Clinical Trial Data: Dabigatran
The RE-LY trial, the first completed evaluation of a novel oral anticoagulant, recruited patients (n=18,113) with AF (mean CHADS2 score 2.1) to open label warfarin or to one of two blinded doses of dabigatran, 110 mg or 150 mg twice daily. The 110 mg dose was similar to warfarin in reducing stroke or systemic embolism but reduced major bleeding by 20%, whereas the 150 mg dose significantly reduced stroke or systemic embolism 35% compared with warfarin with similar major bleeding.1,2 Dabigatran 150 mg dose also significantly reduced ischemic stroke 25% compared to warfarin. Both dabigatran doses markedly reduced intracranial bleeding by 60-70% compared with warfarin. Dabigatran 150 mg was associated with a significant 50% increase in gastrointestinal bleeding compared to warfarin whereas the 110 mg dose resulted in similar gastrointestinal bleeding. Dabigatran was discontinued more frequently than warfarin.3 The only symptom leading to more frequent discontinuation of dabigatran was dyspepsia with 2.1% of patients reporting dyspepsia as the cause of their stopping medication permanently.81 Dyspepsia occurs in both the 110 mg and 150 mg groups (6.2% and 5.7 % of subjects respectively) compared to 1.4% per year in the warfarin group. For patients with a CHADS2 score >3, excess major bleeding (mostly gastrointestinal in origin) was seen in the 150 mg dose but not in the 110 mg dose. A similar finding was seen when subjects were stratified by age. Patients aged < 75 years had less major bleeding with the 110 mg dose compared with warfarin.4
The U.S. Food and Drug Administration (FDA) has recently reported that “real world” data in 134,414 Medicare patients closely reflect data reported from RE-LY for the dabigatran 150 mg twice daily dose. In a general practice setting, dabigatran associated with a reduced risk of ischemic stroke, intracranial hemorrhage, and death compared with warfarin but an increased the risk of gastrointestinal bleeding.5
Dabigatran is dosed 150 mg twice daily for creatinine clearance >30 mL/min. The FDA approved dabigatran 75 mg twice daily for patients with a creatinine clearance of 15-30 ml/min for use in the United States.6 In all other countries, dabigatran 110 mg twice daily is approved for patients at a higher bleeding risk and for those over the age of 80 years. Dabigatran may be taken with or without food.
1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation.N Engl J Med.2009;361(12):1139-1151.
2. Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L. Newly identified events in the RE-LY trial.N Engl J Med.2010;363(19):1875-1876.
3. Wallentin L, Yusuf S, Ezekowitz MD, et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial.Lancet.2010;376(9745):975-983.
4. Boehringer Ingelheim dabigatran briefing document. http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/cardiovascularandrenaldrugsadvisorycommittee/ucm226009.pdf. Accessed March 12, 2011.
5. Graham DJ, Reichman ME, Wernecke M, et al. Cardiovascular, Bleeding, and Mortality Risks in Elderly Medicare Patients Treated with Dabigatran or Warfarin for Non-Valvular Atrial Fibrillation.Circulation.2014; 131(2):157-64.
6. Nagarakanti R, Ezekowitz MD, Oldgren J, et al. Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion.Circulation.2011;123(2):131-136.
Clinical Trial Data: Rivaroxaban
Rivaroxaban has been evaluated in two studies of patients with AF. The ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial1 was a double-blind study of 14,264 patients with AF randomly assigned to rivaroxaban (20 mg once daily or 15 mg once daily for patients with a creatinine clearance ≤50 mL/min) or warfarin. Rivaroxaban was noninferior to warfarin in the reduction of stroke and systemic embolism (hazard ratio, 0.88; 95% CI, 0.74=1.03; p<0.001 for noninferiority; p=0.12 for superiority), with similar major bleeding (hazard ratio 1.03; 95% CI, 0.96-1.11; p=0.44). Intracranial hemorrhage fell significantly with rivaroxaban (hazard ratio 0.67; 95% CI, 0.47-0.93; p=0.02). The J-ROCKET (Rivaroxaban vs. Warfarin in Japanese Patients with Atrial Fibrillation),2 included 1280 Japanese patients and showed similar bleeding outcomes and a reduction in stroke and systemic embolism with rivaroxaban compared with warfarin.
Rivaroxaban is dosed 20 mg once daily for patients with creatinine clearance >50 mL/min and 15 mg once daily for patients with creatinine clearance 15 to ≤50 mL/min. Rivaroxaban should be taken with the evening meal.
1. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.N Engl J Med.2011;365(10):883-891.
2. Hori M, Matsumoto M, Tanahashi N, et al. Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation - the J-ROCKET AF study.Circ J.2012;76(9):2104-2111.
