Principal Findings:

Median time from symptom onset to treatment was 11.3 hours. Final ACS diagnosis was ST-segment elevation myocardial infarction (STEMI) in 38%, non-STEMI in 43%, and unstable angina in 17%. PCI was performed during the index hospitalization in 61% of patients, and cardiac surgery in 4.5% of patients. Almost half of all patients in both arms had received clopidogrel during the index hospitalization prior to randomization (46%).

The primary endpoint of death from vascular causes, MI, or stroke by 12 months occurred less frequently in the ticagrelor group compared with the clopidogrel group (9.8% vs. 11.7%, hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.77-0.92, p < 0.001). This finding was evident by 30 days, and was also evident among patients in whom an invasive treatment was planned (8.9% vs. 10.6%, HR 0.84, 95% CI 0.75-0.94, p = 0.003). Results were consistent in the prespecified subgroups, with the exception of patients weighing less than gender-specific median, those on lipid-lowering drugs at randomization, and those enrolled in North America, for whom the benefit of ticagrelor was attenuated. Among 8,430 STEMI patients, the primary outcome occurred in 9.3% versus 11.0% (p = 0.02), respectively.

There were also significant reductions in several secondary endpoints with ticagrelor, including the composite of all-cause mortality, MI, or stroke (10.2% vs. 12.3%, HR 0.84, 95% CI 0.77-0.92, p < 0.001); the composite of death from vascular causes, MI, stroke, recurrent ischemia, transient ischemic attack, or other arterial thrombotic events (14.6% vs. 16.7%, HR 0.88, 95% CI 0.81-0.95, p < 0.001); and the individual components of MI (5.8% vs. 6.9%, HR 0.84, 95% CI 0.75-0.95, p = 0.005) and vascular death (4.0% vs. 5.1%, HR 0.79, 95% CI 0.69-0.91, p = 0.001). There was no difference in stroke (1.5% vs. 1.3%, HR 1.17, 95% CI 0.91-1.52, p = 0.22), but there were numerically more hemorrhagic strokes in the ticagrelor group (0.2% vs. 0.1%, p = 0.10). All-cause mortality occurred significantly less frequently with ticagrelor (4.5% vs. 5.9%, HR 0.78, 95% CI 0.69-0.91, p < 0.001), as was definite or probable stent thrombosis (2.2% vs. 2.9%, HR 0.75, 95% CI 0.59-0.95, p = 0.02).

Major bleeding rates were similar between treatment groups using both the trial defined endpoint (11.6% for ticagrelor vs. 11.2% for clopidogrel, p = 0.43) and the TIMI criteria (7.9% vs. 7.7%, p = 0.57). Fatal bleeding occurred in 0.3% in each group (p = 0.66). The secondary safety endpoint of noncoronary artery bypass grafting (CABG)–related major bleeding was higher in the ticagrelor group using both the trial defined endpoint (4.5% vs. 3.8%, p = 0.03) and the TIMI criteria (2.8% vs. 2.2%, p = 0.03). CABG-related major bleeding did not differ between groups (7.4% vs. 7.9%, p = 0.32). Major or minor bleeding was higher in the ticagrelor group using the trial defined endpoint (16.1% vs. 14.6%, p = 0.008), but not with the TIMI criteria (11.4% vs. 10.9%, p = 0.33). Discontinuation of study drug was slightly higher in the ticagrelor group (23.4% vs. 21.5%, p = 0.002), as was discontinuation due to an adverse event (7.4% vs. 6.0%, p < 0.001). Dyspnea occurred more frequently in the ticagrelor group (13.8% vs. 7.8%, p < 0.001). In the subgroup of patients who underwent Holter monitoring during the first week of treatment (n = 2,866), ventricular pauses ≥3 seconds were more common in the ticagrelor group (5.8% vs. 3.6%, p = 0.01), but did not differ when the Holter was repeated at 30 days (2.1% vs. 1.7%, p = 0.52).

In a subset of 13,408 patients admitted with an acute coronary syndrome, in whom an invasive strategy was planned, ticagrelor was associated with a significant reduction in the incidence of the primary endpoint (9.0% vs. 10.7%, p = 0.0025). Total major (p = 0.88) and severe (p = 0.38) bleeding was similar between the two arms.

Among the 1,888 patients who experienced a primary endpoint event during follow-up, 318 multiple occurrences were noted. Ticagrelor also reduced time to second occurrence of primary endpoint by a similar margin (HR 0.80, 95% CI 0.70-0.90, p < 0.001). Total ischemic events were similarly reduced. Recurrent bleeding events were not increased by ticagrelor.

Subgroup analysis in patients with chronic obstructive pulmonary disease (COPD): 1-year event rates for the primary endpoint were higher in patients with a history of COPD than those without COPD (17.7% vs. 10.4%, p < 0.001). The benefit of ticagrelor was maintained in this patient population compared with placebo for the primary endpoint: 14.8% vs. 20.6%, p < 0.05. PLATO-major bleeding event rates were similar (14.6% vs. 16.6%, p > 0.05). Dyspnea was more common in patients on ticagrelor (26.1% vs. 16.3%, p < 0.05). No COPD status-by-treatment interactions were observed.