FDA Panel Backs Approval Of Oral Anticoagulant

ADELPHI, MD. — A federal panel agreed that data on the oral anticoagulant rivaroxaban indicate that the drug's benefits in preventing venous thromboembolic events after hip and knee replacement surgery outweigh its potential risks of excess bleeding and potential risk of severe hepatotoxicity.

The Food and Drug Administration's Cardiovascular and Renal Drugs Advisory Committee voted 15–2 that data from four clinical trials showed that rivaroxaban has a favorable risk-benefit profile for the proposed indication—prophylaxis of venous thromboembolism (VTE) in patients undergoing hip or knee replacement surgery. The recommended dosage schedule is 10 mg once daily, for 35 days after hip surgery or 14 days after knee replacement.

Most panelists agreed that potential hepatoxicity should not preclude approval, although long-term data on hepatoxicity are critically needed. Panelists, who were concerned about off-label use of the drug, emphasized the importance of advising clinicians to avoid prescribing the drug for longer periods and for other uses, and of continuing to follow patients on rivaroxaban in clinical trials and clinical practice for hepatoxicity.

If approved, rivaroxaban, an oral, direct Factor Xa inhibitor made by Johnson & Johnson Pharmaceutical Research & Development LLC, would be marketed as Xarelto. It would be the first oral anticoagulant approved for these indications, as well as the first oral anticoagulant approved since warfarin. The drug works by inhibiting direct Factor Xa, which lowers thrombin production and prolongs prothrombin time. The FDA usually follows the recommendations of its advisory panels.

The proposed regimen was compared with enoxaparin in four international studies of more than 12,000 patients (6,183 patients on rivaroxaban) after total hip or knee replacement surgery. Patients with significant liver disease were excluded. The composite end point of venographic evidence of deep vein thrombosis (DVT), nonfatal pulmonary embolus (PE), or death was significantly lower in those treated with rivaroxaban, but patients on the drug had a higher rate of bleeding. The major bleeding rate was 0.4% in those on rivaroxaban and 0.2% in those on enoxaparin. The one bleeding-related death in the studies was in a patient on rivaroxaban.

Serious ALT elevations were more common with rivaroxaban (0.3% vs. 0.2%), as was a composite marker of liver injury (an ALT greater than three times the upper limit of normal with a total bilirubin greater than two times the upper limit of normal, in 0.15% vs. 0.11%), but these were not significant differences.

The consumer representative on the panel was Dr. Sidney Wolfe, director of the Public Citizen Health Research Group. He voted no on the risk-benefit question and said he was concerned about the bleeding risk and was “very uncomfortable about the certainty of long-term use and the absence of long-term safety data on hepatoxicity.” Because there is no need for a regular blood test, as there is with warfarin, he expects it will be used “massively” for off-label indications for which there are no data.

The panel chair, Dr. A. Michael Lincoff, professor of medicine at the Cleveland Clinic Foundation, who was among the majority in favor of the risk-benefit profile, said that “the liver issue is not completely resolved, but I believe the signal for liver injury is very weak” but should be followed.

Rivaroxaban is also being studied for other indications in ongoing trials, including acute coronary syndromes, secondary prevention and long-term treatment of patients who have had a DVT or PE, and prevention of stroke and noncentral nervous system embolism in patients with nonvalvular atrial fibrillation.