Chicago, IL (updated) - The ROCKET AF trial, launched when warfarin was the lone available oral anticoagulant, landed on earth this week during a high-profile presentation at the American Heart Association (AHA) 2010 Scientific Sessions. As reported earlier by heartwire, the pivotal trial for the new oral factor Xa inhibitor rivaroxaban (Xarelto, Bayer/Johnson & Johnson) met its primary end point, with investigators showing the drug was noninferior to dose-adjusted warfarin with regard to all-cause stroke and non-central nervous system (CNS) embolism.

The question of superiority over warfarin, however, is less clear, with two analyses showing disparate findings, at least in terms of statistical significance. In the intention-to-treat superiority analysis, investigators failed to show the drug had an advantage, statistically, over warfarin for the prevention of thromboembolic events in patients with nonvalvular atrial fibrillation. In the intention-to-treat analysis, 269 patients treated with rivaroxaban had a stroke or embolization, compared with 306 patients treated with warfarin (p=0.117).

In an on-treatment analysis addressing the superiority question, however, rivaroxaban fared better, with investigators showing that rivaroxaban significantly reduced the risk of stroke or non-CNS embolization by 21% compared with warfarin.

Dr Robert Califf

On the whole, investigators view the study in a positive light, regardless of how the superiority analysis is performed, intention-to-treat vs on-treatment, with most in agreement about the success of rivaroxaban given that it was noninferior to warfarin without an increase in major bleeding. Speaking during the morning press conference, Dr Robert Califf (Duke Clinical Research Institute, Durham, NC), a co-principal investigator of the ROCKET-AF trial, said the group wanted to first show rivaroxaban was equivalent to warfarin, a drug that was like a "battered old boxer that you'd think had had its day" but that kept on faring well against newer and newer drugs.

The results of ROCKET-AF, however, show that rivaroxaban is a "proven alternative" to warfarin in moderate- or high-risk patients with atrial fibrillation, say investigators.

Speaking with heartwire, Dr Douglas Zipes (Krannert Institute of Cardiology, Indianapolis, IN), who was not affiliated with the trial, said he was impressed with the data.

"If you take away only the conclusion of noninferiority, that's a step up," said Zipes. "Warfarin is a very difficult drug to use. Patients don't like the repeated [international normalized ratio] INR checks, and it's very difficult to maintain control. I have several patients with INRs all over the map, so to have another substitute for that is welcome. However, the on-treatment analysis shows superiority over warfarin, and while that's not the gold standard—call it the silver standard—I'm very impressed with the results. I've already started to switch some patients over to dabigatran [Pradaxa, Boehringer-Ingelheim], and if rivaroxaban gets approved, it would give us another choice."

Flight launch: The ROCKET-AF trial

ROCKET-AF is a double-blind, double-dummy phase 3 study in more than 14 000 patients with atrial fibrillation. Patients were randomized to 20-mg rivaroxaban once daily (or 15 mg in patients with moderate renal impairment at screening) or to dose-adjusted warfarin (titrated to an INR of 2.5). Patients in the trial were considered high risk, with 55% having had a prior stroke and 90% having hypertension. In addition, 90% of the patients had a CHADS₂ score of 3 or higher, much higher than scores of patients enrolled in four comparable studies: Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY), ACTIVE W, AMADEUS, and SPORTIF V.

Overall, rivaroxaban was noninferior to warfarin in terms of the primary end point, a composite of stroke and non-CNS embolism, and as noted, was superior to warfarin when investigators analyzed the risk of stroke and non-CNS embolism in patients who remained on treatment over the course of the 40-month trial. It was not superior to warfarin in the stricter intention-to-treat analysis.