August 29, 2010 (London, United Kingdom) — A RE-LY trial analysis, showing that dabigatran etexilate (Boehringer Ingelheim) is noninferior in the lower dose and superior with the higher dose to warfarin for stroke prevention in patients with atrial fibrillation, regardless of the average international normalized ratio (INR) control achieved in the warfarin comparator group, is now published online August 29, 2010 in the Lancet .
The results of the post hoc analysis are published just weeks before dabigatran goes before the FDA's Cardiovascular and Renal Drugs Advisory Committee on September 20, 2010.
As reported by heartwire at the time, the RE-LY INR analysis was first presented at the American Heart Association (AHA) 2009 Scientific Sessions. Main results of the RE-LY study were presented at the European Society of Cardiology 2009 Congress and published simultaneously in the New England Journal of Medicine . Those results showed that dabigatran prevented strokes and peripheral embolic events in patients with atrial fibrillation significantly better than warfarin at a higher dose and just as well at a lower dose in a huge randomized trial of more than 18 000 patients.
|Dr Lars Wallentin|
The current analysis looked specifically at the level of INR control at the 951 sites participating in the study, with average INR per site serving as an approximation for all patients treated at that center. As lead author Dr Lars Wallentin (Uppsala Clinical Research Center, Uppsala, Sweden) and colleagues write in the Lancet, even in centers where INR control was excellent, dabigatran was noninferior at the 110-mg dose and superior at the 150-mg dose to warfarin for prevention of stroke or systemic embolism, the primary outcome of RE-LY. Rates of intracranial hemorrhage (ICH) were lower at both doses of dabigatran than in the warfarin group, and major bleeding was at least noninferior to warfarin, regardless of INR control across centers. For the 150-mg dose, there were fewer bleeding events in the dabigatran-treated patients than in the warfarin-treated patients in the lower time-in-treatment-range (TTR) groups, and no differences in the higher TTR ranges. For the 110-mg dabigatran dose, major bleeding was lower for the dabigatran patients irrespective of TTR.
The specific numbers in the published paper are slightly different from those reported at the AHA meeting last year, with slightly different definitions for INR quartiles, although the overall conclusions are the same.
RE-LY: Risk of Stroke or Systemic Embolism With Dabigatran in Two Doses vs Warfarin by Center-Based TTR
|TTR (%)||110-mg dabigatran, RR (95% CI)||p||150-mg dabigatran, RR (95% CI)||p|
|<57.1||1.00 (0.68–1.45)||0.57 (0.37–0.88)|
|57.1–65.5||0.81 (0.56–1.17)||0.50 (0.33–0.77)|
|65.5–72.6||0.89 (0.58–1.36)||0.69 (0.44–1.09)|
|>72.6||0.92 (0.59–1.45)||0.95 (0.61–1.48)|
|p for interaction||0.89||0.20|
Summarizing their findings, Wallentin et al write: "These findings support the superiority of 150-mg dabigatran twice daily and the noninferiority of 110-mg dabigatran twice daily vs warfarin for protection against stroke in atrial fibrillation, irrespective of the quality of INR control that a center can achieve. However, there seemed to be lower rates of nonhemorrhagic stroke at higher . . . TTR quartiles in the warfarin group, which is in accordance with previous findings. Accordingly, 150 mg dabigatran was not superior to warfarin at reducing the risk of nonhemorrhagic stroke at higher . . . TTR quartiles."
In an accompanying Comment , Drs Deirdre A Lane and Gregory YH Lip (City Hospital, Birmingham, UK), conclude that the RE-LY INR analysis supports the notion that patients currently excluded from warfarin therapy might be eligible to take newer anticoagulants, such as dabigatran, although only time will tell. In the meantime, attention should turn to the problem of optimizing warfarin dosing, they suggest, noting that TTR in therapeutic range varied widely in the RE-LY study, from 40% to 70%.
"Until the new oral anticoagulants become widely available (a positive advance), we should advocate tight INR control at conventional levels, for which there is a wealth of evidence for benefit, and promote strategies to improve the management of therapy with vitamin-K antagonists [such as warfarin]."
Of note, the Lancet publications, released on the first day of the European Society of Cardiology 2010 Congress, come just as two new oral anticoagulants are moving into the spotlight. Positive results--although not full details--were released in advance of the meeting for both apixaban, in the AVERROES trial, and rivaroxaban, in EINSTEIN DVT, as reported by heartwire . Full results for these two trials will be reported Tuesday on theheart.org.
The RE-LY trial was funded by Boehringer Ingelheim. Wallentin has received consulting and lecture fees, honoraria, and research grants from Boehringer Ingelheim; research grants from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, and Schering-Plough; honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, and Schering-Plough; consultant fees from Athera Biotechnologies, AstraZeneca, Eli Lilly, GlaxoSmithKline, and Regado Biotechnologies; and lecture fees from AstraZeneca and Eli Lilly. Disclosures for the coauthors are listed in the paper.
Heartwire from Medscape © 2010 Medscape, LLC
Cite this: RE-LY INR Analysis Confirms Dabigatran Benefits Across Spectrum of Warfarin Dosing - Medscape - Aug 29, 2010.