Clopidogrel Versus Prasugrel Versus Ticagrelor in Patients with Acute Coronary Syndrome: New Insights from a Large Registry Compared to Randomized Clinical Trials—A Structured Review

Background: Due to inconsistent evidence regarding oral P2Y12 inhibitors in patients with ACS, we critically assessed the results of the PL-ACS registry in comparison to the results of randomized clinical trials (RCTs). Methods: Publications describing 8 RCTs including 40,724 patients with ACS met the inclusion criteria and were compared with the PL-ACS registry report including 15933 patients after propensity score matching. Results: The PL-ACS registry findings were directionally consistent with randomized evidence suggesting better ischemic outcomes with prasugrel- or ticagrelor-based DAPT compared with clopidogrel-based DAPT; however, because of the observational design, propensity score matching, regional availability of selected endpoints, and differences in bleeding ascertainment, these findings should be interpreted as complementary rather than confirmatory. On the other hand, the results of the direct comparison of prasugrel and ticagrelor in the PL-ACS registry, while consistent with the results of the meta-analysis, markedly diverge from the results of the ISAR-REACT 5 study with regard to most efficacy and safety endpoints. Conclusions: Randomized evidence and complementary PL-ACS registry data support better ischemic outcomes with prasugrel- or ticagrelor-based DAPT compared with clopidogrel-based DAPT in ACS, although differences in bleeding risk and the observational nature of registry data require cautious interpretation. Current evidence does not establish definitive superiority of either prasugrel or ticagrelor, as direct randomized evidence remains limited and not fully concordant with registry findings.