Clopidogrel is the most prescribed P2Y12 inhibitor after percutaneous coronary intervention (PCI). It is a prodrug that must be transformed to an active metabolite by CYP2C19 to act appropriately. Approximately one-third of patients are reduced metabolizers with CYP2C19 loss-of-function (LOF) alleles placing them at greater risk for ischemic events post-PCI due to inability to metabolize clopidogrel into the active metabolite.¹ Currently patients are prescribed clopidogrel after PCI without knowledge of CYP2C19 status.

Multiple pharmacokinetic studies have demonstrated that LOF carrier patients have more than 40% reduced active metabolite levels compared to non-carriers. Furthermore, LOF carriers have less inhibition of platelet aggregation when treated with clopidogrel. Those with LOF genotype are at 57% greater risk for ischemic events when treated with clopidogrel compared to non-carriers (predominantly in a post-PCI population).² The Food and Drug Administration added a black box warning ("consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers") to emphasize identification of LOF in those being prescribed clopidogrel. Despite the black box warning, the practice of prescribing without genotype guidance has persisted in the absence of a prospective randomized controlled trial (RCT) demonstrating benefit. The TAILOR PCI trial was designed to address this gap.

TAILOR PCI was a multicenter, international RCT (n=5,302) with the primary endpoint of determining if point-of-care genotype-guided selection of P2Y12 inhibitor would reduce ischemic outcomes by 50% at 12 months in stable coronary artery (16%) disease and acute coronary syndrome (84%) patients undergoing PCI. Among the randomized patients, there was a non-statistically significant 34% reduction in ischemic events in the year following PCI (adjusted hazard ratio [HR] 0.66, P=0.056).³ While the study showed no statistically significant difference in the composite endpoint powered for the study, there are several important findings that provide strong signals for genotype-guided selection. A Bayesian analysis of TAILOR PCI results using non-informative and informative priors demonstrated that the probability of benefit in reducing ischemic events from genotype-guided therapy was 94% (risk ratio [RR] 0.78) and 99% (RR 0.69), respectively.⁴ TAILOR PCI also demonstrated a 40% statistically significant reduction in the total number of ischemic events per patient in those receiving genotype-guided selection (HR 0.60; P=.011). The study demonstrated a 79% reduction (HR 0.21; P=0.001) in adverse events in the first 3 months post-PCI, which is consistent with our knowledge that the effect of antiplatelet therapy is most evident in the first 3 months post-PCI.³

Newer generation P2Y12 inhibitors (ticagrelor and prasugrel) do not require CYP2C19 metabolism to inhibit platelet activity. Simply prescribing these newer agents would seem like the easiest solution, however there are several important considerations. The POPular Genetics study evaluated genotype-guided treatment like TAILOR PCI in which LOF carriers received ticagrelor or prasugrel while non-carriers received clopidogrel. Ticagrelor was prescribed in the standard therapy arm. All patients had ST-elevation myocardial infarctions (STEMI) and underwent PCI. Genetic guidance was non-inferior to standard therapy with ticagrelor for ischemic and bleeding outcomes at 12 months (5.9% for standard therapy vs. 5.1% for genotype-guided; P=< 0.001). There was no significant difference between the two groups when evaluating for ischemic outcomes separately. There was a statistically significant reduction in major or minor bleeding outcomes in the genotype-guided group compared to those receiving ticagrelor in the standard therapy group (9.8% vs. 12.5% at 12 months; P=0.04).⁵

Based on the possibility that TAILOR PCI was not adequately powered to demonstrate superiority, a meta-analysis comprising of seven RCTs including nearly 16,000 patients demonstrated a statistically significant 30% reduction in ischemic events in LOF patients with ticagrelor or prasugrel compared to clopidogrel. There was no difference in outcomes in non-carriers when prescribed ticagrelor or prasugrel as compared to clopidogrel. Therefore, the benefit of ticagrelor or prasugrel compared to clopidogrel in reducing ischemic events is likely due to the presence of CYP2C19 LOF genotype.⁶ A subsequent meta-analysis underscored the key message that a precision medicine approach using genetic and platelet function testing results not only improved ischemic outcomes (major adverse cardiovascular events RR 0.78, P=0.015; statistically significant reductions in cardiovascular death, MI, stent thrombosis, and stroke as well) but also a reduction in minor bleeding events (RR 0.78, P=0.003).⁷

Post-discharge bleeding is a significant cause of morbidity and mortality after PCI and tends to occur within the first 30 days post-PCI.⁸ Prasugrel and ticagrelor can result in an increased risk of bleeding events compared to clopidogrel. Genetic testing can help identify non-carriers (approximately 70% of patients) who can be prescribed clopidogrel and thus reduce bleeding risk without compromising ischemic outcomes. These findings are particularly important in elderly patients who are at a higher bleeding risk and are more likely to receive high-risk PCI (rather than bypass grafting).⁹

The cost of ticagrelor and prasugrel must also be considered. Annual clopidogrel therapy costs approximately $59 while prasugrel and ticagrelor cost considerably more at $117 and $4,865, respectively (based on lowest estimates from GoodRx).¹⁰ Compliance with such expensive medications is likely impacted in a real-world population. A genetic test that could cost <$300 would potentially not be a barrier to pursuing a genotype-guided approach from a cost perspective.

