March 14th, 2015
DAPT ‘Approaching the Point of Diminishing Returns’?
After a myocardial infarction (MI), patients remain at high risk for recurrent events. The precise role of dual antiplatelet therapy (DAPT) to lower this risk has been the subject of considerable disagreement. Now a new study offers fresh evidence that prolonged DAPT can lower risk over a long period, but only at the cost of more bleeding complications.
PEGASUS (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin – Thrombolysis in Myocardial Infarction [TIMI] 54), presented at the American College of Cardiology meeting in San Diego and published simultaneously in the New England Journal of Medicine, randomized 21,162 patients who had a heart attack 1 to 3 years previously to placebo or one of two doses (60 or 90 mg twice daily) of the thienopyridine ticagrelor (Brilinta, AstraZeneca).
After three years the rate of cardiovascular death, MI, or stroke was 7.85% in the high-dose ticagrelor group, 7.77% in the low-dose ticagrelor group, and 9.04% in the placebo group. When compared to placebo the result was highly significant for both ticagrelor groups.
However, the greater efficacy was achieved at the cost of a significant increase in bleeding. The rate of TIMI major bleeding was 2.6% with 90 mg ticagrelor, 2.3% with 60 mg ticagrelor, and 1.06% with placebo. There was no significant difference in intracranial hemorrhage or fatal bleeding.
Over the course of the trial the study drug was discontinued in 32% of patients in the high-dose ticagrelor group, 28.7% in the low-dose ticagrelor group, and 21.4% in the placebo group. One contributing factor was a higher rate of dyspnea in the ticagrelor groups (18.93% and 15.84% versus 6.38%).
In an accompanying editorial, John Keaney writes that the PEGASUS results “prompt speculation as to whether dual platelet inhibition with high-potency agents is approaching the point of diminishing returns.” He calculated that treating 10,000 patients with low-dose ticagrelor “for 1 year would prevent approximately 42 primary end-point events and produce approximately 31 TIMI major bleeding events — close to an even proposition.”
Although there were important differences between PEGASUS and last year’s DAPT trial, the trial investigators said that “broadly speaking, the two trials showed that prolonged P2Y12-receptor blockade reduced the rate of ischemic events and increased the rate of bleeding events among patients with coronary disease.” In his editorial, Keaney said that the results of the two trials were consistent with each other and “remind us of the fragile balance between efficacy and adverse events.”
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