not helpful.
Investigators have tried to develop more complicated scoring systems that employ a combination of these different symptoms. Although some of these clinical scores have some value in distinguishing the various causes of dyspepsia in patients who are referred for endoscopy,17-19 they are cumbersome and have not been validated in unselected patients with dyspepsia in primary care.18
The usefulness of the physical examination has been questioned in 2 studies of patients undergoing endoscopy for dyspepsia. In one study, epigastric tenderness did not accurately distinguish patients with abnormal endoscopy findings from those with normal findings.20 The likelihood ratio (LR) for tenderness to light or deep palpation was near 1, meaning that this maneuver had no diagnostic value. A second study found that an abnormal physical examination was equally likely in patients with an ulcer as in those without one.18
A recent study examined the accuracy of general practitioners’ overall impression based on the history and physical examination.21 Four hundred consecutive unselected patients with dyspepsia were evaluated by their general practitioners and then underwent endoscopy, upper abdominal ultrasonography, and laboratory tests. The physicians’ overall clinical impressions had a low sensitivity for diagnosing organic diseases or functional dyspepsia but were fairly specific for organic diseases Table 3. Note from the LRs that while suspicion of gallstone disease or malignancy significantly increased the likelihood of these conditions, an absence of suspicion in no way ruled them out (negative LR near 1).
Imaging studies and endoscopy
Definitively diagnosing the cause of a patient’s dyspepsia usually requires either upper endoscopy or an upper gastrointestinal (UGI) series. The former is more expensive, may not be readily available in some communities, and has a slight risk of complications (such as a 0.05% perforation rate22). Endoscopy is generally believed to be more accurate than a UGI series. However, most studies that compared the accuracy of these tests have used endoscopy as the gold standard, which creates a bias in favor of endoscopy. The few studies that have used repeat endoscopy for lesions detected by radiography but not the initial endoscopy have still shown that radiography is less accurate than endoscopy, especially for lesions smaller than 5 mm Table 4.23,24 Another advantage of endoscopy is the ability to biopsy lesions suspicious for malignancy and to perform invasive tests for H pylori infection. A patient who has a gastric ulcer detected by a UGI series should be referred for endoscopic biopsy, since up to 3% of these ulcers can harbor malignancy.9
Other imaging studies are not routinely recommended for evaluation of dyspepsia. In the absence of typical symptoms of biliary colic, abdominal ultrasonography has a very low yield11; even if gallstones are detected in a patient with dyspepsia, this may be incidental, and cholecystectomy may not improve the patient’s symptoms. Gastric-emptying studies may be abnormal in nearly 40% of patients with functional dyspepsia,25 but basing therapy on the results of these studies has not been consistently shown to benefit patients.1
Detecting H pylori
Patients with dyspepsia should be evaluated for the presence of H pylori, because this infection has been found in up to 95% of patients with duodenal ulcer and 80% with a gastric ulcer. It occurs in approximately 30% to 40% of patients without an ulcer.26 Patients with ulcers who are H pylori–positive have a markedly reduced recurrence rate after successful eradication therapy.27,28 Therefore, patients with gastric or duodenal ulcers who are infected with H pylori should be treated with a combination of antibiotics and acid suppressive agents to eradicate the infection. Noninvasive options for diagnosing H pylori include immunoglobulin G (IgG) antibody testing in serum or whole blood, urea breath tests, and stool antigen tests Table 4.
There are at least 40 commercially available IgG serologic tests. The median sensitivity and specificity are 92% and 83%, respectively, but the accuracy varies considerably.29 Whole blood serologic tests can be performed on capillary blood obtained from finger sticks, and are therefore more convenient than serum tests that require venipuncture but are not recommended because they are less sensitive.30,31 Because patients may have persistently positive IgG antibodies for many months after eradication therapy, a serologic test will often give a false-positive result during that period.32
Urea breath tests are able to detect an active H pylori infection. Patients ingest a specific food or drink that contains carbon-labeled urea. Gastric urease activity, which is highly specific for active H pylori infection, converts the carbon-labeled urea to labeled carbon dioxide and ammonia. The patient breathes into a container, and a positive test occurs when the labeled carbon dioxide exceeds a threshold level. Both 13Carbon and 14Carbon are used. The latter exposes patients to a negligible amount of radioactivity, but is simple, rapid, and less expensive than the 13 carbon tests. In comparative studies, the urea breath tests are more accurate than serologic tests.33,34
Stool antigen is involved in the most recently developed noninvasive test. The few studies that have been conducted to date have demonstrated that these tests are highly accurate.35 The stool antigen has recently been recommended by the European Helicobacter Pylori Study Group as the preferred initial noninvasive diagnostic test.36
Approach to the patient
There are a variety of possible approaches to the initial management of patients with dyspepsia. These include (1) prompt endoscopy (or UGI) for all patients, (2) prompt endoscopy (or UGI) for patients at highest risk for organic disease, (3) empiric acid suppression therapy for all patients with testing reserved for patients who remain symptomatic, (4) empiric H pylori eradication therapy for all patients, and (5) noninvasive H pylori testing for all patients, followed by empiric eradication therapy for those with positive results and empiric treatment of functional dyspepsia for those with negative results (a “test and treat” approach).
The most recent American, Canadian, and European consensus-based guidelines all recommend that patients younger than 45 years with dyspepsia and no alarm symptoms should be tested for H pylori infection and then given eradication therapy if positive; patients older than 45 years and those with alarm symptoms should have prompt endoscopy.37-39 H pylori–negative patients younger than 45 years and without alarm symptoms should be managed empirically for functional dyspepsia. H pylori–positive or negative patients who do not undergo endoscopy initially should do so if their symptoms persist. An algorithm depicting this approach is presented in the Figure 1. Cost-effectiveness analyses generally support this approach.22,40,41
Direct evidence for these approaches from randomized controlled trials has recently become available.42-45 These studies show that outcomes are similar whether patients received prompt endoscopy or follow a test and treat strategy. Note that patients older than 45 years, using NSAIDs, or with any alarm symptoms for complicated disease were either excluded from these trials or underwent prompt endoscopy.
Although the current evidence supports a test and treat strategy, the results may not be generalizable to all areas. The effectiveness of this approach depends on the prevalence of H pylori infection in patients with ulcers in the community; in some areas, this prevalence may be too low to make this approach effective.46,47 Also, patients not undergoing prompt endoscopy may be less satisfied with their care,42 which is related to the observation that patients with dyspepsia are more likely than physicians to value diagnostic certainty.48 Other data suggest, however, that patient satisfaction is more closely associated with symptom improvement than with having procedures performed.49 With these caveats in mind, it seems most reasonable to inform your patients about the evidence regarding the advantages and disadvantages of the various approaches and allow them to share in the decision-making process.
1. Talley N, Stanghellini V, Heading R, et al. Functional gastroduodenal disorders. Gut 1999;45:1137-42.
2. Heading RC. Prevalence of upper gastrointestinal symptoms in the general population: a systematic review. Scand J Gastroenterol 1999;34(suppl):3-8.
3. Jones RH, Lydeard SE, Hobbs FDR, Kenkre JE, Williams EI, Jones SJ. Dyspepsia in England and Scotland. Gut 1990;31:401-05.
4. Talley NJ, Zinsmeister AR, Schleck CD, Melton LJ. Dyspepsia and dyspepsia subgroups: a population-based study. Gastroenterology 1992;102:1259-68.
5. Marsland DW, Wood M, Mayo F. Content of family practice. Part I: rank order of diagnoses by frequency. Part II: diagnoses by disease category and age/sex distribution. J Fam Pract 1976;3:37-68.
6. Dimenas E. Methodological aspects of evaluation of quality of life in upper gastrointestinal diseases. Scand J Gastroenterol 1993;28(suppl):18-21.
7. Rabeneck L, Wray NP, Graham DY. Managing dyspepsia: what do we know and what do we need to know? Am J Gastroenterol 1998;93:920-24.
8. McNamara DA, Buckley M, O’Morain CA. Nonulcer dyspepsia: current concepts and management. Gastroenterol Clin N Am 2000;29:807-18.
9. Talley NJ, Silverstein MD, Agreus L, Nyren O, Sonnenberg A, Holtmann G. AGA technical review: evaluation of dyspepsia. Gastroenterology 1998;114:582-95.
10. Lundquist P, Seensalu R, Linden B, Nilsson LH, Lindberg G. Symptom criteria do not distinguish between functional and organic dyspepsia. Eur J Surg 1998;164:345-52.
11. Heikkinen MT, Pikkarainen PH, Takala JK, Rasanen HT, Eskelinen MJ, Julkunen RJK. Diagnostic methods in dyspepsia: the usefulness of upper abdominal ultrasound and gastroscopy. Scand J Prim Health Care 1997;15:82-86.
12. Crean GP, Holden RJ, Knill-Jones RP, et al. A database on dyspepsia. Gut 1994;35:191-202.
13. Christie J, Shepherd NA, Codling BW, Valori RM. Gastric cancer below the age of 55: implications for screening patients with uncomplicated dyspepsia. Gut 1997;41:513-17.
14. Kurata JH, Nogawa AN. Meta-analysis of risk factors for peptic ulcer: nonsteroidal antiinflammatory drugs, Helicobacter pylori, and smoking. J Clin Gastroenterol 1997;24:2-17.
15. Johannessen T, Petersen H, Kleveland PM, et al. The predictive value of history in dyspepsia. Scand J Gastroenterol 1990;25:689-97.
16. Mansi C, Savarino V, Mela GS, Picciotto A, Mele MR, Cele G. Are clinical patterns of dyspepsia a valid guideline for appropriate use of endoscopy? A report on 2253 dyspeptic patients. Am J Gastroenterol 1993;88:1011-15.
17. Talley NJ, McNeil D, Piper DW. Discriminant value of dyspeptic symptoms: a study of the clinical presentation of 221 patients with dyspepsia of unknown cause, peptic ulceration, and cholelithiasis. Gut 1987;28:40-46.
18. Numans M, van der Graaf Y, de Wit NJ, Touw-otten FWMM, de Melker RA. How much ulcer is ulcer-like? Diagnostic determinates of peptic ulcer in open access gastroscopy. Fam Pract 1994;11:382-88.
19. Bytzer P, Moller Hansen J, de Muckadell OBS, Malchow-Moller A. Predicting endoscopic diagnosis in the dyspeptic patient: the value of predictive score models. Scand J Gastroenterol 1997;32:118-25.
20. Priebe WM, DaCosta LR, Beck IT. Is epigastric tenderness a sign of peptic ulcer disease? Gastroenterology 1982;82:16-19.
21. Heikkinen M, Pikkarainen P, Eskelinen M, Julkunen R. GPs’ ability to diagnose dyspepsia based only on physical examination and patient history. Scand J Prim Health Care 2000;18:99-104.
22. Ofman JJ, Etchason J, Fullerton S, Kahn KL, Soll AH. Management strategies for Helicobacter pylori–seropositive patients with dyspepsia: clinical and economic consequences. Ann Intern Med 1997;126:280-91.
23. Shaw PC, van Romunde LKJ, Griffioen G, Janssens AR, Kreuning J, Eilers GAM. Peptic ulcer and gastric carcinoma: diagnosis with biphasic radiography compared with fiberoptic endoscopy. Radiology 1987;163:39-42.
24. Dooley CP, Larson AW, Stace NH, Renner IG, Valenzuela JE, Eliasoph J. Double-contrast barium meal and upper gastrointestinal endoscopy: a comparative study. Ann Intern Med 1984;101:538-45.
25. Quartero AO, de Wit NJ, Lodder AC, Numans ME, Smout AJPM, Hoes AW. Disturbed solid-phase gastric emptying in functional dyspepsia: a meta-analysis. Dig Dis Sci 1998;43:2028-33.
26. Peterson W, Fendrick AM, Cave DR, Peura DA, Garabedian-Ruffalo SM, Laine L. Helicobacter pylori–related disease: guidelines for testing and treatment. Arch Intern Med 2000;160:1285-91.
27. Moore RA. Helicobacter pylori and peptic ulcer: a systematic review of effectiveness and an overview of the economic benefits of implementing what is known to be effective. Oxford: Pain Relief Research Unit, 1995; vii:37.
28. Hopkins RJ, Girardi LS, Turney EA. Relationship between Helicobacter pylori eradication and reduced duodenal and gastric ulcer recurrence: a review. Gastroenterology 1996;110:1244-52.
29. Laheij RJF, Straatman H, Jansen JBMJ, Verbeek ALM. Evaluation of commercially available Helicobacter pylori serology kits: a review. J Clin Microbiol 1998;36:2803-09.
30. Chey WD, Murthy U, Shaw S, et al. A comparison of three fingerstick, whole blood antibody tests for Helicobacter pylori infection: a United States, multicenter trial. Am J Gastroenterol 1999;94:1512-16.
31. Faigel DO, Magaret N, Corless C, Lieberman DA, Fennerty MB. Evaluation of rapid antibody tests for the diagnosis of Helicobacter pylori infection. Am J Gastroenterol 2000;95:72-77.
32. Ho B, Marshall BJ. Accurate diagnosis of Helicobacter pylori: serologic testing. Gastroenterol Clin N Am 2000;29:853-62.
33. Cutler AF, Havstad S, Ma CK, Blaser MJ, Perez-Perez GI, Schubert TT. Accuracy of invasive and noninvasive tests to diagnose Helicobacter pylori infection. Gastroenterology 1995;109:136-41.
34. Thijs JC, van Zwet AA, Thijs WJ, et al. Diagnostic tests for Helicobacter pylori: a prospective evaluation of their accuracy, without selecting a single test as the gold standard. Am J Gastroenterol 1996;91:2125-29.
35. Vaira D, Malfertheiner P, Megraud F, et al. Diagnosis of Helicobacter pylori infection with a new non-invasive antigen-based assay. Lancet 1999;354:30-33.
36. Vaira D, Vakil N. Blood, urine, stool, breath, money, and Helicobacter pylori. Gut 2001;48:287-89.
37. American Gastroenterological Association. American Gastroenterological Association medical position statement: evaluation of dyspepsia. Gastroenterology 1998;114:579-81.
38. Hunt RH, Fallone CA, Thomson ABR. Canadian Helicobacter Study Group. Canadian Helicobacter pylori consensus conference update: infection in adults. Can J Gastroenterol 1999;13:213-17.
39. The European Helicobacter Pylori Study Group (EHPSG). Current European concepts in the management of Helicobacter pylori infection: the Maastricht Consensus Report. Gut 1997;41:8-13.
40. Fendrick AM, Chernew ME, Hirth RA, Bloom BS. Immediate endoscopy or initial Helicobacter pylori serological testing for suspected peptic ulcer disease: estimating cost-effectiveness using decision analysis. Yale J Biol Med 1996;69:187-95.
41. Ebell MH, Warbasse L, Brenner C. Evaluation of the dyspeptic patient: a cost-utility study. J Fam Pract 1997;44:545-55.
42. Lassen AT, Pedersen FM, Bytzer P, de Muckadell OBS. Helicobacter pylori test-and-eradicate versus prompt endoscopy for management of dyspeptic patients: a randomised trial. Lancet 2000;356:455-60.
43. Jones R, Tait C, Sladen G, Weston-Baker J. A trial of test-and-treat strategy for Helicobacter pylori–positive dyspeptic patients in general practice. Int J Clin Pract 1999;53:413-16.
44. Heaney A, Collins JSA, Watson RGP, McFarland RJ, Bamford KB, Tham TCK. A prospective randomised trial of a “test and treat” policy versus endoscopy based management in young Helicobacter pylori positive patients with ulcer-like dyspepsia, referred to a hospital clinic. Gut 1999;45:186-90.
45. Asante MA, Mendall M, Patel P, Ballam L, Northfield TC. A randomized trial of endoscopy vs no endoscopy in the management of seronegative Helicobacter pylori dyspepsia. Eur J Gastroenterol Hepatol 1998;10:983-89.
46. Tovey FI, Hobsley M. Is Helicobacter pylori the primary cause of duodenal ulceration? J Gastroenterol Hepatol 1999;14:1053-56.
47. Xia HHX, Kalantar JS, Mitchell HM, Talley NJ. Can Helicobacter pylori serology still be applied as a surrogate marker to identify peptic ulcer disease in dyspepsia? Aliment Pharmacol Ther 2000;14:615-24.
48. Hirth RA, Bloom BS, Chernew ME, Fendrick AM. Patient, physician, and payer perceptions and misperceptions of willingness to pay for diagnostic certainty. Int J Technol Assess Health Care 2000;16:35-49.
49. Kurata JH, Nogawa AN, Chen YK, Parker CE. Dyspepsia in primary care: perceived causes, reasons for improvement, and satisfaction with care. J Fam Pract 1997;44:281-88.
50. Peura DA, Pambianco DJ, Dye KR, et al. Microdose 14C-urea breath test offers diagnosis of Helicobacter pylori in 10 minutes. Am J Gastroenterol 1996;91:233-38.
51. Raju GS, Smith MJ, Morton D, Bardhan KD. Mini-dose (1-microCi) 14C-urea breath test for the detection of Helicobacter pylori. Am J Gastroenterol 1994;89:1027-31.
An international consensus conference has defined dyspepsia as chronic or recurrent pain or discomfort that is centered in the upper abdomen.1 This discomfort includes such symptoms as early satiety, fullness, bloating, and nausea. Up to 50% of people in community surveys in the United States and Europe report having dyspepsia.2 Although only a minority of people with dyspepsia seek care,3,4 this complaint still accounts for 2% to 3% of visits to family physicians.5 Patients with dyspepsia report lower quality of life than asymptomatic people; in one report, they had a quality of life similar to patients with angina.6 This review discusses the evaluation of dyspepsia and will be followed next month by a review of the treatment of dyspepsia.
Differential diagnosis
Information about the differential diagnosis of this condition largely comes from studies in which patients with dyspepsia were referred for upper endoscopy Table 1.7 The most common identifiable conditions were esophagitis, gastric ulcer, and duodenal ulcer. Most patients in these studies did not have any abnormalities on endoscopy and were considered to have functional dyspepsia. The pathophysiology of functional dyspepsia is not well understood and is likely to be multifactorial. Gastroduodenal dysmotility, increased gastric acid secretion, increased visceral sensation to distention and/or gastric acid, psychological distress, and environmental factors such as smoking and Helicobacter pylori infection all may play a role.8
When dyspeptic patients undergo more extensive evaluations and/or are followed up for longer periods of time, a large variety of other conditions have been identified. These include gastroesophageal reflux without esophagitis, lactose intolerance, cholelithiasis, gastroparesis, chronic pancreatitis, pancreatic cancer, celiac disease, giardiasis, and ischemic heart disease.9-11 However, it is not always clear that these diagnoses are completely responsible for a patient’s dyspeptic symptoms. Finally, a variety of medications or other ingestions (such as alcohol) can lead to dyspepsia.12
Using the history and physical examination
The history and physical examination are important in detecting red flags for potentially fatal conditions, such as cancer or complicated ulcers. Alarm symptoms include dysphagia, gastrointestinal bleeding, acute abdominal pain, jaundice, or an abdominal mass. The presence of 1 or more of these symptoms should trigger a consultation with a surgeon or a gastroenterologist and possible endoscopy.
A patient’s age is of some help in diagnosis; older patients are more likely to have identifiable causes for dyspepsia than those who are younger.7,9 This is particularly true for gastric cancer, which is rare in people younger than 45 years in Europe and North America. In 1 study that identified all cases of gastric cancer in a population of 280,500, only 25 of 319 gastric cancers occurred in patients younger than 55 years. Of these patients, 24 of 25 had symptoms or signs of gastric cancer: weight loss (14), dysphagia (8), anemia (7), gastrointestinal bleed (3), previous gastric surgery (3), palpable mass (3), gastrointestinal perforation (1), and cerebral metastases (1).13 Historical and demographic factors that are more likely to be seen in patients with ulcers than in those with functional dyspepsia are male sex, smoking, and nonsteroidal anti-inflammatory drug (NSAID) use.14
Table 2 shows the results of 3 large prospective studies of patients with dyspepsia who were referred for endoscopy.12,15,16 Although certain symptoms are more likely to occur in some conditions than in others, no single item from the history and physical examination clearly establishes a diagnosis. Compared with patients with normal endoscopic examinations, those with ulcers are more likely to have relief of pain with food or antacids; those with gastric cancer are more likely to have lost weight; and those with esophagitis are more likely to have heartburn and pain relief with antacids. Symptoms such as nausea, distinct localization of pain, and nocturnal pain overlap to a large degree among patients with different diagnoses and are therefore not helpful.
Investigators have tried to develop more complicated scoring systems that employ a combination of these different symptoms. Although some of these clinical scores have some value in distinguishing the various causes of dyspepsia in patients who are referred for endoscopy,17-19 they are cumbersome and have not been validated in unselected patients with dyspepsia in primary care.18
The usefulness of the physical examination has been questioned in 2 studies of patients undergoing endoscopy for dyspepsia. In one study, epigastric tenderness did not accurately distinguish patients with abnormal endoscopy findings from those with normal findings.20 The likelihood ratio (LR) for tenderness to light or deep palpation was near 1, meaning that this maneuver had no diagnostic value. A second study found that an abnormal physical examination was equally likely in patients with an ulcer as in those without one.18
A recent study examined the accuracy of general practitioners’ overall impression based on the history and physical examination.21 Four hundred consecutive unselected patients with dyspepsia were evaluated by their general practitioners and then underwent endoscopy, upper abdominal ultrasonography, and laboratory tests. The physicians’ overall clinical impressions had a low sensitivity for diagnosing organic diseases or functional dyspepsia but were fairly specific for organic diseases Table 3. Note from the LRs that while suspicion of gallstone disease or malignancy significantly increased the likelihood of these conditions, an absence of suspicion in no way ruled them out (negative LR near 1).
Imaging studies and endoscopy
Definitively diagnosing the cause of a patient’s dyspepsia usually requires either upper endoscopy or an upper gastrointestinal (UGI) series. The former is more expensive, may not be readily available in some communities, and has a slight risk of complications (such as a 0.05% perforation rate22). Endoscopy is generally believed to be more accurate than a UGI series. However, most studies that compared the accuracy of these tests have used endoscopy as the gold standard, which creates a bias in favor of endoscopy. The few studies that have used repeat endoscopy for lesions detected by radiography but not the initial endoscopy have still shown that radiography is less accurate than endoscopy, especially for lesions smaller than 5 mm Table 4.23,24 Another advantage of endoscopy is the ability to biopsy lesions suspicious for malignancy and to perform invasive tests for H pylori infection. A patient who has a gastric ulcer detected by a UGI series should be referred for endoscopic biopsy, since up to 3% of these ulcers can harbor malignancy.9
Other imaging studies are not routinely recommended for evaluation of dyspepsia. In the absence of typical symptoms of biliary colic, abdominal ultrasonography has a very low yield11; even if gallstones are detected in a patient with dyspepsia, this may be incidental, and cholecystectomy may not improve the patient’s symptoms. Gastric-emptying studies may be abnormal in nearly 40% of patients with functional dyspepsia,25 but basing therapy on the results of these studies has not been consistently shown to benefit patients.1
Detecting H pylori
Patients with dyspepsia should be evaluated for the presence of H pylori, because this infection has been found in up to 95% of patients with duodenal ulcer and 80% with a gastric ulcer. It occurs in approximately 30% to 40% of patients without an ulcer.26 Patients with ulcers who are H pylori–positive have a markedly reduced recurrence rate after successful eradication therapy.27,28 Therefore, patients with gastric or duodenal ulcers who are infected with H pylori should be treated with a combination of antibiotics and acid suppressive agents to eradicate the infection. Noninvasive options for diagnosing H pylori include immunoglobulin G (IgG) antibody testing in serum or whole blood, urea breath tests, and stool antigen tests Table 4.
There are at least 40 commercially available IgG serologic tests. The median sensitivity and specificity are 92% and 83%, respectively, but the accuracy varies considerably.29 Whole blood serologic tests can be performed on capillary blood obtained from finger sticks, and are therefore more convenient than serum tests that require venipuncture but are not recommended because they are less sensitive.30,31 Because patients may have persistently positive IgG antibodies for many months after eradication therapy, a serologic test will often give a false-positive result during that period.32
Urea breath tests are able to detect an active H pylori infection. Patients ingest a specific food or drink that contains carbon-labeled urea. Gastric urease activity, which is highly specific for active H pylori infection, converts the carbon-labeled urea to labeled carbon dioxide and ammonia. The patient breathes into a container, and a positive test occurs when the labeled carbon dioxide exceeds a threshold level. Both 13Carbon and 14Carbon are used. The latter exposes patients to a negligible amount of radioactivity, but is simple, rapid, and less expensive than the 13 carbon tests. In comparative studies, the urea breath tests are more accurate than serologic tests.33,34
Stool antigen is involved in the most recently developed noninvasive test. The few studies that have been conducted to date have demonstrated that these tests are highly accurate.35 The stool antigen has recently been recommended by the European Helicobacter Pylori Study Group as the preferred initial noninvasive diagnostic test.36
Approach to the patient
There are a variety of possible approaches to the initial management of patients with dyspepsia. These include (1) prompt endoscopy (or UGI) for all patients, (2) prompt endoscopy (or UGI) for patients at highest risk for organic disease, (3) empiric acid suppression therapy for all patients with testing reserved for patients who remain symptomatic, (4) empiric H pylori eradication therapy for all patients, and (5) noninvasive H pylori testing for all patients, followed by empiric eradication therapy for those with positive results and empiric treatment of functional dyspepsia for those with negative results (a “test and treat” approach).
The most recent American, Canadian, and European consensus-based guidelines all recommend that patients younger than 45 years with dyspepsia and no alarm symptoms should be tested for H pylori infection and then given eradication therapy if positive; patients older than 45 years and those with alarm symptoms should have prompt endoscopy.37-39 H pylori–negative patients younger than 45 years and without alarm symptoms should be managed empirically for functional dyspepsia. H pylori–positive or negative patients who do not undergo endoscopy initially should do so if their symptoms persist. An algorithm depicting this approach is presented in the Figure 1. Cost-effectiveness analyses generally support this approach.22,40,41
Direct evidence for these approaches from randomized controlled trials has recently become available.42-45 These studies show that outcomes are similar whether patients received prompt endoscopy or follow a test and treat strategy. Note that patients older than 45 years, using NSAIDs, or with any alarm symptoms for complicated disease were either excluded from these trials or underwent prompt endoscopy.
Although the current evidence supports a test and treat strategy, the results may not be generalizable to all areas. The effectiveness of this approach depends on the prevalence of H pylori infection in patients with ulcers in the community; in some areas, this prevalence may be too low to make this approach effective.46,47 Also, patients not undergoing prompt endoscopy may be less satisfied with their care,42 which is related to the observation that patients with dyspepsia are more likely than physicians to value diagnostic certainty.48 Other data suggest, however, that patient satisfaction is more closely associated with symptom improvement than with having procedures performed.49 With these caveats in mind, it seems most reasonable to inform your patients about the evidence regarding the advantages and disadvantages of the various approaches and allow them to share in the decision-making process.
An international consensus conference has defined dyspepsia as chronic or recurrent pain or discomfort that is centered in the upper abdomen.1 This discomfort includes such symptoms as early satiety, fullness, bloating, and nausea. Up to 50% of people in community surveys in the United States and Europe report having dyspepsia.2 Although only a minority of people with dyspepsia seek care,3,4 this complaint still accounts for 2% to 3% of visits to family physicians.5 Patients with dyspepsia report lower quality of life than asymptomatic people; in one report, they had a quality of life similar to patients with angina.6 This review discusses the evaluation of dyspepsia and will be followed next month by a review of the treatment of dyspepsia.
Differential diagnosis
Information about the differential diagnosis of this condition largely comes from studies in which patients with dyspepsia were referred for upper endoscopy Table 1.7 The most common identifiable conditions were esophagitis, gastric ulcer, and duodenal ulcer. Most patients in these studies did not have any abnormalities on endoscopy and were considered to have functional dyspepsia. The pathophysiology of functional dyspepsia is not well understood and is likely to be multifactorial. Gastroduodenal dysmotility, increased gastric acid secretion, increased visceral sensation to distention and/or gastric acid, psychological distress, and environmental factors such as smoking and Helicobacter pylori infection all may play a role.8
When dyspeptic patients undergo more extensive evaluations and/or are followed up for longer periods of time, a large variety of other conditions have been identified. These include gastroesophageal reflux without esophagitis, lactose intolerance, cholelithiasis, gastroparesis, chronic pancreatitis, pancreatic cancer, celiac disease, giardiasis, and ischemic heart disease.9-11 However, it is not always clear that these diagnoses are completely responsible for a patient’s dyspeptic symptoms. Finally, a variety of medications or other ingestions (such as alcohol) can lead to dyspepsia.12
Using the history and physical examination
The history and physical examination are important in detecting red flags for potentially fatal conditions, such as cancer or complicated ulcers. Alarm symptoms include dysphagia, gastrointestinal bleeding, acute abdominal pain, jaundice, or an abdominal mass. The presence of 1 or more of these symptoms should trigger a consultation with a surgeon or a gastroenterologist and possible endoscopy.
A patient’s age is of some help in diagnosis; older patients are more likely to have identifiable causes for dyspepsia than those who are younger.7,9 This is particularly true for gastric cancer, which is rare in people younger than 45 years in Europe and North America. In 1 study that identified all cases of gastric cancer in a population of 280,500, only 25 of 319 gastric cancers occurred in patients younger than 55 years. Of these patients, 24 of 25 had symptoms or signs of gastric cancer: weight loss (14), dysphagia (8), anemia (7), gastrointestinal bleed (3), previous gastric surgery (3), palpable mass (3), gastrointestinal perforation (1), and cerebral metastases (1).13 Historical and demographic factors that are more likely to be seen in patients with ulcers than in those with functional dyspepsia are male sex, smoking, and nonsteroidal anti-inflammatory drug (NSAID) use.14
Table 2 shows the results of 3 large prospective studies of patients with dyspepsia who were referred for endoscopy.12,15,16 Although certain symptoms are more likely to occur in some conditions than in others, no single item from the history and physical examination clearly establishes a diagnosis. Compared with patients with normal endoscopic examinations, those with ulcers are more likely to have relief of pain with food or antacids; those with gastric cancer are more likely to have lost weight; and those with esophagitis are more likely to have heartburn and pain relief with antacids. Symptoms such as nausea, distinct localization of pain, and nocturnal pain overlap to a large degree among patients with different diagnoses and are therefore not helpful.
Investigators have tried to develop more complicated scoring systems that employ a combination of these different symptoms. Although some of these clinical scores have some value in distinguishing the various causes of dyspepsia in patients who are referred for endoscopy,17-19 they are cumbersome and have not been validated in unselected patients with dyspepsia in primary care.18
The usefulness of the physical examination has been questioned in 2 studies of patients undergoing endoscopy for dyspepsia. In one study, epigastric tenderness did not accurately distinguish patients with abnormal endoscopy findings from those with normal findings.20 The likelihood ratio (LR) for tenderness to light or deep palpation was near 1, meaning that this maneuver had no diagnostic value. A second study found that an abnormal physical examination was equally likely in patients with an ulcer as in those without one.18
A recent study examined the accuracy of general practitioners’ overall impression based on the history and physical examination.21 Four hundred consecutive unselected patients with dyspepsia were evaluated by their general practitioners and then underwent endoscopy, upper abdominal ultrasonography, and laboratory tests. The physicians’ overall clinical impressions had a low sensitivity for diagnosing organic diseases or functional dyspepsia but were fairly specific for organic diseases Table 3. Note from the LRs that while suspicion of gallstone disease or malignancy significantly increased the likelihood of these conditions, an absence of suspicion in no way ruled them out (negative LR near 1).
Imaging studies and endoscopy
Definitively diagnosing the cause of a patient’s dyspepsia usually requires either upper endoscopy or an upper gastrointestinal (UGI) series. The former is more expensive, may not be readily available in some communities, and has a slight risk of complications (such as a 0.05% perforation rate22). Endoscopy is generally believed to be more accurate than a UGI series. However, most studies that compared the accuracy of these tests have used endoscopy as the gold standard, which creates a bias in favor of endoscopy. The few studies that have used repeat endoscopy for lesions detected by radiography but not the initial endoscopy have still shown that radiography is less accurate than endoscopy, especially for lesions smaller than 5 mm Table 4.23,24 Another advantage of endoscopy is the ability to biopsy lesions suspicious for malignancy and to perform invasive tests for H pylori infection. A patient who has a gastric ulcer detected by a UGI series should be referred for endoscopic biopsy, since up to 3% of these ulcers can harbor malignancy.9
Other imaging studies are not routinely recommended for evaluation of dyspepsia. In the absence of typical symptoms of biliary colic, abdominal ultrasonography has a very low yield11; even if gallstones are detected in a patient with dyspepsia, this may be incidental, and cholecystectomy may not improve the patient’s symptoms. Gastric-emptying studies may be abnormal in nearly 40% of patients with functional dyspepsia,25 but basing therapy on the results of these studies has not been consistently shown to benefit patients.1
Detecting H pylori
Patients with dyspepsia should be evaluated for the presence of H pylori, because this infection has been found in up to 95% of patients with duodenal ulcer and 80% with a gastric ulcer. It occurs in approximately 30% to 40% of patients without an ulcer.26 Patients with ulcers who are H pylori–positive have a markedly reduced recurrence rate after successful eradication therapy.27,28 Therefore, patients with gastric or duodenal ulcers who are infected with H pylori should be treated with a combination of antibiotics and acid suppressive agents to eradicate the infection. Noninvasive options for diagnosing H pylori include immunoglobulin G (IgG) antibody testing in serum or whole blood, urea breath tests, and stool antigen tests Table 4.
There are at least 40 commercially available IgG serologic tests. The median sensitivity and specificity are 92% and 83%, respectively, but the accuracy varies considerably.29 Whole blood serologic tests can be performed on capillary blood obtained from finger sticks, and are therefore more convenient than serum tests that require venipuncture but are not recommended because they are less sensitive.30,31 Because patients may have persistently positive IgG antibodies for many months after eradication therapy, a serologic test will often give a false-positive result during that period.32
Urea breath tests are able to detect an active H pylori infection. Patients ingest a specific food or drink that contains carbon-labeled urea. Gastric urease activity, which is highly specific for active H pylori infection, converts the carbon-labeled urea to labeled carbon dioxide and ammonia. The patient breathes into a container, and a positive test occurs when the labeled carbon dioxide exceeds a threshold level. Both 13Carbon and 14Carbon are used. The latter exposes patients to a negligible amount of radioactivity, but is simple, rapid, and less expensive than the 13 carbon tests. In comparative studies, the urea breath tests are more accurate than serologic tests.33,34
Stool antigen is involved in the most recently developed noninvasive test. The few studies that have been conducted to date have demonstrated that these tests are highly accurate.35 The stool antigen has recently been recommended by the European Helicobacter Pylori Study Group as the preferred initial noninvasive diagnostic test.36
Approach to the patient
There are a variety of possible approaches to the initial management of patients with dyspepsia. These include (1) prompt endoscopy (or UGI) for all patients, (2) prompt endoscopy (or UGI) for patients at highest risk for organic disease, (3) empiric acid suppression therapy for all patients with testing reserved for patients who remain symptomatic, (4) empiric H pylori eradication therapy for all patients, and (5) noninvasive H pylori testing for all patients, followed by empiric eradication therapy for those with positive results and empiric treatment of functional dyspepsia for those with negative results (a “test and treat” approach).
The most recent American, Canadian, and European consensus-based guidelines all recommend that patients younger than 45 years with dyspepsia and no alarm symptoms should be tested for H pylori infection and then given eradication therapy if positive; patients older than 45 years and those with alarm symptoms should have prompt endoscopy.37-39 H pylori–negative patients younger than 45 years and without alarm symptoms should be managed empirically for functional dyspepsia. H pylori–positive or negative patients who do not undergo endoscopy initially should do so if their symptoms persist. An algorithm depicting this approach is presented in the Figure 1. Cost-effectiveness analyses generally support this approach.22,40,41
Direct evidence for these approaches from randomized controlled trials has recently become available.42-45 These studies show that outcomes are similar whether patients received prompt endoscopy or follow a test and treat strategy. Note that patients older than 45 years, using NSAIDs, or with any alarm symptoms for complicated disease were either excluded from these trials or underwent prompt endoscopy.
Although the current evidence supports a test and treat strategy, the results may not be generalizable to all areas. The effectiveness of this approach depends on the prevalence of H pylori infection in patients with ulcers in the community; in some areas, this prevalence may be too low to make this approach effective.46,47 Also, patients not undergoing prompt endoscopy may be less satisfied with their care,42 which is related to the observation that patients with dyspepsia are more likely than physicians to value diagnostic certainty.48 Other data suggest, however, that patient satisfaction is more closely associated with symptom improvement than with having procedures performed.49 With these caveats in mind, it seems most reasonable to inform your patients about the evidence regarding the advantages and disadvantages of the various approaches and allow them to share in the decision-making process.
1. Talley N, Stanghellini V, Heading R, et al. Functional gastroduodenal disorders. Gut 1999;45:1137-42.
2. Heading RC. Prevalence of upper gastrointestinal symptoms in the general population: a systematic review. Scand J Gastroenterol 1999;34(suppl):3-8.
3. Jones RH, Lydeard SE, Hobbs FDR, Kenkre JE, Williams EI, Jones SJ. Dyspepsia in England and Scotland. Gut 1990;31:401-05.
4. Talley NJ, Zinsmeister AR, Schleck CD, Melton LJ. Dyspepsia and dyspepsia subgroups: a population-based study. Gastroenterology 1992;102:1259-68.
5. Marsland DW, Wood M, Mayo F. Content of family practice. Part I: rank order of diagnoses by frequency. Part II: diagnoses by disease category and age/sex distribution. J Fam Pract 1976;3:37-68.
6. Dimenas E. Methodological aspects of evaluation of quality of life in upper gastrointestinal diseases. Scand J Gastroenterol 1993;28(suppl):18-21.
