SILVER SPRINGS, Md.—The FDA’s Cardiovascular and Renal Drugs Advisory Committee, which ultimately decided not to recommend rivaroxaban (Xarelto, Bayer HealthCare/Janssen Pharmaceuticals) for patients with acute coronary syndromes (ACS) at a May 23 meeting, raised a contentious discussion among the panelists that never really came to a clear resolution—even among the FDA representatives.
Ultimately, the panel voted in a six to four fashion, with one abstention, and the majority of the day’s debate surrounded the data that the trialists didn’t have, coined the “missing data” throughout the day.
“ATLAS failed,” said Thomas Marciniak, MD, the FDA’s clinical team leader in the division of cardiovascular and renal products. “The missing data and quality problems preclude ATLAS from providing substantial evidence of effectiveness.” He also chastised the sponsor for not providing adequate information, because he said trials should have a 99 percent follow-up rate for patient vital statuses.
In response to a question from panel member, Sidney Wolfe, MD, director of the health research group of Public Citizen in Washington, D.C., about whether his clinical concerns were answered by the sponsor consent withdrawal initiative, Marciniak said, “I don’t think I’m satisfied that we know what’s going on with this trial. Missing data remain the major issue with this trial.”
He took one step further, stating that the sponsor's lack of forthcoming information “does not just challenge the results of ATLAS, but invalidates the results.”
However, the FDA did not present a united front of this negative interpretation of the trial. In her presentation, Karen A. Hicks, MD, the FDA’s clinical reviewer of ATLAS, who recommended approval in the original FDA briefing document, summed that “rivaroxaban was effective in reducing the risk of the primary endpoint (composite of CV death, nonfatal MI or nonfatal stroke) in men and women,” adding that rivaroxaban increased the risk of the primary endpoint in women older than 75 years and in those with a history of ischemic stroke or transient ischemic attack.
“Rivaroxaban increased the risk of non-CABG-related TIMI major bleeding in all subgroups except those with a history of congestive heart failure” with rivaroxaban 2.5 mg, said Hicks, adding that patients at higher risk of bleeding are those older than 75 years, those weighing less than 60 kg or greater than 90 kg and those with moderate renal impairment and women.
Yet, based on these bleeding findings, Hicks hinted at a recommendation of a boxed warning, stating it “can be an effective communication tool for bleeding risk.”
Hicks defended her initial recommendation of the drug during the panel meeting, even when Sanjay Kaul, MD, director of the cardiovascular diseases fellowship training program at Cedars-Sinai Heart Institute in Los Angeles, pressed her about the subgroup analysis.
The FDA is not obligated to follow the panel’s recommendation, but often does. After the vote was taken, there was a lengthy conversation about labeling considerations, if the drug is approved. Namely, the panelists discussed the appropriate dose, if rivaroxaban should be used without a thienopyridine, if it should be used with prasugrel or ticagrelor and about its net benefit.
The panel unanimously recommended the 2.5 mg BID dose. The general consensus was that more data are needed to use rivaroxaban without a thienopyridine or with prasugrel/ticagrelor. Also, the panelists seemed to be leaning toward a boxed warning for certain patient populations who experienced more bleeding in the trial.
Steven Nissen, MD, of the Cleveland Clinic, told Cardiovascular Business that he stood by his negative vote after the panel had concluded. “When assessing net clinical benefit, we have to ask ourselves if the patient will do better or worse. Based on the [ATLAS] results, they will fare better by not having a heart attack, but could do worse by having a stroke,” said Nissen, adding that the FDA can always overrule the panel’s recommendation.
“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 the cardiovascular division at Janssen Research & Development, said in a statement after the panel meeting. The Raritan, N.J.-based company expects to hear final decision from the FDA by the end of the second quarter.