FDA advisory panel gives nod to ticagrelor for use in acute coronary syndrome

The Cardiovascular and Renal Drugs Advisory Committee voted 7-1 to recommend approval of the use of ticagrelor for the reduction of thrombotic events in patients with acute coronary syndromes.

Ticagrelor (Brilinta, AstraZeneca), a P2Y12 platelet receptor inhibitor, had been evaluated in the PLATO trial, in which patients with acute coronary syndrome (n=18,624) were given ticagrelor or clopidogrel (Plavix, Sanofi-Aventis), the current standard of care.

Ticagrelor was shown to be superior in terms of reducing the rate of the primary efficacy endpoint of cardiovascular death, MI or stroke in study patients.

Total major bleeding events in patients taking ticagrelor (n=9,333) did not differ significantly from those taking clopidogrel (n=9,291), nor did fatal bleeding or fatal/life-threatening bleeding, although non-CABG bleeding, including non-procedural, was notably higher in the ticagrelor-treated group.

Among the important issues discussed at the meeting were the unfavorable results from the PLATO trial seen in U.S. patients after using ticagrelor. These results were inconsistent with the findings from patients in most other countries represented in the trial.

These results included worse outcomes for all efficacy measures, including major adverse coronary events, MI, stroke and cardiovascular disease. Differences in aspirin dosages between the United States and countries outside the United States were cited as a possible explanation. Patients in the United States were split between dosages of 325 mg and 82 mg vs. 75 mg to 100 mg typically used in other countries.

“Independent analyses done by the academic groups working independently but collaboratively with the sponsor and using a different set of techniques have arrived at the same conclusion — that aspirin appears to explain much of the geographic variation in effect,” Robert A. Harrington, MD, a professor of medicine at the Duke University School of Medicine, said in his presentation. “We do believe then, as an investigative group, that detailed analyses suggest that efficacy is modified by aspirin dose.”

However, according to Robert Fiorentino, MD, a clinical reviewer at the Center for Drug Evaluation and Research, “It does seem unlikely that the unfavorable U.S. outcome can be explained entirely by a single factor alone, including aspirin … and the possibility of a chance outcome cannot be excluded. As of now, there is not a clear biological or pathophysiological explanation for a ticagrelor effect modifier, aspirin or otherwise, that has been identified.”

In its decision, the advisory committee voted to approve ticagrelor for the reduction of thrombotic events in patients with non-ST elevation and ST elevation acute coronary syndrome intended to be managed by percutaneous coronary intervention and those intended to be managed medically.

“I voted yes,” said Ralph B. D’Agostino Sr., PhD, chairman of the mathematics and statistics department and professor of mathematics/statistics and public health at Boston University. “I know we’ve been hung up on the U.S., and for obvious reasons, but there is a lot of consistency across the rest of the study, and the data are compelling and significant.”

“My only trepidation was the issue of the U.S. population,” Mori J. Krantz, MD, associate professor of cardiology at the University of Colorado in Denver, said of his vote against recommendation. “Without the assurance that there was going to be any type of follow-up study to get confirmatory information from the U.S., in the population in which they sought the indication, made me vote the way I did.” – by Brian Ellis

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