7. Rabeneck L, Wray NP, Graham DY. Managing dyspepsia: what do we know and what do we need to know? Am J Gastroenterol 1998;93:920-24.
8. McNamara DA, Buckley M, O’Morain CA. Nonulcer dyspepsia: current concepts and management. Gastroenterol Clin N Am 2000;29:807-18.
9. Talley NJ, Silverstein MD, Agreus L, Nyren O, Sonnenberg A, Holtmann G. AGA technical review: evaluation of dyspepsia. Gastroenterology 1998;114:582-95.
10. Lundquist P, Seensalu R, Linden B, Nilsson LH, Lindberg G. Symptom criteria do not distinguish between functional and organic dyspepsia. Eur J Surg 1998;164:345-52.
11. Heikkinen MT, Pikkarainen PH, Takala JK, Rasanen HT, Eskelinen MJ, Julkunen RJK. Diagnostic methods in dyspepsia: the usefulness of upper abdominal ultrasound and gastroscopy. Scand J Prim Health Care 1997;15:82-86.
12. Crean GP, Holden RJ, Knill-Jones RP, et al. A database on dyspepsia. Gut 1994;35:191-202.
13. Christie J, Shepherd NA, Codling BW, Valori RM. Gastric cancer below the age of 55: implications for screening patients with uncomplicated dyspepsia. Gut 1997;41:513-17.
14. Kurata JH, Nogawa AN. Meta-analysis of risk factors for peptic ulcer: nonsteroidal antiinflammatory drugs, Helicobacter pylori, and smoking. J Clin Gastroenterol 1997;24:2-17.
15. Johannessen T, Petersen H, Kleveland PM, et al. The predictive value of history in dyspepsia. Scand J Gastroenterol 1990;25:689-97.
16. Mansi C, Savarino V, Mela GS, Picciotto A, Mele MR, Cele G. Are clinical patterns of dyspepsia a valid guideline for appropriate use of endoscopy? A report on 2253 dyspeptic patients. Am J Gastroenterol 1993;88:1011-15.
17. Talley NJ, McNeil D, Piper DW. Discriminant value of dyspeptic symptoms: a study of the clinical presentation of 221 patients with dyspepsia of unknown cause, peptic ulceration, and cholelithiasis. Gut 1987;28:40-46.
18. Numans M, van der Graaf Y, de Wit NJ, Touw-otten FWMM, de Melker RA. How much ulcer is ulcer-like? Diagnostic determinates of peptic ulcer in open access gastroscopy. Fam Pract 1994;11:382-88.
19. Bytzer P, Moller Hansen J, de Muckadell OBS, Malchow-Moller A. Predicting endoscopic diagnosis in the dyspeptic patient: the value of predictive score models. Scand J Gastroenterol 1997;32:118-25.
20. Priebe WM, DaCosta LR, Beck IT. Is epigastric tenderness a sign of peptic ulcer disease? Gastroenterology 1982;82:16-19.
21. Heikkinen M, Pikkarainen P, Eskelinen M, Julkunen R. GPs’ ability to diagnose dyspepsia based only on physical examination and patient history. Scand J Prim Health Care 2000;18:99-104.
22. Ofman JJ, Etchason J, Fullerton S, Kahn KL, Soll AH. Management strategies for Helicobacter pylori–seropositive patients with dyspepsia: clinical and economic consequences. Ann Intern Med 1997;126:280-91.
23. Shaw PC, van Romunde LKJ, Griffioen G, Janssens AR, Kreuning J, Eilers GAM. Peptic ulcer and gastric carcinoma: diagnosis with biphasic radiography compared with fiberoptic endoscopy. Radiology 1987;163:39-42.
24. Dooley CP, Larson AW, Stace NH, Renner IG, Valenzuela JE, Eliasoph J. Double-contrast barium meal and upper gastrointestinal endoscopy: a comparative study. Ann Intern Med 1984;101:538-45.
25. Quartero AO, de Wit NJ, Lodder AC, Numans ME, Smout AJPM, Hoes AW. Disturbed solid-phase gastric emptying in functional dyspepsia: a meta-analysis. Dig Dis Sci 1998;43:2028-33.
26. Peterson W, Fendrick AM, Cave DR, Peura DA, Garabedian-Ruffalo SM, Laine L. Helicobacter pylori–related disease: guidelines for testing and treatment. Arch Intern Med 2000;160:1285-91.
27. Moore RA. Helicobacter pylori and peptic ulcer: a systematic review of effectiveness and an overview of the economic benefits of implementing what is known to be effective. Oxford: Pain Relief Research Unit, 1995; vii:37.
28. Hopkins RJ, Girardi LS, Turney EA. Relationship between Helicobacter pylori eradication and reduced duodenal and gastric ulcer recurrence: a review. Gastroenterology 1996;110:1244-52.
29. Laheij RJF, Straatman H, Jansen JBMJ, Verbeek ALM. Evaluation of commercially available Helicobacter pylori serology kits: a review. J Clin Microbiol 1998;36:2803-09.
30. Chey WD, Murthy U, Shaw S, et al. A comparison of three fingerstick, whole blood antibody tests for Helicobacter pylori infection: a United States, multicenter trial. Am J Gastroenterol 1999;94:1512-16.
31. Faigel DO, Magaret N, Corless C, Lieberman DA, Fennerty MB. Evaluation of rapid antibody tests for the diagnosis of Helicobacter pylori infection. Am J Gastroenterol 2000;95:72-77.
32. Ho B, Marshall BJ. Accurate diagnosis of Helicobacter pylori: serologic testing. Gastroenterol Clin N Am 2000;29:853-62.
33. Cutler AF, Havstad S, Ma CK, Blaser MJ, Perez-Perez GI, Schubert TT. Accuracy of invasive and noninvasive tests to diagnose Helicobacter pylori infection. Gastroenterology 1995;109:136-41.
34. Thijs JC, van Zwet AA, Thijs WJ, et al. Diagnostic tests for Helicobacter pylori: a prospective evaluation of their accuracy, without selecting a single test as the gold standard. Am J Gastroenterol 1996;91:2125-29.
35. Vaira D, Malfertheiner P, Megraud F, et al. Diagnosis of Helicobacter pylori infection with a new non-invasive antigen-based assay. Lancet 1999;354:30-33.
36. Vaira D, Vakil N. Blood, urine, stool, breath, money, and Helicobacter pylori. Gut 2001;48:287-89.
37. American Gastroenterological Association. American Gastroenterological Association medical position statement: evaluation of dyspepsia. Gastroenterology 1998;114:579-81.
38. Hunt RH, Fallone CA, Thomson ABR. Canadian Helicobacter Study Group. Canadian Helicobacter pylori consensus conference update: infection in adults. Can J Gastroenterol 1999;13:213-17.
39. The European Helicobacter Pylori Study Group (EHPSG). Current European concepts in the management of Helicobacter pylori infection: the Maastricht Consensus Report. Gut 1997;41:8-13.
40. Fendrick AM, Chernew ME, Hirth RA, Bloom BS. Immediate endoscopy or initial Helicobacter pylori serological testing for suspected peptic ulcer disease: estimating cost-effectiveness using decision analysis. Yale J Biol Med 1996;69:187-95.
41. Ebell MH, Warbasse L, Brenner C. Evaluation of the dyspeptic patient: a cost-utility study. J Fam Pract 1997;44:545-55.
42. Lassen AT, Pedersen FM, Bytzer P, de Muckadell OBS. Helicobacter pylori test-and-eradicate versus prompt endoscopy for management of dyspeptic patients: a randomised trial. Lancet 2000;356:455-60.
43. Jones R, Tait C, Sladen G, Weston-Baker J. A trial of test-and-treat strategy for Helicobacter pylori–positive dyspeptic patients in general practice. Int J Clin Pract 1999;53:413-16.
44. Heaney A, Collins JSA, Watson RGP, McFarland RJ, Bamford KB, Tham TCK. A prospective randomised trial of a “test and treat” policy versus endoscopy based management in young Helicobacter pylori positive patients with ulcer-like dyspepsia, referred to a hospital clinic. Gut 1999;45:186-90.
45. Asante MA, Mendall M, Patel P, Ballam L, Northfield TC. A randomized trial of endoscopy vs no endoscopy in the management of seronegative Helicobacter pylori dyspepsia. Eur J Gastroenterol Hepatol 1998;10:983-89.
46. Tovey FI, Hobsley M. Is Helicobacter pylori the primary cause of duodenal ulceration? J Gastroenterol Hepatol 1999;14:1053-56.
47. Xia HHX, Kalantar JS, Mitchell HM, Talley NJ. Can Helicobacter pylori serology still be applied as a surrogate marker to identify peptic ulcer disease in dyspepsia? Aliment Pharmacol Ther 2000;14:615-24.
48. Hirth RA, Bloom BS, Chernew ME, Fendrick AM. Patient, physician, and payer perceptions and misperceptions of willingness to pay for diagnostic certainty. Int J Technol Assess Health Care 2000;16:35-49.
49. Kurata JH, Nogawa AN, Chen YK, Parker CE. Dyspepsia in primary care: perceived causes, reasons for improvement, and satisfaction with care. J Fam Pract 1997;44:281-88.
50. Peura DA, Pambianco DJ, Dye KR, et al. Microdose 14C-urea breath test offers diagnosis of Helicobacter pylori in 10 minutes. Am J Gastroenterol 1996;91:233-38.
51. Raju GS, Smith MJ, Morton D, Bardhan KD. Mini-dose (1-microCi) 14C-urea breath test for the detection of Helicobacter pylori. Am J Gastroenterol 1994;89:1027-31.
1. Talley N, Stanghellini V, Heading R, et al. Functional gastroduodenal disorders. Gut 1999;45:1137-42.
2. Heading RC. Prevalence of upper gastrointestinal symptoms in the general population: a systematic review. Scand J Gastroenterol 1999;34(suppl):3-8.
3. Jones RH, Lydeard SE, Hobbs FDR, Kenkre JE, Williams EI, Jones SJ. Dyspepsia in England and Scotland. Gut 1990;31:401-05.
4. Talley NJ, Zinsmeister AR, Schleck CD, Melton LJ. Dyspepsia and dyspepsia subgroups: a population-based study. Gastroenterology 1992;102:1259-68.
5. Marsland DW, Wood M, Mayo F. Content of family practice. Part I: rank order of diagnoses by frequency. Part II: diagnoses by disease category and age/sex distribution. J Fam Pract 1976;3:37-68.
6. Dimenas E. Methodological aspects of evaluation of quality of life in upper gastrointestinal diseases. Scand J Gastroenterol 1993;28(suppl):18-21.
7. Rabeneck L, Wray NP, Graham DY. Managing dyspepsia: what do we know and what do we need to know? Am J Gastroenterol 1998;93:920-24.
8. McNamara DA, Buckley M, O’Morain CA. Nonulcer dyspepsia: current concepts and management. Gastroenterol Clin N Am 2000;29:807-18.
9. Talley NJ, Silverstein MD, Agreus L, Nyren O, Sonnenberg A, Holtmann G. AGA technical review: evaluation of dyspepsia. Gastroenterology 1998;114:582-95.
10. Lundquist P, Seensalu R, Linden B, Nilsson LH, Lindberg G. Symptom criteria do not distinguish between functional and organic dyspepsia. Eur J Surg 1998;164:345-52.
11. Heikkinen MT, Pikkarainen PH, Takala JK, Rasanen HT, Eskelinen MJ, Julkunen RJK. Diagnostic methods in dyspepsia: the usefulness of upper abdominal ultrasound and gastroscopy. Scand J Prim Health Care 1997;15:82-86.
12. Crean GP, Holden RJ, Knill-Jones RP, et al. A database on dyspepsia. Gut 1994;35:191-202.
13. Christie J, Shepherd NA, Codling BW, Valori RM. Gastric cancer below the age of 55: implications for screening patients with uncomplicated dyspepsia. Gut 1997;41:513-17.
14. Kurata JH, Nogawa AN. Meta-analysis of risk factors for peptic ulcer: nonsteroidal antiinflammatory drugs, Helicobacter pylori, and smoking. J Clin Gastroenterol 1997;24:2-17.
15. Johannessen T, Petersen H, Kleveland PM, et al. The predictive value of history in dyspepsia. Scand J Gastroenterol 1990;25:689-97.
16. Mansi C, Savarino V, Mela GS, Picciotto A, Mele MR, Cele G. Are clinical patterns of dyspepsia a valid guideline for appropriate use of endoscopy? A report on 2253 dyspeptic patients. Am J Gastroenterol 1993;88:1011-15.
17. Talley NJ, McNeil D, Piper DW. Discriminant value of dyspeptic symptoms: a study of the clinical presentation of 221 patients with dyspepsia of unknown cause, peptic ulceration, and cholelithiasis. Gut 1987;28:40-46.
18. Numans M, van der Graaf Y, de Wit NJ, Touw-otten FWMM, de Melker RA. How much ulcer is ulcer-like? Diagnostic determinates of peptic ulcer in open access gastroscopy. Fam Pract 1994;11:382-88.
19. Bytzer P, Moller Hansen J, de Muckadell OBS, Malchow-Moller A. Predicting endoscopic diagnosis in the dyspeptic patient: the value of predictive score models. Scand J Gastroenterol 1997;32:118-25.
20. Priebe WM, DaCosta LR, Beck IT. Is epigastric tenderness a sign of peptic ulcer disease? Gastroenterology 1982;82:16-19.
21. Heikkinen M, Pikkarainen P, Eskelinen M, Julkunen R. GPs’ ability to diagnose dyspepsia based only on physical examination and patient history. Scand J Prim Health Care 2000;18:99-104.
22. Ofman JJ, Etchason J, Fullerton S, Kahn KL, Soll AH. Management strategies for Helicobacter pylori–seropositive patients with dyspepsia: clinical and economic consequences. Ann Intern Med 1997;126:280-91.
23. Shaw PC, van Romunde LKJ, Griffioen G, Janssens AR, Kreuning J, Eilers GAM. Peptic ulcer and gastric carcinoma: diagnosis with biphasic radiography compared with fiberoptic endoscopy. Radiology 1987;163:39-42.
24. Dooley CP, Larson AW, Stace NH, Renner IG, Valenzuela JE, Eliasoph J. Double-contrast barium meal and upper gastrointestinal endoscopy: a comparative study. Ann Intern Med 1984;101:538-45.
25. Quartero AO, de Wit NJ, Lodder AC, Numans ME, Smout AJPM, Hoes AW. Disturbed solid-phase gastric emptying in functional dyspepsia: a meta-analysis. Dig Dis Sci 1998;43:2028-33.
26. Peterson W, Fendrick AM, Cave DR, Peura DA, Garabedian-Ruffalo SM, Laine L. Helicobacter pylori–related disease: guidelines for testing and treatment. Arch Intern Med 2000;160:1285-91.
27. Moore RA. Helicobacter pylori and peptic ulcer: a systematic review of effectiveness and an overview of the economic benefits of implementing what is known to be effective. Oxford: Pain Relief Research Unit, 1995; vii:37.
28. Hopkins RJ, Girardi LS, Turney EA. Relationship between Helicobacter pylori eradication and reduced duodenal and gastric ulcer recurrence: a review. Gastroenterology 1996;110:1244-52.
29. Laheij RJF, Straatman H, Jansen JBMJ, Verbeek ALM. Evaluation of commercially available Helicobacter pylori serology kits: a review. J Clin Microbiol 1998;36:2803-09.
30. Chey WD, Murthy U, Shaw S, et al. A comparison of three fingerstick, whole blood antibody tests for Helicobacter pylori infection: a United States, multicenter trial. Am J Gastroenterol 1999;94:1512-16.
31. Faigel DO, Magaret N, Corless C, Lieberman DA, Fennerty MB. Evaluation of rapid antibody tests for the diagnosis of Helicobacter pylori infection. Am J Gastroenterol 2000;95:72-77.
32. Ho B, Marshall BJ. Accurate diagnosis of Helicobacter pylori: serologic testing. Gastroenterol Clin N Am 2000;29:853-62.
33. Cutler AF, Havstad S, Ma CK, Blaser MJ, Perez-Perez GI, Schubert TT. Accuracy of invasive and noninvasive tests to diagnose Helicobacter pylori infection. Gastroenterology 1995;109:136-41.
34. Thijs JC, van Zwet AA, Thijs WJ, et al. Diagnostic tests for Helicobacter pylori: a prospective evaluation of their accuracy, without selecting a single test as the gold standard. Am J Gastroenterol 1996;91:2125-29.
35. Vaira D, Malfertheiner P, Megraud F, et al. Diagnosis of Helicobacter pylori infection with a new non-invasive antigen-based assay. Lancet 1999;354:30-33.
36. Vaira D, Vakil N. Blood, urine, stool, breath, money, and Helicobacter pylori. Gut 2001;48:287-89.
37. American Gastroenterological Association. American Gastroenterological Association medical position statement: evaluation of dyspepsia. Gastroenterology 1998;114:579-81.
38. Hunt RH, Fallone CA, Thomson ABR. Canadian Helicobacter Study Group. Canadian Helicobacter pylori consensus conference update: infection in adults. Can J Gastroenterol 1999;13:213-17.
39. The European Helicobacter Pylori Study Group (EHPSG). Current European concepts in the management of Helicobacter pylori infection: the Maastricht Consensus Report. Gut 1997;41:8-13.
40. Fendrick AM, Chernew ME, Hirth RA, Bloom BS. Immediate endoscopy or initial Helicobacter pylori serological testing for suspected peptic ulcer disease: estimating cost-effectiveness using decision analysis. Yale J Biol Med 1996;69:187-95.
41. Ebell MH, Warbasse L, Brenner C. Evaluation of the dyspeptic patient: a cost-utility study. J Fam Pract 1997;44:545-55.
42. Lassen AT, Pedersen FM, Bytzer P, de Muckadell OBS. Helicobacter pylori test-and-eradicate versus prompt endoscopy for management of dyspeptic patients: a randomised trial. Lancet 2000;356:455-60.
43. Jones R, Tait C, Sladen G, Weston-Baker J. A trial of test-and-treat strategy for Helicobacter pylori–positive dyspeptic patients in general practice. Int J Clin Pract 1999;53:413-16.
44. Heaney A, Collins JSA, Watson RGP, McFarland RJ, Bamford KB, Tham TCK. A prospective randomised trial of a “test and treat” policy versus endoscopy based management in young Helicobacter pylori positive patients with ulcer-like dyspepsia, referred to a hospital clinic. Gut 1999;45:186-90.
45. Asante MA, Mendall M, Patel P, Ballam L, Northfield TC. A randomized trial of endoscopy vs no endoscopy in the management of seronegative Helicobacter pylori dyspepsia. Eur J Gastroenterol Hepatol 1998;10:983-89.
46. Tovey FI, Hobsley M. Is Helicobacter pylori the primary cause of duodenal ulceration? J Gastroenterol Hepatol 1999;14:1053-56.
47. Xia HHX, Kalantar JS, Mitchell HM, Talley NJ. Can Helicobacter pylori serology still be applied as a surrogate marker to identify peptic ulcer disease in dyspepsia? Aliment Pharmacol Ther 2000;14:615-24.
48. Hirth RA, Bloom BS, Chernew ME, Fendrick AM. Patient, physician, and payer perceptions and misperceptions of willingness to pay for diagnostic certainty. Int J Technol Assess Health Care 2000;16:35-49.
49. Kurata JH, Nogawa AN, Chen YK, Parker CE. Dyspepsia in primary care: perceived causes, reasons for improvement, and satisfaction with care. J Fam Pract 1997;44:281-88.
50. Peura DA, Pambianco DJ, Dye KR, et al. Microdose 14C-urea breath test offers diagnosis of Helicobacter pylori in 10 minutes. Am J Gastroenterol 1996;91:233-38.
51. Raju GS, Smith MJ, Morton D, Bardhan KD. Mini-dose (1-microCi) 14C-urea breath test for the detection of Helicobacter pylori. Am J Gastroenterol 1994;89:1027-31.
The Evaluation and Treatment of Children with Acute Otitis Media
Between 1993 and 1995 more than 20 million visits were provided to children younger than 15 years for otitis media; 77% of these were for children aged 4 years and younger.1 Acute otitis media (AOM) is the most frequent primary diagnosis in preschool children and accounts for almost 20% of ambulatory care visits in this age group. By the age of 3 months, 10% of children will be given at least 1 diagnosis of otitis media and more than 90% by the age of 2 years.2 Peak incidence occurs between the ages 6 and 15 months, although there is a second peak at approximately age 5 years that is thought to be associated with entrance into school.3 In the mid-1990s, treatment of otitis media cost $3.8 billion per year4; 20% of the more than 110 million prescriptions for oral antibiotics are for otitis media.5
The most important contributor to AOM is a dysfunction of the eustachian tube, allowing reflux of fluid and bacteria into the middle ear space from the nasopharynx.6 This dysfunction is usually multifactorial and is likely a combination of anatomy (shorter and more flexible eustachian tubes) and function (inefficiency at clearing secretions and equilibrating negative intratympanic pressures) in younger children.7 Acute viral upper respiratory infections create inflammation and secretions that magnify this eustachian tube dysfunction and predispose to or induce AOM.
The 3 most common bacteria in AOM are Streptococcus pneumoniae, Haemophilus species, and Branhamella catarrhalis. A recent study showed that both bacteria and viruses were isolated in the middle ear fluid of 65% of children with otitis media. In fact, 35% had viruses isolated as the sole middle ear pathogen.8 Other studies have failed to identify a specific infectious agent in a significant number of middle ear fluid aspirates.9
Diagnosis
The diagnosis of AOM in children is often based on a combination of symptoms and physical findings. It is usually defined as bulging or opacification of the tympanic membrane with or without erythema, middle ear effusion, marked decrease or absence of tympanic membrane mobility, and accompanied by at least one of the following signs and symptoms of acute infection: fever, otalgia, irritability, otorrhea, lethargy, anorexia, vomiting, or diarrhea.10 Although the best reference standard for the diagnosis of AOM is myringotomy or tympanocentesis, no published studies were identified in which this reference was performed in all study patients. Most published studies use pneumatic otoscopy combined with tympanocentesis or myringotomy as the reference standard when middle ear effusion is suspected.
Most symptoms are not specific for AOM. In a survey of patients seeing general practitioners in Finland,11 the symptoms that most increased the likelihood of diagnosing AOM were earache (relative risk [RR]=5.4; 95% confidence interval [CI], 3.3-8.9), rubbing of the ear (RR=5.0; 95% CI, 2.9-8.6), and excessive crying (RR=2.8; 95% CI, 1.8-4.3). Although fever, earache, or excessive crying were present in 90% of children considered to have AOM, one or more of these symptoms were also present in 72% of children who did not have otitis media. In another survey of children aged younger than 4 years with a diagnosis of AOM, 40% did not have otalgia, and 30% did not have fever.12
Physical examination findings are of variable reliability. Findings that physicians rely on to diagnose AOM, such as a bulging or erythematous tympanic membrane, may occasionally be found in normal ears.13 One study compared the 3 most commonly documented otoscopic findings (color, position, and mobility of the tympanic membrane) with those of pneumatic otoscopy and myringotomy.14 Only 65% of patients with a distinctly red tympanic membrane and 16% with a slightly red tympanic membrane had AOM. A cloudy tympanic membrane was the most predictive color change, with an 80% positive predictive value (PPV), the percentage of patients with the symptom who have AOM. A bulging tympanic membrane was most predictive of AOM (PPV=89%), despite its 27% false-negative rate. Retraction was found in only 19% of children with AOM and had a PPV of only 50%. Distinctly impaired mobility was predictive of otitis media (PPV=78%), but diminished mobility was also found in 30% of children without middle ear effusion. These data and those presented in Table 1 show that each of these otoscopic examination elements (color, position, mobility) alone is inadequate for discriminating between cases in which the diagnosis of AOM is uncertain.
However, combining these signs can be useful.15 A cloudy (opaque), bulging, and immobile tympanic membrane on pneumatic otoscopy was nearly 100% predictive of otitis media in children with acute symptoms. In addition, 94% of children with the combination of distinctly red erythema, bulging, and immobility had AOM. No combination of findings that included only slight redness was more than 53% predictive of AOM.
In children aged younger than 1 year in whom otoscopy can be quite difficult, tympanometry can be a useful tool for detecting a middle ear effusion.16 An abnormal type B tympanogram (flat curve with no distinct peak) in infants presenting with acute symptoms is strong evidence in favor of AOM, although a normal test is not helpful in ruling out the diagnosis.
The diagnosis of AOM can be influenced by the physician’s perception of parental expectations for antibiotics.17 A study of children presenting with ear pain or other upper respiratory symptoms found that physicians diagnosed AOM 49% of the time when they perceived parents wanted antibiotics and only 13% of the time when they thought parents did not want antibiotics. Physicians were 23 times more likely to prescribe an antibiotic for an upper respiratory illness if they perceived that parents expected antimicrobials.
Treatment
A recent systematic review18 found that the symptoms of AOM (mainly otalgia) spontaneously resolved in two thirds of children by 24 hours and in 80% at 2 to 7 days. This was also observed in 2 earlier meta-analyses.10,19 Seventeen children would need to be treated with antibiotics (vs placebo) for 1 child to have less pain at 2 to 7 days (number needed to treat [NNT]=17). There were no differences between antibiotic and placebo groups in other clinical outcomes, such as tympanometry findings, perforation, and recurrences. Also, children treated with antibiotics were almost twice as likely to have vomiting, diarrhea, or a rash.
Initially not treating uncomplicated AOM with antibiotics is an acceptable alternative. In a study by van Buchem and colleagues,20 90% of children with AOM recovered (symptoms resolved) in the first 4 days with nose drops and oral analgesics and without the use of antibiotics. Only 3% of the 4860 children in this study had a clinical course that required further treatment with antibiotics or myringotomy. A recent randomized controlled trial of 315 children demonstrated that children treated immediately with antibiotics had 1 less day of symptoms, but that 1 in 5 of these had diarrhea.21 The group not treated with antibiotics had no serious sequellae and used more analgesics. There were no differences in the number of missed school days, and more than 75% of the parents were satisfied with this “wait and see” approach. These studies also emphasize that antibiotics have a very modest effect on the clinical course of AOM and seem to decrease the duration of symptoms only to a small degree.
Physicians often recommend other symptomatic treatments for ear infections. Non–aspirin analgesics are effective in relieving pain,21 as are ibuprofen22 and Auralgan.23 Antihistamine-decongestant preparations offer no added benefit in resolution of symptoms and have no effect on clinical outcomes when given with antibiotics.24,25
If antibiotics are used, the meta-analysis by Rosenfeld and colleagues10 showed there were no differences in outcomes between treatment with cefaclor, cefixime, erythromycin, trimethoprim-sulfamethoxazole, amoxicillin clavulanate, or erythromycin sulfisoxazole, and treatment with amoxicillin or ampicillin. Broader spectrum and/or more expensive antibiotics therefore offer no advantage over amoxicillin for the initial treatment of AOM. In another meta-analysis, Kozyrskyj and coworkers26 showed that a 5-day antibiotic course was an acceptable alternative to a 8- to 14-day treatment course. There was a slightly increased risk of treatment failure at 1-month follow-up with the shortened course of antibiotics; the NNT to prevent 1 excess failure at 30 days was 17. There were no differences in long-term outcomes (2-3 months) or medication side effects (vomiting, diarrhea, rash) between the short and long antibiotic courses. The broader spectrum azithromycin and intramuscular ceftriaxone offered no advantage over amoxicillin. Children aged younger than 2 years deserve special mention, since they are at higher risk for treatment failures,27,28 persistent symptoms,29 and recurrent otitis media.30 Few well-designed studies exist to guide treatment in this age group. Although children aged younger than 2 years were not excluded, neither review by Glasziou and colleagues18 or Rosenfeld and coworkers10 specifically examined this age group.
Another review demonstrated that (as with older children) routinely using antibiotics initially does not seem to add any clinical benefit.31 A recent randomized controlled trial of 240 children demonstrated that 8 children in this age group would have to be treated with amoxicillin for 1 child to have fewer symptoms (fever, crying, irritability) at 4 days (NNT=8).32 The major benefit of amoxicillin in this study was 1 day less of fever (P=.004). Adverse effects were almost twice as likely in the amoxicillin group, although this difference was not statistically significant. There were also no differences between the groups in clinical failure rates at 11 days or in the likelihood of recurrent otitis media, antibiotic use, specialist referrals, or surgery at 6 weeks. Effects on hearing were not measured. The authors conclude that “this modest effect does not justify prescription of antibiotics at the first visit, provided close surveillance can be guaranteed.” Also, Kozyrskyj and colleagues26 demonstrated in their meta-analysis that as a subgroup there were no differences in clinical failures between 5 and 10 days of antibiotics in children aged younger than 2 years. However, there were only 118 children in this age group. Table 2 shows treatment options for AOM.
In recent years, there has been an increasing concern about worldwide bacterial resistance to antimicrobial drugs33-35 by the World Health Organization36 and the Centers for Disease Control and Prevention (CDC).37 In response to the increasing antimicrobial resistance patterns seen in the common middle ear pathogens, especially S pneumoniae, the CDC Drug-resistant Streptococcus pneumoniae Therapeutic Working Group recommends doubling the dosage of amoxicillin to 80 to 90 mg per kg per day in the empiric treatment of AOM.38 These recommendations are based on in vitro mean inhibitory concentration data of S pneumoniae cultures from middle ear fluid and nasopharyngeal swabs. However, there currently is no patient-oriented evidence to suggest that increasing the amoxicillin dosage actually decreases suppurative or invasive complications of AOM (meningitis, mastoiditis, and so forth), affects recurrence rates or treatment success, affects long-term outcomes of AOM, or even decreases the rate of drug-resistant S pneumoniae. Also, bacteriologic outcomes do not correlate with clinical outcomes. In the meta-analysis by Rosenfeld and coworkers,10 89% of middle ear pathogens from treatment failures were susceptible in vitro to the antibiotic prescribed, and 13% of isolates from clinical cures were resistant in vitro to the prescribed antibiotic. We must use extreme caution in extrapolating the microbiologic findings to the clinical care of the child with AOM.
Prognosis
There are insufficient data to suggest that routine antibiotic use in AOM results in fewer cases of mastoiditis or meningitis. In the systematic reviews cited, the incidence of these suppurative complications was rare. In the Cochrane review by Glasziou and colleagues,18 only 1 case of mastoiditis developed in 2202 children, and this was in a child treated with penicillin. In the Netherlands among 4860 consecutive children with AOM, 2 experienced mastoiditis (both responded to outpatient antibiotic therapy), and there were no cases of meningitis.20 In the meta-analysis by Rosenfeld and coworkers,10 there were no suppurative complications in the 5400 children studied. Although mastoiditis has been quoted as being more common in the preantibiotic era, it is unclear if the current rarity of this condition is due to antibiotic treatment, changes in organism virulence or host defenses, or the assertion that uncomplicated otitis media was often not reported, thus increasing the relative rate of mastoiditis.27 In a recent review,39 antibiotics did not seem to have an appreciable effect on complication rates, leading the authors to conclude that “antibiotic treatment for AOM cannot be considered as a safeguard against the development of complications.” Even in developing countries where the burden of otitis media is great, mastoiditis is quite rare, with a prevalence rate of much less than 1%.40
Antibiotic use does influence bacterial resistance rates. In children previously treated with antibiotics for AOM, there is a 3-fold increased risk of isolating drug-resistant organisms from middle ear effusions with subsequent bouts of otitis media.41,42 In the Netherlands and Iceland, routinely not treating AOM with antibiotics has resulted in a reduction in antibiotic resistance.33,43 The most important risk factors for a poor outcome are age younger than 2 years and attendance at a daycare center.40 Children in daycare have a higher risk of requiring a hospital admission and up to a 50% increased risk of repeated or recurrent ear infections.44,45 Children with chronic underlying illnesses or chronic otitis media with effusion have added risks of poor outcomes that are beyond the scope of this review.
Conclusions
Thus, the natural course of AOM in children is quite favorable. If left untreated, 80% will recover spontaneously within 2 weeks. The addition of antibiotics provides at best a modest reduction in symptoms, while adding cost, adverse drug effects, and increasing bacterial resistance in the patient and community. Minimizing the use of antibiotics in patients with AOM does not increase the risks of perforation, deafness, or contralateral or recurrent AOM.
1. Freid VM, Makuc DM, Rooks RN. Ambulatory health care visits by children: principal diagnosis and place of visit. Vital Health Stat Series 13: data from the National Health Survey. 1998;137:1-23.
2. Klein J. Epidemiology of acute otitis media. Infect Dis 1989;8(suppl 1):89.-
3. Daly KA, Giebink GS. Clinical epidemiology of otitis media. Pediatr Infect Dis J 2000;19:S31-36.
4. Gates GA. Cost-effectiveness considerations in otitis media treatment. Otolaryngol Head Neck Surg 1996;114:525-30.
5. McCaig LF, Hughes JM. Trends in antimicrobial drug prescribing among office-based physicians in the United States. JAMA 1995;273:214-19.
6. Taylor RB, ed. Family medicine. Principles and practice. 4th ed. Heidelberg, Germany: Springer-Verlag; 1994.
7. Bluestone CD, Doyle WJ. Anatomy and physiology of eustachian tube and middle ear related to otitis media. J Allergy Clin Immunol 1988;81:997-1003.
8. Heikkinen T, Thint M, Chonmaitree T. Prevalence of various respiratory viruses in the middle ear during acute otitis media. N Engl J Med 1999;340:260-64.
9. Ruuskanen O, Heikkinin AM, Ziegler T. Viruses in acute otitis media: increasing evidence for clinical significance. Pediatr Infect Dis J 1991;10:425-27.
10. Rosenfeld RM, Vertrees JE, Carr J, et al. Clinical efficacy of antimicrobial drugs for acute otitis media: meta-analysis of 5400 children from thirty-three randomized trials. J Pediatr 1994;124:355-67.
11. Niemela M, Uhari M, Juonio-Ervasti K, Luotonen J, Alho O, Vierimaa E. Lack of specific symptomatology in children with acute otitis media. Pediatr Infect Dis J 1994;13:765-68.
12. Heikkinen T, Ruuskanen O. Signs and symptoms predicting acute otitis media. Arch Pediatr Adolesc Med 1995;149:26-29.
13. Aorla M, Ruuskanen O, Ziegler T, et al. Clinical role of respiratory virus infection in acute otitis media. Pediatrics 1990;86:848-55.
14. Karma PH, Penttila MA, Sipila MM, Kataja MJ. Otoscopic diagnosis of middle ear effusion in acute and non-acute otitis media. I. The value of different otoscopic findings. Int J Pediatr Otolaryngol 1989;17:37-49.
15. Karma PH, Sipila MM, Kataja MJ, Penttila MA. Pneumatic otoscopy and otitis media: the value of different tympanic membrane findings and their combinations. In: Kim DJ, Bluestone CD, Klein JO, Nelson JD, Ogra PL, eds. Recent advances in otitis media: proceedings of the Fifth International Symposium. Burlington, Ontario, Canada: Decker; 1993;41-45.
16. Palmu A, Puhakka H, Rahko T, Takala AK. Diagnostic value of tympanometry in infants in clinical practice. Int J Ped Otorhinolaryngol 1999;49:207-13.
17. Mangione-Smith R, McGlynn EA, Elliott MN, Krogstad P, Brook RH. The relationship between perceived parental expectations and pediatrician antimicrobial prescribing behavior. Pediatrics 1999;103:711-18.
18. Glasziou PP, Del Mar CB, Hayem M, Sanders SL. Antibiotics for acute otitis media in children (Cochrane review). In: The Cochrane library Issue 4. Oxford, England: Update Software; 2000.
19. Del Mar C, Glasziou P, Hayem M. Are antibiotics indicated as initial treatment for children with acute otitis media? A meta-analysis. BMJ 1997;314:1526-29.
20. Van Buchem FL, Peeters MF, van’t Hof MA. Acute otitis media: a new treatment strategy. BMJ 1985;290:1033-37.
21. Little P, Gould C, Williamson I, Moore M, Warner G, Dunleavey J. Pragmatic randomised controlled trial of two prescribing strategies for childhood acute otitis media. BMJ 2001;332:336-42.
22. Bertin L, Pons G, d’Athis P, et al. A randomized double blind multicentre controlled trial of ibuprofen versus acetaminophen and placebo for symptoms of acute otitis media in children. Fundam Clin Parmacol 1996;10:387-92.
23. Hoberman A, Paradise JL, Reynolds EA, Urkin J. Efficacy of Auralgan for treating ear pain in children with acute otitis media. Arch Pediatr Adolesc Med 1997;151:675-78.
24. Schnore SK, Sangster JF, Gerace TM, Bass MJ. Are antihistamine-decongestants of value in the treatment of acute otitis media in children? J Fam Pract 1986;22:39-43.
25. Bhambhani K, Foulds DM, Swamy KN, Eldis FE, Fischel JE. Acute otitis media in children: are decongestants or antihistamines necessary? Ann Emerg Med 1983;12:13-16.
26. Kozyrskyj AL, Hildes-Ripstein GE, Longstaffe SEA, et al. Short course antibiotics for acute otitis media (Cochrane review). In: The Cochrane library Issue 4. Oxford, England: Update Software; 2000.
27. Froom J, Culpepper L, Jacobs M, et al. Antimicrobials for acute otitis media? A review from the International Primary Care Network. BMJ 1997;315:98-102.
28. Iino Y, Nakamura Y, Koizumi T, Toriyama M. Prognostic factors for persistent middle ear effusion after acute otitis media in children. Acta Oto-Laryngologica 1993;113:761-65.
29. Paradise JL. Short-course antimicrobial treatment for acute otitis media: not best for infants and young children. JAMA 1997;278:1640-42.
