February 25, 2009
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FDA advisory committee recommends prasugrel for approval

Prasugrel reduced noncardiovascular death, nonfatal MI and nonfatal stroke.

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On Tuesday, the Cardiovascular and Renal Drugs Advisory Committee voted nine to zero to recommend that the FDA approve prasugrel to treat patients with acute coronary syndromes undergoing percutaneous coronary intervention.

This recommendation comes after two prior delays from the FDA; it originally granted the drug priority review in February 2008.

The decision was based on data from the TRITON-TIMI 38 trial, which was published in The New England Journal of Medicine in 2007. The study included 13,608 patients with moderate- to high-risk ACS who were scheduled for PCI. Patients were randomly assigned to receive either prasugrel (Effient; Eli Lilly, Daiichi Sankyo) or clopidogrel (Plavix; Sanofi Aventis,Bristol Myers Squibb).

Results from the trial suggested that patients with ACS undergoing PCI who received prasugrel had a reduced RR for the combined primary efficacy endpoint of non-cardiovascular death, nonfatal MI and nonfatal stroke (P<.001). However, these patients also had an increased risk for bleeding events (P=.03), including an increased risk for life-threatening bleeding (P=.01), compared with the patients assigned clopidogrel.

The advisory panel recommended that warnings about the bleeding risks of prasugrel be added to the drug’s labeling and that the use of the drug be limited to selected patients.

“It is a somewhat complicated risk-benefit tradeoff, because there clearly is an incremental benefit over risk for the cardiac events,” Marvin A. Konstam, MD,professor of medicine at the Tufts University School of Medicine, director of The Cardiovascular Center at Tufts Medical Center, and acting chair of the advisory panel, said after the vote. “It is an individual decision to be made by the clinician with the patient in front of him or her.”

“There is a compelling need for a drug that has more predictable pharmacokinetics and pharmacodynamics than clopidogrel,” Richard Cannon, MD, clinical director of the division of intramural research of the clinical cardiology section of the National Heart, Lung, and Blood Institute in Bethesda, Md., said at the meeting. “The issue of clopidogrel resistance is real, it matters, and this drug is a major advance in that regard.” – by Eric Raible

N Eng J Med. 2007;357:2001-2015.

PERSPECTIVE

Medications that block P2Y12 receptors on platelets are important in reducing ischemic complications in patients with acute coronary syndromes and/or who receive an intracoronary stent. Currently, clopidogrel is widely used in these patients, but up to 25% of patients will have limited response to the drug. Recent studies have shown that this is likely due to polymorphisms in the CYP2C19 gene, which influence the way clopidogrel is metabolized from pro-drug to active form. The TRITON-TIMI 38 study showed that ischemic complications were reduced in patients with acute coronary syndromes treated with prasugrel compared to clopidogrel but at a cost of increased bleeding. The pharmacokinetics of prasugrel are more predictable than clopidogrel and the availability of prasugrel will provide an alternative therapy for individuals who are 'non-responders' to clopidogrel.

– Rick Stouffer, MD

Professor of Medicine and Director of Interventional Cardiology, University of North Carolina