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FDA Reviewer Slams Xarelto for Stroke Prevention in Afib

By Emily P. Walker, Washington Correspondent,
Reviewed by
September 06, 2011

Review

WASHINGTON -- Rivaroxaban (Xarelto) is not as effective as warfarin for preventing strokes in patients with atrial fibrillation and should not be approved for the new indication, according to an FDA reviewer.

That opinion was set forth in briefing documents prepared for the FDA's Cardiovascular and Renal Drugs Advisory Committee meeting Thursday. The committee will review Johnson & Johnson's application to extend marketing approval for its direct oral factor Xa inhibitor rivaroxaban to include prevention of stroke and systemic embolism in patients with nonvalvular approved atrial fibrillation.

But, in its briefing documents the company argued that the "benefits of treatment with rivaroxaban clearly outweigh the risks when compared with warfarin therapy."

Results from the company-sponsored ROCKET-AF study found that rivaroxaban (Xarelto) was at least as good as warfarin for stroke prevention in atrial fibrillation, with a similar rate of major bleeding and greater ease of use. Johnson & Johnson is seeking approval that indicates their drug works better at preventing strokes than warfarin.

But the briefing documents held no joy for J & J as one of the three FDA reviewers concluded that the company failed to prove that rivaroxaban was superior to warfarin for stroke prevention. The reviewer is recommending that the agency issue a complete response letter to the company rather than approve the new indication. Rivaroxaban is approved for prevention of DVT in patients undergoing joint replacement surgery.

The FDA reviewers pored over results from the ROCKET-AF study, which enrolled more than 14,000 adults with nonvalvular atrial fibrillation who were at a high risk for thrombotic events. Patients were evenly randomized to 20 mg of rivaroxaban daily or to warfarin. The primary endpoint was time to a composite endpoint of stroke or systemic embolism.

The time period for the primary efficacy endpoint was any thrombotic events occurring while the patient was "on treatment," which was defined as last dose plus two days. By that standard, rivaroxaban was superior to warfarin (P=0.01).

But there were more strokes and embolisms in the rivaroxaban group than in the warfarin group during the period when patients stopped taking their study drug and transitioned to warfarin or other appropriate therapy for the open-label portion of the study. Based on those "intent-to-treat" data, rivaroxaban was no longer superior to warfarin. It was, however, shown to work at least as well as warfarin.

After the ROCKET-AF study was completed, the company developed instructions detailing a treatment plan for transitioning patients from rivaroxaban to warfarin, but those instructions haven't been evaluated. A study testing how to transition patients would have to be done before rivaroxaban could be approved, according to the FDA reviewer.

The FDA requires that drugs approved for life-threatening conditions -- such as stroke -- be shown to be at least as effective as other available drugs. But as the FDA reviewer pointed out, the agency "generally prefer[s] an intention-to-treat analysis as the basis of a superiority claim."

Additionally, according to the FDA reviewer, the per-protocol analyses where rivaroxaban came out a winner is "misleading" because improper dosing of warfarin may have been to blame. The company did not show that when warfarin -- which is notoriously tricky to correctly dose -- is used "skillfully" that rivaroxaban would work any better, the reviewer said.

"Thus, the data do not convincingly demonstrate that rivaroxaban is as effective in preventing strokes and systemic emboli as warfarin when warfarin is used skillfully," the reviewer said.

Another warfarin study -- RE-LY -- found that the direct thrombin inhibitor dabigatran (Pradaxa) was more effective in preventing strokes in high-risk patients than warfarin (and that study did a better job at correctly dosing warfarin, the reviewer said). Last October, dabigatran received marketing approval for prevention of stroke in patients with nonvalvular atrial fibrillation.

The reviewer noted that there are no data available from a rivaroxaban versus dabigatran match-up, and left open the question of whether such a study was in order.

In its briefing documents, the company stressed the ease of use and management of rivaroxaban, which does not require INR monitoring, nor does it require dietary restrictions -- both of which are required with warfarin therapy.

"Additional medications such as rivaroxaban would give the physician a wider range of therapeutic options that can be tailored to the individual patient," the company said.

But the FDA reviewer didn't see approval as a benefit for patients: If rivaroxaban is approved, he wrote, "patients taking it might be at greater risk of harm from stroke and/or bleeding than if they were treated with warfarin used skillfully."

"In the opinion of this reviewer, rivaroxaban should not be approved unless the sponsor submits convincing information that it is as safe and effective for its target indication as warfarin when it is used skillfully or that it is as safe and effective as another approved agent, such as dabigatran," the reviewer said.

Despite the overwhelmingly negative tone of the FDA review, there were no new safety issues uncovered, the reviewers said.

In fact, rivaroxaban-treated patients experienced numerically fewer critical organ bleeds, intracranial hemorrhages, hemorrhagic strokes, and fatal bleeds compared with patients treated with warfarin.

The Cardiovascular and Renal Drugs Advisory Committee will vote Thursday afternoon on whether rivaroxaban should be approved, and, if so, whether its label should state it works better than warfarin at preventing strokes.