RE-LY: Stroke Risk at AF Cardioversion Similar on Dabigatran or Warfarin

January 10, 2011

January 7, 2011 (Dallas, Texas) — The 30-day risk of stroke or systemic embolism in the setting of cardioversion for nonvalvular atrial fibrillation (AF) is similarly low whether the accompanying anticoagulation is with warfarin or newly availabledabigatran (Pradaxa, Boehringer Ingelheim) at the recommended dosage of 150 mg twice daily, suggests a post hoc analysis of the >18 000-patient Randomized Evaluation of Long-Term Anticoagulant Therapy(RE-LY) trial [1]. Rates of major bleeding after cardioversion, achieved in 1270 patients, were also low and not significantly different in the dabigatran 150-mg-twice-daily and warfarin groups.

"The RE-LY trial confirmed the efficacy and safety of warfarin in cardioversion in a large cohort of warfarin-treated patients. It also allowed comparison with the new oral anticoagulant dabigatran. The results show that the two drugs are comparable in this setting," write the authors, led by Dr Rangadham Nagarakanti (Louisiana State University, New Orleans) in their report published online January 3, 2011 in Circulation.

That confirmation is welcome, they point out, because the current recommendation for anticoagulation for at least three weeks prior and four weeks after cardioversion, whether electrical or pharmacologic, to cut the risk of associated thromboembolism is actually based on limited data.

"It was surprising to us that there was so little literature on it," Dr Michael D Ezekowitz (Lankenau Institute for Medical Research, Wynnewood, PA) told heartwire , adding that because of its size and strength of its findings, RE-LY is a "major contribution" to the cardioversion-anticoagulation evidence base. Ezekowitz is a RE-LY co–primary investigator.

As previously reported by heartwire , the open-label RE-LY trial compared dabigatran at 110 mg or 150 mg twice daily against a conventional warfarin regimen in patients with nonvalvular AF. Those who took the 150-mg dose showed a 34% drop in rate of stroke or peripheral embolism compared with those on warfarin (p<0.001) over a median of two years.

A total of 1983 cardioversions were performed in 1270 of the trial's patients, under transesophageal echocardiography (TEE) guidance in about one-fourth of those on dabigatran and about 13% of those on warfarin. The need for cardioversion and any TEE guidance were at physicians' discretion.

The stroke/embolism end point occurred within 30 days of cardioversion in 0.77% of the low-dose dabigatran group, 0.30% of the higher-dose dabigatran group, and 0.60% of the warfarin recipients. No differences between groups were significant.

The event rates were very low in all three groups, according to Ezekowitz; the analysis suggests that "in patients who require cardioversion, cardioverting them on dabigatran 150 [mg twice daily], the approved dose, is--taking the most conservative view--at least as good as [warfarin] and probably a little better."

Hazard Ratio (95% CI) for Outcomes Within 30 Days of Cardioversion, by Treatment Group, in RE-LY

Outcome 30 days after cardioversion

Dabigatran 110 mg twice daily vs warfarin

Dabigatran 150 mg twice daily vs warfarin

Dabigatran 150 vs 110 mg twice daily

Stroke or systemic embolism

1.28 (0.35–4.76)

0.49 (0.09–2.69)

0.39 (0.07–1.98)

Major bleeding

2.82 (0.90–8.82)

0.99 (0.25–3.93)

0.35 (0.11–1.09)

Major bleeding rates were also low in the cardioversion cohort: 1.7%, 0.60%, and 0.60% for dabigatran at 110 mg twice daily and 150 mg twice daily and warfarin, respectively (p=0.06 for dabigatran 110 mg vs warfarin). Although the rates for higher-dose dabigatran and warfarin were similar, oddly, it was substantially increased in the low-dose dabigatran group.

"That was totally counterintuitive. We triple-checked the data, and the data were correct. We have no explanation for it," Ezekowitz said. Probably, he added, the increase was just by chance, given the low number of events.

Dabigatran avoids some of warfarin's drawbacks in the setting of cardioversion, some related to its "delayed onset of action" and others to difficulties in achieving and maintaining an appropriate degree of anticoagulation, the group's report observes. For example, bridging with parenteral anticoagulation therapy is sometimes needed before cardioversion.

"Because dabigatran achieves therapeutic blood levels within two hours and steady-state concentration in two to three days after twice-daily administration, it has the advantage of being more suitable for outpatient management, and its use may prove economical by avoiding hospitalization."

The study was funded by a grant from Boehringer Ingelheim. Ezekowitz reports receiving research grants, consulting fees, and lecture fees from Boehringer Ingelheim. Disclosures for the coauthors are listed in the paper.

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