Connolly SJ, et al. "Dabigatran versus warfarin in patients with atrial fibrillation". The New England Journal of Medicine. 2009. 361(12):1139-51.
Among individuals with chronic atrial fibrillation, how does dabigatran compare to warfarin in terms of stroke risk and the risk of major bleeding?
The RE-LY study demonstrated that compared to warfarin, high-dose dabigatran reduces stroke risk without increasing the risk of major bleeding among patients with atrial fibrillation.
Prior to RE-LY, warfarin was the primary anticoagulant used in the prevention of thromboembolic stroke among patients with atrial fibrillation (AF). Warfarin's advantages included its inexpensive cost and once daily dosing. Warfarin is less than ideal, however, because of the variable amount of vitamin K in food, its steep dose-response relationship, interactions with other drugs, and the fact that only 60% of patients are maintained within an INR of 2.0 to 3.0. Dabigatran is a new direct thrombin inhibitor marketed under the name Pradaxa. It use in prevention of stroke in atrial fibrillation was not known.
Published in 2009, the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial was a non-inferiority study randomizing 18,000 patients with nonvalvular AF and a moderate-to-high risk of thromboembolic stroke to either high- or low-dose dabigatran or to warfarin. At a median follow-up of 2 years, high-dose dabigatran reduced the incidence of stroke (1.11% vs. 1.69%) without a concomitant rise in major bleeding events (3.11% vs. 3.36%). Although the study was designed to test the non-inferiority of either dose compared to warfarin, the final analysis ultimately demonstrated superiority of high-dose dabigatran over warfarin. Of note, both high and low doses of dabigatran were associated with a statistically significant increase in MI (0.74% and 0.72%, respectively, vs. 0.53% for placebo).
A 2013 FDA mini-sentinel study did not demonstrate an increased risk of bleeding with dabigatran when compared to warfarin. There is some anecdotal evidence that obese patients and those with elevated GFRs may not attain therapeutic levels of the drug.
As of July 2013, there are three drugs with FDA-approved indications for the prevention of systemic thromboembolism in nonvalvular atrial fibrillation: dabigatran, apixaban (based upon ARISTOTLE; 2011), and rivaroxaban (based upon ROCKET AF; 2011).
- Guidelines on management of atrial fibrillation from the ACCF/AHA have yet to include dabigatran.
- 2012 American College of Chest Physicians guidelines suggest use of dabigatran 150 mg twice daily rather than a vitamin K antagonist (grade 2B).
- An AHA/ASA 2012 science advisory recommends dabigatran for prevention of CVA in patients with non-valvular atrial fibrillation (class I, level B)
- Multicenter, parallel-group, randomized controlled trial
- Low-dose dabigatran (n=6,015)
- High-dose dabigatran (n=6,076)
- Warfarin (n=6,022)
- Setting: 951 centers in 44 countries
- Enrollment: 2005-2007
- Follow-up: median 2 years
- Analysis: Intention-to-treat, non-inferiority
- Age ≥75 years or 65-74 years with T2DM, HTN, or CAD
- AF documented on EKG within 6 months of screening
- One of the following:
- Prior stroke or TIA
- LVEF <40%
- NYHA class II-IV within 6 months of screening
- Severe valvular disease
- Stroke within 14 days
- Severe stroke within 6 months of screening
- Condition conveying an increased risk of hemorrhage
- Creatinine clearance <30 ml/min
- Active liver disease
From the low-dose dabigatran group.
- Demographics: Age 71 years, male 64%
- Baseline health data: Weight 83 kg, BP 131/77
- Type of AF: Persistent 32%, paroxysmal 32%, permanent 35%
- CHADS2 score:
- 0 or 1: 33%
- 2: 35%
- 3 to 6: 33%
- PMH: stroke/TIA 20%, MI 17%, HF 32%, DM 23%, HTN 79%
- Medications: Aspirin 40%, ARB/ACE-inhibitor 66%, beta-blocker 63%, amiodarone 10%, statin 45%, PPI 14%, H2-antagonist 4%, long-term vitamin K antagonist therapy 50%
- Randomly assigned to one of two doses of dabigatran or warfarin
- Low-dose dabigatran (110mg BID)
- High-dose dabigatran (150mg BID)
- Warfarin adjusted to INR 2.0-3.0
- Quinidine use permitted until 2 years after trial initiation, once it became known that quinidine interacts with dabigatran
- Post-randomization follow-up visits at 14 days, 1 month, 3 months, every 3 months for 1 year, then every 4 months until study completion
- LFTs monthly during first year
- Stroke or systemic embolism
- Low-dose dabigatran vs. warfarin:
- 1.53% vs. 1.69% (RR 0.91, 95% CI 0.74-1.11, P<0.001 for noninferiority)
- High-dose dabigatran vs. warfarin:
- 1.11% vs. 1.69% (RR 0.66, 95% CI 0.53-0.82, P<0.001 for superiority)
Low-dose dabigatran vs. warfarin
- 1.4% vs. 1.6% (P=0.41)
- 0.72% vs. 0.53% (HR 1.35; 95% CI 0.98-1.87; P=0.07)
- 0.12% vs. 0.09% (P=0.56)
- 19.4% vs. 20.8% (P=0.003)
- Vascular death
- 2.43% vs. 2.69% (P=0.21)
- All-cause mortality
- 3.75% vs. 4.13% (P=0.13)
- Major hemorrhage
- 2.71% vs. 3.36% (P=0.003)
High-dose dabigatran vs. warfarin
- 1.0% vs. 1.6% (P<0.001)
- 0.74% vs. 0.53% (HR 1.38; 95% CI 1.00-1.91; P=0.048)
- 0.09% vs. 0.09% (P=0.56)
- 20.2% vs. 20.8% (P=0.21)
- Vascular death
- 2.28% vs. 2.69% (P=0.04)
- All-cause mortality
- 3.64% vs. 4.13% (P=0.051)
- Major hemorrhage
- 3.11% vs. 3.36% (P=0.031)
- RE-LY reported a higher rate of major bleeding in warfarin-treated patients compared to other studies of warfarin in AF
- Therapeutic INR reached only 64% of the time, dabigatran may only be better than poorly controlled anticoagulation with warfarin
- Guiding dosing by serum levels of the medication may improve outcomes
- Increased rates of MI is concerning for a platelet-activating effect of the medication and necessitates further studying
- Expensive therapy
Supported by a grant from Boehringer Ingelheim, with authors disclosing support from multiple sources within pharmaceutical industry.
- Soutworth MR, et al. "Dabigatran and Postmarketing Reports of Bleeding." The New England Journal of Medicine. 2013;368:1272-1274.
- Breuer L, et al. "Correspondence: Ischemic Stroke in an Obese Patient Receiving Dabigatran." The New England Journal of Medicine. 2013;368:2440-2442.
- Wann LS, et al. "2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation." JACC. 57.2 (2011): 223-242.
- You JJ, et al. "Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines." Chest(2012)141;2.
- 2012 AHA/ASA Science Advisory
- Multiple authors. "Correspondence: Dabigatran versus warfarin in patients with atrial fibrillaiton." The New England Journal of Medicine. 2009;361:2671-2675.