Dabigatran for atrial fibrillation: Why we can not rely on RE-LY
Therapeutics Letter Issue 80 / Jan - Mar 2011
Dabigatran (Pradax®), a direct thrombin inhibitor oral anticoagulant, was licensed in Canada in November 2010 for stroke prevention in patients with non-valvular atrial fibrillation. It is being promoted as an alternative to warfarin with the purported advantage that coagulation monitoring is not required. Do we know enough about dabigatran? It took over 50 years to learn how to use warfarin with reasonable effectiveness and safety for this use.
Dabigatran 150 mg BID reduced fatal and disabling strokes by 0.5% compared with 110 mg BID and reduced all ischemic strokes by 0.8% (not shown). However, dabigatran 150 mg BID was also more harmful, causing a 1.1% absolute increase in bleeding leading to hospitalization. Total hospitalizations provides an estimate of net health benefit; the numerical difference (1.6%) favouring the lower dose barely misses statistical significance. The FDA approved only the 150 mg BID dose of dabigatran for patients with non-valvular atrial fibrillation3. Health Canada approved the 150 mg BID for most patients and the 110 mg BID for those over 80 years old or patients with risk factors for bleeding and the European Medicines Agency also approved both 150 and 110 mg BID4. Alternative interpretations of the data shown in Table 1 are that 110 mg BID provides a net health benefit over 150 mg BID, or that this single trial has not established the optimal dose of dabigatran.
The use of antiplatelet agents in addition to anticoagulants was surprisingly prevalent in all 3 arms of the RE-LY trial. During the trial approximately 40% of patients took aspirin and 7% took clopidogrel at some time. Taking either antiplatelet drug doubled the incidence of major bleeding events, an absolute increase of > 2% per year. This effect was similar for both doses of dabigatran and for warfarin.
- Licensing of dabigatran 150 mg BID for atrial fibrillation is premature, pharmacologically irrational and unsafe for many patients.
- The optimal dose of dabigatran for non-valvular atrial fibrillation is not yet clear.
- An independent audit of RE-LY is needed to check for irregularities in conduct, sources of bias and the cause of the unusually high incidence of intracranial hemorrhage in the warfarin arm.
- An independently conducted double-blind RCT comparing dabigatran with warfarin in patients with non-valvular atrial fibrillation is required.
- Taking antiplatelet drugs in combination with oral anticoagulants doubles the incidence of major bleeding events.
The draft of this Therapeutics Letter was submitted for review to 60 experts and primary care physicians in order to correct any inaccuracies and to ensure that the information is concise and relevant to clinicians.
- Connolly SJ, Ezekowitz MD, Yusuf S et al. Dabigatran versus warfarin in patients with atrial fibrillation. New Engl J Med 2009;361:1139-1151.
- US Federal Drug Administration. Pradaxa (dabigatran) Medical Review, NDA 22-512. Sep 2010. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMateria...
- Beasley BN, Unger EF, Temple R. Anticoagulant options – Why the FDA approved a higher but not a lower dose of dabigatran. New Engl J Med 2011; 364: 1788-1790.
- European Medicines Agency. Summary of opinion (post authorisation) for Pradaxa (dabigatran etexilate mesilate). Apr 2011. http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion/...
- SPORTIF executive steering committee for the SPORTIF V investigators. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. A randomised trial. JAMA 2005;293: 690-698.
- Executive steering committee on behalf of the SPORTIF III investigators. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with nonvalvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 2003; 362: 1691-1698.
- Aguilar MI, Hart R. Oral anticoagulants for preventing stroke in patients with non-valvular atrial fibrillation and no previous history of stroke or transient ischemic attacks. Cochrane Database of Systematic Reviews 2005, Issue 3. Art. No.: CD001927. DOI: 10.1002/14651858.CD001927.pub2.
- Aguilar MI, Hart R, Pearce LA. Oral anticoagulants versus antiplatelet therapy for preventing stroke in patients with non-valvular atrial fibrillation and no history of stroke or transient ischemic attacks. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD006186. DOI: 10.1002/14651858.CD006186.pub2.