Study Summary

Many patients have an inadequate response to clopidogrel owing to genetic variations in hepatic cytochrome P450 enzymes. In the POPular Genetics trial, a genotype-guided strategy for selecting the oral P2Y12 inhibitor was compared with standard therapy (ticagrelor or prasugrel) among patients with STEMI undergoing primary PCI. In the genotype-guided group, carriers of CYP2C19*2 or CYP2C19*3 loss-of-function alleles received ticagrelor or prasugrel (n = 1,242) and noncarriers received clopidogrel (n = 1,246). The primary combined outcome (all-cause death, myocardial infarction, stent thrombosis, stroke, or major bleeding) occurred in 5.1% of the genotype-guided group versus 5.9% of the standard of care group (P <0.001 for noninferiority). Major or minor bleeding occurred in 9.8% of the genotype-guided group and in 12.5% of the standard of care group (HR 0.78; P = 0.04) and was mainly driven by minor bleeding.

Commentary

Study Strengths: In previous trials, the definition of net clinical benefit has often included only BARC type 2 bleeding. In this study, major bleeding, which has an effect on morbidity and mortality similar to thrombotic outcomes, was included.

Study Limitations: Although a blinded independent committee adjudicated all outcomes, the trial had an open-label design. The lower than expected incidence of the primary outcome made the prespecified noninferiority margin proportionally wider with respect to the event rate in the control group. There are more polymorphisms of CYP2C19, potentially associated with increased thrombotic or bleeding risk, that were not assessed.

Next Steps/Clinical Perspective: This trial showed how genotype-guided therapy might be used to improve the risk–benefit ratio of antiplatelet therapy. However, the guidelines are unlikely to change until the results of TAILOR-PCI (genotype-guided therapy compared with standard of care > 5,000 patients with ACS or stable CAD) are released.

Trial Reference

+
Claassens  DM, Vos  GJ, Bergmeyer  TO, et al. A Genotype-Guided Strategy for Oral P2Y12 Inhibitors in Primary PCI (POPular Genetics). N. Engl. J. Med. doi: 10.1056/NEJMoa1907096.