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By Emily P. Walker, Washington Correspondent, MedPage Today
Published: May 23, 2012
WASHINGTON -- An FDA advisory committee has voted 6-4, with one abstention, against expanding the marketing indications for the factor Xa inhibitor rivaroxaban (Xarelto) to include treatment of acute coronary syndrome (ACS).
The vote by the Cardiovascular and Renal Drugs Advisory Committee was somewhat surprising given the positive review from FDA staff released two days before the meeting, but it signals a growing reluctance to expand indications based on data from a single trial.
In the case of rivaroxaban, the advisers may have been especially cautious since other oral anticoagulants in the same class -- apixaban (Eliquis) which is also a factor Xa inhibitor and an investigational agent, darexaban -- failed in ACS when both were found to increase bleeding in this population.
Rivaroxaban already has FDA marketing approval for prevention of stroke in patients with nonvalvular atrial fibrillation and for prevention of deep vein thrombosis in patients undergoing joint replacement surgery.
Wednesday's panel seemed in agreement that the drug worked well at reducing the rate of cardiovascular death in patients with ACS, but worried about missing data in the ATLAS ACS trial, which did find that the drug rivaroxaban reduced the composite rate of death from cardiovascular causes, myocardial infarction, and stroke to 8.9% compared with 10.7% among those on antiplatelet therapy alone (P=0.008).
The study evaluated the safety and efficacy of rivaroxaban in more than 19,000 ACS patients in addition to aspirin with or without thienopyridine therapy.
Patients taking rivaroxaban had a significant reduction in the occurrence of the composite primary endpoint of cardiovascular death, myocardial infarction, or stroke, compared with placebo (P=0.025). Most of that reduction was driven by a reduction in cardiovascular death.
But there was an increase in bleeding that was three to four times greater overall in the rivaroxaban group.
"I'm worried about exposing thousands of Americans to bleeding, maybe stroke," said panelist Steve Nissen, MD, chairman of the department of cardiology at the Cleveland Clinic, who voted against expanding rivaroxaban's indication. "I wasn't ready to go there yet."
Nissen said if the FDA decides to expand the indication for rivaroxaban, it would be an endorsement to treat ACS patients with three drugs (aspirin, thienopyridine, and rivaroxaban).
"Before we go that far, I want to make sure that this strategy of adding something else to dual antiplatelet therapy is robustly better," he said. "And I just wasn't convinced."
He added that a second trial might change his mind.
Panelists spent much of Wednesday taking the drug's sponsor -- Janssen, a Johnson & Johnson company -- to task for the missing data in the study, namely the more than 2,400 patients who dropped out of the trials early, and for "incomplete follow-up and uncounted deaths."
The panelists told the company it wasn't acceptable to not know whether 9% of their patients were alive or dead at the end of the study.
Nissen even suggested that the design of the study may have encouraged patients to drop out, which could benefit the company because then if the patient died, it wouldn't negatively effect the overall results.
"The missing data in this is troubling and concerning," said panelist Sanjay Kaul, MD, a cardiologist at Cedars-Sinai Medical Center in Los Angeles, who also voted against approving rivaroxaban for ACS.
Early in the day, the panel heard a review from Tom Marciniak, MD, a reviewer with the FDA's Department of Cardiovascular and Renal Products. Marciniak has been known to deliver a scathing review of cardiovascular drug trials in the past, including GlaxoSmithKline's RECORD trial for rosiglitazone).
Wednesday was no different.
"ATLAS failed, not shrugged," he said.
Panelists also were concerned with the differences between the two doses studied in the trial.
For instance, patients treated with the 2.5-mg dose of rivaroxaban had a reduced occurrence of the composite primary endpoint of cardiovascular death, myocardial infarction, or stroke, compared with placebo, but the 5-mg dose did not show a statistically significant reduction in the primary endpoint. In addition, the 5-mg dose also increased the risk of bleeding.
Another FDA reviewer told the panel that using rivaroxaban to treat ACS could be expected to prevent 115 cases of the composite endpoint of cardiovascular death, myocardial infarction, or stroke for every 10,000 patient years, but that would come at the cost of having an additional 516 bleeding events.
The FDA is expected to make a final decision on rivaroxaban by the end of June. The agency doesn't have to follow the advice of its advisory committees, but it often does.
"We appreciate the thoroughness of the committee's review and will ensure the questions raised today are addressed with the FDA," Paul Burton, MD, PhD, vice president of Janssen's cardiovascular franchise division, said in a press release sent after the vote.
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Emily Walker
Washington Correspondant
Emily P. Walker, MedPage Today Washington Correspondent, covers Congress, FDA, other health agencies in Washington. She also covers an array of healthcare events in the nation’s capital, focusing on intersection of policy and medicine. After earning a BA in journalism and political science at Western Michigan University, she worked at the Kalamazoo Gazette, Congressional Quartely, and wrote for several medical newsletters.
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