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


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.





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Thomas Joseph Povsic

Adjunct Professor of Medicine

Erik Magnus Ohman

Professor of Medicine

Dr. Ohman, Professor of Medicine, received medical degrees from the Royal College of Surgeons in Ireland and the National University of Ireland (1984, Fellowship 1984-1987), and completed his training in cardiology at Duke University (1987-1991), where he has remained on faculty. In 2001, he became Chief of Cardiology at the University of North Carolina at Chapel Hill, where he founded the UNC Heart Center and became its first director. In 2005 he returned to Duke to pursue his interest in advanced coronary disease as the Director of the Program for Advanced Coronary Disease. Since that time, he has been appointed to Associate Director of the Duke Heart Center, the Kent and Siri Rawson Director for the Program for Advanced Coronary Disease, and most recently, Vice-Chair of Development and Innovation in the Department of Medicine.

Dr. Ohman’s clinical and research interests include interventional cardiology and high-risk supported PCI, and treatment of patients with advanced/complex coronary disease. He has researched how to improve patient care through the use of guidelines-based therapies and adherence, and examining global cardiovascular risk and health. He has been a participant on numerous guidelines writing committees, served on the ACC/AHA oversight committee for guidelines development, and has served on the steering committees for trials on ST-elevation myocardial infarction and non-ST-elevation ACS. He is a consultant to the National Institutes of Health, and a consultant for the FDA Advisory Panel for Cardiovascular Devices. 

Dr. Ohman has published over 600 peer-reviewed papers and three books in cardiovascular medicine. He holds three U.S. patents in reperfusion therapy. He is an associate editor for the American Heart Journal and serves on the editorial boards of the Journal of the American College of Cardiology and the American Journal of Cardiology.  He is a Fellow of the Royal College of Physicians in Ireland, the Royal Society of Medicine (U.K.), the European Society of Cardiology, the Society of Cardiac Angiography and Interventions, and the American College of Cardiology. 


Matthew Todd Roe

Adjunct Professor in the Department of Medicine

My clinical activities focus upon general, preventive, and acute care cardiology.  I round regularly on the inpatient general cardiology and coronary care unit (CCU) services and i have a particular interest in the treatment and management of patients with acute myocardial infarction and cardiogenic shock.  In my outpatient clinic, I care for patients with a variety of cardiovascular conditions include chronic coronary artery disease, hypertension, hyperlipidemia, atrial fibrillation, congestive heart failure, aortic aneurysms, and peripheral arterial disease.  In this setting, I have a particular interest in cardiovascular risk factor modification and long-term treatment strategies to mitigate the risk of future cardiovascular events.

My research activities at the Duke Clinical Research Institute focus upon the coordination and leadership of randomized clinical trials evaluating new therapies for a variety of cardiovascular conditions (acute myocardial infarction, hyperlipidemia, coronary stent placement, peripheral arterial disease, and coronary artery disease) as well as observational registries that evaluate the same disease conditions.


Frank Wesley Rockhold

Professor of Biostatistics & Bioinformatics

Frank is a full time Professor of Biostatistics and Bioinformatics and Faculty Director for Biostatistics at Duke University Medical Center, Affiliate Professor of Biostatistics at Virginia Commonwealth University, and Strategic Consultant at Hunter Rockhold, Inc.  His 40+-year career includes senior research positions at Lilly, Merck, and GlaxoSmithKline, where he retired as Chief Safety Officer and Senior Vice President of Global Clinical Safety and Pharmacovigilance.  He has held faculty appointments at six different universities.    Dr. Rockhold served for 9 years on the board of directors of the non-profit CDISC, most recently as Chairman, and is past president of the Society for Clinical Trials and a past member of the PCORI Clinical Trials Advisory Panel. He is currently Chair of the Board of the Frontier Science and Technology Research Foundation and a technical advisor to EMA.

Dr. Rockhold has diverse research interests and consulting experience in industry and academia including clinical trials design, data monitoring, benefit/risk, safety and pharmacovigilance and has been a leader in the scientific community in promoting data disclosure and transparency in clinical research.    Frank is widely published in major scientific journals across a wide variety of research topics.

Frank holds a BA in Statistics from The University of Connecticut, an ScM in Biostatistics from The Johns Hopkins University, and a PhD in Biostatistics from the Medical College of Virginia at Virginia Commonwealth University. Frank is an Elected Fellow of both the American Statistical Association and the Society for Clinical Trials, a Fellow of the Royal Statistical Society, an Accredited Professional Statistician, PStat®, and a Chartered Statistician, CStat.  

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