Author + information
- Received May 22, 2017
- Revision received July 7, 2017
- Accepted July 11, 2017
- Published online January 15, 2018.
- Larisa H. Cavallari, PharmDa,∗ (, )
- Craig R. Lee, PharmD, PhDb,
- Amber L. Beitelshees, PharmD, MPHc,
- Rhonda M. Cooper-DeHoff, PharmD, MSa,d,
- Julio D. Duarte, PharmD, PhDe,∗,
- Deepak Voora, MDf,
- Stephen E. Kimmel, MDg,
- Caitrin W. McDonough, PhDa,
- Yan Gong, PhDa,
- Chintan V. Dave, PharmD, PhDh,
- Victoria M. Pratt, PhDi,
- Tameka D. Alestock, MSc,
- R. David Anderson, MDd,
- Jorge Alsip, MDj,
- Amer K. Ardati, MDk,
- Brigitta C. Brott, MDj,
- Lawrence Brown, MDl,
- Supatat Chumnumwat, PharmDe,
- Michael J. Clare-Salzler, MDm,
- James C. Coons, PharmDn,
- Joshua C. Denny, MD, MSo,
- Chrisly Dillon, MDp,
- Amanda R. Elsey, MHAa,
- Issam S. Hamadeh, PharmDa,†,
- Shuko Harada, MDq,
- William B. Hillegass, MDr,
- Lindsay Hines, PhDs,
- Richard B. Horenstein, MDc,‡,
- Lucius A. Howell, MDt,
- Linda J.B. Jeng, MD, PhDc,
- Mark D. Kelemen, MDc,
- Yee Ming Lee, PharmDe,§,
- Oyunbileg Magvanjav, MAa,
- May Montasser, PhDc,
- David R. Nelson, MDu,
- Edith A. Nutescu, PharmD, MSe,v,
- Devon C. Nwaba, MPHc,
- Ruth E. Pakyz, MSc,
- Kathleen Palmer, BSNc,
- Josh F. Peterson, MD, MPHo,
- Toni I. Pollin, MS, PhDc,
- Alison H. Quinn, PharmDe,
- Shawn W. Robinson, MDc,l,
- Jamie Schub, MDc,
- Todd C. Skaar, PhDw,
- D. Max Smith, PharmDa,
- Vindhya B. Sriramoju, MDt,
- Petr Starostik, MDm,
- Tomasz P. Stys, MDx,
- James M. Stevenson, PharmD, MSn,
- Nicholas Varunok, MSt,
- Mark R. Vesely, MDc,l,
- Dyson T. Wake, PharmDa,‖,
- Karen E. Weck, MDy,
- Kristin W. Weitzel, PharmDa,
- Russell A. Wilke, MDx,
- James Willig, MDj,
- Richard Y. Zhao, PhDz,
- Rolf P. Kreutz, MDw,
- George A. Stouffer, MDt,
- Philip E. Empey, PharmD, PhDn,
- Nita A. Limdi, PharmD, PhDaa,
- Alan R. Shuldiner, MDc,
- Almut G. Winterstein, PhDh,bb,
- Julie A. Johnson, PharmDa,d,
- on behalf of the IGNITE Network
- aDepartment of Pharmacotherapy and Translational Research, University of Florida, Gainesville, Florida
- bDivision of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy and McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
- cDepartment of Medicine, University of Maryland, Baltimore, Maryland
- dDepartment of Medicine, Division of Cardiovascular Medicine, University of Florida, Gainesville, Florida
- eDepartment of Pharmacy Practice, University of Illinois at Chicago College of Pharmacy, Chicago, Illinois
- fDepartment of Medicine, Center for Applied Genomics & Precision Medicine, Duke University, Durham, North Carolina
- gUniversity of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
- hDepartment of Pharmaceutical Outcomes and Policy, University of Florida, Gainesville, Florida
- iDepartment of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
- jDivision of Cardiovascular Sciences, Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
- kDepartment of Medicine, University of Illinois at Chicago College of Medicine, Chicago, Illinois
- lVeterans Administration Medical Center, Baltimore, Maryland
- mDepartment of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida
- nDepartment of Pharmacy and Therapeutics, Center for Clinical Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania
- oDepartments of Biomedical Informatics and Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- pDepartment of Neurology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
- qDepartment of Pathology and Hugh Kaul Personalized Medicine Institute, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
- rHeart South Cardiovascular Group, Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama
- sDepartment of Neuropsychology, University of North Dakota, Fargo, North Dakota
- tDivision of Cardiology and McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
- uCollege of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, Florida
- vDepartment of Pharmacy Systems, Outcomes and Policy and Center for Pharmacoepidemiology and Pharmacoeconomic Research, University of Illinois at Chicago College of Pharmacy, Chicago, Illinois
- wDepartment of Medicine, Krannert Institute of Cardiology & Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana
- xDepartment of Medicine, University of South Dakota, Sanford School of Medicine, Sioux Falls, South Dakota
- yDepartment of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
- zDepartment of Pathology, University of Maryland School of Medicine, Baltimore, Maryland
- aaDepartment of Neurology and Hugh Kaul Personalized Medicine Institute, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
- bbDepartment of Epidemiology, Colleges of Medicine and Public Health and Health Professions, University of Florida, Gainesville, Florida
- ↵∗Address for correspondence:
Dr. Larisa H. Cavallari, Department of Pharmacotherapy and Translational Research, University of Florida, 1333 Center Drive, P.O. Box 100486, Gainesville, Florida 32610.
