MUNICH — The investigational antiplatelet drug prasugrel was particularly effective for cutting ischemic events in patients with diabetes and relatively less effective in patients without diabetes in a prespecified analysis of the more than 13,000 patients in the drug's pivotal trial.
Initial results reported in November 2007 from the Trial to Assess Improvements in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI-38) showed that in moderate- to high-risk patients with acute coronary syndrome who were scheduled to undergo percutaneous coronary intervention treatment with prasugrel led to a 19% relative risk reduction in the rate of cardiovascular death, myocardial infarction, or stroke, compared with patients treated with the standard drug, clopidogrel (N. Engl. J. Med. 2007;357:2001–15). But because prasugrel treatment was also linked with a 32% relative increase in major bleeding events, compared with clopidogrel, some physicians wondered whether the benefits of prasugrel were worth its increased risk.
“Prasugrel is not a drug for all patients,” Dr. Stephen D. Wiviott said while presenting a poster on the diabetes analysis at the annual congress of the European Society of Cardiology. “Physicians need to weigh things like a patient's age, their bleeding risk, and their risk for ischemic events.”
A higher risk for ischemic events in diabetics is one reason prasugrel was especially effective for those patients. The combination of higher clinical event rates and a greater relative treatment effect in patients with diabetes led to markedly greater absolute event reductions in diabetes patients, compared with those without diabetes, reported Dr. Wiviott and his associates.
Prasugrel is under review by the Food and Drug Administration; at press time, no decision had been announced.
The study enrolled 3,146 patients with diabetes (23% of all enrolled patients), and 10,462 patients without diabetes. Among the diabetic patients, 776 required insulin treatment (25% of the diabetic subgroup). The incidence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (the combined primary end point for the study) was relatively 32% higher among the diabetic patients not taking insulin, compared with the nondiabetics. The event rate was relatively 84% higher in the patients on insulin, compared with the nondiabetic patients.
Patients with unstable angina or ST-elevation myocardial infarction were randomized to treatment with either prasugrel or clopidogrel prior to undergoing percutaneous coronary intervention, and continued on the study medication for a median of 14.5 months, which was also the median time for tallying the incidence of clinical end points. The average age of the patients was 61 years.
In all patients with diabetes, the incidence of the combined primary end point was 12.2% among the patients treated with prasugrel and 17% among those treated with clopidogrel, a 30% relative risk reduction by prasugrel that was statistically significant. In contrast, among patients without diabetes, the event rate was 9.2% in patients treated with prasugrel and 10.6% in those treated with clopidogrel, a relative risk reduction by prasugrel of 14% that was still large enough to be statistically significant, reported Dr. Wiviott, a cardiologist at Brigham and Women's Hospital and Harvard University in Boston.
The added benefit from prasugrel, compared with clopidogrel, was even more dramatic in the insulin-requiring diabetics. Within this subgroup of 776 patients, the combined event rate on prasugrel was 14%, compared with 22% in the clopidogrel group, a 37% relative risk reduction. Among the 2,370 patients with diabetes who did not require insulin, prasugrel treatment produced an 11.5% combined event rate and clopidogrel had a 15.3% rate, for a relative risk reduction of 26%.
The extra benefit from prasugrel in patients with diabetes was not associated with an increased risk in major bleeds. In all of the diabetes patients the major bleeding rate was 2.5% with prasugrel and 2.6% with clopidogrel. The excess of major bleeds linked with prasugrel seen in the entire study was entirely driven by the excess in patients without diabetes.
The study was sponsored by Daiichi Sankyo Co. and by Eli Lilly & Co. Dr. Wiviott said that he has received research grants and lecture fees from both companies.