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Genotype-Guided Oral P2Y12 Inhibitor Therapy
Quick Takes
- Genotype-guided P2Y12 inhibitor selection did not improve clinical outcomes compared to conventional therapy.
- Post hoc analysis showed a significant reduction in clinical events at 0-3 months with the tailored approach.
Study Questions:
What is the effect of a genotype-guided oral P2Y12 inhibitor strategy on ischemic outcomes in CYP2C19 loss of function (LOF) carriers after percutaneous coronary intervention (PCI)?
Methods:
This was an open-label randomized clinical trial of 5,302 patients undergoing PCI for acute coronary syndrome (ACS) or stable coronary artery disease (CAD) at 40 international sites from May 2013 through October 2018. Point-of-care genotyping was performed and LOF carriers were prescribed ticagrelor and noncarriers were prescribed clopidogrel. The primary endpoint was a composite of cardiovascular death, myocardial infarction (MI), stroke, stent thrombosis, and severe recurrent ischemia at 12 months. A secondary endpoint was major or minor bleeding at 12 months.
Results:
Among 5,302 patients randomized (median age, 62 years; 25% women), 82% had ACS and 18% had stable CAD; 94% completed the trial. The primary endpoint occurred in 35 of 903 CYP2C19 LOF carriers (4.0%) in the genotype-guided therapy group and 54 of 946 (5.9%) in the conventional therapy group at 12 months (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.43-1.02; p = 0.06). None of the 11 prespecified secondary endpoints showed significant differences, including major or minor bleeding in CYP2C19 LOF carriers in the genotype-guided group (1.9%) versus the conventional therapy group (1.6%) at 12 months (HR, 1.22; 95% CI, 0.60-2.51; p = 0.58). Among all randomized patients, the primary endpoint occurred in 113 of 2,641 (4.4%) in the genotype-guided group and 135 of 2,635 (5.3%) in the conventional group (HR, 0.84; 95% CI, 0.65-1.07; p = 0.16).
Conclusions:
Among CYP2C19 LOF carriers with ACS and stable CAD undergoing PCI, genotype-guided selection of an oral P2Y12 inhibitor, compared with conventional clopidogrel therapy without point-of-care genotyping, resulted in no statistically significant difference in a composite endpoint of cardiovascular death, MI, stroke, stent thrombosis, and severe recurrent ischemia based on the prespecified analysis plan and the treatment effect that the study was powered to detect at 12 months.
Perspective:
The utility of genotype-tailored P2Y12 inhibitor therapy has been suggested as a way to reduce ischemic events among carriers of CYP2C19 LOF allele. This study is the only randomized controlled trial assessing clinical outcomes using point-of-care genotyping among patients undergoing PCI. After 12 months of follow-up, there was no difference in cardiovascular death, MI, stroke, or stent thrombosis among patients who received genotype-guided therapy (ticagrelor) versus those who were on conventional therapy (clopidogrel). Although overall trial results are negative, the authors’ prespecified plan reached for a 50% event reduction rate between the two groups and post hoc analysis showed significant reduction in the primary endpoint at 0-3 months. The latter finding (though not prespecified) suggests that the benefit of a tailored approach may be in the early phase when risk of stent thrombosis due to inadequate platelet suppression is the highest.
Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Cardiovascular Care Team, Invasive Cardiovascular Angiography and Intervention, Atherosclerotic Disease (CAD/PAD), Anticoagulation Management and ACS, Interventions and ACS, Interventions and Coronary Artery Disease
Keywords: Acute Coronary Syndrome, Anticoagulants, Blood Platelets, Coronary Artery Disease, Genotype, Hemorrhage, Myocardial Infarction, Myocardial Ischemia, Percutaneous Coronary Intervention, Stents, Stroke, Thrombosis, Vascular Diseases
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