Genotyping to Guide Clopidogrel Treatment: An In-Depth Analysis of the TAILOR-PCI Trial
Clopidogrel is the most widely prescribed P2Y12 inhibitor.1,2 It is a prodrug that requires CYP2C19, a cytochrome P450 enzyme, for transformation to its active thiol metabolite. Only this active metabolite targets the P2Y12 receptor on platelets, resulting in inhibition of platelet aggregation. Patients with CYP2C19 loss-of-function genetic variation (CYP2C19*2 and CYP2C19*3) have low active metabolite levels, less on-treatment platelet inhibition, and are at increased risk for ischemic events.3 In 2010, the US Food and Drug Administration (FDA) issued a black box warning against the use of clopidogrel in patients who are poor metabolizers, noted the availability of CYP2C19 genetic testing to identify such patients, and suggested treatment with alternative P2Y12 inhibitors. Among patients with coronary artery disease (CAD) who are treated with clopidogrel, studies demonstrate increased ischemic events in patients who specifically undergo percutaneous coronary interventions (PCI).3-7 However, the use of clopidogrel in this setting without CYP2C19 genetic testing remains ubiquitous in clinical practice. Current clinical guidelines also do not recommend the routine use of CYP2C19 genetic testing in patients who need P2Y12 inhibitors after PCI owing to the lack of randomized data demonstrating benefit from prospective testing.1,8 The TAILOR-PCI (Tailored Antiplatelet Initiation to Lessen Outcomes due to Decreased Clopidogrel Response after Percutaneous Coronary Intervention) trial was designed specifically to address this evidence gap.
The TAILOR-PCI trial was a prospective, open-label, multi-center, randomized clinical trial with the goal to assess the efficacy of genotype-guided P2Y12 inhibitor strategy versus conventional therapy. The investigators hypothesized that CYP2C19 genotype-guided use of oral P2Y12 inhibitors compared with non-genotype-guided conventional clopidogrel therapy would significantly reduce ischemic events in CYP2C19 loss-of-function carriers after PCI.9 Using a precision medicine and individualized approach to identify the most vulnerable patient (clopidogrel non-responder due to CYP2C19 loss-of-function alleles), it was hypothesized that within the randomized groups it would be the CYP2C19 loss-of-function carriers who would most benefit when treated with ticagrelor compared to clopidogrel. For sample size calculations in this study, a lower hazard ratio (HR) of 0.5 was selected that was over and above what is used with ticagrelor for all patients irrespective of genotype status, such as that observed in the PLATO (Platelet Inhibition and Patient Outcomes) trial (HR 0.84) and based on the large effect size of the CYP2C19 genotype. If a difference in ischemic events was observed in this subgroup of patients identified by CYP2C19 genotype, it would be important for the medical practitioner to consider genetic testing prior to prescribing clopidogrel. This innovative study is a novel example of using precision medicine to demonstrate a difference in outcomes with individualized therapy. The trial was not powered to discern a difference in events in the overall randomized point of care genetic testing versus conventional arms.
Patients over the age of 18 years with acute coronary syndromes (ACS) or stable CAD who underwent PCI with planned 12 months of dual antiplatelet therapy (DAPT) were eligible. Patients were enrolled at 40 centers in the United States, Canada, South Korea, and Mexico from 2013 to 2018 with follow-up completed in October 2019. Patients were randomized in a 1:1 ratio and stratified by age, sex, enrolling site, and CAD presentation. FDA-approved point-of-care genotyping was used to test patients in the genotype-guided arm. In the genotype-guided group, patients with CYP2C19*2 or CYP2C19*3 loss-of-function alleles were prescribed ticagrelor; noncarriers or those with inconclusive results were prescribed clopidogrel. Patients randomized to the conventional arm were prescribed clopidogrel without prospective genotyping. All subjects had blood samples drawn for laboratory-based genotyping using the ABI TaqMan assay after completion of DAPT (12 months post PCI). The primary outcome was a composite of cardiovascular death, myocardial infarction, stroke, definite or probable stent thrombosis, and severe recurrent ischemia at 12 months after PCI. Secondary endpoints included major or minor bleeding as defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria.
