POPular Genetics Trial Validates CYP2C19-Guided Antiplatelet Selection After Primary PCI
This landmark NEJM trial randomised nearly 2,500 patients undergoing primary PCI to genotype-guided P2Y12 inhibitor selection versus standard ticagrelor or prasugrel. The genotype-guided strategy was noninferior for thrombotic events and reduced major or minor bleeding by 22%. The findings establish CYP2C19 testing as a clinically validated tool for personalising antiplatelet therapy and represent one of the strongest RCT-level demonstrations of pharmacogenomic utility in cardiology.
The original study
A Genotype-Guided Strategy for Oral P2Y
- Authors
- Claassens DMF, Vos GJA, Bergmeijer TO, Hermanides RS, van 't Hof AWJ, van der Harst P, et al.
- Journal
- The New England journal of medicine
- Type
- Equivalence Trial, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't
- PMID
- 31479209
Original abstract
BACKGROUND: It is unknown whether patients undergoing primary percutaneous coronary intervention (PCI) benefit from genotype-guided selection of oral P2Y12 inhibitors. METHODS: We conducted a randomized, open-label, assessor-blinded trial in which patients undergoing primary PCI with stent implantation were assigned in a 1:1 ratio to receive either a P2Y12 inhibitor on the basis of early CYP2C19 genetic testing (genotype-guided group) or standard treatment with either ticagrelor or prasugrel (standard-treatment group) for 12 months. In the genotype-guided group, carriers of CYP2C19*2 or CYP2C19*3 loss-of-function alleles received ticagrelor or prasugrel, and noncarriers received clopidogrel. The two primary outcomes were net adverse clinical events - defined as death from any cause, myocardial infarction, definite stent thrombosis, stroke, or major bleeding defined according to Platelet Inhibition and Patient Outcomes (PLATO) criteria - at 12 months (primary combined outcome; tested for noninferiority, with a noninferiority margin of 2 percentage points for the absolute difference) and PLATO major or minor bleeding at 12 months (primary bleeding outcome). RESULTS: For the primary analysis, 2488 patients were included: 1242 in the genotype-guided group and 1246 in the standard-treatment group. The primary combined outcome occurred in 63 patients (5.1%) in the genotype-guided group and in 73 patients (5.9%) in the standard-treatment group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.0 to 0.7; P<0.001 for noninferiority). The primary bleeding outcome occurred in 122 patients (9.8%) in the genotype-guided group and in 156 patients (12.5%) in the standard-treatment group (hazard ratio, 0.78; 95% CI, 0.61 to 0.98; P = 0.04). CONCLUSIONS: In patients undergoing primary PCI, a CYP2C19 genotype-guided strategy for selection of oral P2Y12 inhibitor therapy was noninferior to standard treatment with ticagrelor or prasugrel at 12 months with respect to thrombotic events and resulted in a lower incidence of bleeding. (Funded by the Netherlands Organization for Health Research and Development; POPular Genetics ClinicalTrials.gov number, NCT01761786; Netherlands Trial Register number, NL2872.).