30. Rasmussen F. Recurrence of acute otitis media at preschool age in Sweden. J Epidemiol Comm Health. 1994;48:33-35.
31. Damoiseaux RA, van Balen FA, Hoes AW, de Melker RA. Antibiotic treatment of acute otitis media in children under two years of age: evidence based? Br J Gen Pract 1998;48:1861-64.
32. Damoiseaux RAMJ, van Balen FAM, Hoes AW, Verheij TJM, de Melker RA. Primary care based randomised, double blind trial of amoxicillin versus placebo for acute otitis media in children aged under 2 years. BMJ 2000;320:350-54.
33. Neu HC. The crisis in antibiotic resistance. Science 1992; 257:1036-38. 34. Breiman RF, Butler JC, Tenover FC, Elliott JA, Facklan RR. Emergence of drug-resistant pneumococcal infections in the United States. JAMA 1994;271:1831-35.
35. Cohen ML. Epidemiology of drug-resistance: implications for the post-antimicrobial era. Science 1992;257:1050-55.
36. LeDuc JW. World Health Organization strategy for emerging infectious diseases. JAMA 1996;275:318-20.
37. Interagency Task Force on Antimicrobial Resistance. A public health action plan to combat antimicrobial resistance. Available at: www.cdc.gov/drugresistance/actionplan/index.htm.
38. Dowell SF, Butler JC, Giebink GS, et al. Acute otitis media: management and surveillance in an era of pneumococcal resistance—a report from the Drug-resistant Streptococcus pneumoniae Therapeutic Working group. Ped Infect Dis J 1999;18:1-9.
39. Dhooge IJM, Albers FWJ, van Cauwenberge PB. Intratemporal and intracranial complications of acute suppurative otitis media in children: renewed interest. Internat J Ped Otorhinolaryngol 1999;49:S109-14.
40. Berman S. Otitis media in developing countries. Pediatrics 1995;96:126-31.
41. Harrison CJ, Marks MI, Welch DF. Microbiology of recently treated acute otitis media compared with previously untreated acute otitis media. Pediatr Infect Dis J 1985;4:641-46.
42. Ford KL, Mason EO, Jr, Kaplan SL, Lamberth LB, Tillman J. Factors associated with middle ear isolates of Streptococcus pneumoniae resistant to penicillin in a children’s hospital. J Pediatrics 1991;119:941-44.
43. Stephenson J. Icelandic researchers are showing the way to bring down rates of antibiotic-resistant bacteria. JAMA 1996;275:175.
44. Hardy AM, Fowler MG. Child care arrangements and repeated ear infections in young children. Am J Public Health 1993;83:1321-25.
45. Louhiala PJ, Jaakkola N, Ruotsalainen R, Jaakkola JJ. Form of day care and respiratory infection among Finnish children. Am J Public 1995;85:1109-12. 46.
Between 1993 and 1995 more than 20 million visits were provided to children younger than 15 years for otitis media; 77% of these were for children aged 4 years and younger.1 Acute otitis media (AOM) is the most frequent primary diagnosis in preschool children and accounts for almost 20% of ambulatory care visits in this age group. By the age of 3 months, 10% of children will be given at least 1 diagnosis of otitis media and more than 90% by the age of 2 years.2 Peak incidence occurs between the ages 6 and 15 months, although there is a second peak at approximately age 5 years that is thought to be associated with entrance into school.3 In the mid-1990s, treatment of otitis media cost $3.8 billion per year4; 20% of the more than 110 million prescriptions for oral antibiotics are for otitis media.5
The most important contributor to AOM is a dysfunction of the eustachian tube, allowing reflux of fluid and bacteria into the middle ear space from the nasopharynx.6 This dysfunction is usually multifactorial and is likely a combination of anatomy (shorter and more flexible eustachian tubes) and function (inefficiency at clearing secretions and equilibrating negative intratympanic pressures) in younger children.7 Acute viral upper respiratory infections create inflammation and secretions that magnify this eustachian tube dysfunction and predispose to or induce AOM.
The 3 most common bacteria in AOM are Streptococcus pneumoniae, Haemophilus species, and Branhamella catarrhalis. A recent study showed that both bacteria and viruses were isolated in the middle ear fluid of 65% of children with otitis media. In fact, 35% had viruses isolated as the sole middle ear pathogen.8 Other studies have failed to identify a specific infectious agent in a significant number of middle ear fluid aspirates.9
Diagnosis
The diagnosis of AOM in children is often based on a combination of symptoms and physical findings. It is usually defined as bulging or opacification of the tympanic membrane with or without erythema, middle ear effusion, marked decrease or absence of tympanic membrane mobility, and accompanied by at least one of the following signs and symptoms of acute infection: fever, otalgia, irritability, otorrhea, lethargy, anorexia, vomiting, or diarrhea.10 Although the best reference standard for the diagnosis of AOM is myringotomy or tympanocentesis, no published studies were identified in which this reference was performed in all study patients. Most published studies use pneumatic otoscopy combined with tympanocentesis or myringotomy as the reference standard when middle ear effusion is suspected.
Most symptoms are not specific for AOM. In a survey of patients seeing general practitioners in Finland,11 the symptoms that most increased the likelihood of diagnosing AOM were earache (relative risk [RR]=5.4; 95% confidence interval [CI], 3.3-8.9), rubbing of the ear (RR=5.0; 95% CI, 2.9-8.6), and excessive crying (RR=2.8; 95% CI, 1.8-4.3). Although fever, earache, or excessive crying were present in 90% of children considered to have AOM, one or more of these symptoms were also present in 72% of children who did not have otitis media. In another survey of children aged younger than 4 years with a diagnosis of AOM, 40% did not have otalgia, and 30% did not have fever.12
Physical examination findings are of variable reliability. Findings that physicians rely on to diagnose AOM, such as a bulging or erythematous tympanic membrane, may occasionally be found in normal ears.13 One study compared the 3 most commonly documented otoscopic findings (color, position, and mobility of the tympanic membrane) with those of pneumatic otoscopy and myringotomy.14 Only 65% of patients with a distinctly red tympanic membrane and 16% with a slightly red tympanic membrane had AOM. A cloudy tympanic membrane was the most predictive color change, with an 80% positive predictive value (PPV), the percentage of patients with the symptom who have AOM. A bulging tympanic membrane was most predictive of AOM (PPV=89%), despite its 27% false-negative rate. Retraction was found in only 19% of children with AOM and had a PPV of only 50%. Distinctly impaired mobility was predictive of otitis media (PPV=78%), but diminished mobility was also found in 30% of children without middle ear effusion. These data and those presented in Table 1 show that each of these otoscopic examination elements (color, position, mobility) alone is inadequate for discriminating between cases in which the diagnosis of AOM is uncertain.
However, combining these signs can be useful.15 A cloudy (opaque), bulging, and immobile tympanic membrane on pneumatic otoscopy was nearly 100% predictive of otitis media in children with acute symptoms. In addition, 94% of children with the combination of distinctly red erythema, bulging, and immobility had AOM. No combination of findings that included only slight redness was more than 53% predictive of AOM.
In children aged younger than 1 year in whom otoscopy can be quite difficult, tympanometry can be a useful tool for detecting a middle ear effusion.16 An abnormal type B tympanogram (flat curve with no distinct peak) in infants presenting with acute symptoms is strong evidence in favor of AOM, although a normal test is not helpful in ruling out the diagnosis.
The diagnosis of AOM can be influenced by the physician’s perception of parental expectations for antibiotics.17 A study of children presenting with ear pain or other upper respiratory symptoms found that physicians diagnosed AOM 49% of the time when they perceived parents wanted antibiotics and only 13% of the time when they thought parents did not want antibiotics. Physicians were 23 times more likely to prescribe an antibiotic for an upper respiratory illness if they perceived that parents expected antimicrobials.
Treatment
A recent systematic review18 found that the symptoms of AOM (mainly otalgia) spontaneously resolved in two thirds of children by 24 hours and in 80% at 2 to 7 days. This was also observed in 2 earlier meta-analyses.10,19 Seventeen children would need to be treated with antibiotics (vs placebo) for 1 child to have less pain at 2 to 7 days (number needed to treat [NNT]=17). There were no differences between antibiotic and placebo groups in other clinical outcomes, such as tympanometry findings, perforation, and recurrences. Also, children treated with antibiotics were almost twice as likely to have vomiting, diarrhea, or a rash.
Initially not treating uncomplicated AOM with antibiotics is an acceptable alternative. In a study by van Buchem and colleagues,20 90% of children with AOM recovered (symptoms resolved) in the first 4 days with nose drops and oral analgesics and without the use of antibiotics. Only 3% of the 4860 children in this study had a clinical course that required further treatment with antibiotics or myringotomy. A recent randomized controlled trial of 315 children demonstrated that children treated immediately with antibiotics had 1 less day of symptoms, but that 1 in 5 of these had diarrhea.21 The group not treated with antibiotics had no serious sequellae and used more analgesics. There were no differences in the number of missed school days, and more than 75% of the parents were satisfied with this “wait and see” approach. These studies also emphasize that antibiotics have a very modest effect on the clinical course of AOM and seem to decrease the duration of symptoms only to a small degree.
Physicians often recommend other symptomatic treatments for ear infections. Non–aspirin analgesics are effective in relieving pain,21 as are ibuprofen22 and Auralgan.23 Antihistamine-decongestant preparations offer no added benefit in resolution of symptoms and have no effect on clinical outcomes when given with antibiotics.24,25
If antibiotics are used, the meta-analysis by Rosenfeld and colleagues10 showed there were no differences in outcomes between treatment with cefaclor, cefixime, erythromycin, trimethoprim-sulfamethoxazole, amoxicillin clavulanate, or erythromycin sulfisoxazole, and treatment with amoxicillin or ampicillin. Broader spectrum and/or more expensive antibiotics therefore offer no advantage over amoxicillin for the initial treatment of AOM. In another meta-analysis, Kozyrskyj and coworkers26 showed that a 5-day antibiotic course was an acceptable alternative to a 8- to 14-day treatment course. There was a slightly increased risk of treatment failure at 1-month follow-up with the shortened course of antibiotics; the NNT to prevent 1 excess failure at 30 days was 17. There were no differences in long-term outcomes (2-3 months) or medication side effects (vomiting, diarrhea, rash) between the short and long antibiotic courses. The broader spectrum azithromycin and intramuscular ceftriaxone offered no advantage over amoxicillin. Children aged younger than 2 years deserve special mention, since they are at higher risk for treatment failures,27,28 persistent symptoms,29 and recurrent otitis media.30 Few well-designed studies exist to guide treatment in this age group. Although children aged younger than 2 years were not excluded, neither review by Glasziou and colleagues18 or Rosenfeld and coworkers10 specifically examined this age group.
Another review demonstrated that (as with older children) routinely using antibiotics initially does not seem to add any clinical benefit.31 A recent randomized controlled trial of 240 children demonstrated that 8 children in this age group would have to be treated with amoxicillin for 1 child to have fewer symptoms (fever, crying, irritability) at 4 days (NNT=8).32 The major benefit of amoxicillin in this study was 1 day less of fever (P=.004). Adverse effects were almost twice as likely in the amoxicillin group, although this difference was not statistically significant. There were also no differences between the groups in clinical failure rates at 11 days or in the likelihood of recurrent otitis media, antibiotic use, specialist referrals, or surgery at 6 weeks. Effects on hearing were not measured. The authors conclude that “this modest effect does not justify prescription of antibiotics at the first visit, provided close surveillance can be guaranteed.” Also, Kozyrskyj and colleagues26 demonstrated in their meta-analysis that as a subgroup there were no differences in clinical failures between 5 and 10 days of antibiotics in children aged younger than 2 years. However, there were only 118 children in this age group. Table 2 shows treatment options for AOM.
In recent years, there has been an increasing concern about worldwide bacterial resistance to antimicrobial drugs33-35 by the World Health Organization36 and the Centers for Disease Control and Prevention (CDC).37 In response to the increasing antimicrobial resistance patterns seen in the common middle ear pathogens, especially S pneumoniae, the CDC Drug-resistant Streptococcus pneumoniae Therapeutic Working Group recommends doubling the dosage of amoxicillin to 80 to 90 mg per kg per day in the empiric treatment of AOM.38 These recommendations are based on in vitro mean inhibitory concentration data of S pneumoniae cultures from middle ear fluid and nasopharyngeal swabs. However, there currently is no patient-oriented evidence to suggest that increasing the amoxicillin dosage actually decreases suppurative or invasive complications of AOM (meningitis, mastoiditis, and so forth), affects recurrence rates or treatment success, affects long-term outcomes of AOM, or even decreases the rate of drug-resistant S pneumoniae. Also, bacteriologic outcomes do not correlate with clinical outcomes. In the meta-analysis by Rosenfeld and coworkers,10 89% of middle ear pathogens from treatment failures were susceptible in vitro to the antibiotic prescribed, and 13% of isolates from clinical cures were resistant in vitro to the prescribed antibiotic. We must use extreme caution in extrapolating the microbiologic findings to the clinical care of the child with AOM.
Prognosis
There are insufficient data to suggest that routine antibiotic use in AOM results in fewer cases of mastoiditis or meningitis. In the systematic reviews cited, the incidence of these suppurative complications was rare. In the Cochrane review by Glasziou and colleagues,18 only 1 case of mastoiditis developed in 2202 children, and this was in a child treated with penicillin. In the Netherlands among 4860 consecutive children with AOM, 2 experienced mastoiditis (both responded to outpatient antibiotic therapy), and there were no cases of meningitis.20 In the meta-analysis by Rosenfeld and coworkers,10 there were no suppurative complications in the 5400 children studied. Although mastoiditis has been quoted as being more common in the preantibiotic era, it is unclear if the current rarity of this condition is due to antibiotic treatment, changes in organism virulence or host defenses, or the assertion that uncomplicated otitis media was often not reported, thus increasing the relative rate of mastoiditis.27 In a recent review,39 antibiotics did not seem to have an appreciable effect on complication rates, leading the authors to conclude that “antibiotic treatment for AOM cannot be considered as a safeguard against the development of complications.” Even in developing countries where the burden of otitis media is great, mastoiditis is quite rare, with a prevalence rate of much less than 1%.40
Antibiotic use does influence bacterial resistance rates. In children previously treated with antibiotics for AOM, there is a 3-fold increased risk of isolating drug-resistant organisms from middle ear effusions with subsequent bouts of otitis media.41,42 In the Netherlands and Iceland, routinely not treating AOM with antibiotics has resulted in a reduction in antibiotic resistance.33,43 The most important risk factors for a poor outcome are age younger than 2 years and attendance at a daycare center.40 Children in daycare have a higher risk of requiring a hospital admission and up to a 50% increased risk of repeated or recurrent ear infections.44,45 Children with chronic underlying illnesses or chronic otitis media with effusion have added risks of poor outcomes that are beyond the scope of this review.
Conclusions
Thus, the natural course of AOM in children is quite favorable. If left untreated, 80% will recover spontaneously within 2 weeks. The addition of antibiotics provides at best a modest reduction in symptoms, while adding cost, adverse drug effects, and increasing bacterial resistance in the patient and community. Minimizing the use of antibiotics in patients with AOM does not increase the risks of perforation, deafness, or contralateral or recurrent AOM.
Between 1993 and 1995 more than 20 million visits were provided to children younger than 15 years for otitis media; 77% of these were for children aged 4 years and younger.1 Acute otitis media (AOM) is the most frequent primary diagnosis in preschool children and accounts for almost 20% of ambulatory care visits in this age group. By the age of 3 months, 10% of children will be given at least 1 diagnosis of otitis media and more than 90% by the age of 2 years.2 Peak incidence occurs between the ages 6 and 15 months, although there is a second peak at approximately age 5 years that is thought to be associated with entrance into school.3 In the mid-1990s, treatment of otitis media cost $3.8 billion per year4; 20% of the more than 110 million prescriptions for oral antibiotics are for otitis media.5
The most important contributor to AOM is a dysfunction of the eustachian tube, allowing reflux of fluid and bacteria into the middle ear space from the nasopharynx.6 This dysfunction is usually multifactorial and is likely a combination of anatomy (shorter and more flexible eustachian tubes) and function (inefficiency at clearing secretions and equilibrating negative intratympanic pressures) in younger children.7 Acute viral upper respiratory infections create inflammation and secretions that magnify this eustachian tube dysfunction and predispose to or induce AOM.
The 3 most common bacteria in AOM are Streptococcus pneumoniae, Haemophilus species, and Branhamella catarrhalis. A recent study showed that both bacteria and viruses were isolated in the middle ear fluid of 65% of children with otitis media. In fact, 35% had viruses isolated as the sole middle ear pathogen.8 Other studies have failed to identify a specific infectious agent in a significant number of middle ear fluid aspirates.9
Diagnosis
The diagnosis of AOM in children is often based on a combination of symptoms and physical findings. It is usually defined as bulging or opacification of the tympanic membrane with or without erythema, middle ear effusion, marked decrease or absence of tympanic membrane mobility, and accompanied by at least one of the following signs and symptoms of acute infection: fever, otalgia, irritability, otorrhea, lethargy, anorexia, vomiting, or diarrhea.10 Although the best reference standard for the diagnosis of AOM is myringotomy or tympanocentesis, no published studies were identified in which this reference was performed in all study patients. Most published studies use pneumatic otoscopy combined with tympanocentesis or myringotomy as the reference standard when middle ear effusion is suspected.
Most symptoms are not specific for AOM. In a survey of patients seeing general practitioners in Finland,11 the symptoms that most increased the likelihood of diagnosing AOM were earache (relative risk [RR]=5.4; 95% confidence interval [CI], 3.3-8.9), rubbing of the ear (RR=5.0; 95% CI, 2.9-8.6), and excessive crying (RR=2.8; 95% CI, 1.8-4.3). Although fever, earache, or excessive crying were present in 90% of children considered to have AOM, one or more of these symptoms were also present in 72% of children who did not have otitis media. In another survey of children aged younger than 4 years with a diagnosis of AOM, 40% did not have otalgia, and 30% did not have fever.12
Physical examination findings are of variable reliability. Findings that physicians rely on to diagnose AOM, such as a bulging or erythematous tympanic membrane, may occasionally be found in normal ears.13 One study compared the 3 most commonly documented otoscopic findings (color, position, and mobility of the tympanic membrane) with those of pneumatic otoscopy and myringotomy.14 Only 65% of patients with a distinctly red tympanic membrane and 16% with a slightly red tympanic membrane had AOM. A cloudy tympanic membrane was the most predictive color change, with an 80% positive predictive value (PPV), the percentage of patients with the symptom who have AOM. A bulging tympanic membrane was most predictive of AOM (PPV=89%), despite its 27% false-negative rate. Retraction was found in only 19% of children with AOM and had a PPV of only 50%. Distinctly impaired mobility was predictive of otitis media (PPV=78%), but diminished mobility was also found in 30% of children without middle ear effusion. These data and those presented in Table 1 show that each of these otoscopic examination elements (color, position, mobility) alone is inadequate for discriminating between cases in which the diagnosis of AOM is uncertain.
However, combining these signs can be useful.15 A cloudy (opaque), bulging, and immobile tympanic membrane on pneumatic otoscopy was nearly 100% predictive of otitis media in children with acute symptoms. In addition, 94% of children with the combination of distinctly red erythema, bulging, and immobility had AOM. No combination of findings that included only slight redness was more than 53% predictive of AOM.
In children aged younger than 1 year in whom otoscopy can be quite difficult, tympanometry can be a useful tool for detecting a middle ear effusion.16 An abnormal type B tympanogram (flat curve with no distinct peak) in infants presenting with acute symptoms is strong evidence in favor of AOM, although a normal test is not helpful in ruling out the diagnosis.
The diagnosis of AOM can be influenced by the physician’s perception of parental expectations for antibiotics.17 A study of children presenting with ear pain or other upper respiratory symptoms found that physicians diagnosed AOM 49% of the time when they perceived parents wanted antibiotics and only 13% of the time when they thought parents did not want antibiotics. Physicians were 23 times more likely to prescribe an antibiotic for an upper respiratory illness if they perceived that parents expected antimicrobials.
Treatment
A recent systematic review18 found that the symptoms of AOM (mainly otalgia) spontaneously resolved in two thirds of children by 24 hours and in 80% at 2 to 7 days. This was also observed in 2 earlier meta-analyses.10,19 Seventeen children would need to be treated with antibiotics (vs placebo) for 1 child to have less pain at 2 to 7 days (number needed to treat [NNT]=17). There were no differences between antibiotic and placebo groups in other clinical outcomes, such as tympanometry findings, perforation, and recurrences. Also, children treated with antibiotics were almost twice as likely to have vomiting, diarrhea, or a rash.
Initially not treating uncomplicated AOM with antibiotics is an acceptable alternative. In a study by van Buchem and colleagues,20 90% of children with AOM recovered (symptoms resolved) in the first 4 days with nose drops and oral analgesics and without the use of antibiotics. Only 3% of the 4860 children in this study had a clinical course that required further treatment with antibiotics or myringotomy. A recent randomized controlled trial of 315 children demonstrated that children treated immediately with antibiotics had 1 less day of symptoms, but that 1 in 5 of these had diarrhea.21 The group not treated with antibiotics had no serious sequellae and used more analgesics. There were no differences in the number of missed school days, and more than 75% of the parents were satisfied with this “wait and see” approach. These studies also emphasize that antibiotics have a very modest effect on the clinical course of AOM and seem to decrease the duration of symptoms only to a small degree.
Physicians often recommend other symptomatic treatments for ear infections. Non–aspirin analgesics are effective in relieving pain,21 as are ibuprofen22 and Auralgan.23 Antihistamine-decongestant preparations offer no added benefit in resolution of symptoms and have no effect on clinical outcomes when given with antibiotics.24,25
If antibiotics are used, the meta-analysis by Rosenfeld and colleagues10 showed there were no differences in outcomes between treatment with cefaclor, cefixime, erythromycin, trimethoprim-sulfamethoxazole, amoxicillin clavulanate, or erythromycin sulfisoxazole, and treatment with amoxicillin or ampicillin. Broader spectrum and/or more expensive antibiotics therefore offer no advantage over amoxicillin for the initial treatment of AOM. In another meta-analysis, Kozyrskyj and coworkers26 showed that a 5-day antibiotic course was an acceptable alternative to a 8- to 14-day treatment course. There was a slightly increased risk of treatment failure at 1-month follow-up with the shortened course of antibiotics; the NNT to prevent 1 excess failure at 30 days was 17. There were no differences in long-term outcomes (2-3 months) or medication side effects (vomiting, diarrhea, rash) between the short and long antibiotic courses. The broader spectrum azithromycin and intramuscular ceftriaxone offered no advantage over amoxicillin. Children aged younger than 2 years deserve special mention, since they are at higher risk for treatment failures,27,28 persistent symptoms,29 and recurrent otitis media.30 Few well-designed studies exist to guide treatment in this age group. Although children aged younger than 2 years were not excluded, neither review by Glasziou and colleagues18 or Rosenfeld and coworkers10 specifically examined this age group.
Another review demonstrated that (as with older children) routinely using antibiotics initially does not seem to add any clinical benefit.31 A recent randomized controlled trial of 240 children demonstrated that 8 children in this age group would have to be treated with amoxicillin for 1 child to have fewer symptoms (fever, crying, irritability) at 4 days (NNT=8).32 The major benefit of amoxicillin in this study was 1 day less of fever (P=.004). Adverse effects were almost twice as likely in the amoxicillin group, although this difference was not statistically significant. There were also no differences between the groups in clinical failure rates at 11 days or in the likelihood of recurrent otitis media, antibiotic use, specialist referrals, or surgery at 6 weeks. Effects on hearing were not measured. The authors conclude that “this modest effect does not justify prescription of antibiotics at the first visit, provided close surveillance can be guaranteed.” Also, Kozyrskyj and colleagues26 demonstrated in their meta-analysis that as a subgroup there were no differences in clinical failures between 5 and 10 days of antibiotics in children aged younger than 2 years. However, there were only 118 children in this age group. Table 2 shows treatment options for AOM.
In recent years, there has been an increasing concern about worldwide bacterial resistance to antimicrobial drugs33-35 by the World Health Organization36 and the Centers for Disease Control and Prevention (CDC).37 In response to the increasing antimicrobial resistance patterns seen in the common middle ear pathogens, especially S pneumoniae, the CDC Drug-resistant Streptococcus pneumoniae Therapeutic Working Group recommends doubling the dosage of amoxicillin to 80 to 90 mg per kg per day in the empiric treatment of AOM.38 These recommendations are based on in vitro mean inhibitory concentration data of S pneumoniae cultures from middle ear fluid and nasopharyngeal swabs. However, there currently is no patient-oriented evidence to suggest that increasing the amoxicillin dosage actually decreases suppurative or invasive complications of AOM (meningitis, mastoiditis, and so forth), affects recurrence rates or treatment success, affects long-term outcomes of AOM, or even decreases the rate of drug-resistant S pneumoniae. Also, bacteriologic outcomes do not correlate with clinical outcomes. In the meta-analysis by Rosenfeld and coworkers,10 89% of middle ear pathogens from treatment failures were susceptible in vitro to the antibiotic prescribed, and 13% of isolates from clinical cures were resistant in vitro to the prescribed antibiotic. We must use extreme caution in extrapolating the microbiologic findings to the clinical care of the child with AOM.
Prognosis
There are insufficient data to suggest that routine antibiotic use in AOM results in fewer cases of mastoiditis or meningitis. In the systematic reviews cited, the incidence of these suppurative complications was rare. In the Cochrane review by Glasziou and colleagues,18 only 1 case of mastoiditis developed in 2202 children, and this was in a child treated with penicillin. In the Netherlands among 4860 consecutive children with AOM, 2 experienced mastoiditis (both responded to outpatient antibiotic therapy), and there were no cases of meningitis.20 In the meta-analysis by Rosenfeld and coworkers,10 there were no suppurative complications in the 5400 children studied. Although mastoiditis has been quoted as being more common in the preantibiotic era, it is unclear if the current rarity of this condition is due to antibiotic treatment, changes in organism virulence or host defenses, or the assertion that uncomplicated otitis media was often not reported, thus increasing the relative rate of mastoiditis.27 In a recent review,39 antibiotics did not seem to have an appreciable effect on complication rates, leading the authors to conclude that “antibiotic treatment for AOM cannot be considered as a safeguard against the development of complications.” Even in developing countries where the burden of otitis media is great, mastoiditis is quite rare, with a prevalence rate of much less than 1%.40
Antibiotic use does influence bacterial resistance rates. In children previously treated with antibiotics for AOM, there is a 3-fold increased risk of isolating drug-resistant organisms from middle ear effusions with subsequent bouts of otitis media.41,42 In the Netherlands and Iceland, routinely not treating AOM with antibiotics has resulted in a reduction in antibiotic resistance.33,43 The most important risk factors for a poor outcome are age younger than 2 years and attendance at a daycare center.40 Children in daycare have a higher risk of requiring a hospital admission and up to a 50% increased risk of repeated or recurrent ear infections.44,45 Children with chronic underlying illnesses or chronic otitis media with effusion have added risks of poor outcomes that are beyond the scope of this review.
Conclusions
Thus, the natural course of AOM in children is quite favorable. If left untreated, 80% will recover spontaneously within 2 weeks. The addition of antibiotics provides at best a modest reduction in symptoms, while adding cost, adverse drug effects, and increasing bacterial resistance in the patient and community. Minimizing the use of antibiotics in patients with AOM does not increase the risks of perforation, deafness, or contralateral or recurrent AOM.
1. Freid VM, Makuc DM, Rooks RN. Ambulatory health care visits by children: principal diagnosis and place of visit. Vital Health Stat Series 13: data from the National Health Survey. 1998;137:1-23.
2. Klein J. Epidemiology of acute otitis media. Infect Dis 1989;8(suppl 1):89.-
3. Daly KA, Giebink GS. Clinical epidemiology of otitis media. Pediatr Infect Dis J 2000;19:S31-36.
4. Gates GA. Cost-effectiveness considerations in otitis media treatment. Otolaryngol Head Neck Surg 1996;114:525-30.
5. McCaig LF, Hughes JM. Trends in antimicrobial drug prescribing among office-based physicians in the United States. JAMA 1995;273:214-19.
6. Taylor RB, ed. Family medicine. Principles and practice. 4th ed. Heidelberg, Germany: Springer-Verlag; 1994.
7. Bluestone CD, Doyle WJ. Anatomy and physiology of eustachian tube and middle ear related to otitis media. J Allergy Clin Immunol 1988;81:997-1003.
8. Heikkinen T, Thint M, Chonmaitree T. Prevalence of various respiratory viruses in the middle ear during acute otitis media. N Engl J Med 1999;340:260-64.
9. Ruuskanen O, Heikkinin AM, Ziegler T. Viruses in acute otitis media: increasing evidence for clinical significance. Pediatr Infect Dis J 1991;10:425-27.
10. Rosenfeld RM, Vertrees JE, Carr J, et al. Clinical efficacy of antimicrobial drugs for acute otitis media: meta-analysis of 5400 children from thirty-three randomized trials. J Pediatr 1994;124:355-67.
11. Niemela M, Uhari M, Juonio-Ervasti K, Luotonen J, Alho O, Vierimaa E. Lack of specific symptomatology in children with acute otitis media. Pediatr Infect Dis J 1994;13:765-68.
12. Heikkinen T, Ruuskanen O. Signs and symptoms predicting acute otitis media. Arch Pediatr Adolesc Med 1995;149:26-29.
13. Aorla M, Ruuskanen O, Ziegler T, et al. Clinical role of respiratory virus infection in acute otitis media. Pediatrics 1990;86:848-55.
14. Karma PH, Penttila MA, Sipila MM, Kataja MJ. Otoscopic diagnosis of middle ear effusion in acute and non-acute otitis media. I. The value of different otoscopic findings. Int J Pediatr Otolaryngol 1989;17:37-49.
15. Karma PH, Sipila MM, Kataja MJ, Penttila MA. Pneumatic otoscopy and otitis media: the value of different tympanic membrane findings and their combinations. In: Kim DJ, Bluestone CD, Klein JO, Nelson JD, Ogra PL, eds. Recent advances in otitis media: proceedings of the Fifth International Symposium. Burlington, Ontario, Canada: Decker; 1993;41-45.
16. Palmu A, Puhakka H, Rahko T, Takala AK. Diagnostic value of tympanometry in infants in clinical practice. Int J Ped Otorhinolaryngol 1999;49:207-13.
17. Mangione-Smith R, McGlynn EA, Elliott MN, Krogstad P, Brook RH. The relationship between perceived parental expectations and pediatrician antimicrobial prescribing behavior. Pediatrics 1999;103:711-18.
18. Glasziou PP, Del Mar CB, Hayem M, Sanders SL. Antibiotics for acute otitis media in children (Cochrane review). In: The Cochrane library Issue 4. Oxford, England: Update Software; 2000.
19. Del Mar C, Glasziou P, Hayem M. Are antibiotics indicated as initial treatment for children with acute otitis media? A meta-analysis. BMJ 1997;314:1526-29.
20. Van Buchem FL, Peeters MF, van’t Hof MA. Acute otitis media: a new treatment strategy. BMJ 1985;290:1033-37.
21. Little P, Gould C, Williamson I, Moore M, Warner G, Dunleavey J. Pragmatic randomised controlled trial of two prescribing strategies for childhood acute otitis media. BMJ 2001;332:336-42.
22. Bertin L, Pons G, d’Athis P, et al. A randomized double blind multicentre controlled trial of ibuprofen versus acetaminophen and placebo for symptoms of acute otitis media in children. Fundam Clin Parmacol 1996;10:387-92.
23. Hoberman A, Paradise JL, Reynolds EA, Urkin J. Efficacy of Auralgan for treating ear pain in children with acute otitis media. Arch Pediatr Adolesc Med 1997;151:675-78.
24. Schnore SK, Sangster JF, Gerace TM, Bass MJ. Are antihistamine-decongestants of value in the treatment of acute otitis media in children? J Fam Pract 1986;22:39-43.
25. Bhambhani K, Foulds DM, Swamy KN, Eldis FE, Fischel JE. Acute otitis media in children: are decongestants or antihistamines necessary? Ann Emerg Med 1983;12:13-16.
26. Kozyrskyj AL, Hildes-Ripstein GE, Longstaffe SEA, et al. Short course antibiotics for acute otitis media (Cochrane review). In: The Cochrane library Issue 4. Oxford, England: Update Software; 2000.
27. Froom J, Culpepper L, Jacobs M, et al. Antimicrobials for acute otitis media? A review from the International Primary Care Network. BMJ 1997;315:98-102.
28. Iino Y, Nakamura Y, Koizumi T, Toriyama M. Prognostic factors for persistent middle ear effusion after acute otitis media in children. Acta Oto-Laryngologica 1993;113:761-65.
29. Paradise JL. Short-course antimicrobial treatment for acute otitis media: not best for infants and young children. JAMA 1997;278:1640-42.
30. Rasmussen F. Recurrence of acute otitis media at preschool age in Sweden. J Epidemiol Comm Health. 1994;48:33-35.
31. Damoiseaux RA, van Balen FA, Hoes AW, de Melker RA. Antibiotic treatment of acute otitis media in children under two years of age: evidence based? Br J Gen Pract 1998;48:1861-64.
32. Damoiseaux RAMJ, van Balen FAM, Hoes AW, Verheij TJM, de Melker RA. Primary care based randomised, double blind trial of amoxicillin versus placebo for acute otitis media in children aged under 2 years. BMJ 2000;320:350-54.
33. Neu HC. The crisis in antibiotic resistance. Science 1992; 257:1036-38. 34. Breiman RF, Butler JC, Tenover FC, Elliott JA, Facklan RR. Emergence of drug-resistant pneumococcal infections in the United States. JAMA 1994;271:1831-35.
35. Cohen ML. Epidemiology of drug-resistance: implications for the post-antimicrobial era. Science 1992;257:1050-55.
36. LeDuc JW. World Health Organization strategy for emerging infectious diseases. JAMA 1996;275:318-20.
37. Interagency Task Force on Antimicrobial Resistance. A public health action plan to combat antimicrobial resistance. Available at: www.cdc.gov/drugresistance/actionplan/index.htm.
38. Dowell SF, Butler JC, Giebink GS, et al. Acute otitis media: management and surveillance in an era of pneumococcal resistance—a report from the Drug-resistant Streptococcus pneumoniae Therapeutic Working group. Ped Infect Dis J 1999;18:1-9.
39. Dhooge IJM, Albers FWJ, van Cauwenberge PB. Intratemporal and intracranial complications of acute suppurative otitis media in children: renewed interest. Internat J Ped Otorhinolaryngol 1999;49:S109-14.
40. Berman S. Otitis media in developing countries. Pediatrics 1995;96:126-31.
41. Harrison CJ, Marks MI, Welch DF. Microbiology of recently treated acute otitis media compared with previously untreated acute otitis media. Pediatr Infect Dis J 1985;4:641-46.
42. Ford KL, Mason EO, Jr, Kaplan SL, Lamberth LB, Tillman J. Factors associated with middle ear isolates of Streptococcus pneumoniae resistant to penicillin in a children’s hospital. J Pediatrics 1991;119:941-44.
43. Stephenson J. Icelandic researchers are showing the way to bring down rates of antibiotic-resistant bacteria. JAMA 1996;275:175.
44. Hardy AM, Fowler MG. Child care arrangements and repeated ear infections in young children. Am J Public Health 1993;83:1321-25.
45. Louhiala PJ, Jaakkola N, Ruotsalainen R, Jaakkola JJ. Form of day care and respiratory infection among Finnish children. Am J Public 1995;85:1109-12. 46.
1. Freid VM, Makuc DM, Rooks RN. Ambulatory health care visits by children: principal diagnosis and place of visit. Vital Health Stat Series 13: data from the National Health Survey. 1998;137:1-23.
2. Klein J. Epidemiology of acute otitis media. Infect Dis 1989;8(suppl 1):89.-
3. Daly KA, Giebink GS. Clinical epidemiology of otitis media. Pediatr Infect Dis J 2000;19:S31-36.
4. Gates GA. Cost-effectiveness considerations in otitis media treatment. Otolaryngol Head Neck Surg 1996;114:525-30.
5. McCaig LF, Hughes JM. Trends in antimicrobial drug prescribing among office-based physicians in the United States. JAMA 1995;273:214-19.
6. Taylor RB, ed. Family medicine. Principles and practice. 4th ed. Heidelberg, Germany: Springer-Verlag; 1994.
7. Bluestone CD, Doyle WJ. Anatomy and physiology of eustachian tube and middle ear related to otitis media. J Allergy Clin Immunol 1988;81:997-1003.
8. Heikkinen T, Thint M, Chonmaitree T. Prevalence of various respiratory viruses in the middle ear during acute otitis media. N Engl J Med 1999;340:260-64.
9. Ruuskanen O, Heikkinin AM, Ziegler T. Viruses in acute otitis media: increasing evidence for clinical significance. Pediatr Infect Dis J 1991;10:425-27.
10. Rosenfeld RM, Vertrees JE, Carr J, et al. Clinical efficacy of antimicrobial drugs for acute otitis media: meta-analysis of 5400 children from thirty-three randomized trials. J Pediatr 1994;124:355-67.
11. Niemela M, Uhari M, Juonio-Ervasti K, Luotonen J, Alho O, Vierimaa E. Lack of specific symptomatology in children with acute otitis media. Pediatr Infect Dis J 1994;13:765-68.
12. Heikkinen T, Ruuskanen O. Signs and symptoms predicting acute otitis media. Arch Pediatr Adolesc Med 1995;149:26-29.
13. Aorla M, Ruuskanen O, Ziegler T, et al. Clinical role of respiratory virus infection in acute otitis media. Pediatrics 1990;86:848-55.
14. Karma PH, Penttila MA, Sipila MM, Kataja MJ. Otoscopic diagnosis of middle ear effusion in acute and non-acute otitis media. I. The value of different otoscopic findings. Int J Pediatr Otolaryngol 1989;17:37-49.
