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The FDA has approved rivaroxaban (Xarelto) for prevention of stroke in patients with nonvalvular atrial fibrillation, making it the first oral direct factor Xa inhibitor to win an indication for stroke prevention.
The drug had already been approved for prevention of deep vein thrombosis in patients undergoing joint replacement surgery at a dose of 10 mg once a day.
For the new indication, the FDA approved doses of 15 and 20 mg daily depending on creatinine clearance. Patients with a creatinine clearance greater than 50 mL/min should take the 20-mg dose and those with a creatinine clearance of 15 to 50 mL/min should take the 15-mg dose with the evening meal, according to the updated label.
Patients with a creatinine clearance level below 15 mL/min should not take the drug.
The approval was supported by findings from the ROCKET-AF trial, which showed that the 20-mg dose of rivaroxaban was as effective as warfarin at preventing stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Rivaroxaban was associated with a similar rate of major bleeding but a significantly lower rate of intracranial hemorrhage.
However, one of three FDA reviewers who scoured the trial data felt that drugmaker Janssen Pharmaceuticals, a Johnson & Johnson company, failed to prove that the drug is as effective as warfarin because of suboptimal warfarin administration in the trial.
The reviewer recommended against approval in documents prepared for the FDA's Cardiovascular and Renal Drugs Advisory Committee meeting in September.
Nevertheless, the committee -- by a vote of 9-2 with one abstention -- recommended approval for the stroke prevention indication.
The July approval by the FDA for prevention of deep vein thrombosis in patients undergoing knee or hip replacement surgery was based mainly on the RECORD 1, 2, and 3 trials, which showed that rivaroxaban was significantly better than enoxaparin at preventing deep vein thrombosis.
Rivaroxaban becomes the second in a wave of new anticoagulants aimed at improving on warfarin's success in preventing stroke in patients with atrial fibrillation to be approved by the FDA. Last year, dabigatran (Pradaxa), a direct thrombin inhibitor, received approval.
Added to the existing boxed warning regarding risk of spinal and epidural hematomas in patients receiving neuraxial anesthesia or undergoing spinal puncture is a warning about an increased risk of thrombotic events in patients with nonvalvular atrial fibrillation who discontinue rivaroxaban.
If the drug needs to be discontinued for any reason other than pathological bleeding, another anticoagulant should be considered, according to the warning.
According to a statement from Janssen, the FDA has required a Risk Evaluation and Mitigation Strategy (REMS) for rivaroxaban to communicate the risks of thrombotic events, including stroke, if the drug is discontinued without an alternative anticoagulant and also to alert to the potential decreased efficacy if the drug is not taken with the evening meal.
There are other oral direct factor Xa inhibitors under development for stroke prevention in atrial fibrillation, including apixaban, which was recently shown to be superior to warfarin in the ARISTOTLE trial, and edoxaban, which is currently being evaluated in the ENGAGE trial.
From the American Heart Association: