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Effect of Genotype-Guided Oral P2Y12 Inhibitor Selection vs Conventional Clopidogrel Therapy on Ischemic Outcomes After Percutaneous Coronary InterventionThe TAILOR-PCI Randomized Clinical Trial

Educational Objective
To understand the role of genotype-guided antiplatelet therapy for patients undergoing percutaneous coronary intervention.
1 Credit CME
Key Points

Question  Does CYP2C19 genotype–guided prescription of oral P2Y12 inhibitor therapy after percutaneous coronary intervention (PCI) improve ischemic outcomes in patients with acute coronary syndromes and stable coronary artery disease?

Findings  In this randomized clinical trial that included 5302 patients undergoing PCI and included 1849 patients with CYP2C19 loss-of-function alleles in the primary analysis, genotype-guided selection of oral P2Y12 inhibitor therapy, compared with conventional therapy using clopidogrel, resulted in no significant difference in a composite end point of cardiovascular death, myocardial infarction, stroke, stent thrombosis, or severe recurrent ischemia at 12 months (4.0% vs 5.9%, respectively; hazard ratio, 0.66).

Meaning  Among patients with CYP2C19 loss-of-function alleles who underwent PCI, genotype-guided selection of an oral P2Y12 inhibitor, compared with conventional clopidogrel therapy, did not significantly reduce ischemic events based on the treatment effect that the study was powered to detect at 12 months.

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

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Corresponding Author: Naveen L. Pereira, MD, Department of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 (pereira.naveen@mayo.edu).

Accepted for Publication: June 25, 2020.

Author Contributions: Drs Pereira and Bailey had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Pereira and Farkouh were coprimary first authors.

Concept and design: Pereira, Farkouh, So, Lennon, Mathew, Jeong, Baudhuin, Fu, Goodman, Hasan, Iturriaga, Lerman, Wang, Weinshilboum, Bailey, Rihal.

Acquisition, analysis, or interpretation of data: Pereira, Farkouh, So, Lennon, Geller, Mathew, Bell, Bae, Chavez, Gordon, Abbott, Cagin, Hasan, Lerman, Sidhu, Tanguay, Weinshilboum, Welsh, Rosenberg, Bailey, Rihal.

Drafting of the manuscript: Pereira, Farkouh, So, Lennon, Bae, Jeong, Fu, Hasan, Weinshilboum, Rihal.

Critical revision of the manuscript for important intellectual content: Pereira, Farkouh, So, Lennon, Geller, Mathew, Bell, Chavez, Gordon, Abbott, Cagin, Baudhuin, Goodman, Hasan, Iturriaga, Lerman, Sidhu, Tanguay, Wang, Weinshilboum, Welsh, Rosenberg, Bailey, Rihal.

Statistical analysis: Lennon, Geller, Hasan, Bailey, Rihal.

Obtained funding: Pereira, Farkouh, Lennon, Goodman, Lerman, Wang, Weinshilboum.

Administrative, technical, or material support: Pereira, Mathew, Bae, Jeong, Gordon, Baudhuin, Fu, Goodman, Iturriaga, Weinshilboum, Welsh, Rosenberg, Bailey, Rihal.

Supervision: Pereira, Farkouh, Lennon, Bae, Chavez, Goodman, Tanguay, Weinshilboum, Rosenberg, Bailey, Rihal.

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.

Funding/Support: Funding for this research was provided by the NIH (grants U01HL128606 and U01HL128626).

Role of the Funder/Sponsor: The NIH established an independent data and safety monitoring board to monitor adverse events but had no role in the design of the study; collection, management, and interpretation of the data; preparation of the manuscript; or decision to submit the manuscript for publication.

Disclaimer: The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the NHLBI, the NIH, or the US Department of Health and Human Services.

Data Sharing Statement: See Supplement 4.

Additional Contributions: We are grateful for the effort and assistance from Daniel Crusan, BS, Monica Olson, MBA, and Julia Byrne, BS, Mayo Clinic; Spartan, Applied Health Research Centre (AHRC), DREAM CIS, Biospecimens Accessioning and Processing (BAP) at Mayo Clinic, and the TAILOR-PCI clinical trial site principal investigators and their study coordinators. The TAILOR-PCI clinical trial site principal investigators include Khaled Abdul-Nour, MD, Henry Ford Health System; Amir Darki, MD, Loyola University Medical Center; Payam Dehghani, MD, Regina General Hospital; Josh Doll, MD, Greenville Health System; Mohammed El-Hajjar, MD, Albany Medical Center; Jorge Escobedo, MD, Mexico-La Raza, Centro Medico; Adam Frank, MD, NCH Healthcare System; Wilson Ginete, MD, and Alok Bachuwar, MD, Essentia Institute of Rural Health; Ronald Goldberg, MD, Sharp Healthcare Center for Research; John Graham, MD, St. Michael’s Hospital; Cameron Guild, MD, and William Campbell, MD, University of Mississippi Medical Center; Sang Wook Kim, MD, Chung-Ang University Hospital; Louie Kostopoulis, MD, Aurora Research Institute; Gary Lane, MD, Mayo Clinic in Florida; Hong-seok Lim, MD, Ajou University Hospital; Andrea MacDougall, MD, Thunder Bay Regional Research Institute; Mina Madan, MD, Sunnybrook Research Institute; Kevin Marzo, MD, Winthrop University Hospital; Tamim Nazif, MD, Columbia University Medical Center; Fearghas O’Cochlain, MD, Mayo Clinic Health System—Eau Claire Hospital Inc; Christopher Overgaard, MD, and Vlad Dzavik, MD, Toronto General Hospital; Ganesh Raveendran, MD, University of Minnesota; Louai Razzouk, MD, NYU Langone Medical Center; Carl Reimers, MD, and Kirk Garratt, MD, The Feinstein Institute for Medical Research-Lenox Hill; Jorge Saucedo, MD, and Justin Levisay, MD, NorthShore University Health System; Jacqueline Saw, MD, Vancouver General Hospital; D.P. Suresh, MD, St. Elizabeth Healthcare; John Sweeney, MD, Mayo Clinic in Arizona; Irving Tiong, MD, Humber River Hospital; Steven Weitz, MD, Cardiology Associates of Schenectady; and Alan Wu, PhD, Zuckerberg San Francisco General Hospital. None of these individuals received any compensation for their role in the study.

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