Dabigatran Etexilate mesylate Capsules (Pradaxa®)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD, Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.
The first oral thrombin inhibitor has been approved by the FDA for reducing the risk of stroke in patients with atrial fibrillation. Dabigatran, which is taken twice a day and does not require monitoring, may be an alternative to warfarin for many patients with atrial fibrillation. Dabigatran is marketed by Boehringer Ingelheim Pharmaceuticals as Pradaxa®.
Dabigatran is indicated for reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation.1
The recommended dose is based on the patient's creatinine clearance (CrCl). For those with CrCl > 30 mL/min, the dose is 150 mg twice daily. For those with CrCl 15-30 mL/min, the dose is 75 mg twice daily.1
Dabigatran is available as 75 mg and 150 mg capsules.
Compared to an adjusted-dose warfarin, dabigatran (150 mg twice daily) was associated with a lower rate of stroke and systemic embolism.1,2 Dabigatran does not require monitoring of INR and is neither metabolized by, nor affects the activity of, the CYP 450 isoenzymes.
Gastrointestinal adverse events were more common with dabigatran than warfarin in clinical studies (35% vs 24%).1 Twenty-one percent of patients discontinued participation in the clinical trial compared to 16% for warfarin. There is a higher rate of gastrointestinal bleed (1.6% vs 1%) and myocardial infarction (0.74 %/year vs 0.53%/year) with dabigatran.2 Dabigatran does not have a specific antidote. Rifampin, a P-gp inducer, decreases the systemic exposure to dabigatran and should be avoided.
Dabigatran is an oral, selective, competitive, reversible inhibitor of human thrombin. Its efficacy in reducing the risk of stroke was shown in a 2-year study, the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study.1,2 More than 18,000 patients with atrial fibrillation were randomized to dabigatran (110 mg twice daily), dabigatran (150 mg twice daily), or adjusted-dose warfarin. The mean age was 71 years, 83.6% were men, and the mean CHAD2 score was 2.1. The primary efficacy outcome was stroke or systemic embolism and primary safety outcome was major hemorrhage. The primary net clinical benefit outcome was the composite of stroke, systemic embolism, pulmonary embolism, myocardial infarction, death, or major hemorrhage. Since the 110 mg dose was not approved, only the results of the 150 mg twice daily dose compared to warfarin will be discussed here.
The rate of primary outcome was superior for dabigatran (1.11 %/year compared to warfarin 1.69%/year; relative risk, 0.66; 95% confidence interval, 0.53-0.82). This difference was not evident in study sites with better INR control (median of 67% or higher). There was no difference in major bleeding (3.11%/year vs 3.36 %/year). Rate of hemorrhagic stroke was lower for dabigatran (0.10%/year vs 0.38%/year), as was intracranial bleed (0.30%/year vs 0.74%/year); mortality was numerically better for dabigatran (3.64% vs 4.13%), but did not each statistical significance (P = 0.051). Myocardial infarction was numerically higher with dabigatran (0.74%/year vs. 0.53%/year; P = 0.07). There was no significant difference in net clinical benefit outcome (6.91%/year vs 7.64%/year; P = 0.10). In patients with previous stroke of transient ischemic attack (n = 2428) the effect of dabigatran (150 mg twice daily) was similar to warfarin in terms of the rate of stroke or systemic embolism and major bleed.3
Dabigatran is the first oral anticoagulant to be approved and is the first serious competitor to warfarin. Warfarin therapy requires INR monitoring as well as awareness of food and drug interactions. Dabigatran has been shown to be superior to warfarin, particularly in patients enrolled in centers with less-than-optimal INR control (median time in therapeutic range less than 67%). Potential drawbacks include a possible increase in myocardial infarction, gastrointestinal adverse events, lack of an antidote, and lack of long-term safety. The 75 mg dose was not approved based on efficacy, but rather on dose-proportional pharmacokinetics and renal clearance. Several other oral anticoagulants are in the pipeline including the factor X inhibitors, apixaban, rivaroxaban, and edoxaban.
1. Pradaxa Prescribing Information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; October 2010.
2. Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-1151.
3. Diener HC, et al. Dabigatran compared with warfarin in patients with atrial fibrillation and previous transient ischaemic attack or stroke: A subgroup analysis of the RE-LY trial. Lancet Neurology 2010 Nov 6; Epub ahead of print.