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Targeting neuropathic pain: Consider these alternatives
Anticonvulsants, antidepressants, and opioids are the most frequently prescribed medications for neuropathic pain.1 But some patients are unable to tolerate the adverse effects of these drugs, and others achieve only partial pain relief. What can you offer them?
Combinations of prescription medications are generally considered more effective than monotherapy for painful peripheral neuropathy,1 but it is unclear which combinations are best. Alternative therapies—several of which have some evidence of safety and efficacy in treating peripheral neuropathy—are another option. Yet trials with alternative therapies, alone or in combination with prescription drugs, are rarely considered.
In fact, physicians are often unfamiliar with these therapies. Many are concerned about the absence of US Food and Drug Administration approval for alternative therapies and the variability in quality control associated with the lack of oversight, as well. Making recommendations about the duration of therapy also presents a challenge because most studies of supplements are relatively short. What’s more, alternative treatments are rarely covered by third-party payers.
Nonetheless, the therapies detailed in the text and TABLE2-12 that follow are generally well tolerated and appear to be safe. Adding them to your arsenal of therapeutic choices for patients with painful peripheral neuropathy may increase your ability to provide successful treatment.
Acetyl-L-carnitine (ALC)
ALC occurs naturally in the body as L-carnitine and acetyl-carnitine esters, which are converted to carnitines by intracellular enzymes and cell membrane transporters.2 ALC has been studied in patients with neuropathy associated with human immunodeficiency virus (HIV), cancer, and diabetes. Potential mechanisms of action include the correction of a deficiency that may be causing the neuropathy (which sometimes occurs in HIV-positive patients13 or those taking anticonvulsants14), a direct antioxidant effect, or an enhanced response to nerve growth factor.13
ALC can be given intramuscularly (IM) or orally in doses of 2000 to 3000 mg/d. In one randomized placebo-controlled trial (N=333), patients with diabetic neuropathy received 1000 mg IM followed by an oral dose of 2000 mg every day for a year.6 Mean pain scores decreased by 39%, with 67% of those receiving ALC vs 23% of those on placebo showing moderate to marked improvement.
In a pooled analysis (N=1257) of 2 randomized controlled trials (RCTs), patients with diabetes took 1000 mg ALC 3 times daily or placebo for a year.7 Cohort pain scores improved by 40% from baseline in the ALC group compared with a 24% improvement for those in the placebo group.
THE BOTTOM LINE ALC is well tolerated, with minor adverse effects such as headache and nausea reported.6,7 It should not be given to patients taking acenocoumarol or warfarin, however. A major interaction causing an elevated international normalized ratio has been found to occur when either agent is combined with L-carnitine2 and could theoretically occur with ALC, as well. No other drug-drug interactions have been documented.2
Alpha lipoic acid (ALA)
Both a fat- and a water-soluble vitamin that is usually obtained from the diet, ALA regenerates endogenous antioxidants like vitamins C and E and glutathione. It is this regenerative mechanism that it is believed to alleviate diabetic neuropathy.2 ALA 600 mg/d appears to be effective, although studies suggest that intravenous (IV) use is more effective than oral administration.
A meta-analysis of 4 RCTs (N=653), 2 with ALA taken orally and 2 involving IV administration, is a case in point.3 The pooled standardized mean difference estimated from all trials showed a reduction in total symptom scores of −2.26 (95% confidence interval [CI], −3.12 to −1.41; P=.00001), with 0 indicating no symptoms, 3 indicating severe symptoms, and a maximum score of 14.64 if all symptoms were severe and continuous. Subgroup analyses revealed a reduction of −1.78 (95% CI, −2.45 to −1.10; P=.00001) for oral ALA and −2.81 (95% CI, −4.16 to −1.46; P=.0001) for IV administration. Doses >600 mg/d did not improve efficacy, but did increase adverse effects such as nausea, vomiting, and dizziness.
In a multicenter RCT (N=460) of ALA 600 mg/d for 4 years, however, no improvement in the primary endpoint (a composite of neuropathy impairment scores and 7 neurophysiologic tests) was found.15 Although there was a statistically significant improvement in symptoms of neuropathy (−0.68 with ALA compared with +0.61 with placebo), the change was too small to be considered clinically significant.
ALA did slow the progression of neuropathy, however, with 29% of patients in the treatment group experiencing worsening symptoms compared with 38% of those on placebo. There was no difference in tolerability or discontinuation of treatment between the 2 groups.
A recent observational study (N=101) compared the efficacy of pregabalin, carbamazepine, and ALA over a 21-month period.4 Although those taking pregabalin had the best response rate, all 3 treatments led to significant improvement in the burning associated with neuropathic pain.
ALA 100 mg bid has been investigated as part of a 3-drug combination (with pregabalin 75 mg bid and methylcobalamin 750 mcg bid) compared with monotherapy (pregabalin 75 mg bid) in an open randomized study (N=30) for 12 weeks.16 While there was a trend toward improvement in pain relief, sleep interference, and nerve function in the combination therapy group, no statistically significant difference between the 2 groups was found. Nonetheless, more than a third (36%) had a global assessment rating of “excellent” vs one in 5 (20%) of those on pregabalin alone.
THE BOTTOM LINE Overall, ALA is well tolerated; the most common adverse effects are nausea and skin rash. IV administration is more effective than oral administration, but may cause nausea, headache, and an allergic reaction at the injection site.2 ALA does have the potential for an interaction with chemotherapy and thyroid hormone and may decrease the effectiveness of these therapies.2
B vitamins
Deficiencies of vitamin B1 (thiamine), B6 (pyridoxine), B12 (cyanocobalamin), and folate are known causes of neuropathy, and correcting them often improves or eliminates the symptoms.13 Vitamin B12 deficiency is commonly seen in patients taking metformin;14 these patients may benefit from supplementation with B12 1000 mcg/d.
Many of the B vitamins have been studied for treatment of neuropathy, but benfotiamine (a lipid-soluble form of thiamine) is thought to be the best option because it is better absorbed across cell membranes than other B vitamins.9 A Cochrane review found that benfotiamine alone may be effective for both diabetic and alcoholic neuropathy and that short-term use of higher doses of vitamin B complex (25 mg B1 or 320 mg benfotiamine + 50-720 mg B6 + 1000 mcg B12 daily) may reduce neuropathic pain.9
A randomized multicenter trial (N=214) found that adding a supplement containing L-methylfolate 3 mg, pyridoxal 5-phosphate 35 mg, and methylcobalamin 2 mg twice daily to other medications (eg, pregabalin, gabapentin, or duloxetine) improved symptoms of diabetic neuropathy.10 At 24 weeks, those receiving the combination therapy had a 26% decrease in pain symptoms compared with a 15% decrease for those on medication alone, with no significant adverse effects.
THE BOTTOM LINE Overall, vitamin B supplementation is well tolerated and appears to be more effective in relieving neuropathic pain than medication alone.9,14 But larger studies are needed before its efficacy in treating patients who do not have a deficiency can be established.
Capsaicin
Capsaicin, an ingredient found in peppers, works by binding to nociceptors to selectively stimulate afferent C fibers. This causes the release of substance P, a neurotransmitter that mediates pain, leading to its depletion and resulting in desensitization.2 Several meta-analyses and systematic reviews have found that topical capsaicin can be very effective, both as an adjunctive treatment and as monotherapy for neuropathic pain.11,17,18 The concentration used in the studies was 0.075% capsaicin cream, applied 3 to 4 times a day for 6 to 12 weeks, compared with placebo creams. In all categories studied, capsaicin was either statistically significant or trending in its favor, with the exception of adverse effects.
Capsaicin led to an improvement in daily activities and ability to sleep and a reduction in pain as measured with a visual analog scale and physician global evaluation.11,17,18
The most notable adverse effects were a burning sensation on the skin and coughing and sneezing caused by inhalation of dried cream. Although the adverse effects were expected to improve after 2 to 7 days of use, a significant number of participants withdrew from the study.
A 7-study meta-analysis showed the effectiveness of an 8% capsaicin patch for treatment of post-herpetic neuralgia and HIV-associated neuropathy.12 The patch, available only by prescription, was worn every day for 4 weeks (60 minutes daily for post-herpetic neuralgia and 30 minutes a day for HIV-associated neuropathy). The pooled results were statistically significant, but the patch was less effective for patients ages 18 to 40 years and for those of Asian descent. It can be used with other analgesics or as monotherapy, with few adverse reactions.12,19
THE BOTTOM LINE Since capsaicin is a topical medication, there are no relevant drug-drug interactions. Patients should be cautioned to wash their hands after application, however, and to avoid contact with eyes and open wounds.
Gamma linolenic acid (GLA)
Also known as evening primrose oil, GLA is an omega-6 fatty acid that’s an important constituent of neuronal cell membranes—and believed to decrease neuropathic pain by having some anti-inflammatory effects.2 This suggests that therapy with GLA has the potential to improve neuronal phospholipid structure and microcirculation.2
Two placebo-controlled trials (N=22,111) showed improvement in pain scores and multiple neurophysiologic assessments in patients with diabetes treated with GLA (360-480 mg/d).20,21 The treatment was well tolerated, but the beneficial effect was more pronounced in those with less severe diabetes.
THE BOTTOM LINE The dose of GLA studied (8 to 12 capsules daily) could lead to problems with patient adherence. In addition, GLA should be used with caution in patients who are taking antiplatelet medication or have seizure disorders.2
Magnesium (Mg)
Mg is highly involved in multiple enzyme systems throughout the body. Although it is very well absorbed from dietary sources,2 patients with diabetes, liver disease, and hormonal imbalances, as well as the elderly, are often deficient in Mg. It is unclear how this affects peripheral neuropathy.13
Mg may have an antinociceptive effect by decreasing intracellular calcium influx and antagonizing N-methyl-D-aspartate receptors and associated nerve signaling.22 A small RCT (N=80) showed Mg to decrease the severity of neuropathic back pain.22 Patients received Mg sulfate 1 g IV, given over 4 hours, every day for 2 weeks. The infusion was then replaced with Mg oxide 400 mg plus Mg gluconate 100 mg, taken orally twice daily for 4 weeks. An improvement in mean pain score was seen as early as 2 weeks, and scores had decreased by 2.8 points (on a 0-10-point scale) at 6 months.
Another small RCT (N=45) gave patients with neuropathy of postherpetic, traumatic, or surgical (but not diabetic) origin Mg chloride 838 mg orally 3 times a day for 4 weeks.23 The supplement was taken with meals. Mean pain scores in the treatment group decreased by 3 points, but this was not significantly different from the improvement seen in those on placebo.
In a similar study, patients (N=110) with type 1 diabetes and a normal serum Mg but an insufficiency as measured by erythrocyte Mg were given Mg gluconate 300 mg or placebo daily for 5 years.8 The supplement slowed the progression of peripheral neuropathy (only 12% of those receiving Mg gluconate experienced a significant worsening of symptoms over the course of the study, compared with 61% of those in the placebo group), but in most cases, it did not lead to an improvement.
No consistent approach to Mg supplementation has been studied, which makes recommending a particular route, dose, or formulation challenging. There is evidence that oral Mg, particularly in the form of Mg oxide, can cause diarrhea, especially in doses >350 mg/d. Mg gluconate and Mg chloride are better tolerated; Mg carbonate should be avoided due to poor oral absorption.2
BOTTOM LINE Mg supplementation appears to slow the progression of diabetic peripheral neuropathy, but is unsafe for patients with renal dysfunction, cardiac conduction abnormalities, or elevated Mg levels.2 Caution is required, too, when considering Mg supplementation for patients taking anticoagulants, bisphosphonates, digoxin, potassium-sparing diuretics, or tetracycline antibiotics.2
CORRESPONDENCE
Mary Onysko, PharmD, BCPS, University of Wyoming, School of Pharmacy Health Sciences Center, Room 292, 1000 E. University Avenue, Laramie, WY 82071; [email protected]
1. Chaparro LE, Wiffen PJ, Moore RA, et al. Combination pharmacotherapy for the treatment of neuropathic pain in adults. Cochrane Database Syst Rev. 2012:(7):CD008943.
2. Natural Medicines Comprehensive Database. Natural Medicines Comprehensive Database Web site. Available at: http://naturaldatabase.therapeuticresearch.com. Accessed January 4, 2015.
3. Mijnhout GS, Kollen BJ, Alkhalaf A, et al. Alpha lipoic acid for symptomatic peripheral neuropathy in patients with diabetes: a meta-analysis of randomized controlled trials. Int J Endocrinol. 2012;2012:456279.
4. Patel N, Mishra V, Patel P, et al. A study of the use of carbamazepine, pregabalin and alpha lipoic acid in patients of diabetic neuropathy. J Diabetes Metab Disord. 2014;13:62.
5. Bertolotto F, Massone A. Combination of alpha lipoic acid and superoxide dismutase leads to physiological and symptomatic improvements in diabetic neuropathy. Drugs R D. 2012;12:29-34.
6. De Grandis D, Minardi C. Acetyl-L-carnitine (levacecarnine) in the treatment of diabetic neuropathy. A long-term, randomised, double-blind, placebo-controlled study. Drugs R D. 2002;3:223-231.
7. Sima AA, Calvani M, Mehra M, et al; Acetyl-L-Carnitine Study Group. Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials. Diabetes Care. 2005;28:89-94.
