RE-LY Subanalysis: Choose Dabigatran in Atrial Fib Even After Successful Warfarin Therapy?

September 03, 2009

September 3, 2009 (Barcelona, Spain) — Hypothetically, should patients with atrial fibrillation (AF) who appear to be doing well on warfarin be switched over to a different, easier-to-take oral thrombin inhibitor, in particular, the one that was safer and at least as effective against thromboembolic events in the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY)?

The trial's findings [1] suggesting that twice-daily fixed-dose dabigatran etexilate (Boehringer-Ingelheim) could be the long-sought alternative to the much older and widely disliked oral anticoagulant in AF seemed to thrill about everyone when they were presented August 30 here at the European Society of Cardiology 2009 Congress.

The trial suggested that patients with AF who had never troubled with warfarin might never have to be on the drug. For those already on it, questions remain. Should they switch drugs, they might eventually have to stop taking dabigatran, RE-LY suggests. In the trial, the rate of dabigatran withdrawal was about 21% over the average two-year follow-up, significantly higher than the rate of warfarin withdrawal and partly attributable to an increased risk of gastrointestinal upset or bleeding with the drug.

Today, RE-LY investigator Dr Michael D Ezekowitz (Lankenau Institute for Medical Research, Wynnewood PA) presented what he called the trial's only prespecified subanalysis: outcomes in patients described as "warfarin-experienced" compared with those called "warfarin-naive." The trial's total population of 18 113 patients with AF and at least one other stroke risk factor were, by design, about evenly divided between the two camps.

The trial defined patients as warfarin-naive if they had less than two months' exposure to the drug; longer than that counted as experience.

It turned out that the overall RE-LY outcomes, which included a 34% drop in the annualized risk of stroke or peripheral embolic events (p<0.001) (at the higher of two tested dosages) and a 74% decline in the annualized hemorrhagic stroke risk (p<0.001) with dabigatran (at the lower dosage) compared with warfarin, as reported by heartwire , were mirrored in both subgroups to about the same extent. Dyspepsia and bleeding occurred at similar rates, and similar proportions of dabigatran recipients in the two groups went off the drug, Ezekowitz reported.

If they have previously done well on vitamin-K antagonists, then we should question whether dabigatran is necessary. We would first have to look at the patient's bleeding risk.

A history of warfarin or no such history resulted in the same dabigatran benefits and downsides at about the same convincing levels of statistical significance, the trial suggests.

But whether to start a patient with AF on the new drug, based on RE-LY, actually depends on a number of considerations, including the patient's risk of bleeding, according to Dr Jean-Philippe Collet (Hôpital La Pitié Salpêtrière, Paris, France), the featured discussant following Ezekowitz's presentation.

RE-LY appears sufficient to recommend dabigatran in patients with AF who have truly never previously been on warfarin, "but if you want to switch a patient who is doing fine on vitamin-K antagonists, we need to know a little bit more," he told heartwire .

About 70% of patients in RE-LY who had been classified as warfarin-naive actually had had some exposure to the drug, as allowed by the trial's definition of "naive," Collet observed. Did they not go further with warfarin because they bled too much? The information was not reported, he said.

A truly warfarin-naive patient is a prime candidate for dabigatran, according to Collet, "but if they have previously done well on vitamin-K antagonists, then we should question whether dabigatran is necessary. We would first have to look at the patient's bleeding risk. If the patient is high risk, you may consider dabigatran given its very good safety profile," he said, even if they had previously been on warfarin with success.

The RE-LY trial is revolutionary, but we need some more data.

"If they have a low bleeding risk, it's a different question, because there is a quite high rate of [dabigatran] discontinuation."

Collet cautioned that his recommendations about patient selection for dabigatran are speculation based on available evidence.

On the other hand, about 15% of the AF patients for whom dabigatran is under consideration have severe renal failure, yet severe renal failure was cause for exclusion from the RE-LY, he observed. Currently, such patients should not take the drug whether they are warfarin-naive or -experienced, Collet said.

"The RE-LY trial is revolutionary, but we need some more data."

RE-LY was supported by Boehringer-Ingelheim. Ezekowitz reports receiving consulting fees, lecture fees, and grant support from Boehringer-Ingelheim and Aryx Therapeutics, consulting fees from Sanofi-Aventis, and lecture fees and grant support from Portola Pharmaceuticals. Collet reports receiving research grants from Sanofi-Aventis, Bristol-Myers Squibb, Medtronic, and Boston Scientific and lecture and/or consulting fees from Sanofi-Aventis, Bristol-Myers Squibb, Boehringer-Ingelheim, and St Jude Medical.