Clinical Trial Data: Apixaban
Two large trials have been conducted studying apixaban for stroke prevention in AF, one with aspirin and the other with warfarin as the comparator.1,2 AVERROES included 5,599 patients who were deemed “unsuitable” for warfarin and who were randomized to aspirin (mostly 81 mg per day) versus apixaban (5 mg twice a day, or 2.5 mg twice a day for patients with at least 2 of 3 criteria of age ≥ 80 years, creatinine ≥ 1.5 mg/dL, weight ≤ 60 kg). Apixaban yielded a 55% relative reduction in stroke or systemic embolism, a 13% non-significant increase in major bleeding, and numerically fewer ICH (11 vs. 13) versus aspirin. Apixaban was well tolerated, as reflected by fewer patients prematurely stopping apixaban than aspirin.1
ARISTOTLE included 18,206 patients with atrial fibrillation and at least one additional risk factor for stroke who were randomized to warfarin (target INR 2.0 to 3.0) or apixaban. Apixaban reduced stroke or systemic embolism by 21%, resulted in a 31% lower rate of major bleeding, and reduced all-cause mortality by 11%. Similar to the other direct acting oral anticoagulants, apixaban showed a 50% relative risk reduction in hemorrhagic stroke.2
Apixaban is dosed 5 mg twice daily with a dose reduction to 2.5 mg twice daily for patients with at least 2 of the following characteristics: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL. Apixaban can be taken with or without food.
1. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation.N Engl J Med.2011;364(9):806-817.
2. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation.N Engl J Med.2011;365(11):981-992.
Clinical Trial Data: Edoxaban
ENGAGE AF-TIMI 48, a double-blind, double-dummy clinical trial, randomized 21,105 patients with moderate-high risk AF to two dosing regimens of once daily edoxaban (60 mg and 30 mg) or to warfarin (goal INR 2.0 to 3.0). A dose reduction of 50% was performed for edoxaban patients who had at least one of the following criteria: creatinine clearance 30-50 mL/min, body weight <60 kg, or were taking selected strong P-glycoprotein inhibitors (quinidine, verapamil or dronedarone).1 Both edoxaban dose regimens proved noninferior to warfarin in prevention of stroke or systemic embolism during the on-treatment period (warfarin: 1.50%/year, edoxaban 60 mg: 1.18%/year [HR 0.79, 97.5% CI 0.63 to 0.99; p<0.001 for noninferiority], edoxaban 30 mg: 1.61%/year [HR 1.07; 97.5% CI, 0.87-1.31; p=0.005 for noninferiority]). However, the lower dose regimen was less effective than warfarin in preventing ischemic stroke (HR 1.41, 95% CI, 1.19 to 1.67;P<0.001), while the higher dose edoxaban regimen and warfarin showed similar prevention of ischemic stroke (HR 1.00, 95% CI, 0.83 to 1.19; P = 0.97). The annualized rates of major bleeding were 3.43% with warfarin, 2.75% with edoxaban 60 mg (HR 0.80, 95%CI 0.71-0.91; p<0.001) and 1.61% (HR 0.47; 95%CI 0.41-0.55; p<0.001) with edoxaban 30 mg. The corresponding annualized rates of cardiovascular death were 3.17%, 2.74% (HR 0.86, p=0.013), and 2.71% (HR 0.85, p=0.008). Both regimens of edoxaban showed significantly better net outcomes across a variety of combinations of cardiovascular events, bleeding, and death. There were no excesses in adverse events, hepatic events, or malignancies with edoxaban.
Only the higher-dose regimen of edoxaban was put forward for regulatory approval. Edoxaban is approved in the US for patients with a calculated creatinine clearance ≤ 95 mL/min based on post hoc subgroup analyses demonstrated reduced efficacy in patients with creatinine clearance >95 mL/min. Edoxaban is dosed 60 mg once daily for patients with a creatinine clerance >50 and ≤ 95 mL/min with a dose reduction to 30 mg once daily for patients with a creatinine clearance 15 to 50 mL/min. For the AF population, a dose adjustment is not recommended for patients with body weight ≤ 60 kg or patients taking concomitant P-glycoprotein inhibitors. Edoxaban can be taken with or without food. Edoxaban is currently undergoing regulatory review in Europe and elsewhere.
1 Salazar DE, Mendell J, Kastrissios H, et al. Modelling and simulation of edoxaban exposure and response relationships in patients with atrial fibrillation.Thromb Haemost.2012;107(5):925-936.
AF Action Initiative Video Interview: Dr. Marc Estes covers Periprocedural Management of Novel Oral Anticoagulants.
AF Action Initiative Video Interview: Dr. Guigliano discusses the use of Novel Oral Anticoagulants in Atrial Fibrillation
AF Action Initiative Audio Interview: Dr. Ansell covers the Use and Utility of Laboratory Coagulation Tests
AF Action Initiative Video Interview: Dr. Piazza compares Novel Oral Anticoagulants