8. De Leeuw, Engelen W, De Block C, et al. Long term magnesium supplementation influences favourably the natural evolution of neuropathy in Mg-depleted type 1 diabetic patients (T1dm). Magnes Res. 2004;17:109-114.
9. Ang CD, Alviar MJM, Dans AL, et al. Vitamin B for treating peripheral neuropathy. Cochrane Database Syst Rev. 2008;(3):CD004573.
10. Fonseca VA, Lavery LA, Thethi TK, et al. Metanx in type 2 diabetes
with peripheral neuropathy: a randomized trial. Am J Med. 2013;126:141-149.
11. Mason L, Moore RA, Derry S, et al. Systematic review of topical capsaicin for the treatment of chronic pain. BMJ. 2004;328:991.
12. Mou J, Paillard F, Turnbull B, et al. Efficacy of Qutenza® (capsaicin) 8% patch for neuropathic pain: a meta-analysis of the Qutenza Clinical Trials Database. Pain. 2013;154:1632-1639.
13. Head KA. Peripheral neuropathy: pathogenic mechanisms and alternative therapies. Altern Med Rev. 2006; 11:294-329.
14. Miranda-Massari JR, Gonzalez MJ, Jimenez FJ, et al. Metabolic correction in the management of diabetic peripheral neuropathy: improving clinical results beyond symptom control. Curr Clin Pharmacol. 2011; 6:260-273.
15. Ziegler D, Low PA, Litchy WJ, et al. Efficacy and safety of antioxidant treatment with a-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes Care. 2011;34:2054-2060.
16. Vasudevan D, Naik MM, Mukaddam QI. Efficacy and safety of methylcobalamin, alpha lipoic acid and pregabalin combination versus pregabalin monotherapy in improving pain and nerve conduction velocity in type 2 diabetes associated impaired peripheral neuropathic condition. [MAINTAIN]: Results of a pilot study. Ann Indian Acad Neurol. 2014;17:19-24.
17. Halat KM, Dennehy CE. Botanicals and dietary supplements in diabetic peripheral neuropathy. J Am Board Fam Pract. 2003;16:47-57.
18. Donofrio P, Walker F, Hunt V, et al. Treatment of painful diabetic neuropathy with topical capsaicin: A multicenter, double-blind, vehicle-controlled study. Arch Int Med. 1991;151:2225-2229.
19. Derry S, Rice ASC, Cole P, et al. Topical capsaicin (high concentration) for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2013;(2):CD007393.
20. Keen H, Payan J, Allawi J, et al. Treatment of diabetic neuropathy with gamma-linolenic acid. The gamma-Linolenic Acid Multicenter Trial Group. Diabetes Care. 1993;16:8-15.
21. Jamal GA, Carmichael H. The effect of gamma linolenic acid on human diabetic peripheral neuropathy: a double blind placebo controlled trial. Diabetic Med. 1990;7:319-323.
22. Yousef AA, Al-deeb AE. A double-blinded randomised controlled study of the value of sequential intravenous and oral magnesium therapy in patients with chronic low back pain with a neuropathic component. Anaesthesia. 2013;68:260-266.
23. Pickering G, Morel V, Simen E. Oral magnesium treatment in patients with neuropathic pain: a randomized clinical trial. Magnes Res. 2011;24:28-35.
Anticonvulsants, antidepressants, and opioids are the most frequently prescribed medications for neuropathic pain.1 But some patients are unable to tolerate the adverse effects of these drugs, and others achieve only partial pain relief. What can you offer them?
Combinations of prescription medications are generally considered more effective than monotherapy for painful peripheral neuropathy,1 but it is unclear which combinations are best. Alternative therapies—several of which have some evidence of safety and efficacy in treating peripheral neuropathy—are another option. Yet trials with alternative therapies, alone or in combination with prescription drugs, are rarely considered.
In fact, physicians are often unfamiliar with these therapies. Many are concerned about the absence of US Food and Drug Administration approval for alternative therapies and the variability in quality control associated with the lack of oversight, as well. Making recommendations about the duration of therapy also presents a challenge because most studies of supplements are relatively short. What’s more, alternative treatments are rarely covered by third-party payers.
Nonetheless, the therapies detailed in the text and TABLE2-12 that follow are generally well tolerated and appear to be safe. Adding them to your arsenal of therapeutic choices for patients with painful peripheral neuropathy may increase your ability to provide successful treatment.
Acetyl-L-carnitine (ALC)
ALC occurs naturally in the body as L-carnitine and acetyl-carnitine esters, which are converted to carnitines by intracellular enzymes and cell membrane transporters.2 ALC has been studied in patients with neuropathy associated with human immunodeficiency virus (HIV), cancer, and diabetes. Potential mechanisms of action include the correction of a deficiency that may be causing the neuropathy (which sometimes occurs in HIV-positive patients13 or those taking anticonvulsants14), a direct antioxidant effect, or an enhanced response to nerve growth factor.13
ALC can be given intramuscularly (IM) or orally in doses of 2000 to 3000 mg/d. In one randomized placebo-controlled trial (N=333), patients with diabetic neuropathy received 1000 mg IM followed by an oral dose of 2000 mg every day for a year.6 Mean pain scores decreased by 39%, with 67% of those receiving ALC vs 23% of those on placebo showing moderate to marked improvement.
In a pooled analysis (N=1257) of 2 randomized controlled trials (RCTs), patients with diabetes took 1000 mg ALC 3 times daily or placebo for a year.7 Cohort pain scores improved by 40% from baseline in the ALC group compared with a 24% improvement for those in the placebo group.
THE BOTTOM LINE ALC is well tolerated, with minor adverse effects such as headache and nausea reported.6,7 It should not be given to patients taking acenocoumarol or warfarin, however. A major interaction causing an elevated international normalized ratio has been found to occur when either agent is combined with L-carnitine2 and could theoretically occur with ALC, as well. No other drug-drug interactions have been documented.2
Alpha lipoic acid (ALA)
Both a fat- and a water-soluble vitamin that is usually obtained from the diet, ALA regenerates endogenous antioxidants like vitamins C and E and glutathione. It is this regenerative mechanism that it is believed to alleviate diabetic neuropathy.2 ALA 600 mg/d appears to be effective, although studies suggest that intravenous (IV) use is more effective than oral administration.
A meta-analysis of 4 RCTs (N=653), 2 with ALA taken orally and 2 involving IV administration, is a case in point.3 The pooled standardized mean difference estimated from all trials showed a reduction in total symptom scores of −2.26 (95% confidence interval [CI], −3.12 to −1.41; P=.00001), with 0 indicating no symptoms, 3 indicating severe symptoms, and a maximum score of 14.64 if all symptoms were severe and continuous. Subgroup analyses revealed a reduction of −1.78 (95% CI, −2.45 to −1.10; P=.00001) for oral ALA and −2.81 (95% CI, −4.16 to −1.46; P=.0001) for IV administration. Doses >600 mg/d did not improve efficacy, but did increase adverse effects such as nausea, vomiting, and dizziness.
In a multicenter RCT (N=460) of ALA 600 mg/d for 4 years, however, no improvement in the primary endpoint (a composite of neuropathy impairment scores and 7 neurophysiologic tests) was found.15 Although there was a statistically significant improvement in symptoms of neuropathy (−0.68 with ALA compared with +0.61 with placebo), the change was too small to be considered clinically significant.
ALA did slow the progression of neuropathy, however, with 29% of patients in the treatment group experiencing worsening symptoms compared with 38% of those on placebo. There was no difference in tolerability or discontinuation of treatment between the 2 groups.
A recent observational study (N=101) compared the efficacy of pregabalin, carbamazepine, and ALA over a 21-month period.4 Although those taking pregabalin had the best response rate, all 3 treatments led to significant improvement in the burning associated with neuropathic pain.
ALA 100 mg bid has been investigated as part of a 3-drug combination (with pregabalin 75 mg bid and methylcobalamin 750 mcg bid) compared with monotherapy (pregabalin 75 mg bid) in an open randomized study (N=30) for 12 weeks.16 While there was a trend toward improvement in pain relief, sleep interference, and nerve function in the combination therapy group, no statistically significant difference between the 2 groups was found. Nonetheless, more than a third (36%) had a global assessment rating of “excellent” vs one in 5 (20%) of those on pregabalin alone.
THE BOTTOM LINE Overall, ALA is well tolerated; the most common adverse effects are nausea and skin rash. IV administration is more effective than oral administration, but may cause nausea, headache, and an allergic reaction at the injection site.2 ALA does have the potential for an interaction with chemotherapy and thyroid hormone and may decrease the effectiveness of these therapies.2
B vitamins
Deficiencies of vitamin B1 (thiamine), B6 (pyridoxine), B12 (cyanocobalamin), and folate are known causes of neuropathy, and correcting them often improves or eliminates the symptoms.13 Vitamin B12 deficiency is commonly seen in patients taking metformin;14 these patients may benefit from supplementation with B12 1000 mcg/d.
Many of the B vitamins have been studied for treatment of neuropathy, but benfotiamine (a lipid-soluble form of thiamine) is thought to be the best option because it is better absorbed across cell membranes than other B vitamins.9 A Cochrane review found that benfotiamine alone may be effective for both diabetic and alcoholic neuropathy and that short-term use of higher doses of vitamin B complex (25 mg B1 or 320 mg benfotiamine + 50-720 mg B6 + 1000 mcg B12 daily) may reduce neuropathic pain.9
A randomized multicenter trial (N=214) found that adding a supplement containing L-methylfolate 3 mg, pyridoxal 5-phosphate 35 mg, and methylcobalamin 2 mg twice daily to other medications (eg, pregabalin, gabapentin, or duloxetine) improved symptoms of diabetic neuropathy.10 At 24 weeks, those receiving the combination therapy had a 26% decrease in pain symptoms compared with a 15% decrease for those on medication alone, with no significant adverse effects.
THE BOTTOM LINE Overall, vitamin B supplementation is well tolerated and appears to be more effective in relieving neuropathic pain than medication alone.9,14 But larger studies are needed before its efficacy in treating patients who do not have a deficiency can be established.
Capsaicin
Capsaicin, an ingredient found in peppers, works by binding to nociceptors to selectively stimulate afferent C fibers. This causes the release of substance P, a neurotransmitter that mediates pain, leading to its depletion and resulting in desensitization.2 Several meta-analyses and systematic reviews have found that topical capsaicin can be very effective, both as an adjunctive treatment and as monotherapy for neuropathic pain.11,17,18 The concentration used in the studies was 0.075% capsaicin cream, applied 3 to 4 times a day for 6 to 12 weeks, compared with placebo creams. In all categories studied, capsaicin was either statistically significant or trending in its favor, with the exception of adverse effects.
Capsaicin led to an improvement in daily activities and ability to sleep and a reduction in pain as measured with a visual analog scale and physician global evaluation.11,17,18
The most notable adverse effects were a burning sensation on the skin and coughing and sneezing caused by inhalation of dried cream. Although the adverse effects were expected to improve after 2 to 7 days of use, a significant number of participants withdrew from the study.
A 7-study meta-analysis showed the effectiveness of an 8% capsaicin patch for treatment of post-herpetic neuralgia and HIV-associated neuropathy.12 The patch, available only by prescription, was worn every day for 4 weeks (60 minutes daily for post-herpetic neuralgia and 30 minutes a day for HIV-associated neuropathy). The pooled results were statistically significant, but the patch was less effective for patients ages 18 to 40 years and for those of Asian descent. It can be used with other analgesics or as monotherapy, with few adverse reactions.12,19
THE BOTTOM LINE Since capsaicin is a topical medication, there are no relevant drug-drug interactions. Patients should be cautioned to wash their hands after application, however, and to avoid contact with eyes and open wounds.
Gamma linolenic acid (GLA)
Also known as evening primrose oil, GLA is an omega-6 fatty acid that’s an important constituent of neuronal cell membranes—and believed to decrease neuropathic pain by having some anti-inflammatory effects.2 This suggests that therapy with GLA has the potential to improve neuronal phospholipid structure and microcirculation.2
Two placebo-controlled trials (N=22,111) showed improvement in pain scores and multiple neurophysiologic assessments in patients with diabetes treated with GLA (360-480 mg/d).20,21 The treatment was well tolerated, but the beneficial effect was more pronounced in those with less severe diabetes.
THE BOTTOM LINE The dose of GLA studied (8 to 12 capsules daily) could lead to problems with patient adherence. In addition, GLA should be used with caution in patients who are taking antiplatelet medication or have seizure disorders.2
Magnesium (Mg)
Mg is highly involved in multiple enzyme systems throughout the body. Although it is very well absorbed from dietary sources,2 patients with diabetes, liver disease, and hormonal imbalances, as well as the elderly, are often deficient in Mg. It is unclear how this affects peripheral neuropathy.13
Mg may have an antinociceptive effect by decreasing intracellular calcium influx and antagonizing N-methyl-D-aspartate receptors and associated nerve signaling.22 A small RCT (N=80) showed Mg to decrease the severity of neuropathic back pain.22 Patients received Mg sulfate 1 g IV, given over 4 hours, every day for 2 weeks. The infusion was then replaced with Mg oxide 400 mg plus Mg gluconate 100 mg, taken orally twice daily for 4 weeks. An improvement in mean pain score was seen as early as 2 weeks, and scores had decreased by 2.8 points (on a 0-10-point scale) at 6 months.
