Stroke Prevention in AF: Study Finds Some Differences Among New OACs

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Study Should Be Approached "With Extreme Caution"

Dr. Christopher P. Cannon and Dr. Payal Kohli argued that studies such as this one should be approached “with extreme caution,” and that “the picture remains a bit confusing” for the individual agents relative to one other.

For example, they noted, Dr. Lip and colleagues reported no significant differences in myocardial infarction rates among the agents, whereas within the individual trials, the rate of myocardial infarction was higher with dabigatran, but not with either rivaroxaban or apixaban, as compared with warfarin. “These conflicting results lend support to the conclusion that such methods for indirect comparisons may not be the most accurate due to several sources of confounding.”

The statistical limitations of the methods used in this analysis mean that the reported differences “are not robust enough to be relied upon for the clinical care of patients,” Dr. Cannon and Dr. Kohli wrote.

Dr. Christopher Cannon

Barring head-to-head comparison evidence, they argued, “we would turn to direct evidence from trials and the indications put forth by the FDA [U.S. Food and Drug Administration] to select the appropriate agent, at the dose tested, for use in the patient population studied within the trial.”

DR. CANNON is with Brigham and Women’s Hospital in Boston and DR. KOHLI is with the University of California, San Francisco. These remarks were taken from an editorial accompanying Dr. Lip’s report (J. Am. Coll. Cardiol. 2012;60:747-8). Dr. Cannon disclosed advisory relationships with Alnylam, Bristol-Myers Squibb, and Pfizer; equity in Automedics Medical Systems; and grant support from Accumetrics, AstraZeneca, and other companies. Dr. Kohli disclosed an advisory relationship with Daiichi Sankyo.



A study indirectly comparing three oral anticoagulant drugs – dabigatran, rivaroxaban, and apixaban – has revealed potential differences among the agents in their relative efficacy and safety when used for stroke prevention in atrial fibrillation.

However, its authors found more similarities than differences overall, and stopped short of saying that the differences they found should have meaning for clinicians in choosing one over another. Only a head-to-head trial comparing the new agents could do that, they said.

The study, published in the August issue of the Journal of the American College of Cardiology, used data from phase III, randomized, controlled trials that had enrolled more than 50,000 patients (J. Am. Coll. Cardiol. 2012;60:738-46). The authors, led by Dr. Gregory Y.H. Lip of the University of Birmingham (England) compared each of the agents – including two different doses of dabigatran, 150 mg b.i.d. and 110 mg b.i.d. – with warfarin.

Overall, the investigators found that the newer agents offered significant advantages over warfarin, with 21% reduced risk of stroke or systemic embolism; 23% reduced risk of stroke; 53% lower risk of hemorrhagic stroke; and 12% less risk of all-cause mortality. The risk of major bleeding was 13% lower with the new agents, compared with warfarin.

Dr. Lip and his colleagues reported that they found no profound significant differences in efficacy between apixaban and dabigatran at either dose, or between rivaroxaban and dabigatran 110 mg; dabigatran 150 mg was seen as superior to rivaroxaban for some end points, with a 26% lower risk of stroke or systemic embolism and a 56% lower risk of hemorrhagic stroke.

Some significant differences were also seen for safety end points. The risk of major bleeding was 34% lower for apixaban than for rivaroxaban, and 26% lower for apixaban than for dabigatran 150 mg, but not significantly different between apixaban and dabigatran 110 mg. Compared with rivaroxaban, dabigatran 110 mg was associated with 23% less risk of major bleeding and 54% less intracranial bleeding.

Dr. Lip and his colleagues acknowledged that their study, because it was an indirect comparison analysis, had automatic limitations, such as the fact that it could not adjust for patient demography and stroke risk of the different trial populations; nor could it account for differences in warfarin control between the trials, with mean time in therapeutic range better in some trials than others.

Although indirect comparison "is still considered a reasonable statistical tool to qualify a comparison of effects that have not yet been investigated head to head," only head-to-head comparison, they concluded, would "fully answer the question of efficacy/safety differences between the new drugs for stroke prevention in AF."

Dr. Lip disclosed having served as a consultant for Bayer, Astellas, and other companies; and having been a speaker for Bayer, Pfizer, and other companies. Two of Dr. Lip’s coauthors on the study, Dr. Torben Bjerregaard Larsen and Dr. Lars Hvilsted Rasmussen, disclosed having been speakers for BMS/Pfizer and Boehringer Ingelheim.

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