Comparison of P2Y12 inhibitors after PCI in patients without CYP2C19 LoF allele
Clopidogrel Versus Ticagrelor or Prasugrel After Primary Percutaneous Coronary Intervention According to CYP2C19 Genotype: A POPular Genetics Subanalysis.
Introduction and methods
There is a large variability in anti-platelet effects in clopidogrel-treated patients after PCI, in part due to genetic variations in the CYP2C19 gene . Carriers of a CYP2C19*2 or *3 loss-of-function (LoF) allele are at higher risk for high platelet reactivity when treated with clopidogrel. This reactivity is consequently associated with an increased risk of stent thrombosis and recurrent atherothrombotic events [2,3]. Patients who carry a CYP2C19*17 gain-of-function (GoF) allele might have better efficacy of clopidogrel and a possibly higher risk for bleeding with clopidogrel compared to non-carriers of the variant . However, clinical outcome data in patients with CYP2C19*17 are conflicting and mostly derived from observational studies .
The Popular Genetics trial has previously shown that a CYP2C19 genotype-guided antiplatelet strategy was associated with a lower bleeding risk without increased thrombotic risk compared to recommended ticagrelor or prasugrel treatment . Moreover, a subanalysis of the PLATO trial demonstrated that ticagrelor was not superior to clopidogrel in regard to the thrombotic outcome . So, which antiplatelet therapy is optimal in specific noncarrier CYP2C19 LoF subgroups in patients with STEMI after PCI is still under debate.
This prespecified subanalysis of the POPular Genetics trial assessed the effect of the CYP2C19*17 GoF allele in clopidogrel-treated patients and safety and efficacy of clopidogrel in patients without a CYP2C19*2 or *3 LoF allele compared to patients who received treatment of ticagrelor or prasugrel irrespective of their genotype.
The POPular Genetics trials was an open-label, randomized, multicenter trial that included patients (n=2488) with ST-segment-elevation MI who underwent primary PCI. The primary thrombotic outcome was a composite of CV death, MI, stent thrombosis, and stroke, and the primary bleeding outcome consisted of PLATO major and minor bleeding. CYP2C19*17 homozygotes and heterozygotes (*1/*17 and *17/*17, n=312) were grouped due to a low number of homozygous CYP2C19*17/*17 patients and compared to patients with CYP2C19*1/*1 wild-type alleles (n=420). The second subanalysis was a comparison between clopidogrel-treated patients without a CYP2C19*2 or *3 LoF allele (n=821) and patients receiving ticagrelor or prasugrel (n=1608). Treatment and follow-up was 12 months.
- There were no differences for the combined thrombotic outcome between patients carrying a CYP2C19*17 allele vs. patients with a CYP2C19*1/*1 genotype (3.8% vs. 3.8%, respectively; aHR 0.95, 95% CI: 0.45-2.02). Also, no differences were observed for the combined bleeding outcome in these patients (9.3% vs. 11.2%, respectively; aHR 0.74, 95% CI: 0.48-1.18).
- The rate of the combined thrombotic outcome was similar between clopidogrel-treated patients without a CYP2C19*2 or *3 LoF allele and ticagrelor- or prasugrel-treated patients (3.4% vs. 2.5%, respectively; aHR 1.14, 95% CI: 0.68-1.90).
- The combined bleeding outcome occurred significantly less in clopidogrel-treated patients without a LoF allele compared to patients receiving ticagrelor or prasugrel (9.9% vs. 11.7%, respectively; aHR 0.74, 95% CI: 0.56-0.96, P=0.03). This was mainly driven by a decrease in PLATO minor bleeding outcomes (7.7% vs. 9.9%, respectively; aHR 0.69, 95% CI: 0.51-0.93, P=0.02).
Treatment with clopidogrel was associated with less bleeding without an increase in thrombotic outcomes after PCI in STEMI patients without a CYP2C19*2 or *3 LoF allele, compared to patients with standard ticagrelor or prasugrel treatment. No significant differences in thrombotic or bleeding outcomes were found with use of clopidogrel in carriers of a CYP2C19*17 allele compared to patients with wild-type alleles.