Another small RCT (N=45) gave patients with neuropathy of postherpetic, traumatic, or surgical (but not diabetic) origin Mg chloride 838 mg orally 3 times a day for 4 weeks.23 The supplement was taken with meals. Mean pain scores in the treatment group decreased by 3 points, but this was not significantly different from the improvement seen in those on placebo.
In a similar study, patients (N=110) with type 1 diabetes and a normal serum Mg but an insufficiency as measured by erythrocyte Mg were given Mg gluconate 300 mg or placebo daily for 5 years.8 The supplement slowed the progression of peripheral neuropathy (only 12% of those receiving Mg gluconate experienced a significant worsening of symptoms over the course of the study, compared with 61% of those in the placebo group), but in most cases, it did not lead to an improvement.
No consistent approach to Mg supplementation has been studied, which makes recommending a particular route, dose, or formulation challenging. There is evidence that oral Mg, particularly in the form of Mg oxide, can cause diarrhea, especially in doses >350 mg/d. Mg gluconate and Mg chloride are better tolerated; Mg carbonate should be avoided due to poor oral absorption.2
BOTTOM LINE Mg supplementation appears to slow the progression of diabetic peripheral neuropathy, but is unsafe for patients with renal dysfunction, cardiac conduction abnormalities, or elevated Mg levels.2 Caution is required, too, when considering Mg supplementation for patients taking anticoagulants, bisphosphonates, digoxin, potassium-sparing diuretics, or tetracycline antibiotics.2
CORRESPONDENCE
Mary Onysko, PharmD, BCPS, University of Wyoming, School of Pharmacy Health Sciences Center, Room 292, 1000 E. University Avenue, Laramie, WY 82071; [email protected]
Anticonvulsants, antidepressants, and opioids are the most frequently prescribed medications for neuropathic pain.1 But some patients are unable to tolerate the adverse effects of these drugs, and others achieve only partial pain relief. What can you offer them?
Combinations of prescription medications are generally considered more effective than monotherapy for painful peripheral neuropathy,1 but it is unclear which combinations are best. Alternative therapies—several of which have some evidence of safety and efficacy in treating peripheral neuropathy—are another option. Yet trials with alternative therapies, alone or in combination with prescription drugs, are rarely considered.
In fact, physicians are often unfamiliar with these therapies. Many are concerned about the absence of US Food and Drug Administration approval for alternative therapies and the variability in quality control associated with the lack of oversight, as well. Making recommendations about the duration of therapy also presents a challenge because most studies of supplements are relatively short. What’s more, alternative treatments are rarely covered by third-party payers.
Nonetheless, the therapies detailed in the text and TABLE2-12 that follow are generally well tolerated and appear to be safe. Adding them to your arsenal of therapeutic choices for patients with painful peripheral neuropathy may increase your ability to provide successful treatment.
Acetyl-L-carnitine (ALC)
ALC occurs naturally in the body as L-carnitine and acetyl-carnitine esters, which are converted to carnitines by intracellular enzymes and cell membrane transporters.2 ALC has been studied in patients with neuropathy associated with human immunodeficiency virus (HIV), cancer, and diabetes. Potential mechanisms of action include the correction of a deficiency that may be causing the neuropathy (which sometimes occurs in HIV-positive patients13 or those taking anticonvulsants14), a direct antioxidant effect, or an enhanced response to nerve growth factor.13
ALC can be given intramuscularly (IM) or orally in doses of 2000 to 3000 mg/d. In one randomized placebo-controlled trial (N=333), patients with diabetic neuropathy received 1000 mg IM followed by an oral dose of 2000 mg every day for a year.6 Mean pain scores decreased by 39%, with 67% of those receiving ALC vs 23% of those on placebo showing moderate to marked improvement.
In a pooled analysis (N=1257) of 2 randomized controlled trials (RCTs), patients with diabetes took 1000 mg ALC 3 times daily or placebo for a year.7 Cohort pain scores improved by 40% from baseline in the ALC group compared with a 24% improvement for those in the placebo group.
THE BOTTOM LINE ALC is well tolerated, with minor adverse effects such as headache and nausea reported.6,7 It should not be given to patients taking acenocoumarol or warfarin, however. A major interaction causing an elevated international normalized ratio has been found to occur when either agent is combined with L-carnitine2 and could theoretically occur with ALC, as well. No other drug-drug interactions have been documented.2
Alpha lipoic acid (ALA)
Both a fat- and a water-soluble vitamin that is usually obtained from the diet, ALA regenerates endogenous antioxidants like vitamins C and E and glutathione. It is this regenerative mechanism that it is believed to alleviate diabetic neuropathy.2 ALA 600 mg/d appears to be effective, although studies suggest that intravenous (IV) use is more effective than oral administration.
A meta-analysis of 4 RCTs (N=653), 2 with ALA taken orally and 2 involving IV administration, is a case in point.3 The pooled standardized mean difference estimated from all trials showed a reduction in total symptom scores of −2.26 (95% confidence interval [CI], −3.12 to −1.41; P=.00001), with 0 indicating no symptoms, 3 indicating severe symptoms, and a maximum score of 14.64 if all symptoms were severe and continuous. Subgroup analyses revealed a reduction of −1.78 (95% CI, −2.45 to −1.10; P=.00001) for oral ALA and −2.81 (95% CI, −4.16 to −1.46; P=.0001) for IV administration. Doses >600 mg/d did not improve efficacy, but did increase adverse effects such as nausea, vomiting, and dizziness.
In a multicenter RCT (N=460) of ALA 600 mg/d for 4 years, however, no improvement in the primary endpoint (a composite of neuropathy impairment scores and 7 neurophysiologic tests) was found.15 Although there was a statistically significant improvement in symptoms of neuropathy (−0.68 with ALA compared with +0.61 with placebo), the change was too small to be considered clinically significant.
ALA did slow the progression of neuropathy, however, with 29% of patients in the treatment group experiencing worsening symptoms compared with 38% of those on placebo. There was no difference in tolerability or discontinuation of treatment between the 2 groups.
A recent observational study (N=101) compared the efficacy of pregabalin, carbamazepine, and ALA over a 21-month period.4 Although those taking pregabalin had the best response rate, all 3 treatments led to significant improvement in the burning associated with neuropathic pain.
ALA 100 mg bid has been investigated as part of a 3-drug combination (with pregabalin 75 mg bid and methylcobalamin 750 mcg bid) compared with monotherapy (pregabalin 75 mg bid) in an open randomized study (N=30) for 12 weeks.16 While there was a trend toward improvement in pain relief, sleep interference, and nerve function in the combination therapy group, no statistically significant difference between the 2 groups was found. Nonetheless, more than a third (36%) had a global assessment rating of “excellent” vs one in 5 (20%) of those on pregabalin alone.
THE BOTTOM LINE Overall, ALA is well tolerated; the most common adverse effects are nausea and skin rash. IV administration is more effective than oral administration, but may cause nausea, headache, and an allergic reaction at the injection site.2 ALA does have the potential for an interaction with chemotherapy and thyroid hormone and may decrease the effectiveness of these therapies.2
B vitamins
Deficiencies of vitamin B1 (thiamine), B6 (pyridoxine), B12 (cyanocobalamin), and folate are known causes of neuropathy, and correcting them often improves or eliminates the symptoms.13 Vitamin B12 deficiency is commonly seen in patients taking metformin;14 these patients may benefit from supplementation with B12 1000 mcg/d.
Many of the B vitamins have been studied for treatment of neuropathy, but benfotiamine (a lipid-soluble form of thiamine) is thought to be the best option because it is better absorbed across cell membranes than other B vitamins.9 A Cochrane review found that benfotiamine alone may be effective for both diabetic and alcoholic neuropathy and that short-term use of higher doses of vitamin B complex (25 mg B1 or 320 mg benfotiamine + 50-720 mg B6 + 1000 mcg B12 daily) may reduce neuropathic pain.9
A randomized multicenter trial (N=214) found that adding a supplement containing L-methylfolate 3 mg, pyridoxal 5-phosphate 35 mg, and methylcobalamin 2 mg twice daily to other medications (eg, pregabalin, gabapentin, or duloxetine) improved symptoms of diabetic neuropathy.10 At 24 weeks, those receiving the combination therapy had a 26% decrease in pain symptoms compared with a 15% decrease for those on medication alone, with no significant adverse effects.
THE BOTTOM LINE Overall, vitamin B supplementation is well tolerated and appears to be more effective in relieving neuropathic pain than medication alone.9,14 But larger studies are needed before its efficacy in treating patients who do not have a deficiency can be established.
Capsaicin
Capsaicin, an ingredient found in peppers, works by binding to nociceptors to selectively stimulate afferent C fibers. This causes the release of substance P, a neurotransmitter that mediates pain, leading to its depletion and resulting in desensitization.2 Several meta-analyses and systematic reviews have found that topical capsaicin can be very effective, both as an adjunctive treatment and as monotherapy for neuropathic pain.11,17,18 The concentration used in the studies was 0.075% capsaicin cream, applied 3 to 4 times a day for 6 to 12 weeks, compared with placebo creams. In all categories studied, capsaicin was either statistically significant or trending in its favor, with the exception of adverse effects.
Capsaicin led to an improvement in daily activities and ability to sleep and a reduction in pain as measured with a visual analog scale and physician global evaluation.11,17,18
The most notable adverse effects were a burning sensation on the skin and coughing and sneezing caused by inhalation of dried cream. Although the adverse effects were expected to improve after 2 to 7 days of use, a significant number of participants withdrew from the study.
A 7-study meta-analysis showed the effectiveness of an 8% capsaicin patch for treatment of post-herpetic neuralgia and HIV-associated neuropathy.12 The patch, available only by prescription, was worn every day for 4 weeks (60 minutes daily for post-herpetic neuralgia and 30 minutes a day for HIV-associated neuropathy). The pooled results were statistically significant, but the patch was less effective for patients ages 18 to 40 years and for those of Asian descent. It can be used with other analgesics or as monotherapy, with few adverse reactions.12,19
THE BOTTOM LINE Since capsaicin is a topical medication, there are no relevant drug-drug interactions. Patients should be cautioned to wash their hands after application, however, and to avoid contact with eyes and open wounds.
Gamma linolenic acid (GLA)
Also known as evening primrose oil, GLA is an omega-6 fatty acid that’s an important constituent of neuronal cell membranes—and believed to decrease neuropathic pain by having some anti-inflammatory effects.2 This suggests that therapy with GLA has the potential to improve neuronal phospholipid structure and microcirculation.2
Two placebo-controlled trials (N=22,111) showed improvement in pain scores and multiple neurophysiologic assessments in patients with diabetes treated with GLA (360-480 mg/d).20,21 The treatment was well tolerated, but the beneficial effect was more pronounced in those with less severe diabetes.
THE BOTTOM LINE The dose of GLA studied (8 to 12 capsules daily) could lead to problems with patient adherence. In addition, GLA should be used with caution in patients who are taking antiplatelet medication or have seizure disorders.2
Magnesium (Mg)
Mg is highly involved in multiple enzyme systems throughout the body. Although it is very well absorbed from dietary sources,2 patients with diabetes, liver disease, and hormonal imbalances, as well as the elderly, are often deficient in Mg. It is unclear how this affects peripheral neuropathy.13
Mg may have an antinociceptive effect by decreasing intracellular calcium influx and antagonizing N-methyl-D-aspartate receptors and associated nerve signaling.22 A small RCT (N=80) showed Mg to decrease the severity of neuropathic back pain.22 Patients received Mg sulfate 1 g IV, given over 4 hours, every day for 2 weeks. The infusion was then replaced with Mg oxide 400 mg plus Mg gluconate 100 mg, taken orally twice daily for 4 weeks. An improvement in mean pain score was seen as early as 2 weeks, and scores had decreased by 2.8 points (on a 0-10-point scale) at 6 months.
Another small RCT (N=45) gave patients with neuropathy of postherpetic, traumatic, or surgical (but not diabetic) origin Mg chloride 838 mg orally 3 times a day for 4 weeks.23 The supplement was taken with meals. Mean pain scores in the treatment group decreased by 3 points, but this was not significantly different from the improvement seen in those on placebo.
In a similar study, patients (N=110) with type 1 diabetes and a normal serum Mg but an insufficiency as measured by erythrocyte Mg were given Mg gluconate 300 mg or placebo daily for 5 years.8 The supplement slowed the progression of peripheral neuropathy (only 12% of those receiving Mg gluconate experienced a significant worsening of symptoms over the course of the study, compared with 61% of those in the placebo group), but in most cases, it did not lead to an improvement.
No consistent approach to Mg supplementation has been studied, which makes recommending a particular route, dose, or formulation challenging. There is evidence that oral Mg, particularly in the form of Mg oxide, can cause diarrhea, especially in doses >350 mg/d. Mg gluconate and Mg chloride are better tolerated; Mg carbonate should be avoided due to poor oral absorption.2
BOTTOM LINE Mg supplementation appears to slow the progression of diabetic peripheral neuropathy, but is unsafe for patients with renal dysfunction, cardiac conduction abnormalities, or elevated Mg levels.2 Caution is required, too, when considering Mg supplementation for patients taking anticoagulants, bisphosphonates, digoxin, potassium-sparing diuretics, or tetracycline antibiotics.2
CORRESPONDENCE
Mary Onysko, PharmD, BCPS, University of Wyoming, School of Pharmacy Health Sciences Center, Room 292, 1000 E. University Avenue, Laramie, WY 82071; [email protected]
1. Chaparro LE, Wiffen PJ, Moore RA, et al. Combination pharmacotherapy for the treatment of neuropathic pain in adults. Cochrane Database Syst Rev. 2012:(7):CD008943.