15. Karma PH, Sipila MM, Kataja MJ, Penttila MA. Pneumatic otoscopy and otitis media: the value of different tympanic membrane findings and their combinations. In: Kim DJ, Bluestone CD, Klein JO, Nelson JD, Ogra PL, eds. Recent advances in otitis media: proceedings of the Fifth International Symposium. Burlington, Ontario, Canada: Decker; 1993;41-45.
16. Palmu A, Puhakka H, Rahko T, Takala AK. Diagnostic value of tympanometry in infants in clinical practice. Int J Ped Otorhinolaryngol 1999;49:207-13.
17. Mangione-Smith R, McGlynn EA, Elliott MN, Krogstad P, Brook RH. The relationship between perceived parental expectations and pediatrician antimicrobial prescribing behavior. Pediatrics 1999;103:711-18.
18. Glasziou PP, Del Mar CB, Hayem M, Sanders SL. Antibiotics for acute otitis media in children (Cochrane review). In: The Cochrane library Issue 4. Oxford, England: Update Software; 2000.
19. Del Mar C, Glasziou P, Hayem M. Are antibiotics indicated as initial treatment for children with acute otitis media? A meta-analysis. BMJ 1997;314:1526-29.
20. Van Buchem FL, Peeters MF, van’t Hof MA. Acute otitis media: a new treatment strategy. BMJ 1985;290:1033-37.
21. Little P, Gould C, Williamson I, Moore M, Warner G, Dunleavey J. Pragmatic randomised controlled trial of two prescribing strategies for childhood acute otitis media. BMJ 2001;332:336-42.
22. Bertin L, Pons G, d’Athis P, et al. A randomized double blind multicentre controlled trial of ibuprofen versus acetaminophen and placebo for symptoms of acute otitis media in children. Fundam Clin Parmacol 1996;10:387-92.
23. Hoberman A, Paradise JL, Reynolds EA, Urkin J. Efficacy of Auralgan for treating ear pain in children with acute otitis media. Arch Pediatr Adolesc Med 1997;151:675-78.
24. Schnore SK, Sangster JF, Gerace TM, Bass MJ. Are antihistamine-decongestants of value in the treatment of acute otitis media in children? J Fam Pract 1986;22:39-43.
25. Bhambhani K, Foulds DM, Swamy KN, Eldis FE, Fischel JE. Acute otitis media in children: are decongestants or antihistamines necessary? Ann Emerg Med 1983;12:13-16.
26. Kozyrskyj AL, Hildes-Ripstein GE, Longstaffe SEA, et al. Short course antibiotics for acute otitis media (Cochrane review). In: The Cochrane library Issue 4. Oxford, England: Update Software; 2000.
27. Froom J, Culpepper L, Jacobs M, et al. Antimicrobials for acute otitis media? A review from the International Primary Care Network. BMJ 1997;315:98-102.
28. Iino Y, Nakamura Y, Koizumi T, Toriyama M. Prognostic factors for persistent middle ear effusion after acute otitis media in children. Acta Oto-Laryngologica 1993;113:761-65.
29. Paradise JL. Short-course antimicrobial treatment for acute otitis media: not best for infants and young children. JAMA 1997;278:1640-42.
30. Rasmussen F. Recurrence of acute otitis media at preschool age in Sweden. J Epidemiol Comm Health. 1994;48:33-35.
31. Damoiseaux RA, van Balen FA, Hoes AW, de Melker RA. Antibiotic treatment of acute otitis media in children under two years of age: evidence based? Br J Gen Pract 1998;48:1861-64.
32. Damoiseaux RAMJ, van Balen FAM, Hoes AW, Verheij TJM, de Melker RA. Primary care based randomised, double blind trial of amoxicillin versus placebo for acute otitis media in children aged under 2 years. BMJ 2000;320:350-54.
33. Neu HC. The crisis in antibiotic resistance. Science 1992; 257:1036-38. 34. Breiman RF, Butler JC, Tenover FC, Elliott JA, Facklan RR. Emergence of drug-resistant pneumococcal infections in the United States. JAMA 1994;271:1831-35.
35. Cohen ML. Epidemiology of drug-resistance: implications for the post-antimicrobial era. Science 1992;257:1050-55.
36. LeDuc JW. World Health Organization strategy for emerging infectious diseases. JAMA 1996;275:318-20.
37. Interagency Task Force on Antimicrobial Resistance. A public health action plan to combat antimicrobial resistance. Available at: www.cdc.gov/drugresistance/actionplan/index.htm.
38. Dowell SF, Butler JC, Giebink GS, et al. Acute otitis media: management and surveillance in an era of pneumococcal resistance—a report from the Drug-resistant Streptococcus pneumoniae Therapeutic Working group. Ped Infect Dis J 1999;18:1-9.
39. Dhooge IJM, Albers FWJ, van Cauwenberge PB. Intratemporal and intracranial complications of acute suppurative otitis media in children: renewed interest. Internat J Ped Otorhinolaryngol 1999;49:S109-14.
40. Berman S. Otitis media in developing countries. Pediatrics 1995;96:126-31.
41. Harrison CJ, Marks MI, Welch DF. Microbiology of recently treated acute otitis media compared with previously untreated acute otitis media. Pediatr Infect Dis J 1985;4:641-46.
42. Ford KL, Mason EO, Jr, Kaplan SL, Lamberth LB, Tillman J. Factors associated with middle ear isolates of Streptococcus pneumoniae resistant to penicillin in a children’s hospital. J Pediatrics 1991;119:941-44.
43. Stephenson J. Icelandic researchers are showing the way to bring down rates of antibiotic-resistant bacteria. JAMA 1996;275:175.
44. Hardy AM, Fowler MG. Child care arrangements and repeated ear infections in young children. Am J Public Health 1993;83:1321-25.
45. Louhiala PJ, Jaakkola N, Ruotsalainen R, Jaakkola JJ. Form of day care and respiratory infection among Finnish children. Am J Public 1995;85:1109-12. 46.
Management of the Patient with Otitis Externa
Otitis externa (OE), also referred to as external otitis, is inflammation of the auricle, external ear, or tympanic membrane. The severity can range from mild inflammation to life-threatening infection.1 It is commonly seen by family physicians and affects 4 out of each 1000 Americans every year.2 In most cases the significant pain of OE compels the patient to seek care urgently.
OE can be categorized as localized or diffuse. When it persists for more than 6 months, it is considered chronic and is more commonly bilateral. It is thought to be caused by local trauma to the external canal, diabetes, high humidity, loss of the canal’s protective coating of cerumen, eczema, use of a hearing aid or stethoscope, or glandular obstruction. It is commonly seen in swimmers, particularly in the summer months.1 The most frequent symptoms are discharge, pain, hearing loss, itching, and tinnitus.
Necrotizing (malignant) otitis externa (NOE) is the most severe form of OE and is most often seen in elderly patients with diabetes. One case series in a referral population found a mortality rate of 53%.3 Pain, purulent discharge, bilateral involvement, and external canal granulation tissue are common symptoms.
Pathophysiology
The ear canal is a blind sac with an anterior recess. Trauma to the canal, accumulation of keratin, or a change in pH can trigger inflammation and infection. One study4 found that aerobic bacteria account for 91% of bacterial causes; anaerobes, 4%; and mixed infections, 4%. The most common offending organisms are Pseudomonas aeruginosa (50%), Staphylococcus aureus (23%), anaerobes and gram-negative organisms (12.5%), and yeast, such as Aspergillus and Candida (12.5%). The increased pH of pool water is believed to make infection more likely, since bacteriologic studies fail to show a direct link between swimming pool contamination and the organisms of OE.
Diagnosis
There are no published studies of the accuracy of the medical history, physical examination, or office laboratory tests for the diagnosis of OE. Diagnosis is usually made based on physical examination findings: pain on movement of the auricle, edema, redness, and foul-smelling discharge.5 Swelling often obscures the tympanic membrane.
NOE is also a clinical diagnosis and requires a high index of suspicion. A study by Zaky and colleagues3 considered 2 new cases and 32 that were retrospectively reviewed from the literature. They found the following frequencies of symptoms: pain (100%), purulent discharge (97%), bilateral involvement (21%), and a polyp in the external canal (88%). Diabetes was common in this group of patients (82%), confirming that it is consistently a predisposing risk factor, and 91% of these patients were aged 55 years and older.
Few papers have been published concerning diagnostic studies for NOE. One found that temporal radiographs and tomograms are positive in most cases of NOE but were not necessary for diagnosis.6 The erythrocyte sedimentation rate is usually increased,3 but this is true in many other illnesses. Many studies3,8-9,31-35 have reported that Pseudomonas is the primary offending organism for NOE. Because most ear cultures are positive for Pseudomonas, these cultures are of questionable value.10
There are 4 studies that consider more aggressive diagnostic testing for NOE using conventional temporal radiographs, tomographic temporal radiographs, qualitative and single photon emission computed tomography67 gallium scans, and qualitative and quantitative99 technetium bone scans.6-9 These studies were limited by the use of unclear7 or poor quality6,8 reference standards (radiograph or poor response to antibiotics). The diagnosis of NOE does not require additional studies. Expert opinion supports a diagnosis based on the history and physical examination and poor response to treatment. The most common symptom of NOE is persistent pain that is constant and severe. The leukocyte count may be normal or mildly elevated.3 Physicians should consider the diagnosis of NOE in any patient with diabetes who has OE, particularly older patients. Characteristics of OE and NOE are presented in Table 1.
Treatment
Otitis Externa
The main principles of treatment are local cleansing of debris, drainage of the infection, re-establishment of the normal acidic environment, use of topical and systemic antimicrobials, and prevention of recurrent infections. The evidence regarding these treatments is summarized in Table 2. The best evidence (grade of evidence: A) demonstrates equivalent results with ear cleaning, an ear wick, and any of the choices of topical agents12-13—acidifying agents, antibiotics, antibiotic and steroid combinations, or antifungal agents. Frequent dosing (3 to 4 times daily) for at least 4 days is supported by the studies. Two studies demonstrated equivalent efficacy with topical ciprofloxacin or ofloxacin dosed twice daily compared with antibiotic and steroid combinations dosed 4 times daily.16-17 However, these agents are also more expensive than older topical antibiotics. The evidence for single topical treatments and oral antibiotics is weaker14-29 (grade of evidence: B).
Physicians should treat patients with one of the following regimens for at least 4 days:
- ear cleaning + ear wick + acidifying agent dosed 4 times daily
- ear cleaning + ear wick + topical antibiotic dosed 4 times daily (twice daily if quinolone)
- ear cleaning + ear wick + topical antibiotic/steroid combination dosed 4 times daily (twice daily if quinolone)
The ear is best cleaned by simply irrigating the canal. Be sure to look for a foreign body, particularly in younger patients. For a wick, use either the Pope ear wick (Merocel Corporation, Mystic, Conn) or a fourth-inch sterile gauze. The wick helps draw topical medications into the affected canal, particularly when it is obstructed. The patient should return in approximately 2 days for removal of the wick and reassessment. Do not forget analgesics; this is a painful condition.
Necrotizing Otitis Externa
The treatment for NOE must be aggressive. As the infection invades through the soft tissues into surrounding bony structures, it can be life threatening.10 The evidence for various treatments is presented in Table 3. The studies are weaker than those for treatment of otitis externa (grade of recommendations: B and C). They support twice daily dosing with oral ofloxacin 400 mg orally twice daily or ciprofloxacin 750 mg orally twice daily for up to 3 months.31-33 There is weak evidence that hyperbaric oxygen is effective.34 Intravenous anti-Pseudomonal antibiotics are often used initially, based on expert opinion (grade: D) and the high mortality rate.
The oral fluoroquinolones (ofloxacin and ciprofloxacin) show promise for treating NOE. The choice of parenteral or oral antibiotics still rests with clinician judgment, based on the patient’s clinical presentation. If oral antibiotics are started, the length of treatment should be based on the severity of illness.
Prognosis
The prognosis for cure of OE is excellent, although the actual natural history of untreated disease has not been studied. OE complicated by NEO is more common in persons with diabetes who have a persistent course and granulation tissue visualized in the external auditory canal. Untreated NEO can lead to osteomyelitis and paralysis of cranial nerves. Death can result from sepsis and central nervous system infection.
1. Agius AM, Pickles JM, Burch KL. A prospective study of otitis externa. Clin Otolaryngol 1992;17:150-54.
2. Diagnosis and treatment of acute otitis media: an interdisciplinary update. Proceedings of a roundtable discussion. Ann Otol Rhinol Laryngol 1999;108:2-23.
3. Zaky DA, Bentley DW, Lowy K, Betts RF, Douglas RG. Malignant external otitis: a severe form of otitis in diabetic patients. Am J Med 1976;61:298-302.
4. Clark WB, Brook I, Bianki D, Thompson DH. Microbiology of otitis externa. Otolaryngol Head Neck Surg 1997;116:23-25.
5. Leung AKC, Fong JHS, Leong AG. Otalgia in children. J Natl Med Assoc 2000;92:254-60.
6. Kim BH. Roentgenographic findings of malignant external otitis. Am J Roentgenol Radium Ther Nucl Med 1971;112:366-72.
7. Stokkel MPM, Boot ICN, vanEck-Smit BLF. SPECT gallium scintigraphy in malignant external otitis: initial staging and follow-up: case reports. Laryngoscope 1996;106:338-40.
8. Uri N, Gips S, Front A, Meyer SW, Hardoff R. Quantitative bone and 67Ga scintigraphy in the differentiation of necrotizing external otitis from severe external otitis. Arch Otolarngol Head Neck Surg 1991;117:623-26.
9. Hardoff R, Gips S, Uri N, Front A, Tamir A. Semiquantitative skull planar and SPECT bone scintigraphy in diabetic patients: differentiation of necrotizing (malignant) external otitis from severe external otitis. J Nucl Med 1994;35:411-15.
10. Brook I. Treatment of otitis externa in children. Pediatric Drugs 1999;1:283-89.
11. Densert O, Toremalm NG. Pain relief with indomethacin in external otitis. Arch Otolaryng 1972;95:460-63.
12. Ordonez GE, Kime CE, Updegraff WR, Glassman JM, Soyka JP. Effective treatment of acute diffuse otitis externa: I. a controlled comparison of hydrocortisone-acetic acid, non-aqueous and hydrocortisone-neomycin-polymyxin b-colistin otic solutions. Curr Ther Res 1978;23:ss3-14.
13. Kime CE, Ordonez GU, Updegraff WR, Glassman JM, Soyka JP. Effective Treatment of acute diffuse otitis externa: II. a controlled comparison of hydrocortisone-acetic acid, non-aqueous and hydrocortisone-neomycin-polymyxin b otic solutions. Curr Ther Res 1978;23:ss15-28.
14. Freedman R. Versus placebo in treatment of acute otitis externa. Ear Nose Throat J 1978;57:28-37.
15. Gyde MC, Norris D, Kavalec EC. The weeping ear: clinical re-evaluation of treatment. J Int Med Res 1982;10:333-40.
16. Arnes A, Dibb WL. Otitis externa: clinical comparison of local ciprofloxacin versus local oxytetracycline, polymyxin B, hydrocortisone combination treatment. Curr Med Res Opin 1993;13:182-86.
17. Jones RN, Milazzo J, Seidlin M. Ofloxacin otic solution for treatment of otits externa in children and adults. Arch Otolaryngol Head Neck Surg 1997;123:1193-200.
18. Wadston CJ, Bertilsson CA, Sieradzki H, Edstrom S. A randomized clinical trial of two topical preparations (framycitin/gramicidin and oxytetracycline/hydrocortisone with polymyxin b) in the treatment of external otitis. Arch Otorhinolaryngol 1985;242:135-39.
19. Barton RPE, Wright JLW, Gray RFE. The clinical evaluation of a new clobetasol propionate preparation in the treatment of otitis externa. J Laryngol Otol 1979;93:703-06.
20. Treatment of otitis externa: a clinical trial of local applications. Br J Clin Pract 1967;21:507-10.
21. Bain DJG. A double-blind comparative study of otoseptil ear drops and otosporin: ear drops in otitis externa. J Int Med Res 1976;4:79-81.
22. Worgan D. Treatment of otitis externa: report of a clinical trial. Practitioner 1969;202:817-20.
23. Yelland MJ. The efficacy of oral cotrimoxazole in the treatment of otitis externa in general practice. Med J Aust 1993;158:697-99.
24. Barr GD, Al-Khabori M. A randomized prospective comparison of two methods of administering topical treatment in otitis externa. Clinical Otolaryng Allied Sci 1991;16:547-48.
25. Clayton MI, Osborne JE, Rutherford D, Rivron RP. A double-blind, randomized, prospective trial of a topical antiseptic versus a topical antibiotic in the treatment of otorrhea. Clin Otolaryngol 1990;15:7-10.
26. Cannon S. External otitis: controlled therapeutic trial. Eye Ear Nose Throat Monthly 1970;49:56-61.
27. Slack RWT. A study of three preparations in the treatment of otitis externa. J Laryngol Otol 1987;101:533-35.
28. Smith RB, Moodie J. A general practice study to compare the efficacy and tolerability of a spray (“Otomize”) versus a standard drop formulation (“Sofradex”) in the treatment of patients with otitis externa. Curr Med Res Opin 1990;12:12-18.
29. McGarry GW, Swan IRC. Endoscopic photographic comparison of drug delivery by ear-drops and by aerosol spray. Clin Otolaryngol 1992;17:359-60
30. Wilde AD, England J, Jones AS. An alternative to reguler dressings for otitis externa and chronic supperative otitis media? J Laryngol Otol 1995;109:101-03.
31. Gehanno P. Ciprofloxacin in the treatment of malignant external otitis. Chemotherapy 1994;40:35-40.
32. Levy R, Shpitzer T, Shvero J, Pitlik SD. Oral ofloxacin as treatment of malignant external otitis: a study of 17 cases. Laryngoscope 1990;100:548-51
33. Zikk D, Rapoport Y, Redianu C, Shalit I, Himmelfarb MZ. Oral ofloxacin therapy for invasive external otitis. Ann Otol Rhinol Laryngol 1991;100:632-37.
34. Mader JT, Love JT. Malignant external otitis: cure with adjunctive hyperbaric oxygen therapy. Arch Otolaryngol 1982;108:38-40.
35. Neu HC. Contemporary antibiotic therapy in otolaryngology. Otolaryngol Clin N Am 1984;17:745-60.
Otitis externa (OE), also referred to as external otitis, is inflammation of the auricle, external ear, or tympanic membrane. The severity can range from mild inflammation to life-threatening infection.1 It is commonly seen by family physicians and affects 4 out of each 1000 Americans every year.2 In most cases the significant pain of OE compels the patient to seek care urgently.
OE can be categorized as localized or diffuse. When it persists for more than 6 months, it is considered chronic and is more commonly bilateral. It is thought to be caused by local trauma to the external canal, diabetes, high humidity, loss of the canal’s protective coating of cerumen, eczema, use of a hearing aid or stethoscope, or glandular obstruction. It is commonly seen in swimmers, particularly in the summer months.1 The most frequent symptoms are discharge, pain, hearing loss, itching, and tinnitus.
Necrotizing (malignant) otitis externa (NOE) is the most severe form of OE and is most often seen in elderly patients with diabetes. One case series in a referral population found a mortality rate of 53%.3 Pain, purulent discharge, bilateral involvement, and external canal granulation tissue are common symptoms.
Pathophysiology
The ear canal is a blind sac with an anterior recess. Trauma to the canal, accumulation of keratin, or a change in pH can trigger inflammation and infection. One study4 found that aerobic bacteria account for 91% of bacterial causes; anaerobes, 4%; and mixed infections, 4%. The most common offending organisms are Pseudomonas aeruginosa (50%), Staphylococcus aureus (23%), anaerobes and gram-negative organisms (12.5%), and yeast, such as Aspergillus and Candida (12.5%). The increased pH of pool water is believed to make infection more likely, since bacteriologic studies fail to show a direct link between swimming pool contamination and the organisms of OE.
Diagnosis
There are no published studies of the accuracy of the medical history, physical examination, or office laboratory tests for the diagnosis of OE. Diagnosis is usually made based on physical examination findings: pain on movement of the auricle, edema, redness, and foul-smelling discharge.5 Swelling often obscures the tympanic membrane.
NOE is also a clinical diagnosis and requires a high index of suspicion. A study by Zaky and colleagues3 considered 2 new cases and 32 that were retrospectively reviewed from the literature. They found the following frequencies of symptoms: pain (100%), purulent discharge (97%), bilateral involvement (21%), and a polyp in the external canal (88%). Diabetes was common in this group of patients (82%), confirming that it is consistently a predisposing risk factor, and 91% of these patients were aged 55 years and older.
Few papers have been published concerning diagnostic studies for NOE. One found that temporal radiographs and tomograms are positive in most cases of NOE but were not necessary for diagnosis.6 The erythrocyte sedimentation rate is usually increased,3 but this is true in many other illnesses. Many studies3,8-9,31-35 have reported that Pseudomonas is the primary offending organism for NOE. Because most ear cultures are positive for Pseudomonas, these cultures are of questionable value.10
There are 4 studies that consider more aggressive diagnostic testing for NOE using conventional temporal radiographs, tomographic temporal radiographs, qualitative and single photon emission computed tomography67 gallium scans, and qualitative and quantitative99 technetium bone scans.6-9 These studies were limited by the use of unclear7 or poor quality6,8 reference standards (radiograph or poor response to antibiotics). The diagnosis of NOE does not require additional studies. Expert opinion supports a diagnosis based on the history and physical examination and poor response to treatment. The most common symptom of NOE is persistent pain that is constant and severe. The leukocyte count may be normal or mildly elevated.3 Physicians should consider the diagnosis of NOE in any patient with diabetes who has OE, particularly older patients. Characteristics of OE and NOE are presented in Table 1.
Treatment
Otitis Externa
The main principles of treatment are local cleansing of debris, drainage of the infection, re-establishment of the normal acidic environment, use of topical and systemic antimicrobials, and prevention of recurrent infections. The evidence regarding these treatments is summarized in Table 2. The best evidence (grade of evidence: A) demonstrates equivalent results with ear cleaning, an ear wick, and any of the choices of topical agents12-13—acidifying agents, antibiotics, antibiotic and steroid combinations, or antifungal agents. Frequent dosing (3 to 4 times daily) for at least 4 days is supported by the studies. Two studies demonstrated equivalent efficacy with topical ciprofloxacin or ofloxacin dosed twice daily compared with antibiotic and steroid combinations dosed 4 times daily.16-17 However, these agents are also more expensive than older topical antibiotics. The evidence for single topical treatments and oral antibiotics is weaker14-29 (grade of evidence: B).
Physicians should treat patients with one of the following regimens for at least 4 days:
- ear cleaning + ear wick + acidifying agent dosed 4 times daily
- ear cleaning + ear wick + topical antibiotic dosed 4 times daily (twice daily if quinolone)
- ear cleaning + ear wick + topical antibiotic/steroid combination dosed 4 times daily (twice daily if quinolone)
The ear is best cleaned by simply irrigating the canal. Be sure to look for a foreign body, particularly in younger patients. For a wick, use either the Pope ear wick (Merocel Corporation, Mystic, Conn) or a fourth-inch sterile gauze. The wick helps draw topical medications into the affected canal, particularly when it is obstructed. The patient should return in approximately 2 days for removal of the wick and reassessment. Do not forget analgesics; this is a painful condition.
Necrotizing Otitis Externa
The treatment for NOE must be aggressive. As the infection invades through the soft tissues into surrounding bony structures, it can be life threatening.10 The evidence for various treatments is presented in Table 3. The studies are weaker than those for treatment of otitis externa (grade of recommendations: B and C). They support twice daily dosing with oral ofloxacin 400 mg orally twice daily or ciprofloxacin 750 mg orally twice daily for up to 3 months.31-33 There is weak evidence that hyperbaric oxygen is effective.34 Intravenous anti-Pseudomonal antibiotics are often used initially, based on expert opinion (grade: D) and the high mortality rate.
The oral fluoroquinolones (ofloxacin and ciprofloxacin) show promise for treating NOE. The choice of parenteral or oral antibiotics still rests with clinician judgment, based on the patient’s clinical presentation. If oral antibiotics are started, the length of treatment should be based on the severity of illness.
Prognosis
The prognosis for cure of OE is excellent, although the actual natural history of untreated disease has not been studied. OE complicated by NEO is more common in persons with diabetes who have a persistent course and granulation tissue visualized in the external auditory canal. Untreated NEO can lead to osteomyelitis and paralysis of cranial nerves. Death can result from sepsis and central nervous system infection.
Otitis externa (OE), also referred to as external otitis, is inflammation of the auricle, external ear, or tympanic membrane. The severity can range from mild inflammation to life-threatening infection.1 It is commonly seen by family physicians and affects 4 out of each 1000 Americans every year.2 In most cases the significant pain of OE compels the patient to seek care urgently.
OE can be categorized as localized or diffuse. When it persists for more than 6 months, it is considered chronic and is more commonly bilateral. It is thought to be caused by local trauma to the external canal, diabetes, high humidity, loss of the canal’s protective coating of cerumen, eczema, use of a hearing aid or stethoscope, or glandular obstruction. It is commonly seen in swimmers, particularly in the summer months.1 The most frequent symptoms are discharge, pain, hearing loss, itching, and tinnitus.
Necrotizing (malignant) otitis externa (NOE) is the most severe form of OE and is most often seen in elderly patients with diabetes. One case series in a referral population found a mortality rate of 53%.3 Pain, purulent discharge, bilateral involvement, and external canal granulation tissue are common symptoms.
Pathophysiology
The ear canal is a blind sac with an anterior recess. Trauma to the canal, accumulation of keratin, or a change in pH can trigger inflammation and infection. One study4 found that aerobic bacteria account for 91% of bacterial causes; anaerobes, 4%; and mixed infections, 4%. The most common offending organisms are Pseudomonas aeruginosa (50%), Staphylococcus aureus (23%), anaerobes and gram-negative organisms (12.5%), and yeast, such as Aspergillus and Candida (12.5%). The increased pH of pool water is believed to make infection more likely, since bacteriologic studies fail to show a direct link between swimming pool contamination and the organisms of OE.
Diagnosis
There are no published studies of the accuracy of the medical history, physical examination, or office laboratory tests for the diagnosis of OE. Diagnosis is usually made based on physical examination findings: pain on movement of the auricle, edema, redness, and foul-smelling discharge.5 Swelling often obscures the tympanic membrane.
NOE is also a clinical diagnosis and requires a high index of suspicion. A study by Zaky and colleagues3 considered 2 new cases and 32 that were retrospectively reviewed from the literature. They found the following frequencies of symptoms: pain (100%), purulent discharge (97%), bilateral involvement (21%), and a polyp in the external canal (88%). Diabetes was common in this group of patients (82%), confirming that it is consistently a predisposing risk factor, and 91% of these patients were aged 55 years and older.
Few papers have been published concerning diagnostic studies for NOE. One found that temporal radiographs and tomograms are positive in most cases of NOE but were not necessary for diagnosis.6 The erythrocyte sedimentation rate is usually increased,3 but this is true in many other illnesses. Many studies3,8-9,31-35 have reported that Pseudomonas is the primary offending organism for NOE. Because most ear cultures are positive for Pseudomonas, these cultures are of questionable value.10
There are 4 studies that consider more aggressive diagnostic testing for NOE using conventional temporal radiographs, tomographic temporal radiographs, qualitative and single photon emission computed tomography67 gallium scans, and qualitative and quantitative99 technetium bone scans.6-9 These studies were limited by the use of unclear7 or poor quality6,8 reference standards (radiograph or poor response to antibiotics). The diagnosis of NOE does not require additional studies. Expert opinion supports a diagnosis based on the history and physical examination and poor response to treatment. The most common symptom of NOE is persistent pain that is constant and severe. The leukocyte count may be normal or mildly elevated.3 Physicians should consider the diagnosis of NOE in any patient with diabetes who has OE, particularly older patients. Characteristics of OE and NOE are presented in Table 1.
Treatment
Otitis Externa
The main principles of treatment are local cleansing of debris, drainage of the infection, re-establishment of the normal acidic environment, use of topical and systemic antimicrobials, and prevention of recurrent infections. The evidence regarding these treatments is summarized in Table 2. The best evidence (grade of evidence: A) demonstrates equivalent results with ear cleaning, an ear wick, and any of the choices of topical agents12-13—acidifying agents, antibiotics, antibiotic and steroid combinations, or antifungal agents. Frequent dosing (3 to 4 times daily) for at least 4 days is supported by the studies. Two studies demonstrated equivalent efficacy with topical ciprofloxacin or ofloxacin dosed twice daily compared with antibiotic and steroid combinations dosed 4 times daily.16-17 However, these agents are also more expensive than older topical antibiotics. The evidence for single topical treatments and oral antibiotics is weaker14-29 (grade of evidence: B).
Physicians should treat patients with one of the following regimens for at least 4 days:
- ear cleaning + ear wick + acidifying agent dosed 4 times daily
- ear cleaning + ear wick + topical antibiotic dosed 4 times daily (twice daily if quinolone)
- ear cleaning + ear wick + topical antibiotic/steroid combination dosed 4 times daily (twice daily if quinolone)
The ear is best cleaned by simply irrigating the canal. Be sure to look for a foreign body, particularly in younger patients. For a wick, use either the Pope ear wick (Merocel Corporation, Mystic, Conn) or a fourth-inch sterile gauze. The wick helps draw topical medications into the affected canal, particularly when it is obstructed. The patient should return in approximately 2 days for removal of the wick and reassessment. Do not forget analgesics; this is a painful condition.
Necrotizing Otitis Externa
The treatment for NOE must be aggressive. As the infection invades through the soft tissues into surrounding bony structures, it can be life threatening.10 The evidence for various treatments is presented in Table 3. The studies are weaker than those for treatment of otitis externa (grade of recommendations: B and C). They support twice daily dosing with oral ofloxacin 400 mg orally twice daily or ciprofloxacin 750 mg orally twice daily for up to 3 months.31-33 There is weak evidence that hyperbaric oxygen is effective.34 Intravenous anti-Pseudomonal antibiotics are often used initially, based on expert opinion (grade: D) and the high mortality rate.
The oral fluoroquinolones (ofloxacin and ciprofloxacin) show promise for treating NOE. The choice of parenteral or oral antibiotics still rests with clinician judgment, based on the patient’s clinical presentation. If oral antibiotics are started, the length of treatment should be based on the severity of illness.
Prognosis
The prognosis for cure of OE is excellent, although the actual natural history of untreated disease has not been studied. OE complicated by NEO is more common in persons with diabetes who have a persistent course and granulation tissue visualized in the external auditory canal. Untreated NEO can lead to osteomyelitis and paralysis of cranial nerves. Death can result from sepsis and central nervous system infection.
1. Agius AM, Pickles JM, Burch KL. A prospective study of otitis externa. Clin Otolaryngol 1992;17:150-54.
2. Diagnosis and treatment of acute otitis media: an interdisciplinary update. Proceedings of a roundtable discussion. Ann Otol Rhinol Laryngol 1999;108:2-23.
3. Zaky DA, Bentley DW, Lowy K, Betts RF, Douglas RG. Malignant external otitis: a severe form of otitis in diabetic patients. Am J Med 1976;61:298-302.
4. Clark WB, Brook I, Bianki D, Thompson DH. Microbiology of otitis externa. Otolaryngol Head Neck Surg 1997;116:23-25.
5. Leung AKC, Fong JHS, Leong AG. Otalgia in children. J Natl Med Assoc 2000;92:254-60.
6. Kim BH. Roentgenographic findings of malignant external otitis. Am J Roentgenol Radium Ther Nucl Med 1971;112:366-72.
7. Stokkel MPM, Boot ICN, vanEck-Smit BLF. SPECT gallium scintigraphy in malignant external otitis: initial staging and follow-up: case reports. Laryngoscope 1996;106:338-40.
8. Uri N, Gips S, Front A, Meyer SW, Hardoff R. Quantitative bone and 67Ga scintigraphy in the differentiation of necrotizing external otitis from severe external otitis. Arch Otolarngol Head Neck Surg 1991;117:623-26.
9. Hardoff R, Gips S, Uri N, Front A, Tamir A. Semiquantitative skull planar and SPECT bone scintigraphy in diabetic patients: differentiation of necrotizing (malignant) external otitis from severe external otitis. J Nucl Med 1994;35:411-15.
10. Brook I. Treatment of otitis externa in children. Pediatric Drugs 1999;1:283-89.
11. Densert O, Toremalm NG. Pain relief with indomethacin in external otitis. Arch Otolaryng 1972;95:460-63.
12. Ordonez GE, Kime CE, Updegraff WR, Glassman JM, Soyka JP. Effective treatment of acute diffuse otitis externa: I. a controlled comparison of hydrocortisone-acetic acid, non-aqueous and hydrocortisone-neomycin-polymyxin b-colistin otic solutions. Curr Ther Res 1978;23:ss3-14.
13. Kime CE, Ordonez GU, Updegraff WR, Glassman JM, Soyka JP. Effective Treatment of acute diffuse otitis externa: II. a controlled comparison of hydrocortisone-acetic acid, non-aqueous and hydrocortisone-neomycin-polymyxin b otic solutions. Curr Ther Res 1978;23:ss15-28.
14. Freedman R. Versus placebo in treatment of acute otitis externa. Ear Nose Throat J 1978;57:28-37.
15. Gyde MC, Norris D, Kavalec EC. The weeping ear: clinical re-evaluation of treatment. J Int Med Res 1982;10:333-40.
16. Arnes A, Dibb WL. Otitis externa: clinical comparison of local ciprofloxacin versus local oxytetracycline, polymyxin B, hydrocortisone combination treatment. Curr Med Res Opin 1993;13:182-86.
17. Jones RN, Milazzo J, Seidlin M. Ofloxacin otic solution for treatment of otits externa in children and adults. Arch Otolaryngol Head Neck Surg 1997;123:1193-200.
18. Wadston CJ, Bertilsson CA, Sieradzki H, Edstrom S. A randomized clinical trial of two topical preparations (framycitin/gramicidin and oxytetracycline/hydrocortisone with polymyxin b) in the treatment of external otitis. Arch Otorhinolaryngol 1985;242:135-39.
19. Barton RPE, Wright JLW, Gray RFE. The clinical evaluation of a new clobetasol propionate preparation in the treatment of otitis externa. J Laryngol Otol 1979;93:703-06.
20. Treatment of otitis externa: a clinical trial of local applications. Br J Clin Pract 1967;21:507-10.
21. Bain DJG. A double-blind comparative study of otoseptil ear drops and otosporin: ear drops in otitis externa. J Int Med Res 1976;4:79-81.
22. Worgan D. Treatment of otitis externa: report of a clinical trial. Practitioner 1969;202:817-20.
23. Yelland MJ. The efficacy of oral cotrimoxazole in the treatment of otitis externa in general practice. Med J Aust 1993;158:697-99.
24. Barr GD, Al-Khabori M. A randomized prospective comparison of two methods of administering topical treatment in otitis externa. Clinical Otolaryng Allied Sci 1991;16:547-48.
25. Clayton MI, Osborne JE, Rutherford D, Rivron RP. A double-blind, randomized, prospective trial of a topical antiseptic versus a topical antibiotic in the treatment of otorrhea. Clin Otolaryngol 1990;15:7-10.
26. Cannon S. External otitis: controlled therapeutic trial. Eye Ear Nose Throat Monthly 1970;49:56-61.
27. Slack RWT. A study of three preparations in the treatment of otitis externa. J Laryngol Otol 1987;101:533-35.
28. Smith RB, Moodie J. A general practice study to compare the efficacy and tolerability of a spray (“Otomize”) versus a standard drop formulation (“Sofradex”) in the treatment of patients with otitis externa. Curr Med Res Opin 1990;12:12-18.
29. McGarry GW, Swan IRC. Endoscopic photographic comparison of drug delivery by ear-drops and by aerosol spray. Clin Otolaryngol 1992;17:359-60
30. Wilde AD, England J, Jones AS. An alternative to reguler dressings for otitis externa and chronic supperative otitis media? J Laryngol Otol 1995;109:101-03.
31. Gehanno P. Ciprofloxacin in the treatment of malignant external otitis. Chemotherapy 1994;40:35-40.
32. Levy R, Shpitzer T, Shvero J, Pitlik SD. Oral ofloxacin as treatment of malignant external otitis: a study of 17 cases. Laryngoscope 1990;100:548-51
33. Zikk D, Rapoport Y, Redianu C, Shalit I, Himmelfarb MZ. Oral ofloxacin therapy for invasive external otitis. Ann Otol Rhinol Laryngol 1991;100:632-37.
34. Mader JT, Love JT. Malignant external otitis: cure with adjunctive hyperbaric oxygen therapy. Arch Otolaryngol 1982;108:38-40.
35. Neu HC. Contemporary antibiotic therapy in otolaryngology. Otolaryngol Clin N Am 1984;17:745-60.
1. Agius AM, Pickles JM, Burch KL. A prospective study of otitis externa. Clin Otolaryngol 1992;17:150-54.
2. Diagnosis and treatment of acute otitis media: an interdisciplinary update. Proceedings of a roundtable discussion. Ann Otol Rhinol Laryngol 1999;108:2-23.
3. Zaky DA, Bentley DW, Lowy K, Betts RF, Douglas RG. Malignant external otitis: a severe form of otitis in diabetic patients. Am J Med 1976;61:298-302.
4. Clark WB, Brook I, Bianki D, Thompson DH. Microbiology of otitis externa. Otolaryngol Head Neck Surg 1997;116:23-25.
5. Leung AKC, Fong JHS, Leong AG. Otalgia in children. J Natl Med Assoc 2000;92:254-60.
6. Kim BH. Roentgenographic findings of malignant external otitis. Am J Roentgenol Radium Ther Nucl Med 1971;112:366-72.
7. Stokkel MPM, Boot ICN, vanEck-Smit BLF. SPECT gallium scintigraphy in malignant external otitis: initial staging and follow-up: case reports. Laryngoscope 1996;106:338-40.
