Candace Stuart, Editor, Cardiovascular Business

By now the message is clear: We need a large, randomized clinical trial that allows a head-to-head comparison of novel oral anticoagulants before physicians can with confidence take atrial fibrillation (AF) patients off warfarin. So what’s the holdup?

Researchers have turned to a number of methodologies to answer which of the new drugs developed as alternatives to warfarin is superior: the oral direct thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim); the oral Factor Xa inhibitor rivaroxaban (Xarelto, Janssen Pharmaceuticals, Johnson & Johnson company/Bayer HealthCare); or the oral Factor Xa inhibitor apixaban (Eliquis, Bristol Myers Squibb/Pfizer).

A recent analysis appeared in the Journal of the American College of Cardiology, where Lip et al assessed the relative effect of different treatments using data from clinical trials comparing each drug to warfarin.

The authors emphasized that indirect comparison analyses are “always fraught with major difficulties.” In an accompanying editorial, Christopher P. Cannon, MD, of Brigham and Women’s Hospital in Boston, and Payal Kohli, MD, of the University of California San Francisco, categorized the study’s class effect analysis as “straightforward and statistically sound” but termed the conflicting results from indirect comparison of individual drugs as confusing. They concluded that what differences emerged in the analysis weren’t robust enough to steer clinical decisions.

Schneeweiss et al also tried to tease out an answer using indirect comparison analyses that adjusted for differences in patient populations in the drugs’ three clinical trials: ARISTOTLE, RE-LY and ROCKET-AF. The Lip et al analysis seemed to give the nod to dabigatran while Schneeweiss et al found no standouts in efficacy analyses but determined that apixaban produced fewer major hemorrhages.

It is no surprise, then, that unpublished results from PINNACLE-AF showed that among AF patients prescribed anticoagulants, 87.4 percent still were on warfarin. Dabigatran, which received FDA approval in October 2010, and rivaroxaban, which followed suit in November 2011, were prescribed to 12.6 percent of those AF patients on anticoagulants. Apixaban has yet to be approved for the prevention of stroke in patients with AF.

Both the Lip and Schneeweiss research teams concluded that only a randomized controlled clinical trial definitively will put the question of superiority to rest. Big pharma companies may be reluctant to pay for such an endeavor—after all, it is expensive and their drug might be the loser. But this seems like a compelling comparative-effectiveness research topic that fits the National Institutes of Health’s funding requirements of need and impact. It may be time for the agency to step up to the plate for this growing patient population.  

Candace Stuart
Cardiovascular Business, editor
cstuart@trimedmedia.com