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STOCKHOLM -- Dabigatran, an investigational oral anticoagulant which does not require laboratory monitoring, may be an ideal anticoagulant for atrial fibrillation patients, especially those in centers that are less adept at managing patients taking warfarin, according to a post-hoc analysis from the 18,000-patient RE-LY trial.

Even at centers where warfarin patients were consistently maintained within the therapeutic range of recommended clotting time, dabigatran, a direct thrombin inhibitor, was superior to warfarin for preventing stroke in patients with atrial fibrillation. But its greatest benefit was at centers where international normalized ratio (INR) control was spotty, Lars Wallentin, MD, PhD, of Uppsala Clinical Research Center University Hospital in Uppsala, Sweden, reported at the European Society of Cardiology meeting here. The paper was simultaneously published online by Lancet.

A year ago, the RE-LY investigators reported that a 150-mg dose of dabigatran twice daily was more effective in preventing strokes in high-risk patients than warfarin, while a lower dose -- 110 mg bid -- was comparable to warfarin.

In the new analysis, the researchers assessed the three treatment groups -- two dabigatran arms and the warfarin group -- according to each center's mean time in therapeutic range. They then divided the groups into quartiles, with the lowest quartile representing centers where patients were in therapeutic range less than 57.1% of the time, followed by centers at 57.1 to 65.5%, 65.5 to 72.6%, and more than 72.6%.

There were significant "interactions between [mean time in therapeutic range] and effects of both 110 and 150 mg dabigatran versus warfarin on the composite of all cardiovascular events (interaction P=0.036 and P=0.0006, respectively) and total mortality (interaction P=0.066 and P=0.052, respectively) with reduced event rates at low [mean time in therapeutic range] and similar rates at high [mean time in therapeutic range]."

Michael Ezekowitz, MB, ChB, DPhil, of the Lankenau Institute for Medical Research and Heart Center in Wynnewood, Pa., who was a co-investigator, told MedPage Today that the analysis also demonstrated that even when INR was well controlled with warfarin, the superiority of the higher dose of dabigatran was still apparent as was the noninferiority of the lower dose.

In the Lancet paper, the authors wrote that "there were no significant interactions between [time in therapeutic range] and stroke and systemic embolism in either dose of dabigatran versus warfarin."

"So this makes the findings from RE-LY even more powerful," Ezekowitz said in an interview that was monitored by a public relations person representing Boehringer Ingelheim, the sponsor of the RE-LY trial.

In a commentary that accompanied the Lancet study, Deirdre A. Lane, MD, and Gregory Y.H. Lip, MD, of the University of Birmingham Center for Cardiovascular Sciences in Birmingham, England, echoed Ezekowitz, noting "this post-hoc analysis shows that despite very good [time in therapeutic range], either dose of dabigatran was associated with fewer adverse events than was warfarin."

Clyde Yancy, MD, of Baylor University Medical Center in Dallas, told MedPage Today that he was concerned about the ways in which the analysis might be used to promote dabigatran. "If the message is that centers who don't do a good job of controlling INR should simply switch to this drug, I find that concerning," he said "The ideal would be to get centers to improve INR control." Yancy is past president of the American Heart Association.

Lane and Lip agreed with the need to improve current treatment, recommending that 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."

Beyond its post-hoc design, Wallentin said the new RE-LY analysis was also limited by the decision to use mean time in therapeutic range as a proxy for INR control, noting that it "might not appropriately represent INR control of individual patients and might not represent the full effect of INR control on outcome."

Additionally, they cautioned that time in therapeutic range "does not show the effect of good and poor treatment response."

Dabigatran will be the subject of a Sept. 20 FDA advisory committee meeting, at which the committee will discuss whether the drug should be approved for preventing stroke in atrial fibrillation patients.