8. Uri N, Gips S, Front A, Meyer SW, Hardoff R. Quantitative bone and 67Ga scintigraphy in the differentiation of necrotizing external otitis from severe external otitis. Arch Otolarngol Head Neck Surg 1991;117:623-26.
9. Hardoff R, Gips S, Uri N, Front A, Tamir A. Semiquantitative skull planar and SPECT bone scintigraphy in diabetic patients: differentiation of necrotizing (malignant) external otitis from severe external otitis. J Nucl Med 1994;35:411-15.
10. Brook I. Treatment of otitis externa in children. Pediatric Drugs 1999;1:283-89.
11. Densert O, Toremalm NG. Pain relief with indomethacin in external otitis. Arch Otolaryng 1972;95:460-63.
12. Ordonez GE, Kime CE, Updegraff WR, Glassman JM, Soyka JP. Effective treatment of acute diffuse otitis externa: I. a controlled comparison of hydrocortisone-acetic acid, non-aqueous and hydrocortisone-neomycin-polymyxin b-colistin otic solutions. Curr Ther Res 1978;23:ss3-14.
13. Kime CE, Ordonez GU, Updegraff WR, Glassman JM, Soyka JP. Effective Treatment of acute diffuse otitis externa: II. a controlled comparison of hydrocortisone-acetic acid, non-aqueous and hydrocortisone-neomycin-polymyxin b otic solutions. Curr Ther Res 1978;23:ss15-28.
14. Freedman R. Versus placebo in treatment of acute otitis externa. Ear Nose Throat J 1978;57:28-37.
15. Gyde MC, Norris D, Kavalec EC. The weeping ear: clinical re-evaluation of treatment. J Int Med Res 1982;10:333-40.
16. Arnes A, Dibb WL. Otitis externa: clinical comparison of local ciprofloxacin versus local oxytetracycline, polymyxin B, hydrocortisone combination treatment. Curr Med Res Opin 1993;13:182-86.
17. Jones RN, Milazzo J, Seidlin M. Ofloxacin otic solution for treatment of otits externa in children and adults. Arch Otolaryngol Head Neck Surg 1997;123:1193-200.
18. Wadston CJ, Bertilsson CA, Sieradzki H, Edstrom S. A randomized clinical trial of two topical preparations (framycitin/gramicidin and oxytetracycline/hydrocortisone with polymyxin b) in the treatment of external otitis. Arch Otorhinolaryngol 1985;242:135-39.
19. Barton RPE, Wright JLW, Gray RFE. The clinical evaluation of a new clobetasol propionate preparation in the treatment of otitis externa. J Laryngol Otol 1979;93:703-06.
20. Treatment of otitis externa: a clinical trial of local applications. Br J Clin Pract 1967;21:507-10.
21. Bain DJG. A double-blind comparative study of otoseptil ear drops and otosporin: ear drops in otitis externa. J Int Med Res 1976;4:79-81.
22. Worgan D. Treatment of otitis externa: report of a clinical trial. Practitioner 1969;202:817-20.
23. Yelland MJ. The efficacy of oral cotrimoxazole in the treatment of otitis externa in general practice. Med J Aust 1993;158:697-99.
24. Barr GD, Al-Khabori M. A randomized prospective comparison of two methods of administering topical treatment in otitis externa. Clinical Otolaryng Allied Sci 1991;16:547-48.
25. Clayton MI, Osborne JE, Rutherford D, Rivron RP. A double-blind, randomized, prospective trial of a topical antiseptic versus a topical antibiotic in the treatment of otorrhea. Clin Otolaryngol 1990;15:7-10.
26. Cannon S. External otitis: controlled therapeutic trial. Eye Ear Nose Throat Monthly 1970;49:56-61.
27. Slack RWT. A study of three preparations in the treatment of otitis externa. J Laryngol Otol 1987;101:533-35.
28. Smith RB, Moodie J. A general practice study to compare the efficacy and tolerability of a spray (“Otomize”) versus a standard drop formulation (“Sofradex”) in the treatment of patients with otitis externa. Curr Med Res Opin 1990;12:12-18.
29. McGarry GW, Swan IRC. Endoscopic photographic comparison of drug delivery by ear-drops and by aerosol spray. Clin Otolaryngol 1992;17:359-60
30. Wilde AD, England J, Jones AS. An alternative to reguler dressings for otitis externa and chronic supperative otitis media? J Laryngol Otol 1995;109:101-03.
31. Gehanno P. Ciprofloxacin in the treatment of malignant external otitis. Chemotherapy 1994;40:35-40.
32. Levy R, Shpitzer T, Shvero J, Pitlik SD. Oral ofloxacin as treatment of malignant external otitis: a study of 17 cases. Laryngoscope 1990;100:548-51
33. Zikk D, Rapoport Y, Redianu C, Shalit I, Himmelfarb MZ. Oral ofloxacin therapy for invasive external otitis. Ann Otol Rhinol Laryngol 1991;100:632-37.
34. Mader JT, Love JT. Malignant external otitis: cure with adjunctive hyperbaric oxygen therapy. Arch Otolaryngol 1982;108:38-40.
35. Neu HC. Contemporary antibiotic therapy in otolaryngology. Otolaryngol Clin N Am 1984;17:745-60.
Treatment of the Patient with Deep Vein Thrombosis
Deep vein thrombosis (DVT), defined as a partial or complete occlusion of a deep vein by thrombus, is a relatively uncommon yet important diagnosis in primary care practice. Population-based studies have estimated the age-adjusted incidence of DVT at 48 per 100,000 persons per year, with age-specific rates increasing steadily as the patient grows older.1,2 A typical family physician could expect to diagnose 1 or 2 patients with DVT each year. In addition to age, other personal risk factors for the development of DVT include previous thromboembolism, pregnancy and the postpartum period, malignancy, inherited thrombophilias, and exogenous estrogen therapy. Environmental risk factors include immobility, trauma, surgery, and intensive care. The classic Virchow triad (stasis, vascular damage, and hypercoagulability) describes the basic pathophysiologic factors that alone or more commonly in combination promote the development of thrombosis.
The previous article in this series described the evaluation of the patient with suspected DVT. In this article I will outline an evidence-based approach to treating a patient with a confirmed diagnosis of DVT Figure 1. Special attention will be given to the selection of cost-effective interventions that minimize the likelihood of acute or long-term complications.
Initial Therapy
Prompt anticoagulation with heparin is the first priority in treating the patient with DVT by preventing the local extension, embolization, and recurrence of venous thromboembolic disease. Heparin acts immediately to catalyze the inhibition of several activated coagulation factors and leads to the stabilization of the intravascular thrombus. Heparinization is typically continued for 3 to 5 days until a stable and therapeutic international normalized ratio (INR) is established with oral warfarin therapy. There are 2 approved approaches available for the acute anticoagulant treatment of DVT: intravenous unfractionated heparin (UH) and subcutaneous low-molecular-weight heparin (LMWH). In the case of a significant contraindication to anticoagulation or a recurrent thromboembolic event despite adequate anticoagulation, an inferior vena caval filter is the treatment of choice.
Unfractionated Heparin
Traditionally the initial treatment of DVT has been anticoagulation with intravenous UH; the goal of this therapy is the prompt establishment of an activated partial thromboplastin time (APTT) of 1.5 to 2.5 times the control.3 The failure to achieve a therapeutic APTT within 24 hours has been associated with an increased likelihood of recurrent thromboembolism (23% vs 5%, absolute risk reduction [ARR]=18%; number needed to treat [NNT]=5.5; level of evidence [LOE]=1b).4,5 Several protocols for managing UH therapy have been shown to achieve therapeutic anticoagulation more rapidly than traditional approaches. Figure 2 summarizes a weight-based heparin dosing nomogram that has been proved effective, safe, and superior to standard therapy in a randomized controlled trial; this particular protocol achieved therapeutic anticoagulation in 97% of patients within 24 hours (LOE=1b).6 Patients treated with UH should remain hospitalized until therapeutically anticoagulated with oral warfarin.
Low-Molecular-Weight Heparin
After the approval of enoxaparin for the treatment of DVT in 1998, acute outpatient management of DVT with LMWH became possible. The advantages of LMWH include fixed dosing, a subcutaneous route of administration, and a more predictable anticoagulant response. Laboratory monitoring is unnecessary except in patients with renal insufficiency, as a result of better bioavailability, longer half-life, and dose-independent clearance. If monitoring of LMWH is necessary, an anti-Xa level of 0.4 to 0.7 U per mL is the goal of therapy.7 The only LMWHs currently approved and labeled by the United States Food and Drug Administration for the treatment of acute DVT are enoxaparin at a dosage of 1 mg per kg administered subcutaneously twice daily or 1.5 mg per kg once daily (inpatient therapy only) and tinzaparin at a dosage of 175 anti-Xa IU per kg administered subcutaneously once daily.
The safety and effectiveness of LMWH therapy for acute DVT were demonstrated in a recent meta-analysis of 11 randomized controlled trials with a total of 3674 patients. In comparison with unfractionated heparin, LMWH significantly reduced the risk of death over 3 to 6 months. A trend toward a reduction in recurrent thromboembolic events was also observed. It was concluded that more than 5 negative trials would have to be published in the future and included in a metaanalysis to negate this mortality advantage of LMWH. A summary of this metaanalysis is provided in Table 1 (LOE=1a).8 A subsequent meta-analysis of 13 randomized controlled trials with a total of 4447 patients with venous thromboembolism (DVT or pulmonary embolism) found a similar statistically significant reduction in mortality (ARR=1.6%; NNT=60) yet only a trend toward reduction in the risk of recurrent thromboembolism and major bleeding (LOE=1a).9 From this information it is apparent that LMWH is at least as safe and effective as UH in the treatment of DVT and that 1 death is prevented for every 60 patients treated with LMWH instead of UH.
Several studies have demonstrated the efficacy and safety of administering LMWH at home. One study of 400 patients with DVT compared home therapy with LMWH with inpatient UH and failed to demonstrate any significant difference in risk of recurrent thromboembolism or major bleeding (LOE=1b).10 Additionally, no difference in these clinical outcomes was found in another prospective study comparing patient self-injection with injection by home care nurse (LOE=2b).11 Patients are both capable and willing to participate in this treatment regimen; 91% were pleased with home therapy, and 70% felt comfortable with self-injection of LMWH (LOE=2c).12
A cost-effectiveness analysis published in 1999 studied the economic viability of universal treatment of acute DVT with LMWH. The cost of initial care was higher in hospitalized patients receiving LMWH, but this was partly offset by the reduced costs for early complications. Treatment with LMWH increased the quality-adjusted life expectancy by approximately 0.02 years. The incremental cost-effectiveness of inpatient LMWH treatment was $7820 per additional quality-adjusted life-year. Sensitivity analysis demonstrated that LMWH was cost saving when at least 8% of the patients were treated at home or if late complications were assumed to occur 25% less frequently in patients receiving LMWH. It was concluded that LMWH is highly cost-effective and is the preferred treatment for DVT (LOE=1b).13
Because using LMWH to treat outpatients with DVT has the potential to reduce health care costs, several organizations have published recommendations or guidelines suggesting an outpatient alternative for uncomplicated DVT.3,14,15 It is generally agreed that patients with an uncomplicated DVT, good cardiopulmonary reserve, no excessive bleeding risk, and normal renal function can safely be treated with LMWH at home. Those with the comorbidities or the possible contraindications to anticoagulation noted in Table 2 should typically be hospitalized for initial management. Also, the home therapy patient will require education on the correct dosage and administration of LMWH, recognition of adverse events, and available resources to address problems or questions during the treatment course. Although there is limited evidence to support these specific recommendations, current expert opinion favors a conservative approach in the selection of patients for home treatment of DVT (LOE=5).
Whether patients are treated in the hospital or at home, LMWH should be considered the primary standard treatment for DVT. The relative safety, tolerability, efficacy, and cost-effectiveness of LMWH make it the obvious and preferred therapeutic alternative.
Vena Caval Filter Placement
Placement of an inferior vena caval filter is reserved for patients with a contraindication to anticoagulation, a serious complication of anticoagulation, or recurrent thromboembolism despite adequate anticoagulation. To date there have been no randomized or cohort studies directly comparing inferior vena caval interruption with standard anticoagulation therapy. However, a recent clinical trial of vena caval filter placement in 400 anticoagulated patients revealed a significant decrease in pulmonary embolism assessed at day 12 of therapy (ARR=3.7%; NNT=27) but a significant increase in the rate of recurrent symptomatic DVT over the next 2 years (absolute risk increase [ARI]=9.2%; number needed to harm [NNH]=11; LOE=1b).16 The available evidence does not support the use of vena caval filters in the management of the patient with an initial and uncomplicated DVT.
Activity
Patients with acute DVT have traditionally been confined to bed rest for a period of 3 to 7 days, yet there is no evidence that this practice improves clinical outcomes. A study of 638 patients with DVT who were allowed to ambulate with compression stockings demonstrated a low incidence of pulmonary emboli documented by ventilation-perfusion scan when compared with that in the literature (LOE=4).17 A more recent randomized trial of 126 patients with acute proximal vein thrombosis compared 8 days of strict bed rest with early mobilization; there was no statistically significant difference in the incidence of scintigraphically detectable pulmonary embolism (LOE=1b).18 These studies do not currently support the previous recommendation of bed rest for the acute treatment of DVT.
Extended Therapy
After the initial evaluation, stabilization, and treatment of a patient with DVT, a plan is needed to minimize the risk of recurrent thromboembolism and chronic postphlebitic complications. Although unsupported by specific evidence, most recommendations include the discontinuation and avoidance of any exogenous estrogen therapy. Oral anticoagulation with warfarin decreases the incidence of recurrent thromboembolic events, while the extended use of compression stockings decreases the development of the postphlebitic syndrome.
Oral Anticoagulation with Warfarin
For a patient presenting with a first DVT, oral anticoagulation with warfarin should be initiated on the first day of treatment, after heparin loading is complete. Adequacy of therapy is monitored by measurement of the INR, a standardization of the plasma thromboplastin ratio now used to correct for the variance between laboratories resulting from the use of different thromboplastin reagents. The antithrombotic effect of warfarin is best established after 3 to 5 days; it is for this reason that heparin is overlapped with warfarin during the first several days of therapy. The algorithm in Table 3 has been shown to improve the success of achieving a stable and therapeutic INR by day 5 of therapy with less initial risk of hemorrhagic complication (LOE=1b).19 The heparin may be discontinued when the INR is within the therapeutic range of 2.0 to 3.0 for patients with DVT (LOE=5).14
The optimal duration of oral anticoagulant therapy for a first episode of DVT varies and depends on whether risk factors are transient or persistent. A comparison of 6 weeks versus 6 months of oral anticoagulant therapy found an increased risk of recurrent venous thromboembolism in the 6-week group. The risk decreased from 18.1% with 6 weeks of treatment to 9.5% with 6 months; 12 patients would have to be treated for 6 months instead of 6 weeks to prevent 1 episode of recurrent venous thromboembolism (NNT=12; LOE=1b).20 A subsequent comparison of 3 months of anticoagulation with extended oral anticoagulation for approximately 10 months found a reduction in the risk of recurrent venous thromboembolism (ARR=26%; NNT=4) but an increased risk of major bleeding (ARI=3.8%; NNH=26) in the extended therapy group over a period of 2 years (LOE=1b).21 In general, a longer duration of oral anticoagulant therapy is not surprisingly associated with a decreased risk of venous thromboembolic recurrence and an increased risk of bleeding complications. Using the data from the previously mentioned study, for every 100 patients given extended therapy instead of the traditional 3 months there will be 4 additional major bleeds and 25 fewer episodes of recurrent venous thromboembolism. A recent Cochrane review of 1500 patients in 4 studies similarly found a decreased risk of recurrent venous thromboembolism with prolonged warfarin therapy (0.9% vs 12%, ARR=11.1; NNT=9) but an increased incidence of major bleeding (2.1% vs 0%, ARI=2.1%; NNH=48; LOE=1a).22 In the case of recurrent DVT, lifetime anticoagulant therapy should be considered in the absence of risk factors for bleeding. The specific recommendations for duration of oral anticoagulation have been adapted from the American College of Chest Physicians (LOE=5)15 and are included in Figure 1.
Compression Stockings
The addition of compression stockings to standard oral anticoagulant therapy is supported by a study of 194 patients comparing the use of knee-high 30 to 40 mm Hg custom-fitted graded compression stockings over a 2-year period and a median follow-up of 76 months. The development of mild-moderate postphlebitic syndrome was decreased by 58% (ARR=27.1%; NNT=3.7), and the incidence of severe postphlebitic syndrome was decreased by 51% (ARR=12%; NNT=8.3). Although there was not a significant difference in the rate of recurrent venous thromboembolism, extended use of compression stockings improved the long-term clinical course and should be considered a valuable addition in the long-term management of DVT (LOE=1b).23
Investigation for possible malignancy or coagulation defect
Although there is an increased incidence of cancer at the time of presentation in patients with idiopathic DVT (ie, no clear predisposing cause such as bed rest), a complete medical evaluation including history, physical examination, and basic laboratory studies has been shown to adequately detect malignancy in this setting. A retrospective study of 986 consecutive patients found no difference in cancer incidence over the next 34 months among the 142 DVT patients and 844 patients with DVT ruled out by the clinical evaluation outlined in Table 4 (LOE=4).24 A prospective cohort study of 260 patients with DVT provided 2 years of regular follow-up visits and found that all subsequent cancers were diagnosed because the patient became symptomatic and sought care from a general practitioner (LOE=2b).25 Beyond initial and age-appropriate cancer screening, there is no evidence that an aggressive search for an underlying malignancy is warranted.
Inherited thrombophilias are associated with an increased risk for venous thromboembolic disease, yet the diagnosis of one of these defects does not substantially change the clinical management of initial or recurrent DVT. Likewise, counseling regarding the increased risk associated with prolonged immobilization, surgery, pregnancy, and exogenous estrogen therapy would be unchanged. A sensible approach may be to screen for hereditary thrombophilias (factor V Leiden, protein C deficiency, protein S deficiency, antithrombin III deficiency, antiphospholipid antibodies, and hyperhomocysteinuria) in the case of recurrent DVT, a younger patient, or a family history of thromboembolic disease. In the event that an inherited thrombophilia is diagnosed, further screening and possible identification of other family members could lead to avoidance of known secondary risk factors and subsequent thromboembolic events. The typical patient with an initial episode of DVT will not benefit from the investigation for an inherited coagulation defect.
Conclusions
The clinical and economic outcomes associated with DVT can be improved with a simple evidence-based approach to therapy Figure 1. Management of a first episode of DVT should begin with immediate anticoagulation with LMWH, preferably at home if there are no contraindications to outpatient management. Oral anticoagulation should be instituted at initial presentation and continued for a period of 3 to 6 months depending on individual risk factors for bleeding. The addition of compression stockings provides symptomatic relief and decreases the incidence of symptomatic postphlebitic syndrome. Extensive evaluation for malignancy or an inherited thrombophilia is not warranted in most cases of DVT.
1. Anderson FA, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case fatality rates of deep vein thrombosis and pulmonary embolism: the Worcester DVT study. Arch Intern Med 1991;151:933-38.
2. Silverstein MD, Heit JA, Mohr DN, et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998;158:585-93.
3. Hirsh J, Hoak J. Management of deep vein thrombosis and pulmonary embolism: a statement for healthcare professionals: Council on Thrombosis (in consultation with the Council on Cardiovascular Radiology), American Heart Association. Circulation 1996;93:2212-45.
4. Hull RD, Raskob GE, Hirsh J, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal vein thrombosis. N Engl J Med 1986;315:1109-14.
5. Hull RD, Raskob GE, Brant RF, et al. Relation between the time to achieve the lower limit of the APTT therapeutic range and recurrent venous thromboembolism during heparin treatment for deep vein thrombosis. Arch Intern Med 1997;157:2562-68.
6. Raschke RA, Reilly BM, Guidry JR, et al. The weight-based heparin dosing nomogram compared with a “standard care” nomogram. Ann Intern Med 1993;119:874-81.
7. Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997;337:688-98.
8. Gould MK, Dembitzer AD, Doyle RL, et al. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis: a meta-analysis of randomized, controlled trials. Ann Intern Med 1999;130:800-09.
9. Dolovich LR, Ginsberg JS, Douketis JD, et al. A meta-analysis comparing low-molecular-weight heparins with unfractionated heparin in the treatment of venous thromboembolism. Arch Intern Med 2000;160:181-88.
10. Koopman MMW, Prandoni P, Piovella F, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med 1996;334:682-87.
11. Wells PS, Kovacs MJ, Bormanis J, et al. Expanding eligibility for outpatient treatment of deep venous thrombosis and pulmonary embolism with low-molecular-weight heparin: a comparison of patient self-injection with homecare injection. Arch Intern Med 1998;158:1809-11.
12. Harrison L, McGinnis J, Crowther M, et al. Assessment of outpatient treatment of deep-vein thrombosis with low-molecular-weight heparin. Arch Intern Med 1998;158:2001-03.
13. Gould MK, Dembitzer AD, Sanders GD, et al. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis: a cost-effectiveness analysis. Ann Intern Med 1999;130:789-99.
14. Hyers TM. Antithrombotic therapy for venous thromboembolic disease. Chest 1998;114 (suppl):561S-78S.
15. Institute for Clinical Systems Improvement. Health care guideline: deep vein thrombosis. Bloomington, Minn: Institute for Clinical Systems Improvement; 1999.
16. Decousus H, Leizorovicz A, Parent F, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep vein thrombosis. N Engl J Med 1998;338:409-15.
17. Partsch H, Kechavarz B, Kohn H, et al. The effect of mobilisation of patients during treatment of thromboembolic disorders with low-molecular-weight heparin. Int Angiol 1997;16:189-92.
18. Schellong SM, Schwarz T, Kropp J, et al. Bed rest in deep vein thrombosis and the incidence of scintigraphic pulmonary embolism. Thromb Haemost 1999;82 (suppl):127-29.
19. Crowther MA, Ginsberg JB, Kearon C, et al. A randomized trial comparing 5-mg and 10-mg loading doses. Arch Intern Med 1999;159:46-48.
20. Schulman S, Rhedin AS, Lindmarker P, et al. A comparison of six weeks with 6 months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med 1995;332:1661-65.
21. Kearon C, Gent M, Hirsh J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999;340:901-07.
22. Hutten BA, Prins MH. Duration of treatment with vitamin K antagonists in symptomatic venous thromboembolism (Cochrane review). In: The Cochrane library Issue 4. Oxford, England: Update Software; 2000.
23. Brandjes DPM, Buller HR, Heijboer H, et al. Randomized trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet 1997;349:759-62.
24. Cornuz J, Pearson SD, Creager MA, et al. Importance of findings on the initial evaluation for cancer in patients with symptomatic idiopathic deep vein thrombosis. Ann Intern Med 1996;125:785-93.
25. Prandoni P, Lensing AWA, Buller HR, et al. Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. N Engl J Med 1992;327:1128-33.
Deep vein thrombosis (DVT), defined as a partial or complete occlusion of a deep vein by thrombus, is a relatively uncommon yet important diagnosis in primary care practice. Population-based studies have estimated the age-adjusted incidence of DVT at 48 per 100,000 persons per year, with age-specific rates increasing steadily as the patient grows older.1,2 A typical family physician could expect to diagnose 1 or 2 patients with DVT each year. In addition to age, other personal risk factors for the development of DVT include previous thromboembolism, pregnancy and the postpartum period, malignancy, inherited thrombophilias, and exogenous estrogen therapy. Environmental risk factors include immobility, trauma, surgery, and intensive care. The classic Virchow triad (stasis, vascular damage, and hypercoagulability) describes the basic pathophysiologic factors that alone or more commonly in combination promote the development of thrombosis.
The previous article in this series described the evaluation of the patient with suspected DVT. In this article I will outline an evidence-based approach to treating a patient with a confirmed diagnosis of DVT Figure 1. Special attention will be given to the selection of cost-effective interventions that minimize the likelihood of acute or long-term complications.
Initial Therapy
Prompt anticoagulation with heparin is the first priority in treating the patient with DVT by preventing the local extension, embolization, and recurrence of venous thromboembolic disease. Heparin acts immediately to catalyze the inhibition of several activated coagulation factors and leads to the stabilization of the intravascular thrombus. Heparinization is typically continued for 3 to 5 days until a stable and therapeutic international normalized ratio (INR) is established with oral warfarin therapy. There are 2 approved approaches available for the acute anticoagulant treatment of DVT: intravenous unfractionated heparin (UH) and subcutaneous low-molecular-weight heparin (LMWH). In the case of a significant contraindication to anticoagulation or a recurrent thromboembolic event despite adequate anticoagulation, an inferior vena caval filter is the treatment of choice.
Unfractionated Heparin
Traditionally the initial treatment of DVT has been anticoagulation with intravenous UH; the goal of this therapy is the prompt establishment of an activated partial thromboplastin time (APTT) of 1.5 to 2.5 times the control.3 The failure to achieve a therapeutic APTT within 24 hours has been associated with an increased likelihood of recurrent thromboembolism (23% vs 5%, absolute risk reduction [ARR]=18%; number needed to treat [NNT]=5.5; level of evidence [LOE]=1b).4,5 Several protocols for managing UH therapy have been shown to achieve therapeutic anticoagulation more rapidly than traditional approaches. Figure 2 summarizes a weight-based heparin dosing nomogram that has been proved effective, safe, and superior to standard therapy in a randomized controlled trial; this particular protocol achieved therapeutic anticoagulation in 97% of patients within 24 hours (LOE=1b).6 Patients treated with UH should remain hospitalized until therapeutically anticoagulated with oral warfarin.
Low-Molecular-Weight Heparin
After the approval of enoxaparin for the treatment of DVT in 1998, acute outpatient management of DVT with LMWH became possible. The advantages of LMWH include fixed dosing, a subcutaneous route of administration, and a more predictable anticoagulant response. Laboratory monitoring is unnecessary except in patients with renal insufficiency, as a result of better bioavailability, longer half-life, and dose-independent clearance. If monitoring of LMWH is necessary, an anti-Xa level of 0.4 to 0.7 U per mL is the goal of therapy.7 The only LMWHs currently approved and labeled by the United States Food and Drug Administration for the treatment of acute DVT are enoxaparin at a dosage of 1 mg per kg administered subcutaneously twice daily or 1.5 mg per kg once daily (inpatient therapy only) and tinzaparin at a dosage of 175 anti-Xa IU per kg administered subcutaneously once daily.
The safety and effectiveness of LMWH therapy for acute DVT were demonstrated in a recent meta-analysis of 11 randomized controlled trials with a total of 3674 patients. In comparison with unfractionated heparin, LMWH significantly reduced the risk of death over 3 to 6 months. A trend toward a reduction in recurrent thromboembolic events was also observed. It was concluded that more than 5 negative trials would have to be published in the future and included in a metaanalysis to negate this mortality advantage of LMWH. A summary of this metaanalysis is provided in Table 1 (LOE=1a).8 A subsequent meta-analysis of 13 randomized controlled trials with a total of 4447 patients with venous thromboembolism (DVT or pulmonary embolism) found a similar statistically significant reduction in mortality (ARR=1.6%; NNT=60) yet only a trend toward reduction in the risk of recurrent thromboembolism and major bleeding (LOE=1a).9 From this information it is apparent that LMWH is at least as safe and effective as UH in the treatment of DVT and that 1 death is prevented for every 60 patients treated with LMWH instead of UH.
Several studies have demonstrated the efficacy and safety of administering LMWH at home. One study of 400 patients with DVT compared home therapy with LMWH with inpatient UH and failed to demonstrate any significant difference in risk of recurrent thromboembolism or major bleeding (LOE=1b).10 Additionally, no difference in these clinical outcomes was found in another prospective study comparing patient self-injection with injection by home care nurse (LOE=2b).11 Patients are both capable and willing to participate in this treatment regimen; 91% were pleased with home therapy, and 70% felt comfortable with self-injection of LMWH (LOE=2c).12
A cost-effectiveness analysis published in 1999 studied the economic viability of universal treatment of acute DVT with LMWH. The cost of initial care was higher in hospitalized patients receiving LMWH, but this was partly offset by the reduced costs for early complications. Treatment with LMWH increased the quality-adjusted life expectancy by approximately 0.02 years. The incremental cost-effectiveness of inpatient LMWH treatment was $7820 per additional quality-adjusted life-year. Sensitivity analysis demonstrated that LMWH was cost saving when at least 8% of the patients were treated at home or if late complications were assumed to occur 25% less frequently in patients receiving LMWH. It was concluded that LMWH is highly cost-effective and is the preferred treatment for DVT (LOE=1b).13
Because using LMWH to treat outpatients with DVT has the potential to reduce health care costs, several organizations have published recommendations or guidelines suggesting an outpatient alternative for uncomplicated DVT.3,14,15 It is generally agreed that patients with an uncomplicated DVT, good cardiopulmonary reserve, no excessive bleeding risk, and normal renal function can safely be treated with LMWH at home. Those with the comorbidities or the possible contraindications to anticoagulation noted in Table 2 should typically be hospitalized for initial management. Also, the home therapy patient will require education on the correct dosage and administration of LMWH, recognition of adverse events, and available resources to address problems or questions during the treatment course. Although there is limited evidence to support these specific recommendations, current expert opinion favors a conservative approach in the selection of patients for home treatment of DVT (LOE=5).
Whether patients are treated in the hospital or at home, LMWH should be considered the primary standard treatment for DVT. The relative safety, tolerability, efficacy, and cost-effectiveness of LMWH make it the obvious and preferred therapeutic alternative.
Vena Caval Filter Placement
Placement of an inferior vena caval filter is reserved for patients with a contraindication to anticoagulation, a serious complication of anticoagulation, or recurrent thromboembolism despite adequate anticoagulation. To date there have been no randomized or cohort studies directly comparing inferior vena caval interruption with standard anticoagulation therapy. However, a recent clinical trial of vena caval filter placement in 400 anticoagulated patients revealed a significant decrease in pulmonary embolism assessed at day 12 of therapy (ARR=3.7%; NNT=27) but a significant increase in the rate of recurrent symptomatic DVT over the next 2 years (absolute risk increase [ARI]=9.2%; number needed to harm [NNH]=11; LOE=1b).16 The available evidence does not support the use of vena caval filters in the management of the patient with an initial and uncomplicated DVT.
Activity
Patients with acute DVT have traditionally been confined to bed rest for a period of 3 to 7 days, yet there is no evidence that this practice improves clinical outcomes. A study of 638 patients with DVT who were allowed to ambulate with compression stockings demonstrated a low incidence of pulmonary emboli documented by ventilation-perfusion scan when compared with that in the literature (LOE=4).17 A more recent randomized trial of 126 patients with acute proximal vein thrombosis compared 8 days of strict bed rest with early mobilization; there was no statistically significant difference in the incidence of scintigraphically detectable pulmonary embolism (LOE=1b).18 These studies do not currently support the previous recommendation of bed rest for the acute treatment of DVT.
Extended Therapy
After the initial evaluation, stabilization, and treatment of a patient with DVT, a plan is needed to minimize the risk of recurrent thromboembolism and chronic postphlebitic complications. Although unsupported by specific evidence, most recommendations include the discontinuation and avoidance of any exogenous estrogen therapy. Oral anticoagulation with warfarin decreases the incidence of recurrent thromboembolic events, while the extended use of compression stockings decreases the development of the postphlebitic syndrome.
Oral Anticoagulation with Warfarin
For a patient presenting with a first DVT, oral anticoagulation with warfarin should be initiated on the first day of treatment, after heparin loading is complete. Adequacy of therapy is monitored by measurement of the INR, a standardization of the plasma thromboplastin ratio now used to correct for the variance between laboratories resulting from the use of different thromboplastin reagents. The antithrombotic effect of warfarin is best established after 3 to 5 days; it is for this reason that heparin is overlapped with warfarin during the first several days of therapy. The algorithm in Table 3 has been shown to improve the success of achieving a stable and therapeutic INR by day 5 of therapy with less initial risk of hemorrhagic complication (LOE=1b).19 The heparin may be discontinued when the INR is within the therapeutic range of 2.0 to 3.0 for patients with DVT (LOE=5).14
The optimal duration of oral anticoagulant therapy for a first episode of DVT varies and depends on whether risk factors are transient or persistent. A comparison of 6 weeks versus 6 months of oral anticoagulant therapy found an increased risk of recurrent venous thromboembolism in the 6-week group. The risk decreased from 18.1% with 6 weeks of treatment to 9.5% with 6 months; 12 patients would have to be treated for 6 months instead of 6 weeks to prevent 1 episode of recurrent venous thromboembolism (NNT=12; LOE=1b).20 A subsequent comparison of 3 months of anticoagulation with extended oral anticoagulation for approximately 10 months found a reduction in the risk of recurrent venous thromboembolism (ARR=26%; NNT=4) but an increased risk of major bleeding (ARI=3.8%; NNH=26) in the extended therapy group over a period of 2 years (LOE=1b).21 In general, a longer duration of oral anticoagulant therapy is not surprisingly associated with a decreased risk of venous thromboembolic recurrence and an increased risk of bleeding complications. Using the data from the previously mentioned study, for every 100 patients given extended therapy instead of the traditional 3 months there will be 4 additional major bleeds and 25 fewer episodes of recurrent venous thromboembolism. A recent Cochrane review of 1500 patients in 4 studies similarly found a decreased risk of recurrent venous thromboembolism with prolonged warfarin therapy (0.9% vs 12%, ARR=11.1; NNT=9) but an increased incidence of major bleeding (2.1% vs 0%, ARI=2.1%; NNH=48; LOE=1a).22 In the case of recurrent DVT, lifetime anticoagulant therapy should be considered in the absence of risk factors for bleeding. The specific recommendations for duration of oral anticoagulation have been adapted from the American College of Chest Physicians (LOE=5)15 and are included in Figure 1.
Compression Stockings
The addition of compression stockings to standard oral anticoagulant therapy is supported by a study of 194 patients comparing the use of knee-high 30 to 40 mm Hg custom-fitted graded compression stockings over a 2-year period and a median follow-up of 76 months. The development of mild-moderate postphlebitic syndrome was decreased by 58% (ARR=27.1%; NNT=3.7), and the incidence of severe postphlebitic syndrome was decreased by 51% (ARR=12%; NNT=8.3). Although there was not a significant difference in the rate of recurrent venous thromboembolism, extended use of compression stockings improved the long-term clinical course and should be considered a valuable addition in the long-term management of DVT (LOE=1b).23
Investigation for possible malignancy or coagulation defect
Although there is an increased incidence of cancer at the time of presentation in patients with idiopathic DVT (ie, no clear predisposing cause such as bed rest), a complete medical evaluation including history, physical examination, and basic laboratory studies has been shown to adequately detect malignancy in this setting. A retrospective study of 986 consecutive patients found no difference in cancer incidence over the next 34 months among the 142 DVT patients and 844 patients with DVT ruled out by the clinical evaluation outlined in Table 4 (LOE=4).24 A prospective cohort study of 260 patients with DVT provided 2 years of regular follow-up visits and found that all subsequent cancers were diagnosed because the patient became symptomatic and sought care from a general practitioner (LOE=2b).25 Beyond initial and age-appropriate cancer screening, there is no evidence that an aggressive search for an underlying malignancy is warranted.
Inherited thrombophilias are associated with an increased risk for venous thromboembolic disease, yet the diagnosis of one of these defects does not substantially change the clinical management of initial or recurrent DVT. Likewise, counseling regarding the increased risk associated with prolonged immobilization, surgery, pregnancy, and exogenous estrogen therapy would be unchanged. A sensible approach may be to screen for hereditary thrombophilias (factor V Leiden, protein C deficiency, protein S deficiency, antithrombin III deficiency, antiphospholipid antibodies, and hyperhomocysteinuria) in the case of recurrent DVT, a younger patient, or a family history of thromboembolic disease. In the event that an inherited thrombophilia is diagnosed, further screening and possible identification of other family members could lead to avoidance of known secondary risk factors and subsequent thromboembolic events. The typical patient with an initial episode of DVT will not benefit from the investigation for an inherited coagulation defect.
Conclusions
The clinical and economic outcomes associated with DVT can be improved with a simple evidence-based approach to therapy Figure 1. Management of a first episode of DVT should begin with immediate anticoagulation with LMWH, preferably at home if there are no contraindications to outpatient management. Oral anticoagulation should be instituted at initial presentation and continued for a period of 3 to 6 months depending on individual risk factors for bleeding. The addition of compression stockings provides symptomatic relief and decreases the incidence of symptomatic postphlebitic syndrome. Extensive evaluation for malignancy or an inherited thrombophilia is not warranted in most cases of DVT.
Deep vein thrombosis (DVT), defined as a partial or complete occlusion of a deep vein by thrombus, is a relatively uncommon yet important diagnosis in primary care practice. Population-based studies have estimated the age-adjusted incidence of DVT at 48 per 100,000 persons per year, with age-specific rates increasing steadily as the patient grows older.1,2 A typical family physician could expect to diagnose 1 or 2 patients with DVT each year. In addition to age, other personal risk factors for the development of DVT include previous thromboembolism, pregnancy and the postpartum period, malignancy, inherited thrombophilias, and exogenous estrogen therapy. Environmental risk factors include immobility, trauma, surgery, and intensive care. The classic Virchow triad (stasis, vascular damage, and hypercoagulability) describes the basic pathophysiologic factors that alone or more commonly in combination promote the development of thrombosis.
The previous article in this series described the evaluation of the patient with suspected DVT. In this article I will outline an evidence-based approach to treating a patient with a confirmed diagnosis of DVT Figure 1. Special attention will be given to the selection of cost-effective interventions that minimize the likelihood of acute or long-term complications.
