P2Y12 Inhibitor Switching in Response to Routine Notification of CYP2C19 Clopidogrel Metabolizer Status Following Acute Coronary Syndromes

Abstract

Importance: Physician behavior in response to knowledge of a patient's CYP2C19 clopidogrel metabolizer status is unknown.

Objective: To investigate the association of mandatory reporting of CYP2C19 pharmacogenomic testing, provided to investigators with no direct recommendations on how to use these results, with changes in P2Y12 inhibitor use, particularly clopidogrel, in the Randomized Trial to Compare the Safety of Rivaroxaban vs Aspirin in Addition to Either Clopidogrel or Ticagrelor in Acute Coronary Syndrome (GEMINI-ACS-1) clinical trial.

Design, setting, and participants: The GEMINI-ACS-1 trial compared rivaroxaban, 2.5 mg twice daily, with aspirin, 100 mg daily, plus open-label clopidogrel or ticagrelor (provided), in patients with recent acute coronary syndromes (ACS). The trial included 371 clinical centers in 21 countries and 3037 patients with ACS. Data were analyzed between May 2017 and February 2019.

Interventions: Investigators were required to prestipulate their planned response to CYP2C19 metabolizer status. In response to a regulatory mandate, results for all patients were reported to investigators approximately 1 week after randomization.

Main outcomes and measures: Reasons for switching P2Y12 inhibitors and occurrence of bleeding and ischemic events were collected.

Results: Of 3037 patients enrolled (mean [SD] age, 62.8 [9.0] years; 2275 men [74.9%], and 2824 white race/ethnicity [93.0%]), investigators initially treated 1704 (56.1%) with ticagrelor and 1333 (43.9%) with clopidogrel. Investigators prestipulated that they would use CYP2C19 metabolizer status to change P2Y12 inhibitor in 48.5% of genotyped clopidogrel-treated patients (n = 642 of 1324) and 5.5% of genotyped ticagrelor-treated patients (n = 93 of 1692). P2Y12 inhibitor switching for any reason occurred in 197 patients and was more common in patients treated with ticagrelor (146 of 1704 [8.6%]) compared with clopidogrel (51 of 1333 [3.8%]). Of patients initially treated with ticagrelor, only 1 (0.1% overall; 0.7% of all who switched) was switched based on CYP2C19 status. Of patients initially treated with clopidogrel, 23 (1.7% overall,;45.1% of all who switched) were switched owing to metabolizer status. Of 48 patients (3.6%) with reduced metabolizer status treated initially with clopidogrel, 15 (31.3%) were switched based on metabolizer status, including 48.1% (13 of 27) in which switching was prestipulated.

Conclusions and relevance: Physicians were evenly split on how to respond to knowledge of CYP2C19 metabolizer status in clopidogrel-treated patients. Mandatory provision of this information rarely prompted P2Y12 inhibitor switching overall, including a minority of patients with reduced metabolizer status. These findings highlight the clinical equipoise among physicians regarding use of this information and the reluctance to use information from routine genotyping in the absence of definitive clinical trial data demonstrating the efficacy of this approach.

Clinical trial registration: ClinicalTrials.gov identifier: NCT02293395.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Roe reports institutional research grants from Janssen Pharmaceuticals, Eli Lilly, Daiichi-Sankyo, Sanofi Aventis, Ferring Pharmaceuticals, Myokardia, AstraZeneca, American College of Cardiology, American Heart Association, and the Familial Hypercholesterolemia Foundation and consulting fees from Eli Lilly, Daiichi-Sankyo, Myokardia, AstraZeneca, PriMed, Boehringer Ingelheim, Merck, Actelion, Amgen, Novartis, Quest Diagnostics, and Elsevier Publishers. Dr Ohman reports institutional research grants from Janssen Pharmaceuticals, Daiichi-Sankyo, and Gilead Sciences and consulting fees from Abbott Vascular, Abiomed, AstraZeneca, Bayer, Biotie, Boehringer Ingelheim, Daiichi-Sankyo, Medscape, Merck, St. Jude Medical, Stealth Peptides, and The Medicines Company. Dr Povsic reports an institutional research grant from Janssen Pharmaceuticals. Dr Rockhold reports research funding from the National Institutes of Health, Patient-Centered Outcomes Research Institute, Duke Clinical Research Institute, Alzheimers Drug Discovery Foundation, AstraZeneca, ReNeuron, American Regent, BMS, Janssen Pharmaceuticals; consulting fees/data monitoring honoraria from the California Institute for Regenerative Medicine, Patient-Centered Outcomes Research Institute, BARDA, Merck Healthcare KGaA, Janssen Pharmaceuticals, resTORbio, Eidos Therapeutics, FuturaMedical, Amgen, Complexa, Adverum Biotechnologies, Amgen, AstraZeneca, Aldeyra, KLSMC, Merck Research Laboratories, Novo Nordisk, and Chimerix; and equity interest from GlaxoSmithKline, DataVant, and Athira. Dr Cornel reports a research grant, consulting fees and nonfinancial support (member of GEMINI steering committee) from Janssen Pharmaceuticals; a research grant from ZonMW; and consulting fees from Bayer, Amgen, and AstraZeneca. Dr Nicolau reports institutional research grants from Janssen Pharmaceuticals, AstraZeneca, Sanofi, Boehringer Ingelheim, and Bristol-Myers Squibb; consulting fees from Janssen Pharmaceuticals, AstraZeneca, Sanofi, and Boehringer Ingelheim; and an educational grant from Bayer. Dr Steg reports consulting fees and nonfinancial support (member of GEMINI steering committee) from Janssen Pharmaceuticals; a research grant from Sanofi; and consulting fees from Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck-Sharpe-Dohme, Novartis, Pfizer, Roche, Medtronic, Sanofi, Servier, The Medicines Company, CSL Behring, Regeneron, and Bristol-Myers Squibb. Dr Welsh reports research grants from Astra Zeneca, Bayer, Boehringer Ingelheim, and Edwards and consulting fees and honoraria from Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, and Pfizer/BMS. Dr Gibson reports research grants from Janssen Pharmaceuticals, Angel Medical Corporation, Bayer, CSL Behring, Johnson & Johnson Pharmaceuticals and consulting fees from Bayer, The Medicines Company, Boston Clinical Research Institute, Cardiovascular Research Foundation, Eli Lilly, Gilead Sciences, Novo Nordisk, Pfizer, WebMD, and UpToDate in Cardiovascular Medicine. No other disclosures were reported.

Figures

Figure.. Flowchart Depicting Switching by Metabolizer Status and Prestipulated Intent in Patients Initially Treated With Clopidogrel

EM indicates extensive metabolizers; IM, intermediate metabolizers; RM, reduced metabolizers; UM, ultrarapid metabolizers.