2. Natural Medicines Comprehensive Database. Natural Medicines Comprehensive Database Web site. Available at: http://naturaldatabase.therapeuticresearch.com. Accessed January 4, 2015.
3. Mijnhout GS, Kollen BJ, Alkhalaf A, et al. Alpha lipoic acid for symptomatic peripheral neuropathy in patients with diabetes: a meta-analysis of randomized controlled trials. Int J Endocrinol. 2012;2012:456279.
4. Patel N, Mishra V, Patel P, et al. A study of the use of carbamazepine, pregabalin and alpha lipoic acid in patients of diabetic neuropathy. J Diabetes Metab Disord. 2014;13:62.
5. Bertolotto F, Massone A. Combination of alpha lipoic acid and superoxide dismutase leads to physiological and symptomatic improvements in diabetic neuropathy. Drugs R D. 2012;12:29-34.
6. De Grandis D, Minardi C. Acetyl-L-carnitine (levacecarnine) in the treatment of diabetic neuropathy. A long-term, randomised, double-blind, placebo-controlled study. Drugs R D. 2002;3:223-231.
7. Sima AA, Calvani M, Mehra M, et al; Acetyl-L-Carnitine Study Group. Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials. Diabetes Care. 2005;28:89-94.
8. De Leeuw, Engelen W, De Block C, et al. Long term magnesium supplementation influences favourably the natural evolution of neuropathy in Mg-depleted type 1 diabetic patients (T1dm). Magnes Res. 2004;17:109-114.
9. Ang CD, Alviar MJM, Dans AL, et al. Vitamin B for treating peripheral neuropathy. Cochrane Database Syst Rev. 2008;(3):CD004573.
10. Fonseca VA, Lavery LA, Thethi TK, et al. Metanx in type 2 diabetes
with peripheral neuropathy: a randomized trial. Am J Med. 2013;126:141-149.
11. Mason L, Moore RA, Derry S, et al. Systematic review of topical capsaicin for the treatment of chronic pain. BMJ. 2004;328:991.
12. Mou J, Paillard F, Turnbull B, et al. Efficacy of Qutenza® (capsaicin) 8% patch for neuropathic pain: a meta-analysis of the Qutenza Clinical Trials Database. Pain. 2013;154:1632-1639.
13. Head KA. Peripheral neuropathy: pathogenic mechanisms and alternative therapies. Altern Med Rev. 2006; 11:294-329.
14. Miranda-Massari JR, Gonzalez MJ, Jimenez FJ, et al. Metabolic correction in the management of diabetic peripheral neuropathy: improving clinical results beyond symptom control. Curr Clin Pharmacol. 2011; 6:260-273.
15. Ziegler D, Low PA, Litchy WJ, et al. Efficacy and safety of antioxidant treatment with a-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes Care. 2011;34:2054-2060.
16. Vasudevan D, Naik MM, Mukaddam QI. Efficacy and safety of methylcobalamin, alpha lipoic acid and pregabalin combination versus pregabalin monotherapy in improving pain and nerve conduction velocity in type 2 diabetes associated impaired peripheral neuropathic condition. [MAINTAIN]: Results of a pilot study. Ann Indian Acad Neurol. 2014;17:19-24.
17. Halat KM, Dennehy CE. Botanicals and dietary supplements in diabetic peripheral neuropathy. J Am Board Fam Pract. 2003;16:47-57.
18. Donofrio P, Walker F, Hunt V, et al. Treatment of painful diabetic neuropathy with topical capsaicin: A multicenter, double-blind, vehicle-controlled study. Arch Int Med. 1991;151:2225-2229.
19. Derry S, Rice ASC, Cole P, et al. Topical capsaicin (high concentration) for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2013;(2):CD007393.
20. Keen H, Payan J, Allawi J, et al. Treatment of diabetic neuropathy with gamma-linolenic acid. The gamma-Linolenic Acid Multicenter Trial Group. Diabetes Care. 1993;16:8-15.
21. Jamal GA, Carmichael H. The effect of gamma linolenic acid on human diabetic peripheral neuropathy: a double blind placebo controlled trial. Diabetic Med. 1990;7:319-323.
22. Yousef AA, Al-deeb AE. A double-blinded randomised controlled study of the value of sequential intravenous and oral magnesium therapy in patients with chronic low back pain with a neuropathic component. Anaesthesia. 2013;68:260-266.
23. Pickering G, Morel V, Simen E. Oral magnesium treatment in patients with neuropathic pain: a randomized clinical trial. Magnes Res. 2011;24:28-35.
1. Chaparro LE, Wiffen PJ, Moore RA, et al. Combination pharmacotherapy for the treatment of neuropathic pain in adults. Cochrane Database Syst Rev. 2012:(7):CD008943.
2. Natural Medicines Comprehensive Database. Natural Medicines Comprehensive Database Web site. Available at: http://naturaldatabase.therapeuticresearch.com. Accessed January 4, 2015.
3. Mijnhout GS, Kollen BJ, Alkhalaf A, et al. Alpha lipoic acid for symptomatic peripheral neuropathy in patients with diabetes: a meta-analysis of randomized controlled trials. Int J Endocrinol. 2012;2012:456279.
4. Patel N, Mishra V, Patel P, et al. A study of the use of carbamazepine, pregabalin and alpha lipoic acid in patients of diabetic neuropathy. J Diabetes Metab Disord. 2014;13:62.
5. Bertolotto F, Massone A. Combination of alpha lipoic acid and superoxide dismutase leads to physiological and symptomatic improvements in diabetic neuropathy. Drugs R D. 2012;12:29-34.
6. De Grandis D, Minardi C. Acetyl-L-carnitine (levacecarnine) in the treatment of diabetic neuropathy. A long-term, randomised, double-blind, placebo-controlled study. Drugs R D. 2002;3:223-231.
7. Sima AA, Calvani M, Mehra M, et al; Acetyl-L-Carnitine Study Group. Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials. Diabetes Care. 2005;28:89-94.
8. De Leeuw, Engelen W, De Block C, et al. Long term magnesium supplementation influences favourably the natural evolution of neuropathy in Mg-depleted type 1 diabetic patients (T1dm). Magnes Res. 2004;17:109-114.
9. Ang CD, Alviar MJM, Dans AL, et al. Vitamin B for treating peripheral neuropathy. Cochrane Database Syst Rev. 2008;(3):CD004573.
10. Fonseca VA, Lavery LA, Thethi TK, et al. Metanx in type 2 diabetes
with peripheral neuropathy: a randomized trial. Am J Med. 2013;126:141-149.
11. Mason L, Moore RA, Derry S, et al. Systematic review of topical capsaicin for the treatment of chronic pain. BMJ. 2004;328:991.
12. Mou J, Paillard F, Turnbull B, et al. Efficacy of Qutenza® (capsaicin) 8% patch for neuropathic pain: a meta-analysis of the Qutenza Clinical Trials Database. Pain. 2013;154:1632-1639.
13. Head KA. Peripheral neuropathy: pathogenic mechanisms and alternative therapies. Altern Med Rev. 2006; 11:294-329.
14. Miranda-Massari JR, Gonzalez MJ, Jimenez FJ, et al. Metabolic correction in the management of diabetic peripheral neuropathy: improving clinical results beyond symptom control. Curr Clin Pharmacol. 2011; 6:260-273.
15. Ziegler D, Low PA, Litchy WJ, et al. Efficacy and safety of antioxidant treatment with a-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes Care. 2011;34:2054-2060.
16. Vasudevan D, Naik MM, Mukaddam QI. Efficacy and safety of methylcobalamin, alpha lipoic acid and pregabalin combination versus pregabalin monotherapy in improving pain and nerve conduction velocity in type 2 diabetes associated impaired peripheral neuropathic condition. [MAINTAIN]: Results of a pilot study. Ann Indian Acad Neurol. 2014;17:19-24.
17. Halat KM, Dennehy CE. Botanicals and dietary supplements in diabetic peripheral neuropathy. J Am Board Fam Pract. 2003;16:47-57.
18. Donofrio P, Walker F, Hunt V, et al. Treatment of painful diabetic neuropathy with topical capsaicin: A multicenter, double-blind, vehicle-controlled study. Arch Int Med. 1991;151:2225-2229.
19. Derry S, Rice ASC, Cole P, et al. Topical capsaicin (high concentration) for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2013;(2):CD007393.
20. Keen H, Payan J, Allawi J, et al. Treatment of diabetic neuropathy with gamma-linolenic acid. The gamma-Linolenic Acid Multicenter Trial Group. Diabetes Care. 1993;16:8-15.
21. Jamal GA, Carmichael H. The effect of gamma linolenic acid on human diabetic peripheral neuropathy: a double blind placebo controlled trial. Diabetic Med. 1990;7:319-323.
22. Yousef AA, Al-deeb AE. A double-blinded randomised controlled study of the value of sequential intravenous and oral magnesium therapy in patients with chronic low back pain with a neuropathic component. Anaesthesia. 2013;68:260-266.
23. Pickering G, Morel V, Simen E. Oral magnesium treatment in patients with neuropathic pain: a randomized clinical trial. Magnes Res. 2011;24:28-35.
Is a novel anticoagulant right for your patient?
› Consider novel oral anticoagualants (NOACs) for patients who have normal renal function, are comlpiant with medication regimens, and have no history of peptic ulcer or gastrointestinal bleeding. B
› Avoid overlapping warfarin with rivaroxaban or apixaban when transitioning a patient from one anticoagulant to the other, as both agents prolong prothrombin time. B
› When initiating a NOAC, it is not necessary to overlap with a parenteral anticoagulant. B
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
CASE 1 Sally J is a 72-year-old Caucasian woman who comes to your clinic after being diagnosed with atrial fibrillation (AF). The patient has a 10-year history of type 2 diabetes; she also has a history of hypertension and chronic kidney disease (CKD), with a baseline creatinine clearance of approximately 40 mL/min. Ms. J tells you she knows people who take warfarin and really dislike it. She asks for your opinion of the new anticoagulants she’s seen advertised on TV, and wonders whether one of them would be right for her.
CASE 2 Bobby W, a 35-year-old African American man, was recently diagnosed with deep vein thrombosis (DVT). This was his second clot in 5 years, and occurred after a long flight home from Europe. The patient explains that he leads a very active lifestyle and doesn’t have the time to come in for the monthly international normalized ratio (INR) checks that warfarin requires. What would you recommend for these patients?
Troubled by warfarin’s narrow therapeutic index, numerous medication and dietary interactions, and need for frequent monitoring, patients requiring long-term oral anticoagulation therapy have been seeking alternatives for years. Finally, they have a choice. The US Food and Drug Administration (FDA) approved 3 oral anticoagulants—dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis)—in less than 4 years. Known as novel oral anticoagulants (NOACs), they are the first such drugs to enter the market in more than 50 years.1,2
While warfarin inhibits a wide range of clotting factors (including II, VII, IX, and X), NOACs work further down the clotting cascade (TABLE 1).1,3-7 Dabigatran, a direct thrombin inhibitor, only inhibits factor IIa.3,5 Rivaroxaban and apixaban directly inhibit factor Xa and indirectly inhibit factor IIa.3,6,7
There are notable advantages to these newer agents, but some disadvantages that must be considered, as well. Appropriate patient selection, guided by a thorough understanding of the benefits and risks of NOACs, is key.
Stroke prevention in atrial fibrillation
All 3 NOACs are approved for stroke prevention in patients with nonvalvular atrial fibrillation (AF). The approvals are based on a small number of well-designed trials: RE-LY (dabigatran), ROCKET-AF (rivaroxaban), and ARISTOTLE (apixaban).8-10 Compared with warfarin, dabigatran is the only oral anticoagulant with a lower rate of both hemorrhagic and ischemic stroke.8 Both rivaroxaban and apixaban were found to decrease overall stroke risk relative to warfarin, but the difference was driven by a lower risk for hemorrhagic, not ischemic, stroke.9,10
In these trials, overall rates of major bleeding were similar to that of warfarin.8-10 Patients taking warfarin generally experienced higher rates of intracranial hemorrhage but lower rates of gastrointestinal (GI) bleeding than those on NOACs. Relative to warfarin, apixaban was the only NOAC that did not have a higher rate of GI bleeding and the only one with a lower rate of major bleeding.8-10 In addition, apixaban remains the only NOAC found to have a statistically significant decrease in all-cause mortality compared with warfarin.10 Although dabigatran and rivaroxaban were associated with a strong trend towards decreased mortality, both studies were underpowered for this secondary outcome.8,9
Adding NOACs to stroke guidelines. The role of NOACs in the prevention of stroke in patients with nonvalvular AF is beginning to be reflected in newer guidelines. The American College of Chest Physicians (ACCP)’s 2012 guidelines recommend dabigatran over warfarin (grade 2B—weak recommendation; moderate quality evidence) unless the patient is well controlled on warfarin.11 The European Society of Cardiology (ESC)’s 2012 guidelines recommend dabigatran, apixaban, and rivaroxaban as broadly preferable to warfarin, while noting that experience with these agents is limited and appropriate patient selection is important.12
Anticoagulation to treat—and prevent—VTE
The standard of care for acute venous thromboembolism (VTE) is to initiate warfarin along with a parenteral anticoagulant, such as unfractionated heparin, low-molecular-weight heparin (LMWH), or fondaparinux.13 Due to warfarin’s slow onset to peak effect, a parenteral anticoagulant is overlapped for ≥5 days—until warfarin reaches a therapeutic level and can be continued as monotherapy.13 But many patients find subcutaneous delivery of LMWH disagreeable and costly and frequent INR monitoring inconvenient, so the new agents offer notable advantages.
