November 1st, 2010
ROCKET AF: Is Rivaroxaban Ready for Blast Off?
Harlan M. Krumholz, MD, SM
With the approval of dabigatran and now the preliminary and partial results of ROCKET AF, we’ll need to be familiar with much more than just warfarin to address the anticoagulation needs of our patients. The early word on ROCKET AF, which will be presented at AHA, is that rivaroxaban is at least as effective as warfarin in preventing stroke and non-CNS embolic events in patients with nonvalvular atrial fibrillation.
What is rivaroxaban? It is a direct factor Xa inhibitor that inhibits the conversion of prothrombin to thrombin — and thrombin is what converts fibrinogen to fibrin. You may remember that factor X is the final common pathway of the intrinsic and extrinsic pathways, placing it at a critical position in the cascade.
Rivaroxaban was approved in 2008 in Canada and Europe for the purpose of preventing venous thrombosis after hip and knee replacement surgery. An FDA panel in 2009 recommended the same for the U.S.
Now we await the ROCKET AF presentation. The key questions will be:
- Were the event rates comparable to what might be expected in practice — or is there evidence that the study population was highly selected?
- Was the warfarin treatment optimized? How well was the INR maintained?
- Are there any safety concerns with rivaroxaban? How do bleeding rates compare?
- Is there any suggestion that the drug is particularly good or bad for a particular subgroup? This would be an exploratory analysis and would not likely be considered definitive.
- Is there any evidence that rivaroxaban is more effective than warfarin?
And then, if at the end of the day, rivaroxaban really looks to be no better than warfarin — will it find a niche in clinical care?
One Response to “ROCKET AF: Is Rivaroxaban Ready for Blast Off?”
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Couple of clarifications.
First, rivaroxaban is not approved for use in the United States. Despite a favorable 15-2 vote by the FDA panel for preventing venous thrombosis after hip and knee replacement surgery, the FDA sent a complete response letter (euphemism for “rejection”), which the sponsors decided not to respond to. I was one of 2 negative votes. I personally had issues with the choice of the endpoints, the pooling of data across the 4 trials, increased bleeding, a signal for hepatotoxicity which could not be excluded, and a signal for cardiotoxicity— reflecting possible “rebound” hypercoagulability after treatment cessation. Given these issues, in my opinion the benefit did not outweigh the risk, and I believe the FDA made the right call.
Second, 90% of patients had CHADS score of 3 or greater implying a higher risk population than that evaluated in recent trials such as RE-LY, ACTIVE A, PROTECT-AF trials. In the real world, about 50% of patients with NVAF have a CHADS score of greater than 1. So, the event rates are expected to be higher in ROCKET-AF than in practice.
Third, the ROCKET-AF is powered to determine noninferiority of rivaroxaban compared with warfarin for prevention of stroke and systemic thromboembolism, the primary efficacy end point. As a conceptual method for comparing rivaroxaban with warfarin, a finding of statistical noninferiority implies that the efficacy of rivaroxaban is “no worse than” warfarin. Technically, an inference of “as good as” (similar to warfarin) cannot be made from noninferiority assessment, even though most of us (including experts) tend to interpret noninferiority as such! The noninferiority boundary was set to be a hazard ratio of 1.46 that ensures that a conclusion of noninferiority implies rivaroxaban would preserve 50% of the benefit of warfarin over placebo based on a meta-analytic estimate derived from 6 trials. Once noninferiority is established, patients and clinicians could then choose rivaroxaban over warfarin on the basis of other factors, such as ease of use (once daily without the need for monitoring), safety (? bleeding,? hepatotoxicity), or tolerability (wider therapeutic index). The sponsor reports that the primary endpoint was met, which implies that noninferiority was established, but says nothing about superiority. If this is the case, then ancillary advantages such as convenience, safety, tolerability, and cost will become in key in therapeutic decision making.