Genotype-Guided Antiplatelet Therapy After PCI
What are the feasibility and sustainability outcomes and clinical impact of using CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention (PCI) in real-world clinical practice?
Adult patients treated at the University of North Carolina Cardiac Catheterization Laboratory with coronary stent and dual antiplatelet therapy (DAPT) were risk-stratified via a clinical algorithm for genotype-guided selection of antiplatelet therapy after PCI in high-risk patients. The CYP2C19 genotype test was subsequently ordered at the discretion of the interventional cardiologist with results available within 1 day after PCI in 75%; alternative therapy was recommended for intermediate and poor metabolizers, but treatment decision was made by the prescriber. Data were retrospectively analyzed in this single-center observational study.
Study Population. Study population included 1,193 adult patients >18 years treated with coronary stent and DAPT from July 2012 through June 2014. Mean patient age was 63 + 12 years with 67.6% male and 20.7% African-American. Of these, 53.8% presented with acute coronary syndromes (ACS), 26.0% were on chronic P2Y12 inhibitor therapy on admission, and 40.1% had bleeding risk factor(s).
Genotype Testing. Genotype testing was performed in 72.8% of patients: 66.6% genotyped during index admission and 6.2% genotyped during prior admission; 30.2% were intermediate (27.5%) or poor (2.8%) metabolizers. Significant predictors of CYP2C19 genotype testing during index admission included ACS, left anterior descending stent, or left main coronary stent. Chronic P2Y12 therapy on admission was negatively associated with genotype testing.
P2Y12 Inhibitor Therapy Selection
- In the entire study population, clopidogrel was ordered in 69.4%, prasugrel was ordered in 30.6%, and ticagrelor was ordered in 3.3%.
- In intermediate and poor metabolizers combined, 28.3% were treated with clopidogrel, 59.9% with prasugrel, and 11.8% with ticagrelor.
- Prasugrel or ticagrelor was used in 83.3% of poor metabolizers; 69.5% of intermediate metabolizers; 23.6% of normal, rapid, or ultrarapid metabolizers; and in 11.1% in whom no genotype was available.
Predictors of P2Y12 Inhibitor Therapy Selection
- Intermediate or poor metabolizer phenotype was a significant independent predictor of prasugrel or ticagrelor therapy or for a change to prasugrel/ticagrelor after index PCI.
- Use of prasugrel or ticagrelor was significantly associated with ACS, left anterior descending stent, or prasugrel/ticagrelor use on admission.
- Clopidogrel selection was significantly associated with chronic clopidogrel use at admission and with higher bleeding risk.
- During follow-up, 11.9% experienced major adverse cardiac and cerebrovascular events (MACCE) and 3.8% experienced significant bleeding event.
- Intermediate and poor metabolizers treated with clopidogrel demonstrated a significantly higher risk of MACCE (26.5%; adjusted hazard ratio 4.65; p < 0.001) than did intermediate and poor metabolizers treated with prasugrel or ticagrelor.
- The highest risk of MACCE (45.2%; adjusted hazard ratio 10.0; p < 0.001) occurred in intermediate and poor metabolizers with ACS who were treated with clopidogrel.
- The risk of significant bleed was not associated with phenotype or antiplatelet therapy.
Sustainability. Four six-month time periods were evaluated. In the first 6 months, 88% were genotyped; this dropped to 61-65% during the next 12 months and increased to 78% during the final period. Treatment with prasugrel or ticagrelor in intermediate or poor metabolizers was initially 83%, was sustained at 78.2% the second 6 months, dropped to 53.8% the third 6 months, and increased to 68.1% the final 6 months.
A strategy of CYP2C19 genotype-guided antiplatelet therapy is both feasible and sustainable in a real-world setting, although consistency may be a challenge. The very high risk of MACCE in intermediate and poor metabolizers treated with clopidogrel provides evidence that use of genotype-guided DAPT may improve clinical outcomes.
The 2011 American College of Cardiology Foundation/American Heart Association/Society for Cardiovascular Angiography and Interventions Guideline for Percutaneous Coronary Intervention cites Class IIB recommendations for genetic testing in high-risk patients post-PCI and use of alternative P2Y12 inhibitor in those whose genotype suggests poor response to clopidogrel. Additional studies published in the Journal of the American College of Cardiology in 2018 have demonstrated 1) increased risk of major adverse cardiovascular events in intermediate and poor metabolizers treated with clopidogrel after PCI, especially those with ACS, and 2) point-of-care genotype testing in patients with ACS influenced providers’ choice of antiplatelet therapy and resulted in fewer ischemic and bleeding events. This study shows the feasibility and sustainability of genotype-guided antiplatelet therapy after PCI in a single academic medical center and demonstrates further evidence that use of genotype-guided antiplatelet therapy post-PCI may improve clinical outcomes.
Keywords: Genotype, Genetic Testing, Phenotype, Percutaneous Coronary Intervention, Angiography, Cardiac Catheterization, Stents, Adenosine, Ticlopidine, Purinergic P2Y Receptor Antagonists, Hemorrhage, Acute Coronary Syndrome, Risk Factors
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