In well-designed studies, dabigatran, rivaroxaban, and apixaban have all been shown to be noninferior to warfarin in the initial treatment of acute DVT and pulmonary embolism (PE).14-17 All 3 agents were also shown to have lower rates of major bleeding than warfarin. Rivaroxaban and apixaban were also superior to warfarin with regard to bleeding events, and dabigatran was noninferior to warfarin for this outcome.14-17
NOACs help prevent recurrence
All 3 NOACs have been studied for long-term prevention of recurrent VTE after 3 to 18 months of anticoagulation, as well. Dabigatran was found in the RE-MEDY trial to be noninferior to warfarin for the risk of recurrent VTE, and to have lower rates of bleeding.18 In separate trials, all 3 agents were superior to placebo in preventing recurrent VTE. Rates of long-term major bleeding were significantly higher than placebo with rivaroxaban and dabigatran, but not with apixaban.15,18,19
Rivaroxaban is the only NOAC to be FDA approved for the treatment of acute DVT and PE, and the ACCP’s 2012 guidelines list it as a viable alternative to parenteral anticoagulation when initiating treatment for acute VTE.6,13 When treating VTE long term, the guidelines continue to recommend warfarin or LMWH rather than dabigatran or rivaroxaban.13 Recommendations may change in coming years, as physicians gain more experience with NOACs and more clinical trials are published.16-19
Starting or converting to NOAC therapy
In patients who have not been on anticoagulant therapy, any NOAC can be initiated immediately, with no need for parenteral, or “bridge” therapy. This is because of the rapid onset of action of the NOACs.12
To transition a patient from warfarin to a NOAC, it is necessary to discontinue warfarin therapy completely and closely monitor INR, then initiate NOAC therapy when INR≤2. No parenteral anticoagulation is necessary (TABLE 2).5-7
If it is necessary to transition a patient from a NOAC to warfarin, the protocol depends on the agent. Because dabigatran has no significant impact on prolongation of prothrombin time (PT), it can be overlapped with warfarin. Rivaroxaban and apixaban have a significant impact on PT prolongation, however, and overlapping either agent with warfarin is not recommended.4 Keep in mind that the recommended dosages for the NOACs are not standardized, and can differ drastically depending on the indication for use as well as on patient-specific factors, including renal function, body weight, and age.
Laboratory monitoring is not required
While warfarin has a great deal of interpatient variability and requires frequent lab monitoring, an oft-cited advantage of the NOACs is that they do not require regular monitoring. However, that also has a downside (TABLE 3).1,3-10,12,14-17,20-22 Monitoring INR in patients on warfarin allows physicians to assess patient compliance. And, if a patient on warfarin requires an invasive procedure, coagulation status and bleeding risk can easily be determined. That is not the case with the NOACs.
While some routine laboratory tests may be elevated in a patient taking a NOAC, the degree of elevation does not correlate well with anticoagulant concentration. And, because each NOAC has a different mechanism of action, different measures will be elevated in a patient taking dabigatran vs apixaban or rivaroxaban.4
Activated partial thromboplastin time (aPTT) is the most readily available lab test to assess the presence or absence of dabigatran.4 A normal aPTT indicates that there is little to no dabigatran present.4 But, while an elevated aPTT suggests the presence of dabigatran, it provides little information about how much.4
PT is a useful test to assess coagulation status in patients on either rivaroxaban or apixaban. A normal PT suggests that minimal amounts (or none) of the NOAC are present in the plasma.4 (A direct thrombin inhibitor assay, calibrated to more accurately assess dabigatran concentration, is being developed for clinical use, but is currently available only for research purposes in the United States; a chromogenic antifactor Xa test specific to apixaban and rivaroxaban is also being developed, but is not yet commercially available.4)
What to do when NOAC reversal is required
Patients often need to stop taking an oral anticoagulation in the days leading up to a planned invasive procedure. In an individual with normal renal function who will undergo a procedure with a standard bleeding risk, a NOAC would generally need to be withheld for one to 2 days prior to surgery, given the relatively short half-life. If a patient has acute renal failure or CKD, however, dabigatran may need to be withheld for a prolonged period (3-6 days) in order to safely proceed to surgery.4,23 NOACs may also need to be withheld for 2 to 6 days prior to any surgery with a high risk for bleeding.4
When speed is of the essence
There is no known antidote to aid in the reversal of dabigatran, rivaroxaban, or apixaban.4 Because of their relatively short half-lives, withholding the medication and providing supportive care is generally sufficient to ensure adequate hemostasis in cases of mild to moderate bleeding.4 If a patient presents with acute ingestion or an overdose, activated charcoal should be administered if the ingestion has occurred within the past 3 hours.4,24 The lack of a clear-cut reversal strategy can be extremely problematic in cases of trauma or life-threatening bleeding, however. (Fresh frozen plasma has not been shown to be effective at reversing NOACs’ effects.4)
In instances of severe bleeding or the need for urgent surgery, a more aggressive approach may be needed. Hemodialysis can be used to assist in the removal of dabigatran, but not rivaroxaban or apixaban.4 However, evidence suggests that the most effective therapy for patients who need rapid reversal of any NOAC is to administer 75 to 80 units/kg of activated prothrombin complex concentrate (aPCC).4,25-27 Recombinant factor VIIa has shown some promise in reversing the anticoagulant effects of these novel agents, but evidence is insufficient to recommend it as first-line therapy at this time.26, 27
Patients are more satisfied
The most obvious advantage of the NOACs as a group compared with warfarin is the lack of need for laboratory monitoring or continuous dose titration. Reliably stable pharmacokinetics make once or twice daily dosing possible. A rapid onset of action negates the need for bridging therapy with parenteral anticoagulants in patients at high risk of thrombosis. This may improve compliance, as many patients are averse to the use of subcutaneous injections or need extensive education before they can safely self-inject. The incidence of heparin-induced thrombocytopenia may also be decreased if unfractionated heparin and LMWH are used less frequently.
NOACs also appear to improve patient satisfaction.20-22 In one study that included patients with AF on dabigatran or warfarin, satisfaction was higher in those taking dabigatran, particularly among those who did not experience significant GI adverse effects.20 Another study showed improved patient satisfaction with rivaroxaban compared with LMWH following lower extremity joint replacement, which led to significantly higher rates of compliance.22
… but problems and pitfalls remain
In addition to the lack of a readily available and clinically validated reversal agent, the absence of a lab test that reliably measures the concentration of NOACs makes it difficult to determine whether patients are following their prescribed regimen.3,4
Medication compliance must be assessed when considering a transition from warfarin to a NOAC. Switching patients with poor INR control on warfarin to a NOAC should be done only after determining that the poor control is not the result of nonadherence. Because of the NOACs’ shorter half-life, patients who don’t take them regularly may be at higher risk for thromboembolic events.1,12
Cost is a serious consideration. While there are some costs associated with the monitoring warfarin requires, the medication itself has been generic for several decades and can be found on many “$4 lists” at pharmacies nationwide. In contrast, all 3 NOACs are available only as branded drugs, and can cost a patient with limited drug coverage anywhere from $250 to $350 per month28—a serious concern, given that the likelihood of noncompliance increases as out-of-pocket costs rise. This was highlighted in a recent study that found patients were twice as likely to discontinue their cholesterol-lowering medication if 100% of the cost was out of pocket, compared with patients who had no prescription copay.29 From the perspective of the US health care system, however, NOACs have been found to be cost effective compared with warfarin, mostly due to the lack of laboratory monitoring.30-32
Adverse effects. The risk of GI bleeds has been shown to be higher in patients taking rivaroxaban and dabigatran vs warfarin.8,9 Dabigatran has also been associated with a significant risk for dyspepsia.5,8,14 In clinical trials, the reported rate for dyspepsia in patients taking dabigatran was 3% to 11%; subsequent investigations have found the incidence to be far higher (33%).8,14,33
Drug interactions. Warfarin has a large number of drug interactions, of course, but because of its long history, these interactions are well established. NOACs also have a number of drug interactions, but the true clinical impact has not yet been established. All 3 agents are substrates for the P-glycoprotein (P-gp) transport system, so any known inhibitors or inducers of the P-gp system should be used cautiously in patients on NOACs.1,3-7,12 Rivaroxaban and apixaban are also substrates for the CYP3A4 hepatic enzyme system, so any drugs known to inhibit or induce this system require caution, as well.1,3-7,12
Who should not take a NOAC?
NOACs should not be prescribed for patients with mechanical heart valves.34 Dabigatran is the only NOAC to have been studied in this patient population, and the phase II trial was stopped prematurely due to increased risk for both bleeding and stroke in patients on dabigatran compared with warfarin.34
Renal impairment must be considered, as well. Do a baseline assessment of renal function in all patients before transitioning them to a NOAC, and periodic reassessment during therapy. While this is important for patients on rivaroxaban and apixaban, it is essential for those on dabigatran, as 80% of the drug is excreted by the kidneys.1,5,12 NOACs have not been adequately assessed in patients with severe renal dysfunction and should be avoided in this patient population. Caution should be exercised in patients with moderate renal dysfunction, as well.5-10,14-19 Apixaban appears to be the safest NOAC for patients with moderate renal dysfunction, as it has the least renal clearance.1,12
Who should take a NOAC?
No well-established criteria for patient selection for NOACs exist, yet appropriate patient selection is crucial. Evidence suggests that NOAC therapy is best suited to those who:
• are relatively young (<65 years)
• have normal renal function
• have poorly controlled INR with warfarin that is unrelated to noncompliance
• are unable to have regular INR monitoring.
Patients best suited for continued use of warfarin would be those whose INR is well controlled, those who have higher goal INR ranges (eg, because of the presence of mechanical heart valves), patients with significant renal dysfunction, and individuals with a history of peptic ulcer disease or GI bleeding. Warfarin may also be the best option for patients with a history of noncompliance and for uninsured or underinsured patients.
CASE 1 Warfarin and any of the NOACs were all feasible options for Ms. J, but apixaban was deemed to be the safest because of her moderate renal dysfunction. However, after she was told that apixaban has little “real world” clinical data, no effective antidote if bleeding were to occur, and a much higher cost than warfarin, she opted for warfarin therapy, despite the laboratory monitoring required.
CASE 2 Mr. W was excited to learn that there were new alternatives to warfarin; he had taken warfarin for 6 months after his last DVT and had a hard time coming in for INR checks. The patient reported that he had no history of bleeding and was compliant with medications. Rivaroxaban was the best option for Mr. W, as it is the only NOAC with FDA approval for the treatment of acute VTE.
CORRESPONDENCE
Jeremy Vandiver, PharmD, BCPS, Swedish Medical Center, Room 3260, 501 East Hampden Avenue, Englewood, CO 80013; [email protected]
1. Wittkowsky AK. Novel oral anticoagulants and their role in clinical practice. Pharmacotherapy. 2011;31:1175-1191.
2. Gums JG. Place of dabigatran in contemporary pharmacotherapy. Pharmacotherapy. 2011;31:335-337.
3. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 suppl):e44S-e88S.
4. Siegal DM, Crowther MA. Acute management of bleeding in patients on novel oral anticoagulants. Eur Heart J. 2013;34:489-496.
5. Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2010.
6. Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2011.
7. Eliquis [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2012.
8. Connolly SJ, Zekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.
9. Patel MR, Mahaffery KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-891.
10. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-992.
11. You JJ, Singer DE, Howard P, et al. Antithrombotic therapy for atrial fibrillation: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 suppl):e531S-e575S.
12. Camm AJ, Lip GYH, De Caterina R, et al. 2012 focused update of the ESC guidelines for the management of atrial fibrillation. Eur Heart J. 2012;33:2719-2747.
13. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 suppl):e419S-e494S.
14. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342-2352.
15. Bauersachs R, Berkowitz SD, Brenner B, et al. Rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499-2510.
16. Büller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287-1297.
17. Agnelli A, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369:799-808.
18. Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368:709-718.
19. Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368:699-708.
20. Michel J, Mundell D, Boga T, et al. Dabigatran for anticoagulation in atrial fibrillation–Early clinical experience in a hospital population and comparison to trial data. Heart Lung Circ. 2013;22:50-55.
21. Kendoff D, Perka C, Fritsche HM, et al. Oral thromboprophylaxis following total hip or knee replacement: review and multicentre experience with dabigatran etexilate. Open Orthop J. 2011;5:395-399.
22. Rogers BA, Phillip S, Foote J, et al. Is there adequate provision of venous thromboembolism prophylaxis following hip arthroplasty? An audit and international survey. Ann R Coll Surg Engl. 2010;92:668-672.
23. Healey JS, Eikelboom J, Douketis J, at al. Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the randomized evaluation of long-term anticoagulation therapy (RE-LY) randomized trial. Circulation. 2012;126:343-348.
