FDA Review Suggests Rough Going for Rivaroxaban in ACS

Shelley Wood and Michael O'Riordan

January 14, 2014

GAITHERSBURG, MD — For the second time, Food and Drug Administration (FDA) advisors are gearing up to take another look at an acute coronary syndrome (ACS) indication for the novel oral anticoagulant rivaroxaban (Xarelto, Bayer Pharma/Janssen Pharmaceuticals) on Thursday.

Specifically, the FDA advisory panel is being asked to determine whether rivaroxaban should be approved for use over a limited time frame to reduce the risk of thrombotic cardiovascular events in patients with ACS.

This time around, the FDA's internal reviews have taken a very cautious approach in their interpretation of the data[1]. The FDA review is based on an analysis of clinical-trial data by the agency's scientists and statisticians, and they appear to be somewhat circumspect about the strength of evidence from the >15 000-patient ATLAS ACS TIMI 51 trial.

For one, there is no second trial to support the conclusions of ATLAS ACS. In addition, the FDA reviewers state the reduction in the risk of cardiovascular death, MI, or stroke in ATLAS ACS was achieved, but based on their analyses, which includes subjects from clinical sites previously excluded, the p value was only 0.032.

In the briefing documents, the FDA points out that the Division of Cardiovascular and Renal Products has generally advised sponsors that a single well-designed and well-conducted outcome trial that includes a composite end point such as the one in ATLAS ACS can be used for drug approval if the p value is <0.01. Regulatory standards for approval, according to FDA guidance documents, also state that "reliance on a single study . . . leaves little room for study imperfections."

In the overall trial, which was reported by heartwire and includes patients treated with the 2.5-mg and 5.0-mg twice-daily doses, the factor Xa inhibitor cut the risk of cardiovascular death, MI, or stroke—the primary end point—by 16% when compared with placebo. The 5-mg dose tested in the trial was associated with an increased bleeding risk that outweighed the drug's benefits.

A Limited Time Frame for Use

The company is seeking an approval for rivaroxaban for use during a limited time frame, possibly for just 30 or 90 days, following an ACS. The clinical-trial data suggested the benefit of rivaroxaban was apparent at 30 days.

The FDA reviewers state this is a reasonable hypothesis—that the benefits of rivaroxaban outweigh the bleeding risks in the time period immediately following ACS—but such an approval also appears to be problematic to the agency. ATLAS ACS was not designed to provide such information, and the sponsor provides insufficient analyses to support an approval based on use during a limited time frame, according to the FDA review.

The agency reviewers go on to note that ATLAS ACS was designed where the effect of rivaroxaban's benefits were expected to be relatively constant over time. "Any analyses performed to address the [limited-time-frame] issue will have been designed over a year after the trial concluded," they write. "Choosing an analysis post hoc that appropriately limits the probability of a spurious finding being accepted as true is highly problematic, if not impossible."

The FDA reviewers point out that the sponsor doesn't even suggest any possible biological mechanisms for why the benefit of rivaroxaban would be greatest in the period immediately following an ACS. "If the label were to limit the duration of use, no reason for doing so could be provided," they write.

A Second Kick at the Can

As previously reported by heartwire , the FDA's Cardiovascular and Renal Drugs Advisory Committee reviewed the sponsor's application for use in ACS patients in May 2012. At that time, the panel voted six to four (with one abstention) against recommending that the FDA approve rivaroxaban for reducing the risk of thrombotic cardiovascular events in patients with ACS or unstable angina in combination with aspirin, aspirin plus clopidogrel, or ticlopidine.

Then, in March 2013, the FDA sent a complete response letter to the sponsor, seeking more information. The company responded with a complete response resubmission on August 15, 2013 "that included assessments of the benefit and risk profile of rivaroxaban at 30, 60, 90, and 120 days after randomization, based on a positive study, to evaluate a duration of treatment that conveys a favorable risk/benefit balance," a company spokesperson confirmed.

In the meantime, European regulators announced May 24, 2013 that they had granted market approval to the oral factor Xa inhibitor for use as secondary prevention in patients with ACS. That's on top of the other indications for which the drug already holds US approval, namely in the setting of atrial fibrillation and deep vein thrombosis (DVT)/pulmonary embolism (PE).

For up-to-the-minute coverage of Thursday's FDA advisory committee meeting, follow @theheartorg on Twitter.


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