Initial Therapy
Prompt anticoagulation with heparin is the first priority in treating the patient with DVT by preventing the local extension, embolization, and recurrence of venous thromboembolic disease. Heparin acts immediately to catalyze the inhibition of several activated coagulation factors and leads to the stabilization of the intravascular thrombus. Heparinization is typically continued for 3 to 5 days until a stable and therapeutic international normalized ratio (INR) is established with oral warfarin therapy. There are 2 approved approaches available for the acute anticoagulant treatment of DVT: intravenous unfractionated heparin (UH) and subcutaneous low-molecular-weight heparin (LMWH). In the case of a significant contraindication to anticoagulation or a recurrent thromboembolic event despite adequate anticoagulation, an inferior vena caval filter is the treatment of choice.
Unfractionated Heparin
Traditionally the initial treatment of DVT has been anticoagulation with intravenous UH; the goal of this therapy is the prompt establishment of an activated partial thromboplastin time (APTT) of 1.5 to 2.5 times the control.3 The failure to achieve a therapeutic APTT within 24 hours has been associated with an increased likelihood of recurrent thromboembolism (23% vs 5%, absolute risk reduction [ARR]=18%; number needed to treat [NNT]=5.5; level of evidence [LOE]=1b).4,5 Several protocols for managing UH therapy have been shown to achieve therapeutic anticoagulation more rapidly than traditional approaches. Figure 2 summarizes a weight-based heparin dosing nomogram that has been proved effective, safe, and superior to standard therapy in a randomized controlled trial; this particular protocol achieved therapeutic anticoagulation in 97% of patients within 24 hours (LOE=1b).6 Patients treated with UH should remain hospitalized until therapeutically anticoagulated with oral warfarin.
Low-Molecular-Weight Heparin
After the approval of enoxaparin for the treatment of DVT in 1998, acute outpatient management of DVT with LMWH became possible. The advantages of LMWH include fixed dosing, a subcutaneous route of administration, and a more predictable anticoagulant response. Laboratory monitoring is unnecessary except in patients with renal insufficiency, as a result of better bioavailability, longer half-life, and dose-independent clearance. If monitoring of LMWH is necessary, an anti-Xa level of 0.4 to 0.7 U per mL is the goal of therapy.7 The only LMWHs currently approved and labeled by the United States Food and Drug Administration for the treatment of acute DVT are enoxaparin at a dosage of 1 mg per kg administered subcutaneously twice daily or 1.5 mg per kg once daily (inpatient therapy only) and tinzaparin at a dosage of 175 anti-Xa IU per kg administered subcutaneously once daily.
The safety and effectiveness of LMWH therapy for acute DVT were demonstrated in a recent meta-analysis of 11 randomized controlled trials with a total of 3674 patients. In comparison with unfractionated heparin, LMWH significantly reduced the risk of death over 3 to 6 months. A trend toward a reduction in recurrent thromboembolic events was also observed. It was concluded that more than 5 negative trials would have to be published in the future and included in a metaanalysis to negate this mortality advantage of LMWH. A summary of this metaanalysis is provided in Table 1 (LOE=1a).8 A subsequent meta-analysis of 13 randomized controlled trials with a total of 4447 patients with venous thromboembolism (DVT or pulmonary embolism) found a similar statistically significant reduction in mortality (ARR=1.6%; NNT=60) yet only a trend toward reduction in the risk of recurrent thromboembolism and major bleeding (LOE=1a).9 From this information it is apparent that LMWH is at least as safe and effective as UH in the treatment of DVT and that 1 death is prevented for every 60 patients treated with LMWH instead of UH.
Several studies have demonstrated the efficacy and safety of administering LMWH at home. One study of 400 patients with DVT compared home therapy with LMWH with inpatient UH and failed to demonstrate any significant difference in risk of recurrent thromboembolism or major bleeding (LOE=1b).10 Additionally, no difference in these clinical outcomes was found in another prospective study comparing patient self-injection with injection by home care nurse (LOE=2b).11 Patients are both capable and willing to participate in this treatment regimen; 91% were pleased with home therapy, and 70% felt comfortable with self-injection of LMWH (LOE=2c).12
A cost-effectiveness analysis published in 1999 studied the economic viability of universal treatment of acute DVT with LMWH. The cost of initial care was higher in hospitalized patients receiving LMWH, but this was partly offset by the reduced costs for early complications. Treatment with LMWH increased the quality-adjusted life expectancy by approximately 0.02 years. The incremental cost-effectiveness of inpatient LMWH treatment was $7820 per additional quality-adjusted life-year. Sensitivity analysis demonstrated that LMWH was cost saving when at least 8% of the patients were treated at home or if late complications were assumed to occur 25% less frequently in patients receiving LMWH. It was concluded that LMWH is highly cost-effective and is the preferred treatment for DVT (LOE=1b).13
Because using LMWH to treat outpatients with DVT has the potential to reduce health care costs, several organizations have published recommendations or guidelines suggesting an outpatient alternative for uncomplicated DVT.3,14,15 It is generally agreed that patients with an uncomplicated DVT, good cardiopulmonary reserve, no excessive bleeding risk, and normal renal function can safely be treated with LMWH at home. Those with the comorbidities or the possible contraindications to anticoagulation noted in Table 2 should typically be hospitalized for initial management. Also, the home therapy patient will require education on the correct dosage and administration of LMWH, recognition of adverse events, and available resources to address problems or questions during the treatment course. Although there is limited evidence to support these specific recommendations, current expert opinion favors a conservative approach in the selection of patients for home treatment of DVT (LOE=5).
Whether patients are treated in the hospital or at home, LMWH should be considered the primary standard treatment for DVT. The relative safety, tolerability, efficacy, and cost-effectiveness of LMWH make it the obvious and preferred therapeutic alternative.
Vena Caval Filter Placement
Placement of an inferior vena caval filter is reserved for patients with a contraindication to anticoagulation, a serious complication of anticoagulation, or recurrent thromboembolism despite adequate anticoagulation. To date there have been no randomized or cohort studies directly comparing inferior vena caval interruption with standard anticoagulation therapy. However, a recent clinical trial of vena caval filter placement in 400 anticoagulated patients revealed a significant decrease in pulmonary embolism assessed at day 12 of therapy (ARR=3.7%; NNT=27) but a significant increase in the rate of recurrent symptomatic DVT over the next 2 years (absolute risk increase [ARI]=9.2%; number needed to harm [NNH]=11; LOE=1b).16 The available evidence does not support the use of vena caval filters in the management of the patient with an initial and uncomplicated DVT.
Activity
Patients with acute DVT have traditionally been confined to bed rest for a period of 3 to 7 days, yet there is no evidence that this practice improves clinical outcomes. A study of 638 patients with DVT who were allowed to ambulate with compression stockings demonstrated a low incidence of pulmonary emboli documented by ventilation-perfusion scan when compared with that in the literature (LOE=4).17 A more recent randomized trial of 126 patients with acute proximal vein thrombosis compared 8 days of strict bed rest with early mobilization; there was no statistically significant difference in the incidence of scintigraphically detectable pulmonary embolism (LOE=1b).18 These studies do not currently support the previous recommendation of bed rest for the acute treatment of DVT.
Extended Therapy
After the initial evaluation, stabilization, and treatment of a patient with DVT, a plan is needed to minimize the risk of recurrent thromboembolism and chronic postphlebitic complications. Although unsupported by specific evidence, most recommendations include the discontinuation and avoidance of any exogenous estrogen therapy. Oral anticoagulation with warfarin decreases the incidence of recurrent thromboembolic events, while the extended use of compression stockings decreases the development of the postphlebitic syndrome.
Oral Anticoagulation with Warfarin
For a patient presenting with a first DVT, oral anticoagulation with warfarin should be initiated on the first day of treatment, after heparin loading is complete. Adequacy of therapy is monitored by measurement of the INR, a standardization of the plasma thromboplastin ratio now used to correct for the variance between laboratories resulting from the use of different thromboplastin reagents. The antithrombotic effect of warfarin is best established after 3 to 5 days; it is for this reason that heparin is overlapped with warfarin during the first several days of therapy. The algorithm in Table 3 has been shown to improve the success of achieving a stable and therapeutic INR by day 5 of therapy with less initial risk of hemorrhagic complication (LOE=1b).19 The heparin may be discontinued when the INR is within the therapeutic range of 2.0 to 3.0 for patients with DVT (LOE=5).14
The optimal duration of oral anticoagulant therapy for a first episode of DVT varies and depends on whether risk factors are transient or persistent. A comparison of 6 weeks versus 6 months of oral anticoagulant therapy found an increased risk of recurrent venous thromboembolism in the 6-week group. The risk decreased from 18.1% with 6 weeks of treatment to 9.5% with 6 months; 12 patients would have to be treated for 6 months instead of 6 weeks to prevent 1 episode of recurrent venous thromboembolism (NNT=12; LOE=1b).20 A subsequent comparison of 3 months of anticoagulation with extended oral anticoagulation for approximately 10 months found a reduction in the risk of recurrent venous thromboembolism (ARR=26%; NNT=4) but an increased risk of major bleeding (ARI=3.8%; NNH=26) in the extended therapy group over a period of 2 years (LOE=1b).21 In general, a longer duration of oral anticoagulant therapy is not surprisingly associated with a decreased risk of venous thromboembolic recurrence and an increased risk of bleeding complications. Using the data from the previously mentioned study, for every 100 patients given extended therapy instead of the traditional 3 months there will be 4 additional major bleeds and 25 fewer episodes of recurrent venous thromboembolism. A recent Cochrane review of 1500 patients in 4 studies similarly found a decreased risk of recurrent venous thromboembolism with prolonged warfarin therapy (0.9% vs 12%, ARR=11.1; NNT=9) but an increased incidence of major bleeding (2.1% vs 0%, ARI=2.1%; NNH=48; LOE=1a).22 In the case of recurrent DVT, lifetime anticoagulant therapy should be considered in the absence of risk factors for bleeding. The specific recommendations for duration of oral anticoagulation have been adapted from the American College of Chest Physicians (LOE=5)15 and are included in Figure 1.
Compression Stockings
The addition of compression stockings to standard oral anticoagulant therapy is supported by a study of 194 patients comparing the use of knee-high 30 to 40 mm Hg custom-fitted graded compression stockings over a 2-year period and a median follow-up of 76 months. The development of mild-moderate postphlebitic syndrome was decreased by 58% (ARR=27.1%; NNT=3.7), and the incidence of severe postphlebitic syndrome was decreased by 51% (ARR=12%; NNT=8.3). Although there was not a significant difference in the rate of recurrent venous thromboembolism, extended use of compression stockings improved the long-term clinical course and should be considered a valuable addition in the long-term management of DVT (LOE=1b).23
Investigation for possible malignancy or coagulation defect
Although there is an increased incidence of cancer at the time of presentation in patients with idiopathic DVT (ie, no clear predisposing cause such as bed rest), a complete medical evaluation including history, physical examination, and basic laboratory studies has been shown to adequately detect malignancy in this setting. A retrospective study of 986 consecutive patients found no difference in cancer incidence over the next 34 months among the 142 DVT patients and 844 patients with DVT ruled out by the clinical evaluation outlined in Table 4 (LOE=4).24 A prospective cohort study of 260 patients with DVT provided 2 years of regular follow-up visits and found that all subsequent cancers were diagnosed because the patient became symptomatic and sought care from a general practitioner (LOE=2b).25 Beyond initial and age-appropriate cancer screening, there is no evidence that an aggressive search for an underlying malignancy is warranted.
Inherited thrombophilias are associated with an increased risk for venous thromboembolic disease, yet the diagnosis of one of these defects does not substantially change the clinical management of initial or recurrent DVT. Likewise, counseling regarding the increased risk associated with prolonged immobilization, surgery, pregnancy, and exogenous estrogen therapy would be unchanged. A sensible approach may be to screen for hereditary thrombophilias (factor V Leiden, protein C deficiency, protein S deficiency, antithrombin III deficiency, antiphospholipid antibodies, and hyperhomocysteinuria) in the case of recurrent DVT, a younger patient, or a family history of thromboembolic disease. In the event that an inherited thrombophilia is diagnosed, further screening and possible identification of other family members could lead to avoidance of known secondary risk factors and subsequent thromboembolic events. The typical patient with an initial episode of DVT will not benefit from the investigation for an inherited coagulation defect.
Conclusions
The clinical and economic outcomes associated with DVT can be improved with a simple evidence-based approach to therapy Figure 1. Management of a first episode of DVT should begin with immediate anticoagulation with LMWH, preferably at home if there are no contraindications to outpatient management. Oral anticoagulation should be instituted at initial presentation and continued for a period of 3 to 6 months depending on individual risk factors for bleeding. The addition of compression stockings provides symptomatic relief and decreases the incidence of symptomatic postphlebitic syndrome. Extensive evaluation for malignancy or an inherited thrombophilia is not warranted in most cases of DVT.
1. Anderson FA, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case fatality rates of deep vein thrombosis and pulmonary embolism: the Worcester DVT study. Arch Intern Med 1991;151:933-38.
2. Silverstein MD, Heit JA, Mohr DN, et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998;158:585-93.
3. Hirsh J, Hoak J. Management of deep vein thrombosis and pulmonary embolism: a statement for healthcare professionals: Council on Thrombosis (in consultation with the Council on Cardiovascular Radiology), American Heart Association. Circulation 1996;93:2212-45.
4. Hull RD, Raskob GE, Hirsh J, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal vein thrombosis. N Engl J Med 1986;315:1109-14.
5. Hull RD, Raskob GE, Brant RF, et al. Relation between the time to achieve the lower limit of the APTT therapeutic range and recurrent venous thromboembolism during heparin treatment for deep vein thrombosis. Arch Intern Med 1997;157:2562-68.
6. Raschke RA, Reilly BM, Guidry JR, et al. The weight-based heparin dosing nomogram compared with a “standard care” nomogram. Ann Intern Med 1993;119:874-81.
7. Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997;337:688-98.
8. Gould MK, Dembitzer AD, Doyle RL, et al. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis: a meta-analysis of randomized, controlled trials. Ann Intern Med 1999;130:800-09.
9. Dolovich LR, Ginsberg JS, Douketis JD, et al. A meta-analysis comparing low-molecular-weight heparins with unfractionated heparin in the treatment of venous thromboembolism. Arch Intern Med 2000;160:181-88.
10. Koopman MMW, Prandoni P, Piovella F, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med 1996;334:682-87.
11. Wells PS, Kovacs MJ, Bormanis J, et al. Expanding eligibility for outpatient treatment of deep venous thrombosis and pulmonary embolism with low-molecular-weight heparin: a comparison of patient self-injection with homecare injection. Arch Intern Med 1998;158:1809-11.
12. Harrison L, McGinnis J, Crowther M, et al. Assessment of outpatient treatment of deep-vein thrombosis with low-molecular-weight heparin. Arch Intern Med 1998;158:2001-03.
13. Gould MK, Dembitzer AD, Sanders GD, et al. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis: a cost-effectiveness analysis. Ann Intern Med 1999;130:789-99.
14. Hyers TM. Antithrombotic therapy for venous thromboembolic disease. Chest 1998;114 (suppl):561S-78S.
15. Institute for Clinical Systems Improvement. Health care guideline: deep vein thrombosis. Bloomington, Minn: Institute for Clinical Systems Improvement; 1999.
16. Decousus H, Leizorovicz A, Parent F, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep vein thrombosis. N Engl J Med 1998;338:409-15.
17. Partsch H, Kechavarz B, Kohn H, et al. The effect of mobilisation of patients during treatment of thromboembolic disorders with low-molecular-weight heparin. Int Angiol 1997;16:189-92.
18. Schellong SM, Schwarz T, Kropp J, et al. Bed rest in deep vein thrombosis and the incidence of scintigraphic pulmonary embolism. Thromb Haemost 1999;82 (suppl):127-29.
19. Crowther MA, Ginsberg JB, Kearon C, et al. A randomized trial comparing 5-mg and 10-mg loading doses. Arch Intern Med 1999;159:46-48.
20. Schulman S, Rhedin AS, Lindmarker P, et al. A comparison of six weeks with 6 months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med 1995;332:1661-65.
21. Kearon C, Gent M, Hirsh J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999;340:901-07.
22. Hutten BA, Prins MH. Duration of treatment with vitamin K antagonists in symptomatic venous thromboembolism (Cochrane review). In: The Cochrane library Issue 4. Oxford, England: Update Software; 2000.
23. Brandjes DPM, Buller HR, Heijboer H, et al. Randomized trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet 1997;349:759-62.
24. Cornuz J, Pearson SD, Creager MA, et al. Importance of findings on the initial evaluation for cancer in patients with symptomatic idiopathic deep vein thrombosis. Ann Intern Med 1996;125:785-93.
25. Prandoni P, Lensing AWA, Buller HR, et al. Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. N Engl J Med 1992;327:1128-33.
1. Anderson FA, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case fatality rates of deep vein thrombosis and pulmonary embolism: the Worcester DVT study. Arch Intern Med 1991;151:933-38.
2. Silverstein MD, Heit JA, Mohr DN, et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998;158:585-93.
3. Hirsh J, Hoak J. Management of deep vein thrombosis and pulmonary embolism: a statement for healthcare professionals: Council on Thrombosis (in consultation with the Council on Cardiovascular Radiology), American Heart Association. Circulation 1996;93:2212-45.
4. Hull RD, Raskob GE, Hirsh J, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal vein thrombosis. N Engl J Med 1986;315:1109-14.
5. Hull RD, Raskob GE, Brant RF, et al. Relation between the time to achieve the lower limit of the APTT therapeutic range and recurrent venous thromboembolism during heparin treatment for deep vein thrombosis. Arch Intern Med 1997;157:2562-68.
6. Raschke RA, Reilly BM, Guidry JR, et al. The weight-based heparin dosing nomogram compared with a “standard care” nomogram. Ann Intern Med 1993;119:874-81.
7. Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997;337:688-98.
8. Gould MK, Dembitzer AD, Doyle RL, et al. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis: a meta-analysis of randomized, controlled trials. Ann Intern Med 1999;130:800-09.
9. Dolovich LR, Ginsberg JS, Douketis JD, et al. A meta-analysis comparing low-molecular-weight heparins with unfractionated heparin in the treatment of venous thromboembolism. Arch Intern Med 2000;160:181-88.
10. Koopman MMW, Prandoni P, Piovella F, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med 1996;334:682-87.
11. Wells PS, Kovacs MJ, Bormanis J, et al. Expanding eligibility for outpatient treatment of deep venous thrombosis and pulmonary embolism with low-molecular-weight heparin: a comparison of patient self-injection with homecare injection. Arch Intern Med 1998;158:1809-11.
12. Harrison L, McGinnis J, Crowther M, et al. Assessment of outpatient treatment of deep-vein thrombosis with low-molecular-weight heparin. Arch Intern Med 1998;158:2001-03.
13. Gould MK, Dembitzer AD, Sanders GD, et al. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis: a cost-effectiveness analysis. Ann Intern Med 1999;130:789-99.
14. Hyers TM. Antithrombotic therapy for venous thromboembolic disease. Chest 1998;114 (suppl):561S-78S.
15. Institute for Clinical Systems Improvement. Health care guideline: deep vein thrombosis. Bloomington, Minn: Institute for Clinical Systems Improvement; 1999.
16. Decousus H, Leizorovicz A, Parent F, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep vein thrombosis. N Engl J Med 1998;338:409-15.
17. Partsch H, Kechavarz B, Kohn H, et al. The effect of mobilisation of patients during treatment of thromboembolic disorders with low-molecular-weight heparin. Int Angiol 1997;16:189-92.
18. Schellong SM, Schwarz T, Kropp J, et al. Bed rest in deep vein thrombosis and the incidence of scintigraphic pulmonary embolism. Thromb Haemost 1999;82 (suppl):127-29.
19. Crowther MA, Ginsberg JB, Kearon C, et al. A randomized trial comparing 5-mg and 10-mg loading doses. Arch Intern Med 1999;159:46-48.
20. Schulman S, Rhedin AS, Lindmarker P, et al. A comparison of six weeks with 6 months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med 1995;332:1661-65.
21. Kearon C, Gent M, Hirsh J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999;340:901-07.
22. Hutten BA, Prins MH. Duration of treatment with vitamin K antagonists in symptomatic venous thromboembolism (Cochrane review). In: The Cochrane library Issue 4. Oxford, England: Update Software; 2000.
23. Brandjes DPM, Buller HR, Heijboer H, et al. Randomized trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet 1997;349:759-62.
24. Cornuz J, Pearson SD, Creager MA, et al. Importance of findings on the initial evaluation for cancer in patients with symptomatic idiopathic deep vein thrombosis. Ann Intern Med 1996;125:785-93.
25. Prandoni P, Lensing AWA, Buller HR, et al. Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. N Engl J Med 1992;327:1128-33.
Evaluation of the Patient with Suspected Deep Vein Thrombosis
Pain and swelling of a leg is a relatively common presenting complaint in primary care practice. In the 1995 National Ambulatory Medical Care Survey, 1.3% of patients presenting to family physicians had a complaint of leg pain or swelling.1 Although this complaint often has a benign cause, it is important to carefully evaluate these patients because they may have deep vein thrombosis (DVT). A population-based study showed that 48 of 100,000 persons are given the diagnosis of DVT every year, which corresponds to 1 to 2 patients per year in a typical family physician’s panel of patients.2
Patients with a clotting abnormality who are pregnant, undergo a period of immobilization, or are diagnosed with a malignancy are at higher than average risk of DVT. In addition to the morbidity associated with DVT, approximately 40% of patients with DVT have a pulmonary embolism (PE), although most of these are clinically silent, and it is not clear whether aggressive work-up to diagnose PE in patients with DVT is indicated.3
This article describes an approach to the evaluation of patients with suspected DVT. The focus will be on making the best possible use of the history and physical examination by using our knowledge of the probability of DVT and validated clinical decision rules. This information will guide the interpretation of diagnostic tests such as d-dimer and duplex venous ultrasound.1
Differential diagnosis
There are many causes of leg pain and edema, including musculoskeletal injury, congestive heart failure, hepatic disease, mechanical obstruction of lymphatic drainage, cellulitis, malnutrition, thyroid disease, Baker cysts, chronic venous insufficiency, and venous thrombosis. Unfortunately, no detailed data are available for the percentage of patients given these diagnoses among all patients presenting with leg pain and swelling. Among all patients with leg pain with and without swelling only 3.3% had thrombophlebitis in a large Dutch series.4
A number of studies reporting data on the percentage of patients with suspected DVT who are referred for diagnostic testing and have the diagnosis confirmed are summarized in Table 1. As a rule of thumb, for every 100 outpatients with suspected DVT 16 will have a proximal DVT and 4 will have a distal DVT.
Using the history and physical examination
Individual signs and symptoms are of relatively little value in the diagnosis of DVT. The well-designed studies5,6 generally find a lower sensitivity or specificity for physical examination findings than poorly designed studies.7 The accuracy of individual history and examination findings are outlined in Table 2 using only data from the highest-quality study. Homan sign (long taught as a useful clinical sign) is of no value in the diagnosis of DVT and should be omitted from the examination.
However, groups of signs and symptoms can be useful. Wells and colleagues developed a clinical rule that combines the results of 9 carefully defined signs and symptoms Figure 1. They subsequently validated this rule in a later study using a different group of patients and found it useful for stratifying patients into separate groups by risk of having a DVT.8-10 This validation study included outpatients referred for the evaluation of suspected DVT to a tertiary care hospital thrombosis clinic. Patients were excluded if they were pregnant, had a lower extremity amputation, were suspected of having a PE, had symptoms for more than 60 days, or were currently using anticoagulants. The mean age was 57.1 years; 40% were men; and 16% were given a diagnosis of DVT. Thus, these data would generalize to a family practice setting. Patients who fell into the low-risk group based on this rule had a 3% risk of DVT; those in the moderate risk group, 17%; and those in the high-risk group, 75%. This information will determine how we interpret the results of the noninvasive tests.
Diagnostic tests
Tests for the diagnosis of DVT include impedance plethysmography, magnetic resonance imaging (MRI), duplex venous ultrasound, and contrast venography. The latter is an invasive test, typically considered the reference standard. The accuracy of noninvasive tests varies with the study population (symptomatic vs asymptomatic) and the type of DVT being diagnosed (proximal, distal, or any). The tests are generally much less accurate in asymptomatic patients and less accurate for distal DVTs. The data for impedance plethysmography and ultrasound are summarized in Table 3 for symptomatic patients.11-13 Although duplex venous ultrasound is clearly the preferred test, impedance plethysmography is an acceptable alternative if ultrasound is not available.
Although there is considerable interest in MRI, studies to date have been small14-16 or have had serious methodologic limitations, such as a failure to blind the radiologists, a retrospective design, or a poor quality reference standard.17-19 In these studies, the sensitivity ranges from 80% to 100% and the specificity from 93% to 100% when compared with contrast venography. Consideration of MRI should currently be limited to cases where venography is considered but there are concerns over the use of contrast, and where there is considerable local experience with the technique.20,21
Some physicians advocate repeating the duplex venous ultrasound in patients with an initial negative test result, if the suspicion for DVT remains. Two studies with a total of 2107 patients repeated the ultrasound 5 to 7 days later, if the first ultrasound result was normal; patients with 2 normal ultrasound results did not receive anticoagulation.22,23 Only 0.6% of these patients had a thromboembolic complication (DVT or pulmonary embolism) during the next 3 months, and only 1 of these occurred during the week between ultrasounds. A third study repeated the ultrasound 1 day and again 6 days later in patients with a normal initial ultrasound results.24 Of 390 patients with 3 normal ultrasound results, only 6 had a thromboembolic complication during the next 3 months. Thus, in patients with 2 normal results 1 week apart, the risk of a thromboembolic complication during the next 3 months is approximately 1%.
D-dimer is a fibrin degradation product, and elevated levels are associated with an increased risk of DVT. Different d-dimer assays vary considerably in their performance. Latex agglutination assays are fast and cheap but not very accurate; they are therefore not recommended. Microplate enzyme-linked immunoassays (ELISAs) are accurate but expensive; membrane ELISAs are less expensive and nearly as accurate. The accuracy of one of the most widely used d-dimer tests (SimpliRED) is shown in Table 3. Note that a negative d-dimer test rersult alone does not rule out DVT; 2% to 5% of patients with suspected DVT and a negative d-dimer result actually have DVT. This is similar to the performance of ultrasound alone in unselected patients with suspected DVT. Because of the differences between tests, clinicians should learn which test is used by their laboratory and should advocate for use of the most accurate available test.
The d-dimer test is most useful in a patient with a moderate risk of DVT and a normal duplex venous ultrasound result. In one study, only 1 of 598 patients with normal ultrasound and normal d-dimer test results (membrane ELISA; Instant-IA d-dimer kit, Stago, Asnieres, France) developed a DVT in the next 3 months. Of 88 patients with normal duplex venous ultrasound results but elevated d-dimer levels, 5 had a DVT detected 1 week later with a repeat ultrasound, and an additional 2 had venous thromboembolic complications during the next 3 months.25
Approaching the patient
Evaluating all patients with suspected DVT in the same way risks overdiagnosing low-risk patients and underdiagnosing high-risk patients. The history and physical examination can guide the selection and interpretation of further diagnostic tests. Begin by using the Wells clinical decision rule Figure 1 to put the patient in the low-, moderate-, or high-risk group. Remember that this rule was developed in nonpregnant patients with a first DVT. For pregnant patients or those with a history of previous DVT, you should have a higher index of suspicion.
Next, use the algorithm in Figure 2 to guide your evaluation. DVT can be considered adequately ruled out in low-risk patients with a negative ultrasound result and in moderate-risk patients with normal d-dimer and normal ultrasound results. Moderate-risk patients with a normal initial result on ultrasound but an abnormal d-dimer level should have a repeat ultrasound in 1 week. Moderate- and high-risk patients with an abnormal ultrasound result should be treated for DVT. High-risk patients with a normal ultrasound result still have a fairly high probability of DVT and should have a venogram to establish the diagnosis. In high-risk patients normal ultrasound and normal d-dimer results do not adequately rule out DVT.
Of course, this algorithm should not be used inflexibly. Patients with new or progressive symptoms (eg, a person with suspected DVT who develops signs and symptoms of PE) should be evaluated immediately. Pregnant patients and patients with a history of DVT should be evaluated more aggressively, because their overall risk of DVT is higher.
All correspondence should be addressed to Mark H. Ebell, MD, MS, 330 Snapfinger Drive, Athens, GA 30605. E-mail: [email protected].
1. US Department of Health and Human Services. National Ambulatory Medical Care Survey (1995). NCHS CD-ROM Series 13, No. 11, SETS Version 1.221. Washington, DC: US Department of Health and Human Services; 1997.
2. Anderson FA, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism: the Worcester DVT study. Arch Intern Med 1991;151:933-38.
3. Meignan M, Rosso J, Gauthier H, et al. Systematic lung scans reveal a high frequency of silent pulmonary embolism in patients with proximal deep venous thrombosis. Arch Intern Med 2000;160:159-65.
4. Lamberts H. In Het Huis van de huisarts. Verslag van het Transitieproject. Lelystad: Meditekst, 2nd edition, 1994.
5. Sandler DA, Duncan JS, Ward P, et al. Diagnosis of deep-vein thrombosis: comparison of clinical evaluation, ultrasound, plethysmography, and venoscan with x-ray venogram. Lancet 1984;2:716-18.
6. O’Donnell TF, Jr, Abbott WM, Athanasoulis CA, Millan VG, Callow AD. Diagnosis of deep venous thrombosis in the outpatient by venography. Surg Gynecol Obstet 1980;150:69-74.
7. McLachlan J, Richards T, Paterson JC. An evaluation of clinical signs in the diagnosis of venous thrombosis. Arch Surg 1962;85:738-44.
8. Wells PS, Hirsh J, Anderson DR, et al. Accuracy of clinical assessment of deep-vein thrombosis. Lancet 1995;345:1326-30.
9. Wells P, Anderson DR, Bormanis J, et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet 1997;350:1795-98.
10. Wells PS, Hirsch J, Anderson DR, et al. A simple clinical model for the diagnosis of deep-vein thrombosis combined with impedance plethysmography: potential for an improvement in the diagnostic process. J Intern Med 1998;243:15-23.
11. Kearon C, Julian JA, Newman TE, Ginsberg JS. for the McMaster Diagnostic Imaging Practice Guidelines Initiative. Noninvasive diagnosis of deep venous thrombosis. Ann Intern Med 1998;128:663-77.
12. Anderson DR, Wells PS, Stiell I, et al. Management of patients with suspected deep vein thrombosis in the Emergency Department: combining use of a clinical diagnosis model with d-dimer testing. J Emerg Med 2000;19:225-30.
13. Wildberger JE, Vorwerk D, Kilbinger M, et al. Bedside testing (SimpliRED) in the diagnosis of deep vein thrombosis: evaluation of 250 patients. Invest Radiol 1998;33:232-35.
14. Spritzer CE, Sostman HD, Wilkes DC, Coleman RE. Deep venous thrombosis: experience with gradient-echo MR imaging in 66 patients. Radiology 1990;177:235-41.
15. Moody AR, Pollock JG, O’Connor AR, Bagnall M. Lower-limb deep venous thrombosis: direct MR imaging of the thrombus. Radiology 1998;209:349-55.
16. Vukov LF, Berquist TH, King BF. Magnetic resonance imaging for calf deep venous thrombophlebitis. Ann Emerg Med 1991;20:497-99.
17. Laissy JP, Cinqualbre A, Loshkajian A, et al. Assessment of deep venous thrombosis in the lower limbs and pelvis: MR venography versus duplex Doppler sonography. Am J Roentgenol 1996;167:971-75.
18. Erdman WA, Jayson HT, Redman HC, et al. Deep venous thrombosis of extremities: role of MR imaging in the diagnosis. Radiology 1990;174:425-31.
19. Spritzer CE, Norconk JJ, Sostman HD, Coleman RE. Detection of deep venous thrombosis by magnetic resonance imaging. Chest 1993;104:54-60.
20. ACCP Consensus Committee on Pulmonary Embolism. Opinions regarding the diagnosis and management of venous thromboembolic disease chest. 1998;113:499-504.
21. American Thoracic Society. The diagnostic approach to acute venous thromboembolism clinical practice guideline. Am J Respir Crit Care Med 1999;160:1043-66.
22. Cogo A, Lensing AW, Koopman MW, et al. Compression ultrasonography for diagnostic management of patients with clinically suspected deep vein thrombosis: prospective cohort study. BMJ 1998;316:17-20.
23. Birdwell BG, Raskob GE, Whitsett TL, et al. The clinical validity of normal compression ultrasonography in outpatients suspected of having deep venous thrombosis. Ann Intern Med 1998;128:1-7.
24. Heijboer H, Buller HR, Lensing AW, et al. A comparison of real-time compression ultrasonography with impedance plethysmography for the diagnosis of deep-vein thrombosis in symptomatic outpatients. N Engl J Med 1993;329:1365-69.
25. Bernardi F, Prandoni P, Lensing AWA, et al. D-dimer testing as an adjunct to ultrasonography in patients with clinically suspected deep vein thrombosis: prospective cohort study. BMJ 1998;317:1037-40.
Pain and swelling of a leg is a relatively common presenting complaint in primary care practice. In the 1995 National Ambulatory Medical Care Survey, 1.3% of patients presenting to family physicians had a complaint of leg pain or swelling.1 Although this complaint often has a benign cause, it is important to carefully evaluate these patients because they may have deep vein thrombosis (DVT). A population-based study showed that 48 of 100,000 persons are given the diagnosis of DVT every year, which corresponds to 1 to 2 patients per year in a typical family physician’s panel of patients.2
Patients with a clotting abnormality who are pregnant, undergo a period of immobilization, or are diagnosed with a malignancy are at higher than average risk of DVT. In addition to the morbidity associated with DVT, approximately 40% of patients with DVT have a pulmonary embolism (PE), although most of these are clinically silent, and it is not clear whether aggressive work-up to diagnose PE in patients with DVT is indicated.3
This article describes an approach to the evaluation of patients with suspected DVT. The focus will be on making the best possible use of the history and physical examination by using our knowledge of the probability of DVT and validated clinical decision rules. This information will guide the interpretation of diagnostic tests such as d-dimer and duplex venous ultrasound.1
Differential diagnosis
There are many causes of leg pain and edema, including musculoskeletal injury, congestive heart failure, hepatic disease, mechanical obstruction of lymphatic drainage, cellulitis, malnutrition, thyroid disease, Baker cysts, chronic venous insufficiency, and venous thrombosis. Unfortunately, no detailed data are available for the percentage of patients given these diagnoses among all patients presenting with leg pain and swelling. Among all patients with leg pain with and without swelling only 3.3% had thrombophlebitis in a large Dutch series.4
A number of studies reporting data on the percentage of patients with suspected DVT who are referred for diagnostic testing and have the diagnosis confirmed are summarized in Table 1. As a rule of thumb, for every 100 outpatients with suspected DVT 16 will have a proximal DVT and 4 will have a distal DVT.
Using the history and physical examination
Individual signs and symptoms are of relatively little value in the diagnosis of DVT. The well-designed studies5,6 generally find a lower sensitivity or specificity for physical examination findings than poorly designed studies.7 The accuracy of individual history and examination findings are outlined in Table 2 using only data from the highest-quality study. Homan sign (long taught as a useful clinical sign) is of no value in the diagnosis of DVT and should be omitted from the examination.
However, groups of signs and symptoms can be useful. Wells and colleagues developed a clinical rule that combines the results of 9 carefully defined signs and symptoms Figure 1. They subsequently validated this rule in a later study using a different group of patients and found it useful for stratifying patients into separate groups by risk of having a DVT.8-10 This validation study included outpatients referred for the evaluation of suspected DVT to a tertiary care hospital thrombosis clinic. Patients were excluded if they were pregnant, had a lower extremity amputation, were suspected of having a PE, had symptoms for more than 60 days, or were currently using anticoagulants. The mean age was 57.1 years; 40% were men; and 16% were given a diagnosis of DVT. Thus, these data would generalize to a family practice setting. Patients who fell into the low-risk group based on this rule had a 3% risk of DVT; those in the moderate risk group, 17%; and those in the high-risk group, 75%. This information will determine how we interpret the results of the noninvasive tests.
Diagnostic tests
Tests for the diagnosis of DVT include impedance plethysmography, magnetic resonance imaging (MRI), duplex venous ultrasound, and contrast venography. The latter is an invasive test, typically considered the reference standard. The accuracy of noninvasive tests varies with the study population (symptomatic vs asymptomatic) and the type of DVT being diagnosed (proximal, distal, or any). The tests are generally much less accurate in asymptomatic patients and less accurate for distal DVTs. The data for impedance plethysmography and ultrasound are summarized in Table 3 for symptomatic patients.11-13 Although duplex venous ultrasound is clearly the preferred test, impedance plethysmography is an acceptable alternative if ultrasound is not available.
Although there is considerable interest in MRI, studies to date have been small14-16 or have had serious methodologic limitations, such as a failure to blind the radiologists, a retrospective design, or a poor quality reference standard.17-19 In these studies, the sensitivity ranges from 80% to 100% and the specificity from 93% to 100% when compared with contrast venography. Consideration of MRI should currently be limited to cases where venography is considered but there are concerns over the use of contrast, and where there is considerable local experience with the technique.20,21
Some physicians advocate repeating the duplex venous ultrasound in patients with an initial negative test result, if the suspicion for DVT remains. Two studies with a total of 2107 patients repeated the ultrasound 5 to 7 days later, if the first ultrasound result was normal; patients with 2 normal ultrasound results did not receive anticoagulation.22,23 Only 0.6% of these patients had a thromboembolic complication (DVT or pulmonary embolism) during the next 3 months, and only 1 of these occurred during the week between ultrasounds. A third study repeated the ultrasound 1 day and again 6 days later in patients with a normal initial ultrasound results.24 Of 390 patients with 3 normal ultrasound results, only 6 had a thromboembolic complication during the next 3 months. Thus, in patients with 2 normal results 1 week apart, the risk of a thromboembolic complication during the next 3 months is approximately 1%.