Modern drug-eluting stents have considerably improved with stent thrombosis occurring about 1% in the first year.¹¹ Identifiable targets for risk modification are necessary to further reduce the rate of ischemic complication in high-risk patients. Identifying patients with high platelet reactivity and harnessing the power of precision medicine using genetic testing is a promising strategy to further improve the safety of modern PCI.¹²

There is a clear signal in the current literature that a genotype-guided approach to prescribing antiplatelet therapy is beneficial. The most apparent advantages are a decrease in bleeding events, equivalent ischemic outcomes, improved side effect profile (dyspnea, etc.), and fewer age/body weight/stroke history considerations compared to ticagrelor/prasugrel for all. The studies summarized above demonstrate the important role for genotype-guidance in the modern practice of cardiology.

References

1. Pereira NL, Rihal CS, So DYF, et al. Clopidogrel pharmacogenetics. Circ Cardiovasc Interv 2019;12:e007811.
2. Mega JL, Simon T, Collet JP, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA 2010;304:1821-30.
3. Pereira NL, Farkouh ME, So D, et al. Effect of genotype-guided oral P2Y12 inhibitor selection vs conventional clopidogrel therapy on ischemic outcomes after percutaneous coronary intervention: the TAILOR-PCI randomized clinical trial. JAMA 2020;324:761-71.
4. Parcha V, Heindl BF, Li P, et al. Genotype-guided P2Y12 inhibitor therapy after percutaneous coronary intervention: a bayesian analysis. Circ Genom Precis Med 2021;14:e003353.
5. Claassens DMF, Vos GJA, Bergmeijer TO, et al. A genotype-guided strategy for oral P2Y12 inhibitors in primary PCI. N Engl J Med 2019;381:1621-31.
6. Pereira NL, Rihal C, Lennon R, et al. Effect of CYP2C19 genotype on ischemic outcomes during oral P2Y12 inhibitor therapy: a meta-analysis. JACC Cardiovasc Interv 2021;14:739-50.
7. Galli M, Benenati S, Capodanno D, et al. Guided versus standard antiplatelet therapy in patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis. Lancet 2021;397:1470-83.
8. Valle JA, Shetterly S, Maddox TM, et al. Postdischarge bleeding after percutaneous coronary intervention and subsequent mortality and myocardial infarction: insights from the HMO Research Network-Stent Registry. Circ Cardiovasc Interv 2016;9:10.1161.
9. Fei Y, Lam CK, Cheung BMY. Efficacy and safety of newer P2Y12 inhibitors for acute coronary syndrome: a network meta-analysis. Sci Rep 2020;10:16794.
10. Mobile application software (goodrx.com). 2018. Available at: https://www.goodrx.com. Accessed 01/05/2022.
11. Tada T, Byrne RA, Simunovic I, et al. Risk of stent thrombosis among bare-metal stents, first-generation drug-eluting stents, and second-generation drug-eluting stents: results from a registry of 18,334 patients. JACC Cardiovasc Interv 2013;6:1267-74.
12. Angiolillo DJ, Capodanno D, Danchin N, et al. Derivation, validation, and prognostic utility of a prediction rule for nonresponse to clopidogrel: the ABCD-GENE Score. JACC Cardiovasc Interv 2020;13:606-17.

Clinical Topics: Acute Coronary Syndromes, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Stable Ischemic Heart Disease, Vascular Medicine, Interventions and ACS, Interventions and Vascular Medicine, Chronic Angina

Keywords: Prasugrel Hydrochloride, Ticagrelor, Clopidogrel, Platelet Aggregation Inhibitors, Cytochrome P-450 CYP2C19, Bayes Theorem, Drug-Eluting Stents, Prodrugs, ST Elevation Myocardial Infarction, Percutaneous Coronary Intervention, Acute Coronary Syndrome, Prospective Studies, Alleles, Precision Medicine, Aftercare, Coronary Vessels, Drug Labeling, Patient Discharge, Platelet Aggregation, Point-of-Care Systems, United States Food and Drug Administration, Genotype, Genetic Testing, Body Weight, Thrombosis, Morbidity, Dyspnea, Stroke

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