TRITON Analysis: Prasugrel Curbs Second MI


WASHINGTON — A new subanalysis of the TRITON-TIMI 38 trial shows that prasugrel significantly reduced the risk of death and subsequent heart attack in patients who had a first MI during the study.

Examining the full response of patients who have an event in any trial provides valuable information about a drug's total effect, Dr. Eugene Braunwald reported at a symposium sponsored by the Cardiovascular Research Institute at the Washington Hospital Center. Most patients who have a primary end point event will survive and stay in the study, although only that first event is included in the outcome analysis.

“The classical analysis we do in all clinical trials doesn't tell the whole story—the number of total events. A subanalysis of what happens to these patients tells you a lot about what the drug actually does,” said Dr. Braunwald of Brigham and Women's Hospital, Boston, and chairman of the TIMI study group.

The TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel—Thrombolysis in Myocardial Infarction) randomized 13,608 patients who had moderate- to high-risk acute coronary syndromes and were scheduled for percutaneous coronary intervention to either the investigational thienopyridine prasugrel (60-mg loading dose followed by 10-mg daily maintenance dosage) or clopidogrel (300-mg loading dose followed by 75-mg daily maintenance dosage), for up to 15 months.

Those taking prasugrel were 19% less likely to experience cardiovascular death, MI, or stroke; the number needed to treat was 46. However, Dr. Braunwald noted, “there was no free lunch.” Prasugrel carried a 6% increased risk of major bleeding, with 35 more incidents than occurred in the clopidogrel group.

The new analysis concluded that even among those 1,424 patients who had a first primary end point event, prasugrel was significantly more effective than clopidogrel at reducing the risk of death and subsequent events.

“After the first event, patients who were assigned to clopidogrel had an additional 113 events, compared to an additional 56 events among those taking prasugrel,” Dr. Braunwald said. “That was a highly significant difference. Additionally, there were 40 deaths after the initial event in the clopidogrel group, but only 14 in the prasugrel group, for a significant risk reduction of 34%.”

He also presented analyses examining prasugrel's sustained reduction in the risk of secondary end point events in the entire study group. Over the 15-month study period, prasugrel reduced urgent target vessel revascularization by 34%. This significant difference appeared within the first 30 days (47% reduction) and continued throughout the next 14 months (21% reduction).

Overall, prasugrel reduced stent thrombosis by 52%, compared with clopidogrel. That difference also emerged quite early, in the first 3 days of administration (51% reduction).

The TIMI study group continues to analyze prasugrel's effect in patients with either bare metal or drug-eluting stents, Dr. Braunwald said. “The analyses are not complete, but I think we can say that the 50% reduction in stent thrombosis will be similar for both bare metal and drug-eluting tents.”

Dr. Braunwald stressed that excess bleeding is the price for more effective platelet inhibition. “While there were no significant differences in the number of instrumented bleeds, there were significantly more spontaneous bleeds. Although the absolute number of events was small, the difference was significant.”

Even the excess bleeding, however, doesn't significantly negate prasugrel's overall benefit, Dr. Deepak Bhatt said while commenting on Dr. Braunwald's presentation. “The net clinical benefit was very significantly in favor of prasugrel even when you consider the bleeding episodes,” said Dr. Bhatt of the Cleveland Clinic. Despite this, he said, it will be important to continue analyzing the incidences of bleeding in both groups.

“Other trials suggest a relationship between bleeding and mortality, apart from the obvious [death resulting from exsanguination]. Bleeding can lead to hypotension, transfusion that may or not be appropriate, and cessation of aspirin or any other form of antithrombotic therapy, either by the doctor or by the patient without the doctor's knowledge. By other pathways, bleeding may lead to ischemia, stent thrombosis, or inflammation, which may contribute to mortality.”

The trial's finding of an attenuated bleeding risk among patients with diabetes (about 3,000) is an intriguing one, Dr. Bhatt noted. In this group, the rates of bleeding were not different between the two study drugs (2.6% prasugrel vs. 2.5% clopidogrel). “This could be a chance finding due to the small patient group, but an alternative explanation is that patients like diabetics, whose platelets are already 'revved up,' are most likely to derive benefit from prasugrel and least likely to suffer harm from it.


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