24. van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate: a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103:1116-1127.
25. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124:1573-1579.
26. Marlu R, Hodaj E, Paris A, et al. Effect of nonspecific reversal agents on anticoagulant activity of dabigatran and rivaroxaban. A randomised crossover ex vivo study in healthy volunteers. Thromb Haemost. 2012;108:217-224.
27. Escolar G, Fernandez-Gallego V, Arellano-Rodrigo E, et al. Reversal of apixaban induced alterations of hemostasis by different coagulation factor concentrates: studies in vitro with circulating human blood. PLOS ONE. 2013;8:e78696.
28. Drug pricing information. Costco Pharmacy Web site. Available at: http://www2.costco.com/Pharmacy/DrugInformation.aspx?p=1. Accessed December 9, 2013.
29. Schneeweiss S, Patrick AR, Maclure M, et al. Adherence to statin therapy under drug cost sharing in patients with and without myocardial infarction: a population-based natural experiment. Circulation. 2007;115:2128-2135.
30. McKeage K. Dabigatran etexilate: a pharmacoeconomic review of its use in the prevention of stroke and systemic embolism in patients with atrial fibrillation. Pharmacoeconomics. 2012;30:841-55.
31. Lee S, Anglade MW, Pham D, et al. Cost–Effectiveness of rivaroxaban compared to warfarin for stroke prevention in atrial fibrillation. Am J Cardiol. 2012;110:845-851.
32. Kamel H, Easton JD, Johnston SC, et al. Cost-effectiveness of apixaban vs warfarin for secondary stroke prevention in atrial fibrillation. Neurology. 2012;79:1428-1434.
33. Schulman S, Shortt B, Robinson M, et al. Adherence to anticoagulant treatment with dabigatran in a real-world setting. J Thromb Haemost. 2013; 11:1295-1299
34. Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369:1206-1214.
› Consider novel oral anticoagualants (NOACs) for patients who have normal renal function, are comlpiant with medication regimens, and have no history of peptic ulcer or gastrointestinal bleeding. B
› Avoid overlapping warfarin with rivaroxaban or apixaban when transitioning a patient from one anticoagulant to the other, as both agents prolong prothrombin time. B
› When initiating a NOAC, it is not necessary to overlap with a parenteral anticoagulant. B
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
CASE 1 Sally J is a 72-year-old Caucasian woman who comes to your clinic after being diagnosed with atrial fibrillation (AF). The patient has a 10-year history of type 2 diabetes; she also has a history of hypertension and chronic kidney disease (CKD), with a baseline creatinine clearance of approximately 40 mL/min. Ms. J tells you she knows people who take warfarin and really dislike it. She asks for your opinion of the new anticoagulants she’s seen advertised on TV, and wonders whether one of them would be right for her.
CASE 2 Bobby W, a 35-year-old African American man, was recently diagnosed with deep vein thrombosis (DVT). This was his second clot in 5 years, and occurred after a long flight home from Europe. The patient explains that he leads a very active lifestyle and doesn’t have the time to come in for the monthly international normalized ratio (INR) checks that warfarin requires. What would you recommend for these patients?
Troubled by warfarin’s narrow therapeutic index, numerous medication and dietary interactions, and need for frequent monitoring, patients requiring long-term oral anticoagulation therapy have been seeking alternatives for years. Finally, they have a choice. The US Food and Drug Administration (FDA) approved 3 oral anticoagulants—dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis)—in less than 4 years. Known as novel oral anticoagulants (NOACs), they are the first such drugs to enter the market in more than 50 years.1,2
While warfarin inhibits a wide range of clotting factors (including II, VII, IX, and X), NOACs work further down the clotting cascade (TABLE 1).1,3-7 Dabigatran, a direct thrombin inhibitor, only inhibits factor IIa.3,5 Rivaroxaban and apixaban directly inhibit factor Xa and indirectly inhibit factor IIa.3,6,7
There are notable advantages to these newer agents, but some disadvantages that must be considered, as well. Appropriate patient selection, guided by a thorough understanding of the benefits and risks of NOACs, is key.
Stroke prevention in atrial fibrillation
All 3 NOACs are approved for stroke prevention in patients with nonvalvular atrial fibrillation (AF). The approvals are based on a small number of well-designed trials: RE-LY (dabigatran), ROCKET-AF (rivaroxaban), and ARISTOTLE (apixaban).8-10 Compared with warfarin, dabigatran is the only oral anticoagulant with a lower rate of both hemorrhagic and ischemic stroke.8 Both rivaroxaban and apixaban were found to decrease overall stroke risk relative to warfarin, but the difference was driven by a lower risk for hemorrhagic, not ischemic, stroke.9,10
In these trials, overall rates of major bleeding were similar to that of warfarin.8-10 Patients taking warfarin generally experienced higher rates of intracranial hemorrhage but lower rates of gastrointestinal (GI) bleeding than those on NOACs. Relative to warfarin, apixaban was the only NOAC that did not have a higher rate of GI bleeding and the only one with a lower rate of major bleeding.8-10 In addition, apixaban remains the only NOAC found to have a statistically significant decrease in all-cause mortality compared with warfarin.10 Although dabigatran and rivaroxaban were associated with a strong trend towards decreased mortality, both studies were underpowered for this secondary outcome.8,9
Adding NOACs to stroke guidelines. The role of NOACs in the prevention of stroke in patients with nonvalvular AF is beginning to be reflected in newer guidelines. The American College of Chest Physicians (ACCP)’s 2012 guidelines recommend dabigatran over warfarin (grade 2B—weak recommendation; moderate quality evidence) unless the patient is well controlled on warfarin.11 The European Society of Cardiology (ESC)’s 2012 guidelines recommend dabigatran, apixaban, and rivaroxaban as broadly preferable to warfarin, while noting that experience with these agents is limited and appropriate patient selection is important.12
Anticoagulation to treat—and prevent—VTE
The standard of care for acute venous thromboembolism (VTE) is to initiate warfarin along with a parenteral anticoagulant, such as unfractionated heparin, low-molecular-weight heparin (LMWH), or fondaparinux.13 Due to warfarin’s slow onset to peak effect, a parenteral anticoagulant is overlapped for ≥5 days—until warfarin reaches a therapeutic level and can be continued as monotherapy.13 But many patients find subcutaneous delivery of LMWH disagreeable and costly and frequent INR monitoring inconvenient, so the new agents offer notable advantages.
In well-designed studies, dabigatran, rivaroxaban, and apixaban have all been shown to be noninferior to warfarin in the initial treatment of acute DVT and pulmonary embolism (PE).14-17 All 3 agents were also shown to have lower rates of major bleeding than warfarin. Rivaroxaban and apixaban were also superior to warfarin with regard to bleeding events, and dabigatran was noninferior to warfarin for this outcome.14-17
NOACs help prevent recurrence
All 3 NOACs have been studied for long-term prevention of recurrent VTE after 3 to 18 months of anticoagulation, as well. Dabigatran was found in the RE-MEDY trial to be noninferior to warfarin for the risk of recurrent VTE, and to have lower rates of bleeding.18 In separate trials, all 3 agents were superior to placebo in preventing recurrent VTE. Rates of long-term major bleeding were significantly higher than placebo with rivaroxaban and dabigatran, but not with apixaban.15,18,19
Rivaroxaban is the only NOAC to be FDA approved for the treatment of acute DVT and PE, and the ACCP’s 2012 guidelines list it as a viable alternative to parenteral anticoagulation when initiating treatment for acute VTE.6,13 When treating VTE long term, the guidelines continue to recommend warfarin or LMWH rather than dabigatran or rivaroxaban.13 Recommendations may change in coming years, as physicians gain more experience with NOACs and more clinical trials are published.16-19
Starting or converting to NOAC therapy
In patients who have not been on anticoagulant therapy, any NOAC can be initiated immediately, with no need for parenteral, or “bridge” therapy. This is because of the rapid onset of action of the NOACs.12
To transition a patient from warfarin to a NOAC, it is necessary to discontinue warfarin therapy completely and closely monitor INR, then initiate NOAC therapy when INR≤2. No parenteral anticoagulation is necessary (TABLE 2).5-7
If it is necessary to transition a patient from a NOAC to warfarin, the protocol depends on the agent. Because dabigatran has no significant impact on prolongation of prothrombin time (PT), it can be overlapped with warfarin. Rivaroxaban and apixaban have a significant impact on PT prolongation, however, and overlapping either agent with warfarin is not recommended.4 Keep in mind that the recommended dosages for the NOACs are not standardized, and can differ drastically depending on the indication for use as well as on patient-specific factors, including renal function, body weight, and age.
Laboratory monitoring is not required
While warfarin has a great deal of interpatient variability and requires frequent lab monitoring, an oft-cited advantage of the NOACs is that they do not require regular monitoring. However, that also has a downside (TABLE 3).1,3-10,12,14-17,20-22 Monitoring INR in patients on warfarin allows physicians to assess patient compliance. And, if a patient on warfarin requires an invasive procedure, coagulation status and bleeding risk can easily be determined. That is not the case with the NOACs.
While some routine laboratory tests may be elevated in a patient taking a NOAC, the degree of elevation does not correlate well with anticoagulant concentration. And, because each NOAC has a different mechanism of action, different measures will be elevated in a patient taking dabigatran vs apixaban or rivaroxaban.4
Activated partial thromboplastin time (aPTT) is the most readily available lab test to assess the presence or absence of dabigatran.4 A normal aPTT indicates that there is little to no dabigatran present.4 But, while an elevated aPTT suggests the presence of dabigatran, it provides little information about how much.4
PT is a useful test to assess coagulation status in patients on either rivaroxaban or apixaban. A normal PT suggests that minimal amounts (or none) of the NOAC are present in the plasma.4 (A direct thrombin inhibitor assay, calibrated to more accurately assess dabigatran concentration, is being developed for clinical use, but is currently available only for research purposes in the United States; a chromogenic antifactor Xa test specific to apixaban and rivaroxaban is also being developed, but is not yet commercially available.4)
What to do when NOAC reversal is required
Patients often need to stop taking an oral anticoagulation in the days leading up to a planned invasive procedure. In an individual with normal renal function who will undergo a procedure with a standard bleeding risk, a NOAC would generally need to be withheld for one to 2 days prior to surgery, given the relatively short half-life. If a patient has acute renal failure or CKD, however, dabigatran may need to be withheld for a prolonged period (3-6 days) in order to safely proceed to surgery.4,23 NOACs may also need to be withheld for 2 to 6 days prior to any surgery with a high risk for bleeding.4
When speed is of the essence
There is no known antidote to aid in the reversal of dabigatran, rivaroxaban, or apixaban.4 Because of their relatively short half-lives, withholding the medication and providing supportive care is generally sufficient to ensure adequate hemostasis in cases of mild to moderate bleeding.4 If a patient presents with acute ingestion or an overdose, activated charcoal should be administered if the ingestion has occurred within the past 3 hours.4,24 The lack of a clear-cut reversal strategy can be extremely problematic in cases of trauma or life-threatening bleeding, however. (Fresh frozen plasma has not been shown to be effective at reversing NOACs’ effects.4)
In instances of severe bleeding or the need for urgent surgery, a more aggressive approach may be needed. Hemodialysis can be used to assist in the removal of dabigatran, but not rivaroxaban or apixaban.4 However, evidence suggests that the most effective therapy for patients who need rapid reversal of any NOAC is to administer 75 to 80 units/kg of activated prothrombin complex concentrate (aPCC).4,25-27 Recombinant factor VIIa has shown some promise in reversing the anticoagulant effects of these novel agents, but evidence is insufficient to recommend it as first-line therapy at this time.26, 27
Patients are more satisfied
The most obvious advantage of the NOACs as a group compared with warfarin is the lack of need for laboratory monitoring or continuous dose titration. Reliably stable pharmacokinetics make once or twice daily dosing possible. A rapid onset of action negates the need for bridging therapy with parenteral anticoagulants in patients at high risk of thrombosis. This may improve compliance, as many patients are averse to the use of subcutaneous injections or need extensive education before they can safely self-inject. The incidence of heparin-induced thrombocytopenia may also be decreased if unfractionated heparin and LMWH are used less frequently.
