Clopidogrel Versus Ticagrelor or Prasugrel After Primary Percutaneous Coronary Intervention According to CYP2C19 Genotype

Abstract

Background: Guidelines favor ticagrelor or prasugrel over clopidogrel in patients with myocardial infarction. However, the POPular Genetics trial (Patient Outcome After Primary Percutaneous Coronary Intervention [PCI]) showed that in patients with primary PCI, a CYP2C19 genotype–guided strategy was associated with a lower bleeding risk without increasing thrombotic risk, compared with routine ticagrelor/prasugrel treatment. Nevertheless, optimal P2Y 12 inhibitor treatment in specific CYP2C19 genetic subgroups is still a subject of debate. Methods: A prespecified subanalysis of the POPular Genetics trial was performed, using patients in whom CYP2C19 *2, *3, and *17 genotypes was determined. Two different analyses were planned. The first assessed the effect of the CYP2C19 *17 allele in clopidogrel-treated patients. The second compared the effect of clopidogrel in noncarriers of a loss-of-function allele with ticagrelor/prasugrel–treated patients, irrespective of CYP2C19 genotype. Main outcomes were a thrombotic outcome (cardiovascular death, myocardial infarction, stent thrombosis, and stroke) and a bleeding outcome (PLATO [Platelet Inhibition and Patient Outcomes] major and minor bleeding) after 12 months. Results: A total of 2429 patients were used for analyses. In the first analysis, the CYP2C19 *17 polymorphism was not found to have a significant influence on thrombotic (adjusted hazard ratio, 0.95 [95% CI, 0.45–2.02]) or bleeding outcomes (adjusted hazard ratio, 0.74 [95% CI, 0.48–1.18]). In the second analysis, clopidogrel was associated with a lower number of bleeding events compared with ticagrelor/prasugrel (9.9% versus 11.7%, adjusted hazard ratio, 0.74 [95% CI, 0.56–0.96]), without a significant increase in thrombotic events (3.4% versus 2.5%, adjusted hazard ratio, 1.14 [95% CI, 0.68–1.90]). Conclusions: In patients with primary PCI not carrying a CYP2C19 loss-of-function allele, the use of clopidogrel compared with ticagrelor or prasugrel was associated with lower bleeding rates, without an increase in thrombotic events. No effect on clinical outcomes was found for the CYP2C19 *17 polymorphism. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01761786. URL: https://www.trialregister.nl/ ; Unique identifier: NL2872.

Clopidogrel versus Ticagrelor in CYP2C19 Loss-of-Function Allele Noncarriers: A Real-World Study in China

“…The subanalysis of POPular Genetics showed that treatment with clopidogrel led to a lower number of bleeding events compared with ticagrelor (adjusted HR, 0.74; 95% CI, 0.56-0.96). 11 However, a meta-analysis involving 18,808 patients from randomized clinical trials and observational studies 28 showed that ticagrelor and prasugrel did not increase bleeding risk compared with clopidogrel, both in CYP2C19 LOF carriers (relative risk, 0.97; 95% CI, 0.68-1.40) and noncarriers (relative risk, 0.99; 95% CI, 0.86-1.13). Our study confirmed that the two P2Y12 inhibitors were safe with low bleeding risks.…”

“…However, the prevalence of other LOF alleles is very low, and the CYP2C19 *17 allele also has a low mutation rate in Chinese people (∼0.8% 32 ). Moreover, the recently published subanalysis of POPular Genetics 11 demonstrated that CYP2C19 *1/*1 carriers and CYP2C19 *17 carriers had comparable thrombotic and bleeding risks when treated with clopidogrel. Third, the rate of clinical events was low overall, which may have limited the statistical power and affected the precision of estimates.…”

Clinical Outcomes After Percutaneous Coronary Intervention Over Time on the Basis of CYP2C19 Polymorphisms

“…In addition, our study did not independently analyze carriers of the gain-of-function CYP2C19 allele (*17), mainly because the data on this allele are still controversial. 27,41 In accordance with other follow-up studies, the use of death from any cause instead of cardiovascular mortality may affect the interpretation of the results. However, full information on the cause of death is rarely acquired; thus, cardiovascular mortality could not be reported in this study.…”

Safety and Efficacy of Selective, Clopidogrel-Based Strategies in Acute Coronary Syndrome: A Study-Level Meta-analysis

“…POPULAR GENETICS included patients with STEMI only (16). As per protocol, from POPULAR GENETICS, we considered patients without CYP2C19*2/*3 Loss of Function allele on clopidogrel vs those on conventional treatment with ticagrelor/prasugrel irrespective of CYP2C19 genotype (36).…”