D-dimer is a fibrin degradation product, and elevated levels are associated with an increased risk of DVT. Different d-dimer assays vary considerably in their performance. Latex agglutination assays are fast and cheap but not very accurate; they are therefore not recommended. Microplate enzyme-linked immunoassays (ELISAs) are accurate but expensive; membrane ELISAs are less expensive and nearly as accurate. The accuracy of one of the most widely used d-dimer tests (SimpliRED) is shown in Table 3. Note that a negative d-dimer test rersult alone does not rule out DVT; 2% to 5% of patients with suspected DVT and a negative d-dimer result actually have DVT. This is similar to the performance of ultrasound alone in unselected patients with suspected DVT. Because of the differences between tests, clinicians should learn which test is used by their laboratory and should advocate for use of the most accurate available test.
The d-dimer test is most useful in a patient with a moderate risk of DVT and a normal duplex venous ultrasound result. In one study, only 1 of 598 patients with normal ultrasound and normal d-dimer test results (membrane ELISA; Instant-IA d-dimer kit, Stago, Asnieres, France) developed a DVT in the next 3 months. Of 88 patients with normal duplex venous ultrasound results but elevated d-dimer levels, 5 had a DVT detected 1 week later with a repeat ultrasound, and an additional 2 had venous thromboembolic complications during the next 3 months.25
Approaching the patient
Evaluating all patients with suspected DVT in the same way risks overdiagnosing low-risk patients and underdiagnosing high-risk patients. The history and physical examination can guide the selection and interpretation of further diagnostic tests. Begin by using the Wells clinical decision rule Figure 1 to put the patient in the low-, moderate-, or high-risk group. Remember that this rule was developed in nonpregnant patients with a first DVT. For pregnant patients or those with a history of previous DVT, you should have a higher index of suspicion.
Next, use the algorithm in Figure 2 to guide your evaluation. DVT can be considered adequately ruled out in low-risk patients with a negative ultrasound result and in moderate-risk patients with normal d-dimer and normal ultrasound results. Moderate-risk patients with a normal initial result on ultrasound but an abnormal d-dimer level should have a repeat ultrasound in 1 week. Moderate- and high-risk patients with an abnormal ultrasound result should be treated for DVT. High-risk patients with a normal ultrasound result still have a fairly high probability of DVT and should have a venogram to establish the diagnosis. In high-risk patients normal ultrasound and normal d-dimer results do not adequately rule out DVT.
Of course, this algorithm should not be used inflexibly. Patients with new or progressive symptoms (eg, a person with suspected DVT who develops signs and symptoms of PE) should be evaluated immediately. Pregnant patients and patients with a history of DVT should be evaluated more aggressively, because their overall risk of DVT is higher.
All correspondence should be addressed to Mark H. Ebell, MD, MS, 330 Snapfinger Drive, Athens, GA 30605. E-mail: [email protected].
Pain and swelling of a leg is a relatively common presenting complaint in primary care practice. In the 1995 National Ambulatory Medical Care Survey, 1.3% of patients presenting to family physicians had a complaint of leg pain or swelling.1 Although this complaint often has a benign cause, it is important to carefully evaluate these patients because they may have deep vein thrombosis (DVT). A population-based study showed that 48 of 100,000 persons are given the diagnosis of DVT every year, which corresponds to 1 to 2 patients per year in a typical family physician’s panel of patients.2
Patients with a clotting abnormality who are pregnant, undergo a period of immobilization, or are diagnosed with a malignancy are at higher than average risk of DVT. In addition to the morbidity associated with DVT, approximately 40% of patients with DVT have a pulmonary embolism (PE), although most of these are clinically silent, and it is not clear whether aggressive work-up to diagnose PE in patients with DVT is indicated.3
This article describes an approach to the evaluation of patients with suspected DVT. The focus will be on making the best possible use of the history and physical examination by using our knowledge of the probability of DVT and validated clinical decision rules. This information will guide the interpretation of diagnostic tests such as d-dimer and duplex venous ultrasound.1
Differential diagnosis
There are many causes of leg pain and edema, including musculoskeletal injury, congestive heart failure, hepatic disease, mechanical obstruction of lymphatic drainage, cellulitis, malnutrition, thyroid disease, Baker cysts, chronic venous insufficiency, and venous thrombosis. Unfortunately, no detailed data are available for the percentage of patients given these diagnoses among all patients presenting with leg pain and swelling. Among all patients with leg pain with and without swelling only 3.3% had thrombophlebitis in a large Dutch series.4
A number of studies reporting data on the percentage of patients with suspected DVT who are referred for diagnostic testing and have the diagnosis confirmed are summarized in Table 1. As a rule of thumb, for every 100 outpatients with suspected DVT 16 will have a proximal DVT and 4 will have a distal DVT.
Using the history and physical examination
Individual signs and symptoms are of relatively little value in the diagnosis of DVT. The well-designed studies5,6 generally find a lower sensitivity or specificity for physical examination findings than poorly designed studies.7 The accuracy of individual history and examination findings are outlined in Table 2 using only data from the highest-quality study. Homan sign (long taught as a useful clinical sign) is of no value in the diagnosis of DVT and should be omitted from the examination.
However, groups of signs and symptoms can be useful. Wells and colleagues developed a clinical rule that combines the results of 9 carefully defined signs and symptoms Figure 1. They subsequently validated this rule in a later study using a different group of patients and found it useful for stratifying patients into separate groups by risk of having a DVT.8-10 This validation study included outpatients referred for the evaluation of suspected DVT to a tertiary care hospital thrombosis clinic. Patients were excluded if they were pregnant, had a lower extremity amputation, were suspected of having a PE, had symptoms for more than 60 days, or were currently using anticoagulants. The mean age was 57.1 years; 40% were men; and 16% were given a diagnosis of DVT. Thus, these data would generalize to a family practice setting. Patients who fell into the low-risk group based on this rule had a 3% risk of DVT; those in the moderate risk group, 17%; and those in the high-risk group, 75%. This information will determine how we interpret the results of the noninvasive tests.
Diagnostic tests
Tests for the diagnosis of DVT include impedance plethysmography, magnetic resonance imaging (MRI), duplex venous ultrasound, and contrast venography. The latter is an invasive test, typically considered the reference standard. The accuracy of noninvasive tests varies with the study population (symptomatic vs asymptomatic) and the type of DVT being diagnosed (proximal, distal, or any). The tests are generally much less accurate in asymptomatic patients and less accurate for distal DVTs. The data for impedance plethysmography and ultrasound are summarized in Table 3 for symptomatic patients.11-13 Although duplex venous ultrasound is clearly the preferred test, impedance plethysmography is an acceptable alternative if ultrasound is not available.
Although there is considerable interest in MRI, studies to date have been small14-16 or have had serious methodologic limitations, such as a failure to blind the radiologists, a retrospective design, or a poor quality reference standard.17-19 In these studies, the sensitivity ranges from 80% to 100% and the specificity from 93% to 100% when compared with contrast venography. Consideration of MRI should currently be limited to cases where venography is considered but there are concerns over the use of contrast, and where there is considerable local experience with the technique.20,21
Some physicians advocate repeating the duplex venous ultrasound in patients with an initial negative test result, if the suspicion for DVT remains. Two studies with a total of 2107 patients repeated the ultrasound 5 to 7 days later, if the first ultrasound result was normal; patients with 2 normal ultrasound results did not receive anticoagulation.22,23 Only 0.6% of these patients had a thromboembolic complication (DVT or pulmonary embolism) during the next 3 months, and only 1 of these occurred during the week between ultrasounds. A third study repeated the ultrasound 1 day and again 6 days later in patients with a normal initial ultrasound results.24 Of 390 patients with 3 normal ultrasound results, only 6 had a thromboembolic complication during the next 3 months. Thus, in patients with 2 normal results 1 week apart, the risk of a thromboembolic complication during the next 3 months is approximately 1%.
D-dimer is a fibrin degradation product, and elevated levels are associated with an increased risk of DVT. Different d-dimer assays vary considerably in their performance. Latex agglutination assays are fast and cheap but not very accurate; they are therefore not recommended. Microplate enzyme-linked immunoassays (ELISAs) are accurate but expensive; membrane ELISAs are less expensive and nearly as accurate. The accuracy of one of the most widely used d-dimer tests (SimpliRED) is shown in Table 3. Note that a negative d-dimer test rersult alone does not rule out DVT; 2% to 5% of patients with suspected DVT and a negative d-dimer result actually have DVT. This is similar to the performance of ultrasound alone in unselected patients with suspected DVT. Because of the differences between tests, clinicians should learn which test is used by their laboratory and should advocate for use of the most accurate available test.
The d-dimer test is most useful in a patient with a moderate risk of DVT and a normal duplex venous ultrasound result. In one study, only 1 of 598 patients with normal ultrasound and normal d-dimer test results (membrane ELISA; Instant-IA d-dimer kit, Stago, Asnieres, France) developed a DVT in the next 3 months. Of 88 patients with normal duplex venous ultrasound results but elevated d-dimer levels, 5 had a DVT detected 1 week later with a repeat ultrasound, and an additional 2 had venous thromboembolic complications during the next 3 months.25
Approaching the patient
Evaluating all patients with suspected DVT in the same way risks overdiagnosing low-risk patients and underdiagnosing high-risk patients. The history and physical examination can guide the selection and interpretation of further diagnostic tests. Begin by using the Wells clinical decision rule Figure 1 to put the patient in the low-, moderate-, or high-risk group. Remember that this rule was developed in nonpregnant patients with a first DVT. For pregnant patients or those with a history of previous DVT, you should have a higher index of suspicion.
Next, use the algorithm in Figure 2 to guide your evaluation. DVT can be considered adequately ruled out in low-risk patients with a negative ultrasound result and in moderate-risk patients with normal d-dimer and normal ultrasound results. Moderate-risk patients with a normal initial result on ultrasound but an abnormal d-dimer level should have a repeat ultrasound in 1 week. Moderate- and high-risk patients with an abnormal ultrasound result should be treated for DVT. High-risk patients with a normal ultrasound result still have a fairly high probability of DVT and should have a venogram to establish the diagnosis. In high-risk patients normal ultrasound and normal d-dimer results do not adequately rule out DVT.
Of course, this algorithm should not be used inflexibly. Patients with new or progressive symptoms (eg, a person with suspected DVT who develops signs and symptoms of PE) should be evaluated immediately. Pregnant patients and patients with a history of DVT should be evaluated more aggressively, because their overall risk of DVT is higher.
All correspondence should be addressed to Mark H. Ebell, MD, MS, 330 Snapfinger Drive, Athens, GA 30605. E-mail: [email protected].
1. US Department of Health and Human Services. National Ambulatory Medical Care Survey (1995). NCHS CD-ROM Series 13, No. 11, SETS Version 1.221. Washington, DC: US Department of Health and Human Services; 1997.
2. Anderson FA, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism: the Worcester DVT study. Arch Intern Med 1991;151:933-38.
3. Meignan M, Rosso J, Gauthier H, et al. Systematic lung scans reveal a high frequency of silent pulmonary embolism in patients with proximal deep venous thrombosis. Arch Intern Med 2000;160:159-65.
4. Lamberts H. In Het Huis van de huisarts. Verslag van het Transitieproject. Lelystad: Meditekst, 2nd edition, 1994.
5. Sandler DA, Duncan JS, Ward P, et al. Diagnosis of deep-vein thrombosis: comparison of clinical evaluation, ultrasound, plethysmography, and venoscan with x-ray venogram. Lancet 1984;2:716-18.
6. O’Donnell TF, Jr, Abbott WM, Athanasoulis CA, Millan VG, Callow AD. Diagnosis of deep venous thrombosis in the outpatient by venography. Surg Gynecol Obstet 1980;150:69-74.
7. McLachlan J, Richards T, Paterson JC. An evaluation of clinical signs in the diagnosis of venous thrombosis. Arch Surg 1962;85:738-44.
8. Wells PS, Hirsh J, Anderson DR, et al. Accuracy of clinical assessment of deep-vein thrombosis. Lancet 1995;345:1326-30.
9. Wells P, Anderson DR, Bormanis J, et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet 1997;350:1795-98.
10. Wells PS, Hirsch J, Anderson DR, et al. A simple clinical model for the diagnosis of deep-vein thrombosis combined with impedance plethysmography: potential for an improvement in the diagnostic process. J Intern Med 1998;243:15-23.
11. Kearon C, Julian JA, Newman TE, Ginsberg JS. for the McMaster Diagnostic Imaging Practice Guidelines Initiative. Noninvasive diagnosis of deep venous thrombosis. Ann Intern Med 1998;128:663-77.
12. Anderson DR, Wells PS, Stiell I, et al. Management of patients with suspected deep vein thrombosis in the Emergency Department: combining use of a clinical diagnosis model with d-dimer testing. J Emerg Med 2000;19:225-30.
13. Wildberger JE, Vorwerk D, Kilbinger M, et al. Bedside testing (SimpliRED) in the diagnosis of deep vein thrombosis: evaluation of 250 patients. Invest Radiol 1998;33:232-35.
14. Spritzer CE, Sostman HD, Wilkes DC, Coleman RE. Deep venous thrombosis: experience with gradient-echo MR imaging in 66 patients. Radiology 1990;177:235-41.
15. Moody AR, Pollock JG, O’Connor AR, Bagnall M. Lower-limb deep venous thrombosis: direct MR imaging of the thrombus. Radiology 1998;209:349-55.
16. Vukov LF, Berquist TH, King BF. Magnetic resonance imaging for calf deep venous thrombophlebitis. Ann Emerg Med 1991;20:497-99.
17. Laissy JP, Cinqualbre A, Loshkajian A, et al. Assessment of deep venous thrombosis in the lower limbs and pelvis: MR venography versus duplex Doppler sonography. Am J Roentgenol 1996;167:971-75.
18. Erdman WA, Jayson HT, Redman HC, et al. Deep venous thrombosis of extremities: role of MR imaging in the diagnosis. Radiology 1990;174:425-31.
19. Spritzer CE, Norconk JJ, Sostman HD, Coleman RE. Detection of deep venous thrombosis by magnetic resonance imaging. Chest 1993;104:54-60.
20. ACCP Consensus Committee on Pulmonary Embolism. Opinions regarding the diagnosis and management of venous thromboembolic disease chest. 1998;113:499-504.
21. American Thoracic Society. The diagnostic approach to acute venous thromboembolism clinical practice guideline. Am J Respir Crit Care Med 1999;160:1043-66.
22. Cogo A, Lensing AW, Koopman MW, et al. Compression ultrasonography for diagnostic management of patients with clinically suspected deep vein thrombosis: prospective cohort study. BMJ 1998;316:17-20.
23. Birdwell BG, Raskob GE, Whitsett TL, et al. The clinical validity of normal compression ultrasonography in outpatients suspected of having deep venous thrombosis. Ann Intern Med 1998;128:1-7.
24. Heijboer H, Buller HR, Lensing AW, et al. A comparison of real-time compression ultrasonography with impedance plethysmography for the diagnosis of deep-vein thrombosis in symptomatic outpatients. N Engl J Med 1993;329:1365-69.
25. Bernardi F, Prandoni P, Lensing AWA, et al. D-dimer testing as an adjunct to ultrasonography in patients with clinically suspected deep vein thrombosis: prospective cohort study. BMJ 1998;317:1037-40.
1. US Department of Health and Human Services. National Ambulatory Medical Care Survey (1995). NCHS CD-ROM Series 13, No. 11, SETS Version 1.221. Washington, DC: US Department of Health and Human Services; 1997.
2. Anderson FA, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism: the Worcester DVT study. Arch Intern Med 1991;151:933-38.
3. Meignan M, Rosso J, Gauthier H, et al. Systematic lung scans reveal a high frequency of silent pulmonary embolism in patients with proximal deep venous thrombosis. Arch Intern Med 2000;160:159-65.
4. Lamberts H. In Het Huis van de huisarts. Verslag van het Transitieproject. Lelystad: Meditekst, 2nd edition, 1994.
5. Sandler DA, Duncan JS, Ward P, et al. Diagnosis of deep-vein thrombosis: comparison of clinical evaluation, ultrasound, plethysmography, and venoscan with x-ray venogram. Lancet 1984;2:716-18.
6. O’Donnell TF, Jr, Abbott WM, Athanasoulis CA, Millan VG, Callow AD. Diagnosis of deep venous thrombosis in the outpatient by venography. Surg Gynecol Obstet 1980;150:69-74.
7. McLachlan J, Richards T, Paterson JC. An evaluation of clinical signs in the diagnosis of venous thrombosis. Arch Surg 1962;85:738-44.
8. Wells PS, Hirsh J, Anderson DR, et al. Accuracy of clinical assessment of deep-vein thrombosis. Lancet 1995;345:1326-30.
9. Wells P, Anderson DR, Bormanis J, et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet 1997;350:1795-98.
10. Wells PS, Hirsch J, Anderson DR, et al. A simple clinical model for the diagnosis of deep-vein thrombosis combined with impedance plethysmography: potential for an improvement in the diagnostic process. J Intern Med 1998;243:15-23.
11. Kearon C, Julian JA, Newman TE, Ginsberg JS. for the McMaster Diagnostic Imaging Practice Guidelines Initiative. Noninvasive diagnosis of deep venous thrombosis. Ann Intern Med 1998;128:663-77.
12. Anderson DR, Wells PS, Stiell I, et al. Management of patients with suspected deep vein thrombosis in the Emergency Department: combining use of a clinical diagnosis model with d-dimer testing. J Emerg Med 2000;19:225-30.
13. Wildberger JE, Vorwerk D, Kilbinger M, et al. Bedside testing (SimpliRED) in the diagnosis of deep vein thrombosis: evaluation of 250 patients. Invest Radiol 1998;33:232-35.
14. Spritzer CE, Sostman HD, Wilkes DC, Coleman RE. Deep venous thrombosis: experience with gradient-echo MR imaging in 66 patients. Radiology 1990;177:235-41.
15. Moody AR, Pollock JG, O’Connor AR, Bagnall M. Lower-limb deep venous thrombosis: direct MR imaging of the thrombus. Radiology 1998;209:349-55.
16. Vukov LF, Berquist TH, King BF. Magnetic resonance imaging for calf deep venous thrombophlebitis. Ann Emerg Med 1991;20:497-99.
17. Laissy JP, Cinqualbre A, Loshkajian A, et al. Assessment of deep venous thrombosis in the lower limbs and pelvis: MR venography versus duplex Doppler sonography. Am J Roentgenol 1996;167:971-75.
18. Erdman WA, Jayson HT, Redman HC, et al. Deep venous thrombosis of extremities: role of MR imaging in the diagnosis. Radiology 1990;174:425-31.
19. Spritzer CE, Norconk JJ, Sostman HD, Coleman RE. Detection of deep venous thrombosis by magnetic resonance imaging. Chest 1993;104:54-60.
20. ACCP Consensus Committee on Pulmonary Embolism. Opinions regarding the diagnosis and management of venous thromboembolic disease chest. 1998;113:499-504.
21. American Thoracic Society. The diagnostic approach to acute venous thromboembolism clinical practice guideline. Am J Respir Crit Care Med 1999;160:1043-66.
22. Cogo A, Lensing AW, Koopman MW, et al. Compression ultrasonography for diagnostic management of patients with clinically suspected deep vein thrombosis: prospective cohort study. BMJ 1998;316:17-20.
23. Birdwell BG, Raskob GE, Whitsett TL, et al. The clinical validity of normal compression ultrasonography in outpatients suspected of having deep venous thrombosis. Ann Intern Med 1998;128:1-7.
24. Heijboer H, Buller HR, Lensing AW, et al. A comparison of real-time compression ultrasonography with impedance plethysmography for the diagnosis of deep-vein thrombosis in symptomatic outpatients. N Engl J Med 1993;329:1365-69.
25. Bernardi F, Prandoni P, Lensing AWA, et al. D-dimer testing as an adjunct to ultrasonography in patients with clinically suspected deep vein thrombosis: prospective cohort study. BMJ 1998;317:1037-40.
The Evaluation and Treatment of Adults with Gastroesophageal Reflux Disease
Gastroesophageal reflux disease (GERD) is defined as symptoms or tissue damage that results from the abnormal reflux of gastric contents into the esophagus. A systematic review of population-based studies estimates that heartburn or regurgitation symptoms occur in 21% to 59% of the population during a given year.1 The frequency of GERD in specific populations is provided in Table 1. Although only 1 in 5 patients with upper intestinal symptoms that occur at least weekly seeks medical attention,2 nearly 1% of all visits to a family physician’s office are for GERD or related conditions.3
GERD significantly affects the quality of patients’ lives. In a survey of patients presenting for upper endoscopy with symptoms of at least 3 months’ duration, those with a diagnosis of GERD reported low scores at baseline for general wellbeing. Fortunately, follow-up data reported 4 weeks after treatment note improvement in gastrointestinal symptoms, general well-being, general health, vitality, and depression.4
Pathophysiology
The pathogenesis of GERD is multifactorial and is thought to involve lower than normal esophageal sphincter pressures. This allows gastric acidic content to reflux into the distal esophagus, which lacks a protective barrier, causing esophagitis. Inflamed tissue impairs the normal clearance of acid, worsening the esophagitis, which inhibits normal motility.
Although Helicobacter pylori is clearly associated with peptic ulcer disease, its association with GERD is still debated. Data from case control studies actually suggest an inverse association; that is, that the presence of H pylori may be protective against the development of GERD.5
Because of the anatomical location of the esophagus, GERD should be considered in the differential diagnosis for presenting complaints other than regurgitation or dyspepsia. For example, approximately 50% of patients with chest pain in whom cardiac etiology is ruled out will ultimately be given a diagnosis of GERD.6 Similarly, 10% of patients with chronic cough7 and 78% of patients with laryngitis have GERD.8 Clear associations between GERD and asthma have been demonstrated, but data from meta-analyses fail to show improvement of asthma symptoms when GERD is appropriately treated.9
Diagnosis
The diagnosis of GERD can usually be made without the use of invasive tests. The accuracy of key tests, including clinical history, is outlined in Table 2. One study of patients presenting with dyspepsia (signs and symptoms referable to the upper gastrointestinal tract) found that 56% also have GERD.10 Another showed that 60% of patients referred for pH monitoring had GERD.11 Since reasonable prevalence estimates for GERD in the family practice setting may be slightly lower, calculations in Table 2 assume that between 40% and 60% of patients with suspected GERD actually have the condition.
Individual symptoms of GERD such as heartburn, regurgitation, belching, or dyspepsia are of limited usefulness in diagnosis. In a survey of patients referred for pH monitoring likelihood ratios hovered near 1, meaning that the presence or absence of the symptom had little impact on the diagnosis.11 The clinician’s overall impression that a patient has GERD, however, is much more useful to rule in disease than any individual symptoms.11 Assuming that half of patients with suspected GERD have the disease, if a clinician suspects GERD, that probability increases to 77%. Most clinicians would find a trial of empiric therapy appropriate at that probability.
The omeprazole test is also helpful in confirming a diagnosis of GERD. It consists of the patient taking 40 mg omeprazole in the morning and 20 mg at night for 1 week. If the symptoms resolve, the test is considered diagnostic of GERD.12 Some consider this approach to be therapeutic, as well as diagnostic. Beginning with an omeprazole test and reserving invasive testing for those not responding to the medication was cost-effective for patients with noncardiac chest pain.13 In a decision analysis, empiric treatment with omeprazole was a cost-effective approach to the management of GERD.14 Of course, initial endoscopy is indicated for patients with “red flags”: signs and symptoms consistent with obstruction, bleeding, or perforation, and those older than 50 years who are at a higher risk of malignancy.
Upper endoscopy, however, is not very accurate in diagnosing GERD. Among patients with GERD, only 22% have esophageal erythema, and only 48% have erosions or ulcerations. Therefore, because of costs and limited resources, the American Society for Gastrointestinal Endoscopy recommends that endoscopy be reserved for patients presenting with possible GERD who also have symptoms of more serious disease (dysphagia, weight loss, gastrointestinal bleeding) and for those not responding to a reasonable trial of therapy.15 The goal is to rule out more serious conditions.
Twenty-four–hour pH monitoring, while more accurate than endoscopy, is also reserved as a second-line test. According to the American Gastro-enterological Association guidelines, pH recording is indicated when endoscopy is normal and reflux symptoms persist despite acid suppression therapy or to evaluate extra-esophageal symptoms that may be GERD (ie, atypical chest pain or chronic cough).16 The goal here is to rule in GERD as the etiology of the patient’s symptoms.
Numerous other tests have been proposed to evaluate the patient with suspected GERD: manometry, scintigraphy, esophograms (as part of upper gastrointestinal series), and the Bernstein test (a provocative challenge with hydrochloric acid infusion). Data on the accuracy of these tests are limited by the lack of an accepted reference standard, and most have fallen out of favor because of their inconvenience or limited accuracy. None are more helpful than pH monitoring or endoscopy, and they are therefore not recommended.
Treatment
Pharmacologic
Treatments for GERD address the pathophysiology of the disease; they tend to target the removal of precipitating factors, using gravity or medications to improve acid clearance, lower the acidity of gastric contents, or improve the esophageal sphincter tone. Short-term treatment goals are to relieve symptoms and heal esophagitis; long-term goals are to prevent relapses and sequelae, such as esophageal stricture formation or adenocarcinoma.
Recommendations for lifestyle modifications to lessen GERD symptoms are extensive and mostly based on pathophysiologic data. Possible triggers for GERD include obesity, tight clothing, fatty foods, alcohol, tobacco, caffeine, onions, peppermint, and chocolate.17-21 Because symptoms are typically worse at night, elevating the head of the bed or avoiding postprandial recumbency is recommended.22,23 Eliminating these factors has been shown to decrease the amount of acid in the distal esophagus or improve the pressure readings on manometry. This is disease-oriented evidence; it does not necessarily translate into reduced symptoms for patients. The only patient-oriented evidence that supports lifestyle modification is a small crossover trial in which subjects had less heartburn and belching following a hamburger meal compared with the same meal with onions on the burger.18 Despite the lack of high-quality evidence of effectiveness, guidelines recommend lifestyle modification as the first-line therapy or adjunct to additional medication.24,25 Because these lifestyle changes are not thought to be harmful and may have other possible health benefits it is reasonable to recommend them to patients until better studies are published.
Promotility agents are a possible treatment of GERD because they improve acid clearance from the esophagus. Older agents such as metoclopramide and bethanecol have little data to support their use26,27 and are further limited by their central nervous system side effects. A meta-analysis of trial data found that cisapride heals esophagitis and decreases symptoms of GERD28 but was taken off the market because of problems with cardiac arrhythmias.
Acid suppression strategies available over-the-counter include antacids, alginates, and H2-blockers (H2Bs). Small, short-term trials have demonstrated mixed results with regard to symptom relief and lessened acid exposure from both antacids and alginates.29,30 Longer follow-up in cohort studies suggests a modest benefit from antacids.31 More than 24 randomized controlled trials (RCTs) have demonstrated the benefits of H2Bs in the treatment of GERD for both healing esophagitis and symptom relief. The number needed to treat (NNT) is 5; that is, for every 5 GERD patients treated with H2Bs instead of placebo, 1 patient benefits.32 H2Bs also prevent the long-term recurrence of symptoms (NNT =15).33 There is no clear benefit of one H2B agent over another. Proton pump inhibitors (PPIs) are also well supported by meta-analyses of RCTs in the short term (NNT = 2) and long term (NNT = 3) treatment of GERD.33 As with H2Bs, no clear advantage is found between different PPI medications.
STEPS. Using the STEPS approach (Safety, Tolerability, Efficacy, Price, Simplicity) to compare H2Bs and PPIs is one way to help guide management of GERD. H2Bs are not associated with any serious long-term complications. PPIs are theoretically linked to malignancy through 2 mechanisms: proliferation of endocrine cells leading to endocrine neoplasia and atrophic gastritis caused by chronic acid suppression as a precursor to gastric adenocarcinoma. However, studies have not borne out these concerns.34 Thus, both H2Bs and PPIs seem equally safe. The best measure of tolerability is the pooled dropout rate, which is the number of patients dropping out of a study for any reason. Dropout rates are about the same for H2Bs and PPIs.35 Meta-analyses of trials comparing the efficacy of H2Bs to PPIs in the short- and long-term treatment of GERD consistently favor PPIs.33,35 Of 100 patients with GERD, approximately 25 will benefit from treatment with an H2B, and 75 to 80 will benefit from treatment with a PPI.33 An interesting comparison of trials suggests that the therapeutic gain of PPIs is greatest in those patients with more severe GERD.36 Little data exist about the prevention of complications of GERD with acid suppression. However, 1 small trial found a decreased rate of esophageal stricture recurrence at 1 year in patients with reflux esophagitis (NNT =7) treated with 30-mg lansoprazole compared with those treated with 300-mg ranitidine.37 These data seem to suggest that high-risk patients are more apt to benefit from PPIs than H2Bs.
Because H2Bs are now available in generic forms, price tips the scales greatly in their favor. The average cost for PPIs is nearly 10 times that of generic H2Bs (3020-mg omeprazole tablets cost $105.55 and 60 150-mg ranitidine tablets cost $10.98 as of 11/0/00). Simplicity is a toss-up: most PPIs are dosed once daily, while H2Bs are given once or twice daily. A general approach is to start patients with GERD on a reasonable dose of H2Bs, and move on to PPIs if symptoms do not resolve in 2 to 4 weeks.25,54 Some insurance companies require documentation of H2B failure before covering the increased costs of PPIs, despite their efficacy advantage.
Surgery
For patients with chronic or recurrent GERD, surgery offers an additional treatment option. Prospective cohort studies note that open Nissen fundoplication produces an 80% to 93% success rate at 10-year follow-up. Laproscopic procedures are producing similar short-term results, but long-term data are pending.38 One randomized trial demonstrated equivalent 3-year outcomes for those undergoing Nissen fundoplication and those taking 40 mg omeprazole daily.39 Decision analysis data favor the cost effectiveness of open Nissen40 if medical treatment will be required for more than 4 years, and laproscopic procedure if medical treatment will be needed for more than 10 years.41
Prognosis
GERD may be a short-term intermittent problem or may be severe and chronic in nature. Untreated, approximately 15% of patients will have symptom relief.32 Antacids can raise that rate to an estimated 20%,31,25 while H2Bs are associated with symptom-free rates of approximately 25%.30 The best outcomes are found with PPIs, where recurrence of GERD symptoms is suppressed in 75% to 82% of patients at 1-year follow-up.33,35
Although many patients will experience recurrences, chronic medications may not be necessary. In 1 study, 677 patients with heartburn and mild esophagitis were randomized to treatment with omeprazole or ranitidine for 2 weeks. If symptoms persisted, the dose of medication was doubled. If symptoms resolved, medication was stopped. Recurrences were treated for 2 to 4 weeks at the previously effective dose. Nearly half the patients were successfully treated with intermittent medication, and nearly 40% of initial responders required no further treatment.42
GERD is associated with esophageal strictures, Barrett esophagus (metaplasia of the distal esophageal columnar cells, thought to be a precursor of dysplasia and cancer) and adenocarcinoma. Limited data are available for the actual incidence of stricture in GERD patients. One retrospective cohort study of patients discharged from veterans’ administration hospitals found that 8.4% of patients with GERD had strictures, and the association between esophageal ulcers and stricture was significant.43 This study likely suffered from significant selection bias, however, and the rate in primary care practice is almost certainly much lower. Barrett was noted in 11.6% of 662 patients with GERD referred from general practice settings for endoscopy.44 Again, though, patients with GERD referred for endoscopy are likely to have more severe disease, and a recent meta-analysis suggests that the actual risk of Barrett in unselected patients is closer to 3% to 4%.45 A longer duration of symptoms was associated with an increase risk. Patients with Barrett esophagus; negative, low-grade, or indefinite dysplasia; and neither aneuploidy or increased 4N on flow cytometry are at very low risk of esophageal cancer (<2% over 5 years). Only approximately 4% of patients with Barrett go on to develop esophageal cancer.46
In a well-conducted case control study in Sweden, reflux symptoms were associated with a 7- to 10-fold increase in the risk of esophageal adenocarcinoma. A dose-response risk was noted for symptom frequency, severity, and duration.47 However, because adenocarcinoma of the esophagus is so rare, the authors note that a family physician would need to perform endoscopy on more than 1400 men older than 40 years who have severe GERD symptoms to identify 1 case of cancer. Further, there are no data to suggest that treating GERD will reduce the likelihood of these more serious sequelae.
1. Heading R. Prevalence of upper gastrointestinal symptoms in the general population: a systematic review. Scand J Gastroenterol 1999;34:3-8.
2. Haycox A, Einarson T, Eggleston A. The health economic impact of upper gastrointestinal symptoms in the general population: Results from DIGEST. Scand J Gastroenterol 1999;231:38-47.
3. Centers for Disease Control and Prevention. 1995 National Ambulatory Medical Care Survey. NCHS CD-ROM Series 13, No. 11, Issued July, 1997.
4. Dimenas E, Glise H, Hallerback B. Quality of life in patients with upper gastrointestinal symptoms: an improved evaluation of treatment regimens? Scan J Gastroenterol 1993;28:681-87.
5. Loffeld RJ, Werdmuller BF, Kuster JG, et al. Colonization with cagA-positive Helicobacter pylori strains inversely associated with reflux esophagitis and Barrett’s esophagus. Digestion 2000;62:95-9.
6. Katz PO, Dalton CB, Richter JE, et al. Esophageal testing of patients with noncardiac chest pain or dysphagia. Results of three years’ experience with 1161 patients. Ann Intern Med 1987;106:593-7.
7. Irwin RS, French CL, Curley FJ, et al. Chronic cough due to gastroesophageal reflux. Clinical, diagnostic and pathogenetic aspects. Chest 1993;194:1511-17.
8. Wiener GJ, Koufman JA, Wu WC, et al. Chronic hoarseness secondary to gastroesohageal reflux disease: documentation with 24-hour ambulatory pH monitoring. Am J Gastroenterol 1989;84:1503-08.
9. Gibson PG, Henry RL, Goughlan JL. Gastro-oesophageal reflux treatment for asthma in adults and children. The Cochrane Library, Issue 2 2000; Update Software, Inc.
10. Haque M, Wyeth JW, Stace NH, et al. Prevalence, severity and associated features of gastro-oesophageal reflux and dyspepsia: a population-based study. N Z Med J 2000;113:178-81.
11. Klauser A, Schindlbeck N, Muller-Lissner S. Symptoms of gastrooesophageal reflux disease. Lancet 1990;335:205-8.
12. Fass R, Fennerty MB, Ofman JJ, et al. The clinical and economic value of a short course of omeprazole in patients with noncardiac chest pain. Gastroenterol 1998;115:42-9.
13. Offman JJ, Gralnek IM, Udani J, et al. The cost-effectiveness of the omeprazole test in patients with noncardiac chest pain. Am J Med 1999;107:219-27.
14. Sonneberg A, Delco F, El-Serag HB. Empirical therapy versus diagnostic tests in gastroesophageal reflux disease. Dig Dis Sci 1998;43:1001-08.
15. The role of endoscopy in the management of GERD: guidelines for clinical application Gastrointest Endosc 1999;49:834-5.
16. Guidelines on the use of esophageal pH recording. Gastroenterol 1996;110:1981.-
17. Becker DJ, Sinclair J, Castell DO, et al. A comparison of high and low fat meals on postprandial esophageal acid exposure. Am J Gastroenterol 1989;782-86.
18. Allen ML, Mellow MH, Robinson MG, et al. The effect of raw onions on acid reflux and reflux symptoms. Am J Gastroent 1990;85:377-80.
19. Sigmund CJ, McNally EF. The action of carminative on the lower esophageal sphincter. Gastroenterol 1969;56:13-18.
20. Murphy DW, Castell DO. Chocolate and heartburn: evidence of increased esophageal acid exposure after chocolate ingestion. Am J Gastroenterol 1988;83:633-36.
21. Waring JP, Eastwood TF, Austin JM, et al. The immediate effects of cessation of cigarette smoking on gastroesophageal reflux. Am J Gastroenterol 1989;84:1076-78.
22. Stanciu C, Bennett JR. Effects of posture on gastro-oesophageal reflux. Digestion 1977;15:104-09.
23. Johnson LF, DeMeester TR. Evaluation of elevation of the head of the bed, bethanechol, and antacid foam tablets on gastroesophageal reflux. Dig Dis Sci 1981;26:673-80.
24. Galmiche JP, Letessier E, Scarpignato C. Treatment of gastro-oesophageal reflux disease in adults. Brit Med J 1998;316:1720-723.
25. DeVault K, Castell D. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol 1999;94:1434-442.
26. McCallum RW, Fink SM, Wiman GR, et al. Metoclopramide in gastroesophageal reflux disease: rationale for its use and results of a double-blind trial. Am J of Gastroenterol 1984;79:165-75.
27. Farrell R, Roling G, Castell D. Cholinergic therapy of chronic heartburn. Ann Int Med 1982;80:573-76.
28. Iskedjian M, Einarson TR. Meta-analyses of cisapride, omeprazole and ranitidine in the treatment of GORD: implications for treating patient subgroups. Clin Drug Invest 1998;16:9-18.
29. Graham DY, Patterson DJ. Double-blind comparison of liquid antacid and placebo in the treatment of symptomatic reflux esophagitis. Dig Dis Sci 1983;28:559-63.
30. Stanciu C, Bennett JR. Alginate/antacide in the reduction of gastroesophageal reflux. Lancet 1974;1:109-11.
31. Leiberman DA. Medical therapy for chronic reflux esophagitis: long-term follow-up. Arch Intern Med 1987;147:1717-720.
32. Pace F, Maconi G, Molteni M, et al. Meta-analysis of the effect of placebo on the outcome of medically treated reflux esophagitis. Scand J of Gastro 1995;30:101-05.
33. Chiba N. Proton pump inhibitors in acute healing and maintenance of erosive or worse esophagitis: a systematic overview. Can J Gastroenterol 1997;11:66B-73B.