NOACs also appear to improve patient satisfaction.20-22 In one study that included patients with AF on dabigatran or warfarin, satisfaction was higher in those taking dabigatran, particularly among those who did not experience significant GI adverse effects.20 Another study showed improved patient satisfaction with rivaroxaban compared with LMWH following lower extremity joint replacement, which led to significantly higher rates of compliance.22
… but problems and pitfalls remain
In addition to the lack of a readily available and clinically validated reversal agent, the absence of a lab test that reliably measures the concentration of NOACs makes it difficult to determine whether patients are following their prescribed regimen.3,4
Medication compliance must be assessed when considering a transition from warfarin to a NOAC. Switching patients with poor INR control on warfarin to a NOAC should be done only after determining that the poor control is not the result of nonadherence. Because of the NOACs’ shorter half-life, patients who don’t take them regularly may be at higher risk for thromboembolic events.1,12
Cost is a serious consideration. While there are some costs associated with the monitoring warfarin requires, the medication itself has been generic for several decades and can be found on many “$4 lists” at pharmacies nationwide. In contrast, all 3 NOACs are available only as branded drugs, and can cost a patient with limited drug coverage anywhere from $250 to $350 per month28—a serious concern, given that the likelihood of noncompliance increases as out-of-pocket costs rise. This was highlighted in a recent study that found patients were twice as likely to discontinue their cholesterol-lowering medication if 100% of the cost was out of pocket, compared with patients who had no prescription copay.29 From the perspective of the US health care system, however, NOACs have been found to be cost effective compared with warfarin, mostly due to the lack of laboratory monitoring.30-32
Adverse effects. The risk of GI bleeds has been shown to be higher in patients taking rivaroxaban and dabigatran vs warfarin.8,9 Dabigatran has also been associated with a significant risk for dyspepsia.5,8,14 In clinical trials, the reported rate for dyspepsia in patients taking dabigatran was 3% to 11%; subsequent investigations have found the incidence to be far higher (33%).8,14,33
Drug interactions. Warfarin has a large number of drug interactions, of course, but because of its long history, these interactions are well established. NOACs also have a number of drug interactions, but the true clinical impact has not yet been established. All 3 agents are substrates for the P-glycoprotein (P-gp) transport system, so any known inhibitors or inducers of the P-gp system should be used cautiously in patients on NOACs.1,3-7,12 Rivaroxaban and apixaban are also substrates for the CYP3A4 hepatic enzyme system, so any drugs known to inhibit or induce this system require caution, as well.1,3-7,12
Who should not take a NOAC?
NOACs should not be prescribed for patients with mechanical heart valves.34 Dabigatran is the only NOAC to have been studied in this patient population, and the phase II trial was stopped prematurely due to increased risk for both bleeding and stroke in patients on dabigatran compared with warfarin.34
Renal impairment must be considered, as well. Do a baseline assessment of renal function in all patients before transitioning them to a NOAC, and periodic reassessment during therapy. While this is important for patients on rivaroxaban and apixaban, it is essential for those on dabigatran, as 80% of the drug is excreted by the kidneys.1,5,12 NOACs have not been adequately assessed in patients with severe renal dysfunction and should be avoided in this patient population. Caution should be exercised in patients with moderate renal dysfunction, as well.5-10,14-19 Apixaban appears to be the safest NOAC for patients with moderate renal dysfunction, as it has the least renal clearance.1,12
Who should take a NOAC?
No well-established criteria for patient selection for NOACs exist, yet appropriate patient selection is crucial. Evidence suggests that NOAC therapy is best suited to those who:
• are relatively young (<65 years)
• have normal renal function
• have poorly controlled INR with warfarin that is unrelated to noncompliance
• are unable to have regular INR monitoring.
Patients best suited for continued use of warfarin would be those whose INR is well controlled, those who have higher goal INR ranges (eg, because of the presence of mechanical heart valves), patients with significant renal dysfunction, and individuals with a history of peptic ulcer disease or GI bleeding. Warfarin may also be the best option for patients with a history of noncompliance and for uninsured or underinsured patients.
CASE 1 Warfarin and any of the NOACs were all feasible options for Ms. J, but apixaban was deemed to be the safest because of her moderate renal dysfunction. However, after she was told that apixaban has little “real world” clinical data, no effective antidote if bleeding were to occur, and a much higher cost than warfarin, she opted for warfarin therapy, despite the laboratory monitoring required.
CASE 2 Mr. W was excited to learn that there were new alternatives to warfarin; he had taken warfarin for 6 months after his last DVT and had a hard time coming in for INR checks. The patient reported that he had no history of bleeding and was compliant with medications. Rivaroxaban was the best option for Mr. W, as it is the only NOAC with FDA approval for the treatment of acute VTE.
CORRESPONDENCE
Jeremy Vandiver, PharmD, BCPS, Swedish Medical Center, Room 3260, 501 East Hampden Avenue, Englewood, CO 80013; [email protected]
› Consider novel oral anticoagualants (NOACs) for patients who have normal renal function, are comlpiant with medication regimens, and have no history of peptic ulcer or gastrointestinal bleeding. B
› Avoid overlapping warfarin with rivaroxaban or apixaban when transitioning a patient from one anticoagulant to the other, as both agents prolong prothrombin time. B
› When initiating a NOAC, it is not necessary to overlap with a parenteral anticoagulant. B
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
CASE 1 Sally J is a 72-year-old Caucasian woman who comes to your clinic after being diagnosed with atrial fibrillation (AF). The patient has a 10-year history of type 2 diabetes; she also has a history of hypertension and chronic kidney disease (CKD), with a baseline creatinine clearance of approximately 40 mL/min. Ms. J tells you she knows people who take warfarin and really dislike it. She asks for your opinion of the new anticoagulants she’s seen advertised on TV, and wonders whether one of them would be right for her.
CASE 2 Bobby W, a 35-year-old African American man, was recently diagnosed with deep vein thrombosis (DVT). This was his second clot in 5 years, and occurred after a long flight home from Europe. The patient explains that he leads a very active lifestyle and doesn’t have the time to come in for the monthly international normalized ratio (INR) checks that warfarin requires. What would you recommend for these patients?
Troubled by warfarin’s narrow therapeutic index, numerous medication and dietary interactions, and need for frequent monitoring, patients requiring long-term oral anticoagulation therapy have been seeking alternatives for years. Finally, they have a choice. The US Food and Drug Administration (FDA) approved 3 oral anticoagulants—dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis)—in less than 4 years. Known as novel oral anticoagulants (NOACs), they are the first such drugs to enter the market in more than 50 years.1,2
While warfarin inhibits a wide range of clotting factors (including II, VII, IX, and X), NOACs work further down the clotting cascade (TABLE 1).1,3-7 Dabigatran, a direct thrombin inhibitor, only inhibits factor IIa.3,5 Rivaroxaban and apixaban directly inhibit factor Xa and indirectly inhibit factor IIa.3,6,7
There are notable advantages to these newer agents, but some disadvantages that must be considered, as well. Appropriate patient selection, guided by a thorough understanding of the benefits and risks of NOACs, is key.
Stroke prevention in atrial fibrillation
All 3 NOACs are approved for stroke prevention in patients with nonvalvular atrial fibrillation (AF). The approvals are based on a small number of well-designed trials: RE-LY (dabigatran), ROCKET-AF (rivaroxaban), and ARISTOTLE (apixaban).8-10 Compared with warfarin, dabigatran is the only oral anticoagulant with a lower rate of both hemorrhagic and ischemic stroke.8 Both rivaroxaban and apixaban were found to decrease overall stroke risk relative to warfarin, but the difference was driven by a lower risk for hemorrhagic, not ischemic, stroke.9,10
In these trials, overall rates of major bleeding were similar to that of warfarin.8-10 Patients taking warfarin generally experienced higher rates of intracranial hemorrhage but lower rates of gastrointestinal (GI) bleeding than those on NOACs. Relative to warfarin, apixaban was the only NOAC that did not have a higher rate of GI bleeding and the only one with a lower rate of major bleeding.8-10 In addition, apixaban remains the only NOAC found to have a statistically significant decrease in all-cause mortality compared with warfarin.10 Although dabigatran and rivaroxaban were associated with a strong trend towards decreased mortality, both studies were underpowered for this secondary outcome.8,9
Adding NOACs to stroke guidelines. The role of NOACs in the prevention of stroke in patients with nonvalvular AF is beginning to be reflected in newer guidelines. The American College of Chest Physicians (ACCP)’s 2012 guidelines recommend dabigatran over warfarin (grade 2B—weak recommendation; moderate quality evidence) unless the patient is well controlled on warfarin.11 The European Society of Cardiology (ESC)’s 2012 guidelines recommend dabigatran, apixaban, and rivaroxaban as broadly preferable to warfarin, while noting that experience with these agents is limited and appropriate patient selection is important.12
Anticoagulation to treat—and prevent—VTE
The standard of care for acute venous thromboembolism (VTE) is to initiate warfarin along with a parenteral anticoagulant, such as unfractionated heparin, low-molecular-weight heparin (LMWH), or fondaparinux.13 Due to warfarin’s slow onset to peak effect, a parenteral anticoagulant is overlapped for ≥5 days—until warfarin reaches a therapeutic level and can be continued as monotherapy.13 But many patients find subcutaneous delivery of LMWH disagreeable and costly and frequent INR monitoring inconvenient, so the new agents offer notable advantages.
In well-designed studies, dabigatran, rivaroxaban, and apixaban have all been shown to be noninferior to warfarin in the initial treatment of acute DVT and pulmonary embolism (PE).14-17 All 3 agents were also shown to have lower rates of major bleeding than warfarin. Rivaroxaban and apixaban were also superior to warfarin with regard to bleeding events, and dabigatran was noninferior to warfarin for this outcome.14-17
NOACs help prevent recurrence
All 3 NOACs have been studied for long-term prevention of recurrent VTE after 3 to 18 months of anticoagulation, as well. Dabigatran was found in the RE-MEDY trial to be noninferior to warfarin for the risk of recurrent VTE, and to have lower rates of bleeding.18 In separate trials, all 3 agents were superior to placebo in preventing recurrent VTE. Rates of long-term major bleeding were significantly higher than placebo with rivaroxaban and dabigatran, but not with apixaban.15,18,19
Rivaroxaban is the only NOAC to be FDA approved for the treatment of acute DVT and PE, and the ACCP’s 2012 guidelines list it as a viable alternative to parenteral anticoagulation when initiating treatment for acute VTE.6,13 When treating VTE long term, the guidelines continue to recommend warfarin or LMWH rather than dabigatran or rivaroxaban.13 Recommendations may change in coming years, as physicians gain more experience with NOACs and more clinical trials are published.16-19
Starting or converting to NOAC therapy
In patients who have not been on anticoagulant therapy, any NOAC can be initiated immediately, with no need for parenteral, or “bridge” therapy. This is because of the rapid onset of action of the NOACs.12
To transition a patient from warfarin to a NOAC, it is necessary to discontinue warfarin therapy completely and closely monitor INR, then initiate NOAC therapy when INR≤2. No parenteral anticoagulation is necessary (TABLE 2).5-7
If it is necessary to transition a patient from a NOAC to warfarin, the protocol depends on the agent. Because dabigatran has no significant impact on prolongation of prothrombin time (PT), it can be overlapped with warfarin. Rivaroxaban and apixaban have a significant impact on PT prolongation, however, and overlapping either agent with warfarin is not recommended.4 Keep in mind that the recommended dosages for the NOACs are not standardized, and can differ drastically depending on the indication for use as well as on patient-specific factors, including renal function, body weight, and age.
Laboratory monitoring is not required
While warfarin has a great deal of interpatient variability and requires frequent lab monitoring, an oft-cited advantage of the NOACs is that they do not require regular monitoring. However, that also has a downside (TABLE 3).1,3-10,12,14-17,20-22 Monitoring INR in patients on warfarin allows physicians to assess patient compliance. And, if a patient on warfarin requires an invasive procedure, coagulation status and bleeding risk can easily be determined. That is not the case with the NOACs.
While some routine laboratory tests may be elevated in a patient taking a NOAC, the degree of elevation does not correlate well with anticoagulant concentration. And, because each NOAC has a different mechanism of action, different measures will be elevated in a patient taking dabigatran vs apixaban or rivaroxaban.4
Activated partial thromboplastin time (aPTT) is the most readily available lab test to assess the presence or absence of dabigatran.4 A normal aPTT indicates that there is little to no dabigatran present.4 But, while an elevated aPTT suggests the presence of dabigatran, it provides little information about how much.4
PT is a useful test to assess coagulation status in patients on either rivaroxaban or apixaban. A normal PT suggests that minimal amounts (or none) of the NOAC are present in the plasma.4 (A direct thrombin inhibitor assay, calibrated to more accurately assess dabigatran concentration, is being developed for clinical use, but is currently available only for research purposes in the United States; a chromogenic antifactor Xa test specific to apixaban and rivaroxaban is also being developed, but is not yet commercially available.4)
What to do when NOAC reversal is required
Patients often need to stop taking an oral anticoagulation in the days leading up to a planned invasive procedure. In an individual with normal renal function who will undergo a procedure with a standard bleeding risk, a NOAC would generally need to be withheld for one to 2 days prior to surgery, given the relatively short half-life. If a patient has acute renal failure or CKD, however, dabigatran may need to be withheld for a prolonged period (3-6 days) in order to safely proceed to surgery.4,23 NOACs may also need to be withheld for 2 to 6 days prior to any surgery with a high risk for bleeding.4
When speed is of the essence
There is no known antidote to aid in the reversal of dabigatran, rivaroxaban, or apixaban.4 Because of their relatively short half-lives, withholding the medication and providing supportive care is generally sufficient to ensure adequate hemostasis in cases of mild to moderate bleeding.4 If a patient presents with acute ingestion or an overdose, activated charcoal should be administered if the ingestion has occurred within the past 3 hours.4,24 The lack of a clear-cut reversal strategy can be extremely problematic in cases of trauma or life-threatening bleeding, however. (Fresh frozen plasma has not been shown to be effective at reversing NOACs’ effects.4)
In instances of severe bleeding or the need for urgent surgery, a more aggressive approach may be needed. Hemodialysis can be used to assist in the removal of dabigatran, but not rivaroxaban or apixaban.4 However, evidence suggests that the most effective therapy for patients who need rapid reversal of any NOAC is to administer 75 to 80 units/kg of activated prothrombin complex concentrate (aPCC).4,25-27 Recombinant factor VIIa has shown some promise in reversing the anticoagulant effects of these novel agents, but evidence is insufficient to recommend it as first-line therapy at this time.26, 27
Patients are more satisfied
The most obvious advantage of the NOACs as a group compared with warfarin is the lack of need for laboratory monitoring or continuous dose titration. Reliably stable pharmacokinetics make once or twice daily dosing possible. A rapid onset of action negates the need for bridging therapy with parenteral anticoagulants in patients at high risk of thrombosis. This may improve compliance, as many patients are averse to the use of subcutaneous injections or need extensive education before they can safely self-inject. The incidence of heparin-induced thrombocytopenia may also be decreased if unfractionated heparin and LMWH are used less frequently.
