Oral P2Y12 Inhibitors in Acute Coronary Syndrome: Meta-Analysis
- Ticagrelor was ranked as the most effective strategy for prevention of CV mortality and all-cause mortality, whereas prasugrel was ranked as the most effective intervention for definite or probable stent thrombosis.
- Regarding major bleeding, clopidogrel was ranked safest.
- The findings of this meta-analysis lie in contrast to those of ISAR-REACT 5, which demonstrated superiority of prasugrel over ticagrelor in acute coronary syndrome.
How do the efficacy and safety profiles of clopidogrel, prasugrel, and ticagrelor compare in the context of acute coronary syndrome (ACS)?
This meta-analysis was conducted with methods recommended by the Cochrane Collaboration. Randomized trials investigating oral P2Y12 inhibitors clopidogrel, prasugrel, or ticagrelor in ACS patients and extending beyond 30-day follow-up were included. Efficacy endpoints were cardiovascular (CV) mortality, all-cause mortality, myocardial infarction (MI), stroke, and definite or probable stent thrombosis. The safety endpoint was major bleeding. The p-score metric was used to assess comparative hierarchy of efficacy and safety of the treatments (range 0-1, with higher values signifying highly effective or safe therapy).
Twelve trials met inclusion criteria (five with open-label design), comprising 52,816 patients. Two trials compared prasugrel with ticagrelor, six compared ticagrelor with clopidogrel, and four compared prasugrel with clopidogrel. In nine trials, all patients underwent invasive evaluation for ACS. Median follow-up time of included studies was 12 months. Mean age of study participants was 63.7 years. ST-segment elevation MI (STEMI) occurred in 29.9% of patients, and non-STEMI (NSTEMI) in 54.8%.
CV mortality occurred in 3.8% of patients (2,035/52,816). Compared with clopidogrel, ticagrelor was associated with a significant reduction in CV mortality (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.72-0.92), whereas prasugrel was not (HR, 0.90; 95% CI, 0.80-1.01). Prasugrel and ticagrelor did not differ significantly regarding CV mortality (HR prasugrel vs. ticagrelor, 1.10; 95% CI, 0.94-1.29). All-cause mortality occurred in 4.8% of patients (2,537/52,816). Compared with clopidogrel, ticagrelor was associated with a significant reduction in all-cause mortality (HR, 0.83; 95% CI, 0.75-0.92), whereas prasugrel was not (HR, 0.92; 95% CI, 0.84-1.02). Prasugrel and ticagrelor did not differ significantly with regard to all-cause mortality (HR prasugrel vs. ticagrelor, 1.12; 95% CI, 0.98-1.28).
MI occurred in 6.5% of patients (3,440/52,816). Compared with clopidogrel, prasugrel was associated with a significant reduction in MI (HR, 0.81; 95% CI, 0.67-0.98), while ticagrelor was not (HR, 0.97; 95% CI, 0.78-1.22). In a sensitivity analysis excluding periprocedural MI, lower risk was observed with both prasugrel (HR, 0.72; 95% CI, 0.59-0.87) and ticagrelor (HR, 0.85; 95% CI, 0.73-0.98) as compared with clopidogrel. As reported in seven trials, definite or probable stent thrombosis occurred in 1.4% of patients (568/40,459). Compared with clopidogrel, both ticagrelor (HR, 0.72; 95% CI, 0.58-0.90) and prasugrel (HR, 0.50; 95% CI, 0.38-0.64) were associated with lower risk of definite or probable stent thrombosis, and prasugrel was associated with a significantly lower risk compared with ticagrelor (HR, 0.68; 95% CI, 0.50-0.93).
Major bleeding events occurred in 5.3% of patients (2,820/52,816). Compared with clopidogrel, both prasugrel (HR, 1.26; 95% CI, 1.01-1.56) and ticagrelor (HR, 1.27; 95% CI, 1.04-1.55) were associated with significantly more major bleeding events. Analyses focused on TIMI criteria, including five trials, showed a significant bleeding increase with prasugrel as compared with clopidogrel, but not with ticagrelor as compared with clopidogrel.
Ticagrelor was ranked as the most effective strategy for prevention of CV mortality (p-score 0.94) and all-cause mortality (p-score 0.97). Prasugrel was ranked as the most effective intervention for definite or probable stent thrombosis (p-score 0.99). Regarding major bleeding, clopidogrel was ranked safest (p-score 0.98).
Among the oral P2Y12 inhibitors, ticagrelor and prasugrel provide the greatest reductions in risk of recurrent MI and stent thrombosis, while clopidogrel confers the lowest bleeding risk. The greater reduction in CV and all-cause mortality seen with ticagrelor as compared with prasugrel may relate to lower bleeding risk with ticagrelor.
Multiple randomized trials have compared each of the potent oral P2Y12 inhibitors to clopidogrel, but only two (both included in this meta-analysis) have compared prasugrel and ticagrelor directly: PRAGUE-18 (Motovska Z, et al., J Am Coll Cardiol 2018;71:371-81) and ISAR-REACT 5 (Schüpke S, et al., N Engl J Med 2019;381:1524-34). In PRAGUE-18, patients were responsible for medication costs following hospital discharge, so over one third of patients switched to clopidogrel; this may have contributed to the lack of differences in outcomes between groups. In ISAR-REACT 5, an open-label trial, the ticagrelor group had a significantly higher risk of the primary composite endpoint of death, MI, and stroke at 1 year (HR, 1.36), driven largely by nonfatal MI (particularly periprocedural MI) and non-CV death. No significant difference in bleeding risk was observed. The findings of the current meta-analysis contrast with those of ISAR-REACT 5, suggesting that further study is needed.
A potential explanation for lower bleeding risk with ticagrelor than with prasugrel is that ticagrelor is a reversible P2Y12 inhibitor, so recovery of platelet function may occur more rapidly after this drug is stopped. However, an important practical consideration in choosing a P2Y12 inhibitor is that twice-daily dosing of ticagrelor may be difficult for patients who struggle with medication adherence.
Clinical Topics: Acute Coronary Syndromes, Invasive Cardiovascular Angiography and Intervention, Prevention, Stable Ischemic Heart Disease, Vascular Medicine, Interventions and ACS, Interventions and Vascular Medicine, Chronic Angina
Keywords: Acute Coronary Syndrome, Hemorrhage, Myocardial Infarction, Percutaneous Coronary Intervention, Platelet Aggregation Inhibitors, Primary Prevention, ST Elevation Myocardial Infarction, Stents, Stroke, Thrombosis
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