34. Pohle T, Domschke W. Results of short- and long-term medical treatment of gastroesophageal reflux disease. Langenbecke Arch Surg 2000;385:317-23.
35. Moore RA, Phillips C. Reflux oesophagitis: quantitative systematic review of the evidence of effectiveness of proton pump inhibitors and histamine agonists. Bandolier Web site: gord.html. Accessed May 30, 2000.
36. Kahrilas PJ. Gastroesophageal reflux disease. J Amer Med Assoc 1996;276:983-88.
37. Swarbrick ET, Gough AL, Foster CS, et al. Prevention of recurrence of oesophageal stricture a comparative study of lansoprazole and high dose ranitidine. Euro J Gastroenterol Hepatol 1996;8:431-38.
38. Guidelines for surgical treatment of gastroesophageal reflux disease (GERD). Society of American Gastrointestinal Endoscopic Surgeons (SAGES). Surg Endosc 1998;12:186-88.
39. Lundell L, Dalenvack J, Hattlevakk J, et al. Omeprazole or antireflux surgery in the long term management of gastroesophageal reflux disease: results of a multicentre, randomized, clinical trial. Gastroenterol 1998;114:A207.-
40. VanDenBoom G, Go P, Hameeteman W, et al. Cost effectiveness of medical versus surgical treatment in patients with severe or refractory gastroesophageal reflux disease in The Netherlands. Scand J Gastroenterol 1996;31:1-9.
41. Heudebert G, Marks R, Wilcox C, et al. Choice of long-term strategy for the management of patients with severe esophagitis: a cost-utility analysis. Gastroenterol 1997;112:1078-86.
42. Bardham KD, Muller-Lissner S, Bigard MA, et al. Symptomatic gastroesophageal reflux disease: double blind controlled study of intermittent treatment with omeprazole or ranitidine. BMJ 1999;318:502-07.
43. El-Serag HB, Sonnenberg A. Associations between different forms of gastrooesophageal reflux disease. Gut 1997;41:594-99.
44. Lieberman DA, Oehlke M, Helfand M. Risk Factors for Barrett’s esophagus in community-based practice. Am J Gastroenterol 1997;92:1293-297.
45. Shaheen NJ, Crosby MA, Bozymski EM, Sandler RS. Is there publication bias in the reporting of cancer risk in Barrett’s esophagus? Gastroenterology 2000;119:333-8.
46. Reid BJ, Levine DS, Longton G, Blount P, Rabinovitch PS. Predictors of progression to cancer in Barrett’s esophagus: baseline histology and flow cytometry identify low and high-risk patient subsets. Am J Gastroenterol 2000;95:1669-676.
47. Lagergren J, Bergstrom R, Lindgren A, et al. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 1999;340:825-31.
48. Isolauri J, Laipala P. Prevalence of symptoms suggestive of gastrooesophageal reflux disease in an adult population. Ann Med 1995;27:67-70.
49. Nebel O, Fornes M, Castell D. Symptomatic gastroesophageal reflux: incidence and precipitating factors. Am J Dig Dis 1976;21:953-56.
50. Raiha IJ, Impivaara O, Seppala M, et al. Prevalence and characteristics of symptomatic gastroesohageal reflux disease in the elderly. J Am Geriatr Soc 1992;40:1209-211.
51. Johnsson F, Loelsson B, Gudmundsson K, et al. Symptoms and endoscopic findings in the diagnosis of gastroesophageal reflux disease. Scand J Gastroenterol 1987;22:714-18.
52. Vitale GC, Cheadle WG, Sadek S, et al. Computerized 24-hour ambulatory esophageal pH monitoring and esophagogastroduodenoscopy in the reflux patient. Ann Surg 1984;200:724-28.
53. Harris RA, Kuppermann M, Richter JE. Proton pump inhibitors or histamine-2 receptor antagonists for the prevention of recurrences of erosive reflux esophagitis: a cost-effectiveness analysis. Am J Gastro 1997;92:2179-86
Gastroesophageal reflux disease (GERD) is defined as symptoms or tissue damage that results from the abnormal reflux of gastric contents into the esophagus. A systematic review of population-based studies estimates that heartburn or regurgitation symptoms occur in 21% to 59% of the population during a given year.1 The frequency of GERD in specific populations is provided in Table 1. Although only 1 in 5 patients with upper intestinal symptoms that occur at least weekly seeks medical attention,2 nearly 1% of all visits to a family physician’s office are for GERD or related conditions.3
GERD significantly affects the quality of patients’ lives. In a survey of patients presenting for upper endoscopy with symptoms of at least 3 months’ duration, those with a diagnosis of GERD reported low scores at baseline for general wellbeing. Fortunately, follow-up data reported 4 weeks after treatment note improvement in gastrointestinal symptoms, general well-being, general health, vitality, and depression.4
Pathophysiology
The pathogenesis of GERD is multifactorial and is thought to involve lower than normal esophageal sphincter pressures. This allows gastric acidic content to reflux into the distal esophagus, which lacks a protective barrier, causing esophagitis. Inflamed tissue impairs the normal clearance of acid, worsening the esophagitis, which inhibits normal motility.
Although Helicobacter pylori is clearly associated with peptic ulcer disease, its association with GERD is still debated. Data from case control studies actually suggest an inverse association; that is, that the presence of H pylori may be protective against the development of GERD.5
Because of the anatomical location of the esophagus, GERD should be considered in the differential diagnosis for presenting complaints other than regurgitation or dyspepsia. For example, approximately 50% of patients with chest pain in whom cardiac etiology is ruled out will ultimately be given a diagnosis of GERD.6 Similarly, 10% of patients with chronic cough7 and 78% of patients with laryngitis have GERD.8 Clear associations between GERD and asthma have been demonstrated, but data from meta-analyses fail to show improvement of asthma symptoms when GERD is appropriately treated.9
Diagnosis
The diagnosis of GERD can usually be made without the use of invasive tests. The accuracy of key tests, including clinical history, is outlined in Table 2. One study of patients presenting with dyspepsia (signs and symptoms referable to the upper gastrointestinal tract) found that 56% also have GERD.10 Another showed that 60% of patients referred for pH monitoring had GERD.11 Since reasonable prevalence estimates for GERD in the family practice setting may be slightly lower, calculations in Table 2 assume that between 40% and 60% of patients with suspected GERD actually have the condition.
Individual symptoms of GERD such as heartburn, regurgitation, belching, or dyspepsia are of limited usefulness in diagnosis. In a survey of patients referred for pH monitoring likelihood ratios hovered near 1, meaning that the presence or absence of the symptom had little impact on the diagnosis.11 The clinician’s overall impression that a patient has GERD, however, is much more useful to rule in disease than any individual symptoms.11 Assuming that half of patients with suspected GERD have the disease, if a clinician suspects GERD, that probability increases to 77%. Most clinicians would find a trial of empiric therapy appropriate at that probability.
The omeprazole test is also helpful in confirming a diagnosis of GERD. It consists of the patient taking 40 mg omeprazole in the morning and 20 mg at night for 1 week. If the symptoms resolve, the test is considered diagnostic of GERD.12 Some consider this approach to be therapeutic, as well as diagnostic. Beginning with an omeprazole test and reserving invasive testing for those not responding to the medication was cost-effective for patients with noncardiac chest pain.13 In a decision analysis, empiric treatment with omeprazole was a cost-effective approach to the management of GERD.14 Of course, initial endoscopy is indicated for patients with “red flags”: signs and symptoms consistent with obstruction, bleeding, or perforation, and those older than 50 years who are at a higher risk of malignancy.
Upper endoscopy, however, is not very accurate in diagnosing GERD. Among patients with GERD, only 22% have esophageal erythema, and only 48% have erosions or ulcerations. Therefore, because of costs and limited resources, the American Society for Gastrointestinal Endoscopy recommends that endoscopy be reserved for patients presenting with possible GERD who also have symptoms of more serious disease (dysphagia, weight loss, gastrointestinal bleeding) and for those not responding to a reasonable trial of therapy.15 The goal is to rule out more serious conditions.
Twenty-four–hour pH monitoring, while more accurate than endoscopy, is also reserved as a second-line test. According to the American Gastro-enterological Association guidelines, pH recording is indicated when endoscopy is normal and reflux symptoms persist despite acid suppression therapy or to evaluate extra-esophageal symptoms that may be GERD (ie, atypical chest pain or chronic cough).16 The goal here is to rule in GERD as the etiology of the patient’s symptoms.
Numerous other tests have been proposed to evaluate the patient with suspected GERD: manometry, scintigraphy, esophograms (as part of upper gastrointestinal series), and the Bernstein test (a provocative challenge with hydrochloric acid infusion). Data on the accuracy of these tests are limited by the lack of an accepted reference standard, and most have fallen out of favor because of their inconvenience or limited accuracy. None are more helpful than pH monitoring or endoscopy, and they are therefore not recommended.
Treatment
Pharmacologic
Treatments for GERD address the pathophysiology of the disease; they tend to target the removal of precipitating factors, using gravity or medications to improve acid clearance, lower the acidity of gastric contents, or improve the esophageal sphincter tone. Short-term treatment goals are to relieve symptoms and heal esophagitis; long-term goals are to prevent relapses and sequelae, such as esophageal stricture formation or adenocarcinoma.
Recommendations for lifestyle modifications to lessen GERD symptoms are extensive and mostly based on pathophysiologic data. Possible triggers for GERD include obesity, tight clothing, fatty foods, alcohol, tobacco, caffeine, onions, peppermint, and chocolate.17-21 Because symptoms are typically worse at night, elevating the head of the bed or avoiding postprandial recumbency is recommended.22,23 Eliminating these factors has been shown to decrease the amount of acid in the distal esophagus or improve the pressure readings on manometry. This is disease-oriented evidence; it does not necessarily translate into reduced symptoms for patients. The only patient-oriented evidence that supports lifestyle modification is a small crossover trial in which subjects had less heartburn and belching following a hamburger meal compared with the same meal with onions on the burger.18 Despite the lack of high-quality evidence of effectiveness, guidelines recommend lifestyle modification as the first-line therapy or adjunct to additional medication.24,25 Because these lifestyle changes are not thought to be harmful and may have other possible health benefits it is reasonable to recommend them to patients until better studies are published.
Promotility agents are a possible treatment of GERD because they improve acid clearance from the esophagus. Older agents such as metoclopramide and bethanecol have little data to support their use26,27 and are further limited by their central nervous system side effects. A meta-analysis of trial data found that cisapride heals esophagitis and decreases symptoms of GERD28 but was taken off the market because of problems with cardiac arrhythmias.
Acid suppression strategies available over-the-counter include antacids, alginates, and H2-blockers (H2Bs). Small, short-term trials have demonstrated mixed results with regard to symptom relief and lessened acid exposure from both antacids and alginates.29,30 Longer follow-up in cohort studies suggests a modest benefit from antacids.31 More than 24 randomized controlled trials (RCTs) have demonstrated the benefits of H2Bs in the treatment of GERD for both healing esophagitis and symptom relief. The number needed to treat (NNT) is 5; that is, for every 5 GERD patients treated with H2Bs instead of placebo, 1 patient benefits.32 H2Bs also prevent the long-term recurrence of symptoms (NNT =15).33 There is no clear benefit of one H2B agent over another. Proton pump inhibitors (PPIs) are also well supported by meta-analyses of RCTs in the short term (NNT = 2) and long term (NNT = 3) treatment of GERD.33 As with H2Bs, no clear advantage is found between different PPI medications.
STEPS. Using the STEPS approach (Safety, Tolerability, Efficacy, Price, Simplicity) to compare H2Bs and PPIs is one way to help guide management of GERD. H2Bs are not associated with any serious long-term complications. PPIs are theoretically linked to malignancy through 2 mechanisms: proliferation of endocrine cells leading to endocrine neoplasia and atrophic gastritis caused by chronic acid suppression as a precursor to gastric adenocarcinoma. However, studies have not borne out these concerns.34 Thus, both H2Bs and PPIs seem equally safe. The best measure of tolerability is the pooled dropout rate, which is the number of patients dropping out of a study for any reason. Dropout rates are about the same for H2Bs and PPIs.35 Meta-analyses of trials comparing the efficacy of H2Bs to PPIs in the short- and long-term treatment of GERD consistently favor PPIs.33,35 Of 100 patients with GERD, approximately 25 will benefit from treatment with an H2B, and 75 to 80 will benefit from treatment with a PPI.33 An interesting comparison of trials suggests that the therapeutic gain of PPIs is greatest in those patients with more severe GERD.36 Little data exist about the prevention of complications of GERD with acid suppression. However, 1 small trial found a decreased rate of esophageal stricture recurrence at 1 year in patients with reflux esophagitis (NNT =7) treated with 30-mg lansoprazole compared with those treated with 300-mg ranitidine.37 These data seem to suggest that high-risk patients are more apt to benefit from PPIs than H2Bs.
Because H2Bs are now available in generic forms, price tips the scales greatly in their favor. The average cost for PPIs is nearly 10 times that of generic H2Bs (3020-mg omeprazole tablets cost $105.55 and 60 150-mg ranitidine tablets cost $10.98 as of 11/0/00). Simplicity is a toss-up: most PPIs are dosed once daily, while H2Bs are given once or twice daily. A general approach is to start patients with GERD on a reasonable dose of H2Bs, and move on to PPIs if symptoms do not resolve in 2 to 4 weeks.25,54 Some insurance companies require documentation of H2B failure before covering the increased costs of PPIs, despite their efficacy advantage.
Surgery
For patients with chronic or recurrent GERD, surgery offers an additional treatment option. Prospective cohort studies note that open Nissen fundoplication produces an 80% to 93% success rate at 10-year follow-up. Laproscopic procedures are producing similar short-term results, but long-term data are pending.38 One randomized trial demonstrated equivalent 3-year outcomes for those undergoing Nissen fundoplication and those taking 40 mg omeprazole daily.39 Decision analysis data favor the cost effectiveness of open Nissen40 if medical treatment will be required for more than 4 years, and laproscopic procedure if medical treatment will be needed for more than 10 years.41
Prognosis
GERD may be a short-term intermittent problem or may be severe and chronic in nature. Untreated, approximately 15% of patients will have symptom relief.32 Antacids can raise that rate to an estimated 20%,31,25 while H2Bs are associated with symptom-free rates of approximately 25%.30 The best outcomes are found with PPIs, where recurrence of GERD symptoms is suppressed in 75% to 82% of patients at 1-year follow-up.33,35
Although many patients will experience recurrences, chronic medications may not be necessary. In 1 study, 677 patients with heartburn and mild esophagitis were randomized to treatment with omeprazole or ranitidine for 2 weeks. If symptoms persisted, the dose of medication was doubled. If symptoms resolved, medication was stopped. Recurrences were treated for 2 to 4 weeks at the previously effective dose. Nearly half the patients were successfully treated with intermittent medication, and nearly 40% of initial responders required no further treatment.42
GERD is associated with esophageal strictures, Barrett esophagus (metaplasia of the distal esophageal columnar cells, thought to be a precursor of dysplasia and cancer) and adenocarcinoma. Limited data are available for the actual incidence of stricture in GERD patients. One retrospective cohort study of patients discharged from veterans’ administration hospitals found that 8.4% of patients with GERD had strictures, and the association between esophageal ulcers and stricture was significant.43 This study likely suffered from significant selection bias, however, and the rate in primary care practice is almost certainly much lower. Barrett was noted in 11.6% of 662 patients with GERD referred from general practice settings for endoscopy.44 Again, though, patients with GERD referred for endoscopy are likely to have more severe disease, and a recent meta-analysis suggests that the actual risk of Barrett in unselected patients is closer to 3% to 4%.45 A longer duration of symptoms was associated with an increase risk. Patients with Barrett esophagus; negative, low-grade, or indefinite dysplasia; and neither aneuploidy or increased 4N on flow cytometry are at very low risk of esophageal cancer (<2% over 5 years). Only approximately 4% of patients with Barrett go on to develop esophageal cancer.46
In a well-conducted case control study in Sweden, reflux symptoms were associated with a 7- to 10-fold increase in the risk of esophageal adenocarcinoma. A dose-response risk was noted for symptom frequency, severity, and duration.47 However, because adenocarcinoma of the esophagus is so rare, the authors note that a family physician would need to perform endoscopy on more than 1400 men older than 40 years who have severe GERD symptoms to identify 1 case of cancer. Further, there are no data to suggest that treating GERD will reduce the likelihood of these more serious sequelae.
Gastroesophageal reflux disease (GERD) is defined as symptoms or tissue damage that results from the abnormal reflux of gastric contents into the esophagus. A systematic review of population-based studies estimates that heartburn or regurgitation symptoms occur in 21% to 59% of the population during a given year.1 The frequency of GERD in specific populations is provided in Table 1. Although only 1 in 5 patients with upper intestinal symptoms that occur at least weekly seeks medical attention,2 nearly 1% of all visits to a family physician’s office are for GERD or related conditions.3
GERD significantly affects the quality of patients’ lives. In a survey of patients presenting for upper endoscopy with symptoms of at least 3 months’ duration, those with a diagnosis of GERD reported low scores at baseline for general wellbeing. Fortunately, follow-up data reported 4 weeks after treatment note improvement in gastrointestinal symptoms, general well-being, general health, vitality, and depression.4
Pathophysiology
The pathogenesis of GERD is multifactorial and is thought to involve lower than normal esophageal sphincter pressures. This allows gastric acidic content to reflux into the distal esophagus, which lacks a protective barrier, causing esophagitis. Inflamed tissue impairs the normal clearance of acid, worsening the esophagitis, which inhibits normal motility.
Although Helicobacter pylori is clearly associated with peptic ulcer disease, its association with GERD is still debated. Data from case control studies actually suggest an inverse association; that is, that the presence of H pylori may be protective against the development of GERD.5
Because of the anatomical location of the esophagus, GERD should be considered in the differential diagnosis for presenting complaints other than regurgitation or dyspepsia. For example, approximately 50% of patients with chest pain in whom cardiac etiology is ruled out will ultimately be given a diagnosis of GERD.6 Similarly, 10% of patients with chronic cough7 and 78% of patients with laryngitis have GERD.8 Clear associations between GERD and asthma have been demonstrated, but data from meta-analyses fail to show improvement of asthma symptoms when GERD is appropriately treated.9
Diagnosis
The diagnosis of GERD can usually be made without the use of invasive tests. The accuracy of key tests, including clinical history, is outlined in Table 2. One study of patients presenting with dyspepsia (signs and symptoms referable to the upper gastrointestinal tract) found that 56% also have GERD.10 Another showed that 60% of patients referred for pH monitoring had GERD.11 Since reasonable prevalence estimates for GERD in the family practice setting may be slightly lower, calculations in Table 2 assume that between 40% and 60% of patients with suspected GERD actually have the condition.
Individual symptoms of GERD such as heartburn, regurgitation, belching, or dyspepsia are of limited usefulness in diagnosis. In a survey of patients referred for pH monitoring likelihood ratios hovered near 1, meaning that the presence or absence of the symptom had little impact on the diagnosis.11 The clinician’s overall impression that a patient has GERD, however, is much more useful to rule in disease than any individual symptoms.11 Assuming that half of patients with suspected GERD have the disease, if a clinician suspects GERD, that probability increases to 77%. Most clinicians would find a trial of empiric therapy appropriate at that probability.
The omeprazole test is also helpful in confirming a diagnosis of GERD. It consists of the patient taking 40 mg omeprazole in the morning and 20 mg at night for 1 week. If the symptoms resolve, the test is considered diagnostic of GERD.12 Some consider this approach to be therapeutic, as well as diagnostic. Beginning with an omeprazole test and reserving invasive testing for those not responding to the medication was cost-effective for patients with noncardiac chest pain.13 In a decision analysis, empiric treatment with omeprazole was a cost-effective approach to the management of GERD.14 Of course, initial endoscopy is indicated for patients with “red flags”: signs and symptoms consistent with obstruction, bleeding, or perforation, and those older than 50 years who are at a higher risk of malignancy.
Upper endoscopy, however, is not very accurate in diagnosing GERD. Among patients with GERD, only 22% have esophageal erythema, and only 48% have erosions or ulcerations. Therefore, because of costs and limited resources, the American Society for Gastrointestinal Endoscopy recommends that endoscopy be reserved for patients presenting with possible GERD who also have symptoms of more serious disease (dysphagia, weight loss, gastrointestinal bleeding) and for those not responding to a reasonable trial of therapy.15 The goal is to rule out more serious conditions.
Twenty-four–hour pH monitoring, while more accurate than endoscopy, is also reserved as a second-line test. According to the American Gastro-enterological Association guidelines, pH recording is indicated when endoscopy is normal and reflux symptoms persist despite acid suppression therapy or to evaluate extra-esophageal symptoms that may be GERD (ie, atypical chest pain or chronic cough).16 The goal here is to rule in GERD as the etiology of the patient’s symptoms.
Numerous other tests have been proposed to evaluate the patient with suspected GERD: manometry, scintigraphy, esophograms (as part of upper gastrointestinal series), and the Bernstein test (a provocative challenge with hydrochloric acid infusion). Data on the accuracy of these tests are limited by the lack of an accepted reference standard, and most have fallen out of favor because of their inconvenience or limited accuracy. None are more helpful than pH monitoring or endoscopy, and they are therefore not recommended.
Treatment
Pharmacologic
Treatments for GERD address the pathophysiology of the disease; they tend to target the removal of precipitating factors, using gravity or medications to improve acid clearance, lower the acidity of gastric contents, or improve the esophageal sphincter tone. Short-term treatment goals are to relieve symptoms and heal esophagitis; long-term goals are to prevent relapses and sequelae, such as esophageal stricture formation or adenocarcinoma.
Recommendations for lifestyle modifications to lessen GERD symptoms are extensive and mostly based on pathophysiologic data. Possible triggers for GERD include obesity, tight clothing, fatty foods, alcohol, tobacco, caffeine, onions, peppermint, and chocolate.17-21 Because symptoms are typically worse at night, elevating the head of the bed or avoiding postprandial recumbency is recommended.22,23 Eliminating these factors has been shown to decrease the amount of acid in the distal esophagus or improve the pressure readings on manometry. This is disease-oriented evidence; it does not necessarily translate into reduced symptoms for patients. The only patient-oriented evidence that supports lifestyle modification is a small crossover trial in which subjects had less heartburn and belching following a hamburger meal compared with the same meal with onions on the burger.18 Despite the lack of high-quality evidence of effectiveness, guidelines recommend lifestyle modification as the first-line therapy or adjunct to additional medication.24,25 Because these lifestyle changes are not thought to be harmful and may have other possible health benefits it is reasonable to recommend them to patients until better studies are published.
Promotility agents are a possible treatment of GERD because they improve acid clearance from the esophagus. Older agents such as metoclopramide and bethanecol have little data to support their use26,27 and are further limited by their central nervous system side effects. A meta-analysis of trial data found that cisapride heals esophagitis and decreases symptoms of GERD28 but was taken off the market because of problems with cardiac arrhythmias.
Acid suppression strategies available over-the-counter include antacids, alginates, and H2-blockers (H2Bs). Small, short-term trials have demonstrated mixed results with regard to symptom relief and lessened acid exposure from both antacids and alginates.29,30 Longer follow-up in cohort studies suggests a modest benefit from antacids.31 More than 24 randomized controlled trials (RCTs) have demonstrated the benefits of H2Bs in the treatment of GERD for both healing esophagitis and symptom relief. The number needed to treat (NNT) is 5; that is, for every 5 GERD patients treated with H2Bs instead of placebo, 1 patient benefits.32 H2Bs also prevent the long-term recurrence of symptoms (NNT =15).33 There is no clear benefit of one H2B agent over another. Proton pump inhibitors (PPIs) are also well supported by meta-analyses of RCTs in the short term (NNT = 2) and long term (NNT = 3) treatment of GERD.33 As with H2Bs, no clear advantage is found between different PPI medications.
STEPS. Using the STEPS approach (Safety, Tolerability, Efficacy, Price, Simplicity) to compare H2Bs and PPIs is one way to help guide management of GERD. H2Bs are not associated with any serious long-term complications. PPIs are theoretically linked to malignancy through 2 mechanisms: proliferation of endocrine cells leading to endocrine neoplasia and atrophic gastritis caused by chronic acid suppression as a precursor to gastric adenocarcinoma. However, studies have not borne out these concerns.34 Thus, both H2Bs and PPIs seem equally safe. The best measure of tolerability is the pooled dropout rate, which is the number of patients dropping out of a study for any reason. Dropout rates are about the same for H2Bs and PPIs.35 Meta-analyses of trials comparing the efficacy of H2Bs to PPIs in the short- and long-term treatment of GERD consistently favor PPIs.33,35 Of 100 patients with GERD, approximately 25 will benefit from treatment with an H2B, and 75 to 80 will benefit from treatment with a PPI.33 An interesting comparison of trials suggests that the therapeutic gain of PPIs is greatest in those patients with more severe GERD.36 Little data exist about the prevention of complications of GERD with acid suppression. However, 1 small trial found a decreased rate of esophageal stricture recurrence at 1 year in patients with reflux esophagitis (NNT =7) treated with 30-mg lansoprazole compared with those treated with 300-mg ranitidine.37 These data seem to suggest that high-risk patients are more apt to benefit from PPIs than H2Bs.
Because H2Bs are now available in generic forms, price tips the scales greatly in their favor. The average cost for PPIs is nearly 10 times that of generic H2Bs (3020-mg omeprazole tablets cost $105.55 and 60 150-mg ranitidine tablets cost $10.98 as of 11/0/00). Simplicity is a toss-up: most PPIs are dosed once daily, while H2Bs are given once or twice daily. A general approach is to start patients with GERD on a reasonable dose of H2Bs, and move on to PPIs if symptoms do not resolve in 2 to 4 weeks.25,54 Some insurance companies require documentation of H2B failure before covering the increased costs of PPIs, despite their efficacy advantage.
Surgery
For patients with chronic or recurrent GERD, surgery offers an additional treatment option. Prospective cohort studies note that open Nissen fundoplication produces an 80% to 93% success rate at 10-year follow-up. Laproscopic procedures are producing similar short-term results, but long-term data are pending.38 One randomized trial demonstrated equivalent 3-year outcomes for those undergoing Nissen fundoplication and those taking 40 mg omeprazole daily.39 Decision analysis data favor the cost effectiveness of open Nissen40 if medical treatment will be required for more than 4 years, and laproscopic procedure if medical treatment will be needed for more than 10 years.41
Prognosis
GERD may be a short-term intermittent problem or may be severe and chronic in nature. Untreated, approximately 15% of patients will have symptom relief.32 Antacids can raise that rate to an estimated 20%,31,25 while H2Bs are associated with symptom-free rates of approximately 25%.30 The best outcomes are found with PPIs, where recurrence of GERD symptoms is suppressed in 75% to 82% of patients at 1-year follow-up.33,35
Although many patients will experience recurrences, chronic medications may not be necessary. In 1 study, 677 patients with heartburn and mild esophagitis were randomized to treatment with omeprazole or ranitidine for 2 weeks. If symptoms persisted, the dose of medication was doubled. If symptoms resolved, medication was stopped. Recurrences were treated for 2 to 4 weeks at the previously effective dose. Nearly half the patients were successfully treated with intermittent medication, and nearly 40% of initial responders required no further treatment.42
GERD is associated with esophageal strictures, Barrett esophagus (metaplasia of the distal esophageal columnar cells, thought to be a precursor of dysplasia and cancer) and adenocarcinoma. Limited data are available for the actual incidence of stricture in GERD patients. One retrospective cohort study of patients discharged from veterans’ administration hospitals found that 8.4% of patients with GERD had strictures, and the association between esophageal ulcers and stricture was significant.43 This study likely suffered from significant selection bias, however, and the rate in primary care practice is almost certainly much lower. Barrett was noted in 11.6% of 662 patients with GERD referred from general practice settings for endoscopy.44 Again, though, patients with GERD referred for endoscopy are likely to have more severe disease, and a recent meta-analysis suggests that the actual risk of Barrett in unselected patients is closer to 3% to 4%.45 A longer duration of symptoms was associated with an increase risk. Patients with Barrett esophagus; negative, low-grade, or indefinite dysplasia; and neither aneuploidy or increased 4N on flow cytometry are at very low risk of esophageal cancer (<2% over 5 years). Only approximately 4% of patients with Barrett go on to develop esophageal cancer.46
In a well-conducted case control study in Sweden, reflux symptoms were associated with a 7- to 10-fold increase in the risk of esophageal adenocarcinoma. A dose-response risk was noted for symptom frequency, severity, and duration.47 However, because adenocarcinoma of the esophagus is so rare, the authors note that a family physician would need to perform endoscopy on more than 1400 men older than 40 years who have severe GERD symptoms to identify 1 case of cancer. Further, there are no data to suggest that treating GERD will reduce the likelihood of these more serious sequelae.
1. Heading R. Prevalence of upper gastrointestinal symptoms in the general population: a systematic review. Scand J Gastroenterol 1999;34:3-8.
2. Haycox A, Einarson T, Eggleston A. The health economic impact of upper gastrointestinal symptoms in the general population: Results from DIGEST. Scand J Gastroenterol 1999;231:38-47.
3. Centers for Disease Control and Prevention. 1995 National Ambulatory Medical Care Survey. NCHS CD-ROM Series 13, No. 11, Issued July, 1997.
4. Dimenas E, Glise H, Hallerback B. Quality of life in patients with upper gastrointestinal symptoms: an improved evaluation of treatment regimens? Scan J Gastroenterol 1993;28:681-87.
5. Loffeld RJ, Werdmuller BF, Kuster JG, et al. Colonization with cagA-positive Helicobacter pylori strains inversely associated with reflux esophagitis and Barrett’s esophagus. Digestion 2000;62:95-9.
6. Katz PO, Dalton CB, Richter JE, et al. Esophageal testing of patients with noncardiac chest pain or dysphagia. Results of three years’ experience with 1161 patients. Ann Intern Med 1987;106:593-7.
7. Irwin RS, French CL, Curley FJ, et al. Chronic cough due to gastroesophageal reflux. Clinical, diagnostic and pathogenetic aspects. Chest 1993;194:1511-17.
8. Wiener GJ, Koufman JA, Wu WC, et al. Chronic hoarseness secondary to gastroesohageal reflux disease: documentation with 24-hour ambulatory pH monitoring. Am J Gastroenterol 1989;84:1503-08.
9. Gibson PG, Henry RL, Goughlan JL. Gastro-oesophageal reflux treatment for asthma in adults and children. The Cochrane Library, Issue 2 2000; Update Software, Inc.
10. Haque M, Wyeth JW, Stace NH, et al. Prevalence, severity and associated features of gastro-oesophageal reflux and dyspepsia: a population-based study. N Z Med J 2000;113:178-81.
11. Klauser A, Schindlbeck N, Muller-Lissner S. Symptoms of gastrooesophageal reflux disease. Lancet 1990;335:205-8.
12. Fass R, Fennerty MB, Ofman JJ, et al. The clinical and economic value of a short course of omeprazole in patients with noncardiac chest pain. Gastroenterol 1998;115:42-9.
13. Offman JJ, Gralnek IM, Udani J, et al. The cost-effectiveness of the omeprazole test in patients with noncardiac chest pain. Am J Med 1999;107:219-27.
14. Sonneberg A, Delco F, El-Serag HB. Empirical therapy versus diagnostic tests in gastroesophageal reflux disease. Dig Dis Sci 1998;43:1001-08.
15. The role of endoscopy in the management of GERD: guidelines for clinical application Gastrointest Endosc 1999;49:834-5.
16. Guidelines on the use of esophageal pH recording. Gastroenterol 1996;110:1981.-
17. Becker DJ, Sinclair J, Castell DO, et al. A comparison of high and low fat meals on postprandial esophageal acid exposure. Am J Gastroenterol 1989;782-86.
18. Allen ML, Mellow MH, Robinson MG, et al. The effect of raw onions on acid reflux and reflux symptoms. Am J Gastroent 1990;85:377-80.
19. Sigmund CJ, McNally EF. The action of carminative on the lower esophageal sphincter. Gastroenterol 1969;56:13-18.
20. Murphy DW, Castell DO. Chocolate and heartburn: evidence of increased esophageal acid exposure after chocolate ingestion. Am J Gastroenterol 1988;83:633-36.
21. Waring JP, Eastwood TF, Austin JM, et al. The immediate effects of cessation of cigarette smoking on gastroesophageal reflux. Am J Gastroenterol 1989;84:1076-78.
22. Stanciu C, Bennett JR. Effects of posture on gastro-oesophageal reflux. Digestion 1977;15:104-09.
23. Johnson LF, DeMeester TR. Evaluation of elevation of the head of the bed, bethanechol, and antacid foam tablets on gastroesophageal reflux. Dig Dis Sci 1981;26:673-80.
24. Galmiche JP, Letessier E, Scarpignato C. Treatment of gastro-oesophageal reflux disease in adults. Brit Med J 1998;316:1720-723.
25. DeVault K, Castell D. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol 1999;94:1434-442.
26. McCallum RW, Fink SM, Wiman GR, et al. Metoclopramide in gastroesophageal reflux disease: rationale for its use and results of a double-blind trial. Am J of Gastroenterol 1984;79:165-75.
27. Farrell R, Roling G, Castell D. Cholinergic therapy of chronic heartburn. Ann Int Med 1982;80:573-76.
28. Iskedjian M, Einarson TR. Meta-analyses of cisapride, omeprazole and ranitidine in the treatment of GORD: implications for treating patient subgroups. Clin Drug Invest 1998;16:9-18.
29. Graham DY, Patterson DJ. Double-blind comparison of liquid antacid and placebo in the treatment of symptomatic reflux esophagitis. Dig Dis Sci 1983;28:559-63.
30. Stanciu C, Bennett JR. Alginate/antacide in the reduction of gastroesophageal reflux. Lancet 1974;1:109-11.
31. Leiberman DA. Medical therapy for chronic reflux esophagitis: long-term follow-up. Arch Intern Med 1987;147:1717-720.
32. Pace F, Maconi G, Molteni M, et al. Meta-analysis of the effect of placebo on the outcome of medically treated reflux esophagitis. Scand J of Gastro 1995;30:101-05.
33. Chiba N. Proton pump inhibitors in acute healing and maintenance of erosive or worse esophagitis: a systematic overview. Can J Gastroenterol 1997;11:66B-73B.
34. Pohle T, Domschke W. Results of short- and long-term medical treatment of gastroesophageal reflux disease. Langenbecke Arch Surg 2000;385:317-23.
35. Moore RA, Phillips C. Reflux oesophagitis: quantitative systematic review of the evidence of effectiveness of proton pump inhibitors and histamine agonists. Bandolier Web site: gord.html. Accessed May 30, 2000.
36. Kahrilas PJ. Gastroesophageal reflux disease. J Amer Med Assoc 1996;276:983-88.
37. Swarbrick ET, Gough AL, Foster CS, et al. Prevention of recurrence of oesophageal stricture a comparative study of lansoprazole and high dose ranitidine. Euro J Gastroenterol Hepatol 1996;8:431-38.
38. Guidelines for surgical treatment of gastroesophageal reflux disease (GERD). Society of American Gastrointestinal Endoscopic Surgeons (SAGES). Surg Endosc 1998;12:186-88.
39. Lundell L, Dalenvack J, Hattlevakk J, et al. Omeprazole or antireflux surgery in the long term management of gastroesophageal reflux disease: results of a multicentre, randomized, clinical trial. Gastroenterol 1998;114:A207.-
40. VanDenBoom G, Go P, Hameeteman W, et al. Cost effectiveness of medical versus surgical treatment in patients with severe or refractory gastroesophageal reflux disease in The Netherlands. Scand J Gastroenterol 1996;31:1-9.
41. Heudebert G, Marks R, Wilcox C, et al. Choice of long-term strategy for the management of patients with severe esophagitis: a cost-utility analysis. Gastroenterol 1997;112:1078-86.
42. Bardham KD, Muller-Lissner S, Bigard MA, et al. Symptomatic gastroesophageal reflux disease: double blind controlled study of intermittent treatment with omeprazole or ranitidine. BMJ 1999;318:502-07.
43. El-Serag HB, Sonnenberg A. Associations between different forms of gastrooesophageal reflux disease. Gut 1997;41:594-99.
44. Lieberman DA, Oehlke M, Helfand M. Risk Factors for Barrett’s esophagus in community-based practice. Am J Gastroenterol 1997;92:1293-297.
45. Shaheen NJ, Crosby MA, Bozymski EM, Sandler RS. Is there publication bias in the reporting of cancer risk in Barrett’s esophagus? Gastroenterology 2000;119:333-8.
46. Reid BJ, Levine DS, Longton G, Blount P, Rabinovitch PS. Predictors of progression to cancer in Barrett’s esophagus: baseline histology and flow cytometry identify low and high-risk patient subsets. Am J Gastroenterol 2000;95:1669-676.
47. Lagergren J, Bergstrom R, Lindgren A, et al. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 1999;340:825-31.
48. Isolauri J, Laipala P. Prevalence of symptoms suggestive of gastrooesophageal reflux disease in an adult population. Ann Med 1995;27:67-70.
49. Nebel O, Fornes M, Castell D. Symptomatic gastroesophageal reflux: incidence and precipitating factors. Am J Dig Dis 1976;21:953-56.
50. Raiha IJ, Impivaara O, Seppala M, et al. Prevalence and characteristics of symptomatic gastroesohageal reflux disease in the elderly. J Am Geriatr Soc 1992;40:1209-211.
51. Johnsson F, Loelsson B, Gudmundsson K, et al. Symptoms and endoscopic findings in the diagnosis of gastroesophageal reflux disease. Scand J Gastroenterol 1987;22:714-18.
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53. Harris RA, Kuppermann M, Richter JE. Proton pump inhibitors or histamine-2 receptor antagonists for the prevention of recurrences of erosive reflux esophagitis: a cost-effectiveness analysis. Am J Gastro 1997;92:2179-86
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