NOACs also appear to improve patient satisfaction.20-22 In one study that included patients with AF on dabigatran or warfarin, satisfaction was higher in those taking dabigatran, particularly among those who did not experience significant GI adverse effects.20 Another study showed improved patient satisfaction with rivaroxaban compared with LMWH following lower extremity joint replacement, which led to significantly higher rates of compliance.22
… but problems and pitfalls remain
In addition to the lack of a readily available and clinically validated reversal agent, the absence of a lab test that reliably measures the concentration of NOACs makes it difficult to determine whether patients are following their prescribed regimen.3,4
Medication compliance must be assessed when considering a transition from warfarin to a NOAC. Switching patients with poor INR control on warfarin to a NOAC should be done only after determining that the poor control is not the result of nonadherence. Because of the NOACs’ shorter half-life, patients who don’t take them regularly may be at higher risk for thromboembolic events.1,12
Cost is a serious consideration. While there are some costs associated with the monitoring warfarin requires, the medication itself has been generic for several decades and can be found on many “$4 lists” at pharmacies nationwide. In contrast, all 3 NOACs are available only as branded drugs, and can cost a patient with limited drug coverage anywhere from $250 to $350 per month28—a serious concern, given that the likelihood of noncompliance increases as out-of-pocket costs rise. This was highlighted in a recent study that found patients were twice as likely to discontinue their cholesterol-lowering medication if 100% of the cost was out of pocket, compared with patients who had no prescription copay.29 From the perspective of the US health care system, however, NOACs have been found to be cost effective compared with warfarin, mostly due to the lack of laboratory monitoring.30-32
Adverse effects. The risk of GI bleeds has been shown to be higher in patients taking rivaroxaban and dabigatran vs warfarin.8,9 Dabigatran has also been associated with a significant risk for dyspepsia.5,8,14 In clinical trials, the reported rate for dyspepsia in patients taking dabigatran was 3% to 11%; subsequent investigations have found the incidence to be far higher (33%).8,14,33
Drug interactions. Warfarin has a large number of drug interactions, of course, but because of its long history, these interactions are well established. NOACs also have a number of drug interactions, but the true clinical impact has not yet been established. All 3 agents are substrates for the P-glycoprotein (P-gp) transport system, so any known inhibitors or inducers of the P-gp system should be used cautiously in patients on NOACs.1,3-7,12 Rivaroxaban and apixaban are also substrates for the CYP3A4 hepatic enzyme system, so any drugs known to inhibit or induce this system require caution, as well.1,3-7,12
Who should not take a NOAC?
NOACs should not be prescribed for patients with mechanical heart valves.34 Dabigatran is the only NOAC to have been studied in this patient population, and the phase II trial was stopped prematurely due to increased risk for both bleeding and stroke in patients on dabigatran compared with warfarin.34
Renal impairment must be considered, as well. Do a baseline assessment of renal function in all patients before transitioning them to a NOAC, and periodic reassessment during therapy. While this is important for patients on rivaroxaban and apixaban, it is essential for those on dabigatran, as 80% of the drug is excreted by the kidneys.1,5,12 NOACs have not been adequately assessed in patients with severe renal dysfunction and should be avoided in this patient population. Caution should be exercised in patients with moderate renal dysfunction, as well.5-10,14-19 Apixaban appears to be the safest NOAC for patients with moderate renal dysfunction, as it has the least renal clearance.1,12
Who should take a NOAC?
No well-established criteria for patient selection for NOACs exist, yet appropriate patient selection is crucial. Evidence suggests that NOAC therapy is best suited to those who:
• are relatively young (<65 years)
• have normal renal function
• have poorly controlled INR with warfarin that is unrelated to noncompliance
• are unable to have regular INR monitoring.
Patients best suited for continued use of warfarin would be those whose INR is well controlled, those who have higher goal INR ranges (eg, because of the presence of mechanical heart valves), patients with significant renal dysfunction, and individuals with a history of peptic ulcer disease or GI bleeding. Warfarin may also be the best option for patients with a history of noncompliance and for uninsured or underinsured patients.
CASE 1 Warfarin and any of the NOACs were all feasible options for Ms. J, but apixaban was deemed to be the safest because of her moderate renal dysfunction. However, after she was told that apixaban has little “real world” clinical data, no effective antidote if bleeding were to occur, and a much higher cost than warfarin, she opted for warfarin therapy, despite the laboratory monitoring required.
CASE 2 Mr. W was excited to learn that there were new alternatives to warfarin; he had taken warfarin for 6 months after his last DVT and had a hard time coming in for INR checks. The patient reported that he had no history of bleeding and was compliant with medications. Rivaroxaban was the best option for Mr. W, as it is the only NOAC with FDA approval for the treatment of acute VTE.
CORRESPONDENCE
Jeremy Vandiver, PharmD, BCPS, Swedish Medical Center, Room 3260, 501 East Hampden Avenue, Englewood, CO 80013; [email protected]
1. Wittkowsky AK. Novel oral anticoagulants and their role in clinical practice. Pharmacotherapy. 2011;31:1175-1191.
2. Gums JG. Place of dabigatran in contemporary pharmacotherapy. Pharmacotherapy. 2011;31:335-337.
3. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 suppl):e44S-e88S.
4. Siegal DM, Crowther MA. Acute management of bleeding in patients on novel oral anticoagulants. Eur Heart J. 2013;34:489-496.
5. Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2010.
6. Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2011.
7. Eliquis [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2012.
8. Connolly SJ, Zekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.
9. Patel MR, Mahaffery KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-891.
10. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-992.
11. You JJ, Singer DE, Howard P, et al. Antithrombotic therapy for atrial fibrillation: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 suppl):e531S-e575S.
12. Camm AJ, Lip GYH, De Caterina R, et al. 2012 focused update of the ESC guidelines for the management of atrial fibrillation. Eur Heart J. 2012;33:2719-2747.
13. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 suppl):e419S-e494S.
14. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342-2352.
15. Bauersachs R, Berkowitz SD, Brenner B, et al. Rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499-2510.
16. Büller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287-1297.
17. Agnelli A, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369:799-808.
18. Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368:709-718.
19. Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368:699-708.
20. Michel J, Mundell D, Boga T, et al. Dabigatran for anticoagulation in atrial fibrillation–Early clinical experience in a hospital population and comparison to trial data. Heart Lung Circ. 2013;22:50-55.
21. Kendoff D, Perka C, Fritsche HM, et al. Oral thromboprophylaxis following total hip or knee replacement: review and multicentre experience with dabigatran etexilate. Open Orthop J. 2011;5:395-399.
22. Rogers BA, Phillip S, Foote J, et al. Is there adequate provision of venous thromboembolism prophylaxis following hip arthroplasty? An audit and international survey. Ann R Coll Surg Engl. 2010;92:668-672.
23. Healey JS, Eikelboom J, Douketis J, at al. Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the randomized evaluation of long-term anticoagulation therapy (RE-LY) randomized trial. Circulation. 2012;126:343-348.
24. van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate: a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103:1116-1127.
25. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124:1573-1579.
26. Marlu R, Hodaj E, Paris A, et al. Effect of nonspecific reversal agents on anticoagulant activity of dabigatran and rivaroxaban. A randomised crossover ex vivo study in healthy volunteers. Thromb Haemost. 2012;108:217-224.
27. Escolar G, Fernandez-Gallego V, Arellano-Rodrigo E, et al. Reversal of apixaban induced alterations of hemostasis by different coagulation factor concentrates: studies in vitro with circulating human blood. PLOS ONE. 2013;8:e78696.
28. Drug pricing information. Costco Pharmacy Web site. Available at: http://www2.costco.com/Pharmacy/DrugInformation.aspx?p=1. Accessed December 9, 2013.
29. Schneeweiss S, Patrick AR, Maclure M, et al. Adherence to statin therapy under drug cost sharing in patients with and without myocardial infarction: a population-based natural experiment. Circulation. 2007;115:2128-2135.
30. McKeage K. Dabigatran etexilate: a pharmacoeconomic review of its use in the prevention of stroke and systemic embolism in patients with atrial fibrillation. Pharmacoeconomics. 2012;30:841-55.
31. Lee S, Anglade MW, Pham D, et al. Cost–Effectiveness of rivaroxaban compared to warfarin for stroke prevention in atrial fibrillation. Am J Cardiol. 2012;110:845-851.
32. Kamel H, Easton JD, Johnston SC, et al. Cost-effectiveness of apixaban vs warfarin for secondary stroke prevention in atrial fibrillation. Neurology. 2012;79:1428-1434.
33. Schulman S, Shortt B, Robinson M, et al. Adherence to anticoagulant treatment with dabigatran in a real-world setting. J Thromb Haemost. 2013; 11:1295-1299
34. Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369:1206-1214.
1. Wittkowsky AK. Novel oral anticoagulants and their role in clinical practice. Pharmacotherapy. 2011;31:1175-1191.
2. Gums JG. Place of dabigatran in contemporary pharmacotherapy. Pharmacotherapy. 2011;31:335-337.
3. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 suppl):e44S-e88S.
4. Siegal DM, Crowther MA. Acute management of bleeding in patients on novel oral anticoagulants. Eur Heart J. 2013;34:489-496.
5. Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2010.
6. Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2011.
7. Eliquis [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2012.
8. Connolly SJ, Zekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.
9. Patel MR, Mahaffery KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-891.
10. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-992.
11. You JJ, Singer DE, Howard P, et al. Antithrombotic therapy for atrial fibrillation: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 suppl):e531S-e575S.
12. Camm AJ, Lip GYH, De Caterina R, et al. 2012 focused update of the ESC guidelines for the management of atrial fibrillation. Eur Heart J. 2012;33:2719-2747.
13. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 suppl):e419S-e494S.
14. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342-2352.
15. Bauersachs R, Berkowitz SD, Brenner B, et al. Rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499-2510.
16. Büller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287-1297.
17. Agnelli A, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369:799-808.
18. Schulman S, Kearon C, Kakkar AK, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368:709-718.
19. Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368:699-708.
20. Michel J, Mundell D, Boga T, et al. Dabigatran for anticoagulation in atrial fibrillation–Early clinical experience in a hospital population and comparison to trial data. Heart Lung Circ. 2013;22:50-55.
21. Kendoff D, Perka C, Fritsche HM, et al. Oral thromboprophylaxis following total hip or knee replacement: review and multicentre experience with dabigatran etexilate. Open Orthop J. 2011;5:395-399.
22. Rogers BA, Phillip S, Foote J, et al. Is there adequate provision of venous thromboembolism prophylaxis following hip arthroplasty? An audit and international survey. Ann R Coll Surg Engl. 2010;92:668-672.
23. Healey JS, Eikelboom J, Douketis J, at al. Periprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the randomized evaluation of long-term anticoagulation therapy (RE-LY) randomized trial. Circulation. 2012;126:343-348.
24. van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate: a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103:1116-1127.
25. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124:1573-1579.
26. Marlu R, Hodaj E, Paris A, et al. Effect of nonspecific reversal agents on anticoagulant activity of dabigatran and rivaroxaban. A randomised crossover ex vivo study in healthy volunteers. Thromb Haemost. 2012;108:217-224.
27. Escolar G, Fernandez-Gallego V, Arellano-Rodrigo E, et al. Reversal of apixaban induced alterations of hemostasis by different coagulation factor concentrates: studies in vitro with circulating human blood. PLOS ONE. 2013;8:e78696.
28. Drug pricing information. Costco Pharmacy Web site. Available at: http://www2.costco.com/Pharmacy/DrugInformation.aspx?p=1. Accessed December 9, 2013.
29. Schneeweiss S, Patrick AR, Maclure M, et al. Adherence to statin therapy under drug cost sharing in patients with and without myocardial infarction: a population-based natural experiment. Circulation. 2007;115:2128-2135.
30. McKeage K. Dabigatran etexilate: a pharmacoeconomic review of its use in the prevention of stroke and systemic embolism in patients with atrial fibrillation. Pharmacoeconomics. 2012;30:841-55.
31. Lee S, Anglade MW, Pham D, et al. Cost–Effectiveness of rivaroxaban compared to warfarin for stroke prevention in atrial fibrillation. Am J Cardiol. 2012;110:845-851.
32. Kamel H, Easton JD, Johnston SC, et al. Cost-effectiveness of apixaban vs warfarin for secondary stroke prevention in atrial fibrillation. Neurology. 2012;79:1428-1434.
33. Schulman S, Shortt B, Robinson M, et al. Adherence to anticoagulant treatment with dabigatran in a real-world setting. J Thromb Haemost. 2013; 11:1295-1299
34. Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369:1206-1214.