Objectives This multicenter pragmatic investigation assessed outcomes following clinical implementation of CYP2C19 genotype–guided antiplatelet therapy after percutaneous coronary intervention (PCI).
Background CYP2C19 loss-of-function alleles impair clopidogrel effectiveness after PCI.
Methods After clinical genotyping, each institution recommended alternative antiplatelet therapy (prasugrel, ticagrelor) in PCI patients with a loss-of-function allele. Major adverse cardiovascular events (defined as myocardial infarction, stroke, or death) within 12 months of PCI were compared between patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy. Risk was also compared between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy. Cox regression was performed, adjusting for group differences with inverse probability of treatment weights.
Results Among 1,815 patients, 572 (31.5%) had a loss-of-function allele. The risk for major adverse cardiovascular events was significantly higher in patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy (23.4 vs. 8.7 per 100 patient-years; adjusted hazard ratio: 2.26; 95% confidence interval: 1.18 to 4.32; p = 0.013). Similar results were observed among 1,210 patients with acute coronary syndromes at the time of PCI (adjusted hazard ratio: 2.87; 95% confidence interval: 1.35 to 6.09; p = 0.013). There was no difference in major adverse cardiovascular events between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy (adjusted hazard ratio: 1.14; 95% confidence interval: 0.69 to 1.88; p = 0.60).
Conclusions These data from real-world observations demonstrate a higher risk for cardiovascular events in patients with a CYP2C19 loss-of-function allele if clopidogrel versus alternative therapy is prescribed. A future randomized study of genotype-guided antiplatelet therapy may be of value.
- antiplatelet therapy
- cardiovascular events
- percutaneous coronary intervention
↵∗ Present address: Department of Pharmacotherapy and Translational Research, University of Florida, Gainesville, Florida.
↵† Present address: Carolinas HealthCare System, Charlotte, North Carolina.
↵§ Present address: University of Chicago Medical Center, Chicago, Illinois.
↵‖ Present address: NorthShore University HealthSystem, Evanston, Illinois.
This work was supported by National Institutes of Health (NIH) grants U01 HG007269 (to Drs. Johnson, Cavallari, Weitzel, Elsey, McDonough, Gong, Cooper-DeHoff, Nelson, Starostik, Smith, Wake, and Skaar), U01 HG007775 (to Drs. Pollin, Horenstein, Jeng, Nelson, Palmer, and Shuldiner), U01 HG007253 (to Drs. Peterson, Wilke, and Denny), and U01 HG007762 (to Dr. Skaar, Pratt, and Kreutz) as part of the NIH IGNITE (Implementing Genomics in Practice) network. Additional support was provided by NIH grants U01 GM074492 and U01 HL105198 (both part of the NIH Pharmacogenomics Research Network); by substantial institutional support from the University of Florida and its Clinical Translational Science Institute (grants UL1 TR000064 and UL1 TR001427 to Drs. Cavallari, Weitzel, Nelson, Clare-Salzler, Wake, Smith, and Johnson); NIH grant U01 HL105198; support from the University of Maryland Medical Center and University of Maryland School of Medicine Program for Personalized and Genomic Medicine (to Drs. Beitelshees, Alestock, Jeng, Brown, Horenstein, Kelemen, Montasser, Nelson, Pakyz, Palmer, Pollin, Robinson, Schub, Vesely, Zhao, and Shuldiner); the University of Illinois at Chicago Offices of the Vice President for Health Affairs and Vice Chancellor for Research (to Drs. Nutescu and Duarte); NIH grant K23 HL112908 (to Dr. Nutescu); NIH grant K23 GM112014 (to Dr. Duarte); the American Society of Health System Pharmacists (to Drs. Empey and Coons); NIH grant UL1TR0000005 (to Dr. Empey); an anonymous donor (to Drs. Empey, Coons, and Stevenson); the Penn Center for Precision Medicine at the Perelman School of Medicine at the University of Pennsylvania to S.T.; NIH grants R01HL092173 and 1K24HL133373, University of Alabama, Birmingham Health Service Foundations’ General Endowment Fund, and NIH grant UL1TR000165 (to Dr. Limdi); and the Indiana University Health – Indiana University School of Medicine Strategic Research Initiative (to Drs. Kreutz and Pratt). Dr. Kimmel has served as a consultant for Pfizer and Bayer, neither related to the content of the study. Dr. Kreutz has received consulting fees and research funding from Haemonetics. Reagents were provided by Nanospere to the University of Maryland. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received May 22, 2017.
- Revision received July 7, 2017.
- Accepted July 11, 2017.
- 2018 American College of Cardiology Foundation