Genotype-guided selection of oral P2Y12 inhibitor therapy can reduce the incidence of bleeding in patients undergoing primary percutaneous coronary intervention (PCI). This finding from the randomized, open-label POPular Genetics trial was presented at the ESC Congress 2019.
Dual antiplatelet therapy with aspirin and a P2Y12 inhibitor is recommended after PCI with stent implantation to prevent recurrent thrombotic events. The P2Y12 inhibitors prasugrel and ticagrelor are more potent than clopidogrel and are, therefore, preferred because of their greater efficacy; however, prasugrel and ticagrelor also increase the risk of bleeding.
Some patients have an inadequate response to clopidogrel therapy because of loss-of-function variation in CYP2C19, such as the CYP2C19*2 or CYP2C19*3 alleles, which impairs the conversion of the prodrug to its active metabolite. However, in patients without these loss-of-function alleles, clopidogrel has been shown to be as effective as prasugrel or ticagrelor, with a lower risk of bleeding. “If we treated patients with the more potent inhibitors ticagrelor and prasugrel only if their CYP2C19 genetic profile showed that they would not metabolize clopidogrel effectively, this [approach] would benefit patient outcomes,” hypothesize the POPular Genetics trial investigators.
A total of 2,488 patients undergoing PCI were randomly assigned to genotype-guided therapy or standard therapy (prasugrel or ticagrelor). Approximately two-thirds of the patients in the genotype-guided group received clopidogrel. The primary combined outcome of net adverse clinical events occurred in 5.1% of the genotype-guided group and 5.9% of the standard-therapy group (P < 0.001 for noninferiority). The rate of the primary bleeding outcome was lower with genotype-guided therapy than with standard therapy (9.8% versus 12.5%; HR 0.78, 95% CI 0.61–0.98, P = 0.04).
“The rate of the primary bleeding outcome was lower with genotype-guided therapy”
The investigators highlight the feasibility of the genotype-guided approach in clinical practice. “The mean time to obtaining genetic results after randomization was just 3 h,” says Danny Claassens. “We were therefore able to adjust the [antiplatelet] treatment, if necessary, within 1 day.”
Claassens, D. M. F. et al. A genotype-guided strategy for oral P2Y12 inhibitors in primary PCI. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa1907096 (2019)
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Lim, G.B. Reduced bleeding with genotype-guided antiplatelet therapy. Nat Rev Cardiol 16, 646–647 (2019). https://doi.org/10.1038/s41569-019-0276-0
Frontiers in Genetics (2020)