Genotype-guided antiplatelet therapy cuts bleeding episodes in STEMI patients

The use of a genotype-guided strategy for selection of oral P2Y₁₂ inhibitor therapy appears to benefit patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI), such that noncarriers of CYP2C19 loss-of-function alleles have favourable bleeding outcomes with clopidogrel vs standard treatment with ticagrelor or prasugrel, according to data from the POPular Genetics* trial.

“In patients with STEMI, the preferred method of reperfusion is primary PCI with stent implantation. In these patients, dual antiplatelet therapy, consisting of aspirin and a P2Y₁₂ inhibitor, is essential to prevent recurrent thrombotic events such as stent thrombosis,” the investigators said.

“Current guidelines favour the more potent platelet inhibitors ticagrelor and prasugrel over clopidogrel because these drugs are more effective for the prevention of thrombotic events. However, this greater efficacy comes with a higher risk of bleeding,” they added. [Eur Heart J 2018;39:119-77; J Am Coll Cardiol 2016;68:1082-115; N Engl J Med 2009;361:1045-57]

Clopidogrel, on the other hand, is a prodrug transformed into its active metabolite. As such, some patients will not be able to metabolize the drug effectively and hence show an inadequate response, the investigators noted.

To determine whether giving the more potent inhibitors to patients whose CYP2C19 genetic profile indicated that they could not convert the prodrug to its active metabolite, the investigators randomly assigned patients undergoing primary PCI with stent implantation to the genotype-guided group given a P2Y₁₂ inhibitor on the basis of early CYP2C19 genetic testing (n=1,242) or the standard treatment group treated with either ticagrelor or prasugrel (n=1,246). In the genotype-guided group, CYP2C19*2 or CYP2C19*3 loss-of-function allele carriers received ticagrelor or prasugrel, while noncarriers received clopidogrel.

At 12 months of treatment, the incidence of the primary composite outcome—death from any cause, myocardial infarction, definite stent thrombosis, stroke, or major bleeding defined according to Platelet Inhibition and Patient Outcomes (PLATO) criteria—did not differ between the genotype-guided and standard-treatment groups (5.1 percent vs 5.9 percent, respectively; p-noninferiority<0.001). [N Engl J Med 2019;381:1621-1631]

Meanwhile, the primary bleeding outcome was significantly more favourable in the genotype-guided group (9.8 percent vs 12.5 percent; hazard ratio, 0.78, 95 percent confidence interval, 0.61–0.98; p=0.04).

The investigators pointed out two key findings from POPular Genetics. “First, the use of a genotype-guided strategy, in which patients without a CYP2C19 loss-of-function allele received clopidogrel, was not associated with a higher risk of combined death from any cause, myocardial infarction, definite stent thrombosis, stroke, or major bleeding 12 months after primary PCI than standard treatment with the more potent P2Y₁₂ inhibitors ticagrelor and prasugrel.

“Second, the use of clopidogrel in the genotype-guided group resulted in a lower risk of (mostly minor) bleeding than standard treatment,” they said.

Data for both the thrombotic and bleeding outcomes from POPular Genetics are in line with the findings from observational studies and smaller trials investigating a genotype-guided strategy. [Am Heart J 2014;168:16.e1-22.e1; Int J Cardiol 2016;225:289-295; Lancet 2012;379:1705-1711; Eur J Clin Pharmacol 2019;75:1201-1210]

In an accompanying editorial, Dr Dan Roden from the Vanderbilt University Medical Center in Nashville, Tennessee, US, wrote: “The POPular Genetics trial provides strong support for a genotype-guided approach to clopidogrel prescribing in patients of European ancestry, in whom the contribution of CYP2C19 variants was first defined.” [N Engl J Med 2019;381:1677-1678]

Roden recognized that the findings may have greater consequences in parts of the world where the said variants are much more common.

“Professional societies, which increasingly view atherosclerosis as a worldwide epidemic, must now rethink their stance with respect to genotyping to improve the effectiveness of clopidogrel therapy,” he added.

*CYP2C19 Genotype-Guided Antiplatelet Therapy in ST-Segment Elevation Myocardial Infarction Patients — Patient Outcome after Primary PCI