FDA advisory committee recommends rivaroxaban for approval

Data demonstrate a favorable risk-benefit profile for the oral anticoagulant.

Yesterday, the FDA Cardiovascular and Renal Drugs Advisory Committee voted to recommend approval of the Factor Xa inhibitor rivaroxaban 10 mg, an oral anticoagulant indicated for prophylactic use against venous thromboembolism in patients undergoing hip or knee replacement surgery.

The panel voted 15-2 to recommend approval, despite an increased risk for bleeding associated with the use of the drug. Rivaroxaban (Bayer AG, Johnson & Johnson) recently received approval in Europe under the brand name Xarelto.

The recommendation for approval was based on pooled results from the four RECORD trials, which compared rivaroxaban once daily to varying doses of enoxaparin (Lovenox, Sanofi-Aventis). The results indicated that rivaroxaban 10 mg daily reduced symptomatic VTE or death by 58% compared with enoxaparin. However, the results also demonstrated a twofold increase in the incidence of major bleeding events: 24 with rivaroxaban group vs. 13 with enoxaparin (P=.08).

“The efficacy data are compelling,” Michael Lincoff, MD, FACC,vice chairman for clinical research at Lerner Research Institute and vice chairman in the department of cardiovascular medicine and professor of medicine at Cleveland Clinic Foundation, said during the vote. “The net clinical benefit, including the bleeding, is still favorable.”

The liver toxicity rate for rivaroxaban was more than double the rate for enoxaparin. However, the clinical evidence does not demonstrate a liver safety signal, according to Paul B. Watkins, MD, Verne S. Caviness Distinguished Professor of Medicine at University of North Carolina, Chapel Hill.

“The liver issue is not completely resolved, but I believe the signal of liver injury is very weak and warrants continued surveillance in both upcoming clinical trials and clinical practice, but does not preclude approval of the drug,” Lincoff said.

The panel also voted against the need for a 5 mg dose of rivaroxaban for the treatment of patients with renal and/or hepatic dysfunction and/or on CYP3A4, P-gp inhibitors.

“While I acknowledge we may reduce bleeding risk, I think we would also jeopardize efficacy, and in the context of the available data in high-risk populations, we don’t see an interaction signal,” said Darren K. McGuire,MD, MHSc, FACC, associate professor of medicine at The University of Texas Southwestern Medical Center. – by Stacey L. Adams

The FDA Advisory's panel decision is a milestone for antithrombotic therapy in the United States, and will pave the way for likely approval of the first oral alternative anticoagulant to the vitamin K antagonist warfarin. The results of ongoing trials of rivaroxaban, other oral factor Xa inhibitors, and oral direct thrombin inhibitors in other prophylactic and therapeutic indications where anticoagulants are widely used, are eagerly awaited.

– Kenneth A. Bauer, MD

HemOnc Today Editorial Board member

The recommendation to approve rivaroxaban is a landmark event: a first new oral anticoagulant to become available after more than 50 years of only having vitamin K antagonists as an oral anticoagulant choice. Rivaroxaban and many of the other new specific oral anticoagulants in development have a number of advantages over vitamin K antagonists: (a) no anticoagulant effect monitoring needed in most patients, (b) limited drug interactions, (c) limited or no food interactions, and (d) quick on- and offset. I expect that these advantages will lead to a higher rate of acceptance of anticoagulant therapy by physicians, as well as patients. The present recommendation for approval for the orthopedic indications also gives a foretaste of the exciting developments that lie ahead, when, pending ongoing large clinical trial results, such new oral anticoagulants may eventually go before the FDA for approval for the major indications where presently vitamin K antagonists are the only long-term anticoagulant choice (atrial fibrillation, venous thromboembolism, etc). We are now one step closer to those exciting times.

– Stephan Moll, MD

Associate Professor, Department of Medicine,
Division of Hematology-Oncology, University of North Carolina, Chapel Hill