PLATelet inhibition and patient Outcomes - PLATO
The goal of the trial was to evaluate the safety and efficacy of treatment with ticagrelor, a novel reversible oral P2Y12 receptor antagonist, compared with clopidogrel among patients with an acute coronary syndrome (ACS) with or without ST-segment elevation.
Countribution to the Literature: Among patients with ACS, treatment with ticagrelor significantly improved cardiovascular outcomes at 12 months compared with clopidogrel, without an excess in major bleeding.
Patients Enrolled: 18,624
Mean Follow-Up: 12 months
Median Patient Age: 62 years
- Hospitalized for potential STE or non-STE ACS with symptom onset in prior 24 hours lasting ≥10 minutes while at rest; either 1) persistent STE ≥1 mm in ≥2 contiguous leads or new LBBB plus planned primary PCI, or 2) ≥2 of the following: STE changes on ECG indicating ischemia, positive biomarker indicating myocardial necrosis, or one of seven clinical risk factors (age ≥60 years, prior MI or CABG, stenosis ≥50% in ≥2 vessels, prior stroke, TIA, carotid stenosis, or cerebral revascularization, diabetes, peripheral artery disease, or chronic renal dysfunction)
- Contraindication to clopidogrel
- Fibrinolytic therapy within 24 hours prior to randomization
- Need for oral anticoagulation therapy
- Increased risk of bradycardia
- Concomitant therapy with a strong cytochrome P-450 3A inhibitor or inducer
- Efficacy: Composite of death from vascular causes, MI, or stroke
- Safety: Any major bleeding event
- Primary efficacy outcome applied to the subgroup of patients with intent for invasive management at randomization
- All-cause mortality, MI, or stroke
- Composite of death from vascular causes, MI, stroke, severe recurrent cardiac ischemia, recurrent cardiac ischemia, TIA, or other arterial thrombotic event
- Individual components of the primary endpoint
- All-cause mortality
Patients were randomized in a double-blind manner to ticagrelor (n = 9,333; loading dose 180 mg followed by 90 mg twice daily) or clopidogrel (n = 9,291; loading dose 300 mg followed by 75 mg daily), with study drug treatment to continue for up to 12 months. An additional dose of study drug was given at the time of percutaneous coronary intervention (PCI) for those undergoing PCI following randomization. Follow-up visits were performed at 1, 3, 6, 9, and 12 months.
Patients were loaded with 325 mg aspirin. If tolerated, all patients received aspirin 75-100 mg daily if no stent was placed and 325 mg daily (for 6 months) if stent was placed.
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.
Among patients with STE or non-STE ACS, treatment with the novel reversible oral P2Y12 receptor antagonist ticagrelor significantly reduced the composite endpoint of death from vascular causes, MI, or stroke by 12 months compared with clopidogrel, without an excess in the primary safety endpoint of major bleeding.
Current guidelines recommend dual antiplatelet treatment with the thienopyridine clopidogrel in addition to aspirin in patients with ACS. However, limitations of clopidogrel include that it is a prodrug with delayed onset of action, has large interpatient variability, and has irreversibility of its platelet inhibition effects. Ticagrelor is the second novel P2Y12 receptor antagonist to undergo large-scale testing with promising results compared to clopidogrel. Prasugrel, another P2Y12 receptor antagonist, recently demonstrated a reduction in cardiovascular death, MI, or stroke compared with clopidogrel in the TRITON-TIMI 38 trial, which included ACS patients undergoing PCI. Prasugrel was associated with an increase in bleeding rates in the trial. The overall bleeding rates with ticagrelor were favorable compared to clopidogrel, although there were some increases in non-CABG–related bleeding, but not in CABG-related bleeding. A significant reduction in mortality occurred with ticagrelor compared to clopidogrel.
Results of post-hoc analyses also suggest that for patients with ACS in whom an invasive strategy is planned, ticagrelor is associated with superior outcomes compared with clopidogrel, without a significant increase in the risk of major bleeding. Similarly, ticagrelor reduces total and subsequent ischemic events in these patients as compared with clopidogrel over 6-12 months, without an increase in recurrent bleeding.
Andell P, James SK, Cannon CP, et al., on behalf of the PLATO Investigators. Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes and Chronic Obstructive Pulmonary Disease: An Analysis From the Platelet Inhibition and Patient Outcomes (PLATO) Trial. J Am Heart Assoc 2015;4:e002490.
Kohli P, Wallentin L, Reyes E, et al. Reduction in first and recurrent cardiovascular events with ticagrelor compared with clopidogrel in the PLATO study. Circulation 2013;127:673-80.
Cannon CP, Harrington RA, James S, et al. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study. Lancet 2010;375:283-93.
Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045-57.
Presented by Dr. Lars C. Wallentin at the European Society of Cardiology Congress, Barcelona, Spain, August 2009.
Presented by Dr. P. Gabriel Steg at the American Heart Association Scientific Sessions, Orlando, FL, November 15, 2009.
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