A total of 5,302 patients was randomized. The mean age was 62 years, and 25% of the patients were women. There were 82% of patients who presented with ACS and the rest with stable CAD. Of the 1,849 CYP2C19 loss-of-function patients, 903 were in the genotype-guided arm and 946 in the conventional arm. Among patients assigned to genotype-guided therapy 85% (764) received ticagrelor and 15% received clopidogrel. Among patients in the conventional group, 99% (932) received clopidogrel. Baseline demographics and procedural characteristics were similar in the 2 randomized groups. Point-of-care genotyping results were available within 24 hours for 99% of the patients.
The primary endpoint was seen in 35 (4.0%) of the genotype-guided arm CYP2C19 loss-of-function carriers versus 54 (5.9%) of the conventional therapy arm CYP2C19 loss-of-function carriers at 12 months. The absolute difference (1.8%) in ischemic outcomes between these 2 groups (HR 0.66; 95% CI, 0.43-1.02) did not meet the predetermined level of statistical significance for superiority, which was HR of 0.5. TIMI major or minor bleeding was observed in 30 patients in the primary analysis cohort with no significant difference between the genotype-guided therapy group and the conventional group (1.9% vs. 1.6%; HR 1.22; 95% CI, 0.60-2.51). When examined in 2 overall randomized groups of point-of-care genetic testing versus no genetic testing, there was no significant difference in the primary endpoint in the genotype-guided group (4.4%) versus the conventional group (5.3%) (HR 0.84; 95% CI, 0.65-1.07). Moreover, there was no difference in TIMI major or minor bleeding episodes in the overall genotype-guided group (1.4%) versus the conventional group (1.2%) (HR 1.13; 95% CI, 0.70-1.84).
The TAILOR-PCI trial results must be interpreted in the context of the treatment effect and the tightness of the confidence intervals and should not be based on the P value alone. The lack of significance at the p = 0.05 level for the primary analysis should not lead to the conclusion that the null hypothesis of no treatment effect is true. In the case of this trial, if the null hypothesis was true, (i.e., no effect of genotype-guided therapy in loss-of-function patients), then an effect as strong as what was observed in the TAILOR PCI trial (HR ≤ 0.66) would only occur in less than 3% of all such studies.
This potential benefit may be even more pronounced early after PCI; post hoc analysis demonstrated an estimated HR of 0.21 (95% CI, 0.08-0.54; p= 0.001) at 3 months post-PCI when stent thrombosis and plaque rupture, ulceration, or erosion are most likely to occur. Post-PCI trials in which newer generation stents have been used support this observation by demonstrating that 3-month DAPT duration may be adequate in reducing ischemic events and that subsequent events may be related to risk factors other than those primarily related to platelet activity. Another caveat is that the primary endpoint analysis was based on time to first event and does not account for recurrent events accrued over the follow-up period, which is more reflective of overall outcomes. A significant relative risk reduction (HR 0.60; 95% CI, 0.41, 0.89) in reducing multiple ischemic events per patient was observed with genotyping guidance, suggesting that a strategy to identify CYP2C19 loss-of-function patients may be beneficial in terms of morbidity and therefore carries significant implications for clinical practice. The reduction in ischemic events observed in CYP2C19 loss-of-function patients with ticagrelor compared to clopidogrel raises the question of whether the overall benefit observed in the PLATO trial was due to CYP2C19 loss-of-function genotype status.
In comparison to the TAILOR-PCI trial, which was designed to address whether genetic testing should be done prior to prescribing clopidogrel, the POPular Genetics (CYP2C19 Genotype-Guided Antiplatelet Therapy in ST-Segment Elevation Myocardial Infarction Patients Patient Outcome After Primary PCI) trial was designed to address whether genotype-guided P2Y12 inhibitor therapy would be non-inferior to prescribing ticagrelor for all. Patients in the POPular Genetics trial (patients with ST-segment elevation myocardial infarction undergoing PCI) were randomized to genotype-guided (clopidogrel for non-carriers and ticagrelor for loss-of-function patients) or standard treatment with ticagrelor10 and demonstrated non-inferiority between the 2 strategies with 1-year event rates of 4.6% and 4.7%, respectively. The ischemic event rate (4.4%) in the overall genotype-guided randomized group in the TAILOR-PCI trial is also similar to the ticagrelor-for-all group in the POPular Genetics trial, supporting the concept of non-inferiority of this approach.
