Balancing the risks and benefits of dual platelet inhibition.

Cardiovascular and cerebrovascular events commonly arise from atherosclerotic plaque rupture that produces platelet activation, thrombus formation, and reduction of blood flow to the brain or heart. The inhibition of platelets with aspirin is effective in the secondary prevention of acute coronary events.1 The addition of clopidogrel (i.e., dual antiplatelet therapy), a platelet P2Y12receptor antagonist, produces even greater secondary prevention of coronary events in highrisk patients for up to 1 year.2 Second-generation P2Y12 inhibitors (i.e., prasugrel and ticagrelor) produce further reductions in the risk of ischemic events over the same time frame, albeit with more bleeding complications.3,4 Dual antiplatelet therapy is recommended for 1 year after an acute coronary syndrome, but the effect of longer-term therapy is not clear. Concern exists regarding the balance between reducing the risk of cardiovascular events and the risk of bleeding complications, because bleeding complications are linked to adverse outcomes in patients with an acute coronary syndrome.5 Bonaca et al., in the Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared with Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial,6 provide insight into this balance in high-risk patients with a previous myocardial infarction. In their study, the results of which are now reported in the Journal, they randomly assigned 21,162 patients to placebo or ticagrelor. Because long-term P2Y12 inhibition increases bleeding risk, the investigators compared two doses of ticagrelor (60 mg and 90 mg) to maximize information derived from the trial concerning drug efficacy versus adverse events. As compared with placebo, either dose of ticagrelor was associated with a 15% decrease in the rate of the primary end point of death from cardiovascular causes, myocardial infarction, or stroke. However, ticagrelor treatment also increased clinically significant bleeding complications by a factor of 2.3 to 2.6 and transfusions by a factor of 3.0 to 3.7. There was similar efficacy in the reduction of the rate of the primary end point with either ticagrelor dose, suggesting that the lower dose should be preferred in this patient population because it may limit clinically significant bleeding events. These data prompt speculation as to whether dual platelet inhibition with high-potency agents is approaching the point of diminishing returns. Bonaca et al. found that, as compared with placebo, ticagrelor was associated with an absolute benefit of 1.19 percentage points (with the 90mg dose) and 1.27 percentage points (with the 60-mg dose) in the primary end point, as well as with absolute increases of 1.54 and 1.24 percentage points, respectively, for clinically significant bleeding and 1.71 and 1.37 percentage points for transfusion. On the basis of the 60-mg ticagrelor dose, treating 10,000 patients for 1 year would prevent approximately 42 primary end-point events and produce approximately 31 TIMI major bleeding events — close to an even proposition. Granted, one could argue that major bleeding events do not have the same effect on patients as ischemic cardiovascular events. Nevertheless, we should note that the patient population studied by Bonaca et al. was at particularly high risk for ischemic events (e.g., diabetes, renal disease, multivessel disease, and recurrent myocardial infarction) and had had no recent bleeding episodes or indication for anticoagulation. Thus, not all patients who have a myocardial infarction will fit these same criteria