As expected, the Food and Drug Administration has declined to approve the oral anticoagulant rivaroxaban for treating acute coronary syndromes.
The manufacturer of the factor Xa inhibitor, Janssen Research & Development, announced on Feb. 14 that the FDA has issued a complete response letter regarding rivaroxaban, for reducing the risk of secondary cardiovascular events (MI, stroke, or death) in patients with ACS. This announcement came a month after the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 10-0 against approval. The company also announced that the FDA issued a complete response letter for the other ACS indication under review, to reduce the risk of stent thrombosis in patients with ACS, in combination with standard antiplatelet therapy.
The FDA issues complete response letters to manufacturers when it decides against approval, with explanations of outstanding issues that need to be resolved before the drug can be reconsidered for approval. The FDA does not publicly announce when these letters are issued, but manufacturers often do so.
Both indications are based on the ATLAS ACS 2 TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Aspirin With/Without Thienopyridine Therapy in Subjects With Acute Coronary Syndrome) trial, a phase III study of more than 15,000 patients with recent ACS, which compared two doses of rivaroxaban plus standard antiplatelet therapy (aspirin and a thienopyridine) to placebo plus standard therapy. The primary endpoint – the risk of a composite of cardiovascular death, MI, or stroke – was significantly reduced (P = .039) by 15% among patients on the 2.5-mg twice-daily dose, compared with patients on placebo (N. Engl. J. Med. 2012;366:9-19).
This is the third time the FDA has rejected approval of rivaroxaban for the ACS indication. The company submitted new analyses of the data which included some missing data, but at the FDA meeting in January, the panel said that missing data remained a problem and the P value for the primary endpoint was not low enough to support approval based on a single trial. Members also expressed continuing concerns about bleeding risk and voted against approval.
The company did not explain in the statement why the FDA had decided against approval.
"We are evaluating the contents of the letters and will determine the appropriate next steps," Dr. Paul Burton, vice president, clinical development, Janssen, said in the company’s statement.
Rivaroxaban, marketed as Xarelto, is approved for several indications, including reduction of the risk of stroke and systemic embolism in nonvalvular atrial fibrillation, treatment of deep vein thrombosis, prevention of deep vein thrombosis after hip or knee replacement surgery, and reduction in the risk of deep vein thrombosis and pulmonary embolism.