The TAILOR-PCI trial did have some limitations. It was not designed to answer the question of whether genetic-testing-guided P2Y12 inhibitor therapy is superior to prescribing clopidogrel for all. With the advent of newer-generation drug-eluting stents and improvement in medical therapy, the primary ischemic event rate in this trial was lower than expected, requiring a recalculation of power. The trial also had an open-label design; however, the conventional therapy group patients were blinded to their genotype status, and adjudication of all events was also blinded.
In conclusion, genotype-guided selection of P2Y12 inhibitors compared to conventional clopidogrel therapy shows potential benefit in reducing ischemic events at 1 year in patients with ACS and stable CAD undergoing PCI. The results of the extended follow-up study of the TAILOR PCI trial that has been funded by the National Heart, Lung, and Blood Institute are awaited, and, by accruing more events, the study may have the power in the intention-to-treat analysis to detect a statistically significant difference between the two arms. A pharmaco-economic analysis of a genotype-guided P2Y12 strategy versus conventional therapy will also be completed to inform clinical decision-making when adopting a precision medicine approach.
- Pereira NL, Rihal CS, So DYF, et al. Clopidogrel Pharmacogenetics. Circ Cardiovasc Interv 2019;12:e007811.
- Lewis JP, Shuldiner AR. Clopidogrel pharmacogenetics: Beyond candidate genes and genome-wide association studies. Clin Pharmacol Ther 2017;101:323-5.
- Pereira NL, Geske JB, Mayr M, Shah SH, Rihal CS. Pharmacogenetics of Clopidogrel: An Unresolved Issue. Circ Cardiovasc Genet 2016;9:185-8.
- Cavallari LH, Lee CR, Beitelshees AL, et al. Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention. JACC Cardiovasc Interv 2018;11:181-91.
- Wei YQ, Wang DG, Yang H, Cao H. Cytochrome P450 CYP 2C19*2 Associated with Adverse 1-Year Cardiovascular Events in Patients with Acute Coronary Syndrome. PLoS One 2015;10:e0132561.
- Liu T, Yin T, Li Y, et al. CYP2C19 polymorphisms and coronary heart disease risk factors synergistically impact clopidogrel response variety after percutaneous coronary intervention. Coron Artery Dis 2014;25:412-20.
- Xi Z, Fang F, Wang J, AlHelal J, Zhou Y, Liu W. CYP2C19 genotype and adverse cardiovascular outcomes after stent implantation in clopidogrel-treated Asian populations: A systematic review and meta-analysis. Platelets 2019;30:229-40.
- Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016;68:1082-115.
- 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.
- Claassens DMF, Vos GJA, Bergmeijer TO, et al. A Genotype-Guided Strategy for Oral P2Y 12 Inhibitors in Primary PCI. N Engl J Med 2019;381:1621-31.
Clinical Topics: Acute Coronary Syndromes, Invasive Cardiovascular Angiography and Intervention, Stable Ischemic Heart Disease, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Interventions and ACS, Interventions and Coronary Artery Disease, Interventions and Vascular Medicine, Chronic Angina
Keywords: Angina, Stable, ST Elevation Myocardial Infarction, Purinergic P2Y Receptor Antagonists, Platelet Aggregation Inhibitors, Follow-Up Studies, Risk Factors, Drug-Eluting Stents, Confidence Intervals, Intention to Treat Analysis, Platelet Aggregation, Coronary Artery Disease, Acute Coronary Syndrome, Percutaneous Coronary Intervention, Genotype, Prodrugs, Blood Platelets, Alleles, Drug Labeling, Decision Making
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