Pharmacy & Therapeutics - March 2009 - (Page 156) MEETING HIGHLIGHTS: FDA Panel and Prasugrel for Acute Coronary Syndromes than 60 kg (132 pounds). After three days, the rates of non-CABG TIMI Major Bleeding were 4.82% for prasugrel in patients 75 years of age and older and 3.62% for those younger than age 75. The sponsors’ recommendation, therefore, was to reduce the prasugrel maintenance dose for patients weighing less than 60 kg and for patients 75 years of age and older. The potential mitigation of bleeding risk may also be achieved by choosing a radial instead of a femoral catheter access during PCI, with prasugrel contraindicated for patients who have had a prior transient ischemic attack (TIA) or stroke. Summing up the public health implications, Dr. Braunwald said that prasugrel had the potential to prevent 23,000 MIs; 8,600 urgent target-vessel revascularizations; 7,400 stent thromboses; and 4,000 deaths—at a cost of 2,300 cases of nonfatal major bleeding (in non-CABG patients). • Ellis F. Unger, MD, Team Leader, General Medicine Branch, FDA Cardiovascular and Renal Drugs Advisory Committee, Center for Biologics Evaluation and Research Largely concurring with the sponsors’ main findings, Dr. Unger noted that patient management in TRITON-TIMI 38 was consistent with contemporary practice and that benefits were persuasive across UA/NSTEMI patients, STEMI patients, and the overall ACS populations. Results were driven by nonfatal MI with positive trends on mortality rates. Stroke findings were neutral. In addition, prasugrel’s superiority generally occurred early in treatment. For STEMI in particular, benefits were experienced immediately, with curves parallel thereafter. Overall, 54% of adverse events (AEs) occurred in the first week, with 45% in the first day. Dr. Unger further noted that positive results were consistent for all demographic subgroups with concomitant diseases, for all stent types, and with the use of glycoprotein (GPIIb/IIIa) inhibitors. Rates of AEs were higher for prasugrel, however, in patients with a history of stroke (19.1% vs. 14.1% for clopidogrel). Bleeding also occurred early during therapy; one-third of AEs were reported on the first day, and nearly half were reported within the initial seven days. In an analysis of TIMI Major or Minor Bleeding (clinically overt bleeding associated with a decrease in hemoglobin of between 3 and 5 g/dL), Dr. Unger emphasized that the relative risk of bleeding with prasugrel was not particularly high in patients who were younger than 70 years of age (1.31%) or in those 70 years of age and older (1.35%). At the same time, however, bleeding was malignant, resulting in fatal hemorrhage in nine of 891 patients receiving prasugrel (1% of patients), compared with one of 894 patients receiving clopidogrel (0.1% of patients). Symptomatic intracranial hemorrhage was reported in 0.8% of prasugrel patients in this subgroup and in 0.3% of patients in the clopidogrel group. Dr. Unger discussed TRITON’s findings of an increased number of new cancers and worsening of existing cancers that could be consistent with tumor stimulation. Citing a lack of a purported mechanism and inconclusive data about neoplasms, he said that the agency’s review indicated that prasugrel did not cause cancer. The sponsors’ report had suggested that ascer tainment bias was responsible for the apparent increase when bleeding led to the discovery of colorectal cancers that otherwise would not have been detected. • Douglas Weaver, MD, Professor of Medicine, Wayne State University, and Division Head of Cardiovascular Medicine, Darin Chair of Cardiology, Director, Henry Ford Cardiovascular Institute, Henry Ford Health System, Detroit, Mich. • Victor L. Serebruany, MD, PhD, Johns Hopkins University Medical School, Baltimore, Maryland • Thomas Marciniak, MD, Medical Team Leader, FDA Cardiovascular and Renal Unit Representing the American College of Cardiology, Dr. Weaver delivered one of two statements offered in the open public hearing portion of the meeting. He called for a postmarketing registry, beyond the usual manufacturer’s postmarketing surveillance, to monitor safety and to ensure the safety profile of this “new but important drug.” The second statement, by well-known platelet researcher Dr. Serebruany, who is also a prasugrel patent application holder with Lilly, reflected less certainty about the drug’s efficacy and some uncertainty about its safety. In a follow-up interview, he expressed dismay that the primary data, now available from the full 357-page FDA report, had not been made public until a few days before the hearing. He further said that cancer rates were much higher and broader than reported. He also dismissed the claim that cancer increases were caused by ascertainment bias. Dr. Serebruany explained that the dramatically more powerful chronic antiplatelet effects of prasugrel could allow pre-existing cancer cell colonies to break through the weakened platelet barrier and facilitate metastatic dissemination. The fact that the difference in cancers becomes apparent at four months after randomization in TRITON clearly supports this hypothesis. His main complaint, however, was over the definition of MI in the primary endpoint, which was changed to include transient increases in biomarkers. If the analysis had considered only those MIs reported by clinicians during PCI, the benefit in the UA/NSTEMI arm, the STEMI cohort, and the overall TRITON population would have disappeared after the first three days. The FDA report clearly acknowledges that the outcome curves are identical and parallel for the rest of the 14.5 months of follow-up. Dr. Marciniak, in the Prasugrel Secondary Review, concluded that the efficacy results showed a small (on the order of one event for every 100 patients), early benefit (in less than 30 days) that was related to a reduction in MIs. He said, “Whether the benefit increases beyond 30 days is less clear, but it is very clear that significant bleeding increases continuously with time, and the potential for tumor promotion remains a serious question for long-term use.” Finally, Dr. Serebruany noted that two oral agents currently in development, Schering’s TRA-SCH 530348 (in phase 3) and Eisai’s E555 (in phase 2), both thrombin receptor antagonists, might be effective with less bleeding risk than prasugrel and clopidogrel because they target the thrombin receptor and “only very slightly” affect adenosine diphosphate and collagen receptors. I 156 P&T® • March 2009 • Vol. 34 No. 3
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