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

Abstract

Importance: After percutaneous coronary intervention (PCI), patients with CYP2C19*2 or *3 loss-of-function (LOF) variants treated with clopidogrel have increased risk of ischemic events. Whether genotype-guided selection of oral P2Y12 inhibitor therapy improves ischemic outcomes is unknown.

Objective: To determine the effect of a genotype-guided oral P2Y12 inhibitor strategy on ischemic outcomes in CYP2C19 LOF carriers after PCI.

Design, setting, and participants: Open-label randomized clinical trial of 5302 patients undergoing PCI for acute coronary syndromes (ACS) or stable coronary artery disease (CAD). Patients were enrolled at 40 centers in the US, Canada, South Korea, and Mexico from May 2013 through October 2018; final date of follow-up was October 2019.

Interventions: Patients randomized to the genotype-guided group (n = 2652) underwent point-of-care genotyping. CYP2C19 LOF carriers were prescribed ticagrelor and noncarriers clopidogrel. Patients randomized to the conventional group (n = 2650) were prescribed clopidogrel and underwent genotyping after 12 months.

Main outcomes and measures: The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia at 12 months. A secondary end point was major or minor bleeding at 12 months. The primary analysis was in patients with CYP2C19 LOF variants, and secondary analysis included all randomized patients. The trial had 85% power to detect a minimum hazard ratio of 0.50.

Results: Among 5302 patients randomized (median age, 62 years; 25% women), 82% had ACS and 18% had stable CAD; 94% completed the trial. Of 1849 with CYP2C19 LOF variants, 764 of 903 (85%) assigned to genotype-guided therapy received ticagrelor, and 932 of 946 (99%) assigned to conventional therapy received clopidogrel. The primary end point 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% CI, 0.43-1.02]; P = .06). None of the 11 prespecified secondary end points showed significant differences, including major or minor bleeding in CYP2C19 LOF carriers in the genotype-guided group (1.9%) vs the conventional therapy group (1.6%) at 12 months (HR, 1.22 [95% CI, 0.60-2.51]; P = .58). Among all randomized patients, the primary end point occurred in 113 of 2641 (4.4%) in the genotype-guided group and 135 of 2635 (5.3%) in the conventional group (HR, 0.84 [95% CI, 0.65-1.07]; P = .16).

Conclusions and relevance: 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 end point of cardiovascular death, myocardial infarction, 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.

Trial registration: ClinicalTrials.gov Identifier: NCT01742117.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Pereira reported receiving grants from the National Heart, Lung, and Blood Institute (NHLBI). Dr Farkouh reported receiving grants from NHLBI, Amgen, Novartis, and Novo Nordisk. Dr So reported receiving grants from Eli Lilly Canada, Spartan Biosciences, Roche Diagnostics, and Aggredyne Inc and receiving personal fees from AstraZeneca Canada, Bayer Canada, and Servier Canada. Dr Lennon reported receiving grants from the National Institutes of Health (NIH)/NHLBI and receiving nonfinancial support from Spartan Biosciences. Dr Abbott reported receiving grants from AstraZeneca, Bristol Myers Squibb, Sino Medical, Biosensors Research USA, Abbott Vascular, and CSL Behring. Dr Goodman reported receiving grants from the Mayo Clinic and NIH; receiving nonfinancial support from Spartan Biosciences; receiving grants and personal fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Eli Lilly Merck, Novartis, Pfizer, and York University Clinical Coordinating Centre; and receiving personal fees from Daiichi-Sankyo/American Regent, Esperion, Ferring Pharmaceuticals, GlaxoSmithKline, HLS Therapeutics, Janssen/Johnson & Johnson, Novo Nordisk A/C, Regeneron, Servier, the Heart and Stroke Foundation of Ontario/University of Toronto (Polo) chair, the Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, Duke Clinical Research Institute, and PERFUSE Research Institute. Dr Lerman reported receiving personal fees from Itamar Medical, Phillips/Volcano, Shahal, and Wei Jian RC Inc. Dr Sidhu reported serving on scientific advisory boards for Sanofi Regeneron and AstraZeneca. Dr Tanguay reported receiving personal fees from Mayo Clinic, AstraZeneca, Bayer, Daiichi-Sankyo, Servier, Novartis, and BMS-Pfizer Alliance. Dr Wang reported receiving grants from NIH and NHLBI. Dr Weinshilboum reported receiving grants from NIH and NHLBI and that he is cofounder of, and stockholder in, OneOme LLC. Dr Welsh reported receiving personal fees from Mayo Clinic; receiving grants from AstraZeneca and Pfizer; and receiving grants and personal fees from Bayer and Boerhinger Ingelheim. Dr Bailey reported receiving grants from NIH. No other disclosures were reported.

Figures

Figure 1.. Study Flow for the TAILOR-PCI Randomized Clinical Trial

Patients randomized in spite of the presence of exclusion criteria were still eligible for analysis. In the 5276 patients eligible for analysis, 5007 (94.9%) either completed follow-up or died during follow-up, including 1760 (95.1%) in the primary analysis cohort. The 269 who withdrew or were lost to follow-up had a mean follow-up time of 3.4 months. Of the 195 with laboratory-based genotyping results not available, the reasons were sample not received at biospecimen processing facility (n = 66), low-quality sample not suitable for analysis (n = 60), no index sample taken (n = 59), withdrew consent for use of DNA (n = 10). LOF indicates loss of function; PCI, percutaneous coronary intervention. aPatients screened for approach but who did not provide consent were not recorded. beTable 2 in the Supplement details the point-of-care genotyping results and the initial antiplatelet therapy according to treatment group and laboratory-based genotyping results.

Figure 2.. Event Rates in the Primary Analysis Cohort

A, Kaplan-Meier estimated event rates in the 2 treatment groups in the primary analysis cohort of CYP2C19 loss-of-function carriers for the primary end point of time to cardiovascular (CV)–related death, myocardial infarction (MI), stroke, stent thrombosis, or severe recurrent ischemia (SRI). B, Kaplan-Meier estimated event rates for the primary adverse event end point of Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding in the primary analysis cohort. The median observation time for the genotype-guided therapy group was 364 days (interquartile range, 360-365) and for the conventional therapy group was 364 days (interquartile range, 353-365). HR indicates hazard ratio.

Figure 3.. Subgroup Analyses of the Primary Outcome

Hazard ratios and 95% CIs for the effect of genotype-guided therapy within CYP2C19 loss-of-function carriers were estimated within clinically relevant prespecified subgroups. The number of events and the sample size of each subgroup as well as the Kaplan-Meier estimated event rates at 12 months are provided according to the 2 treatment groups. P values for tests of interaction have not been adjusted for multiplicity. CAD indicates coronary artery disease; eGFR, estimated glomerular filtration rate; STEMI, ST-segment elevation myocardial infarction. aThe hazard ratio for the Mexico subgroup is not shown, as there were no events in the genotype-guided therapy group and only 1 event in the conventional therapy group. bCalculated as weight in kilograms divided by height in meters squared. ceGFR calculated by Modification of Diet in Renal Disease equation.