Alan S. Go, MD; Daniel E. Singer, MD; Sengwee Toh, ScD; T. Craig Cheetham, PharmD, MS; Marsha E. Reichman, PhD; David J. Graham, MD, MPH; Mary Ross Southworth, PharmD; Rongmei Zhang, PhD; Rima Izem, PhD; Margie R. Goulding, PhD; Monika Houstoun, PharmD; Katrina Mott, MS; Sue Hee Sung, MPH; Joshua J. Gagne, PharmD, ScD
Note: The Sentinel Initiative is a multifaceted effort by the FDA to develop a national electronic surveillance system that will complement existing methods for monitoring the safety of FDA-regulated medical products. Sentinel collaborators include data and academic partners that provide access to health care data and ongoing scientific, technical, methodological, and organizational expertise.
Disclaimer: The opinions or assertions presented herein are the private views and opinions of the authors and are not to be construed as conveying either an official endorsement or criticism by the U.S. Department of Health and Human Services, the U.S. Public Health Service, or the FDA.
Acknowledgment: The authors thank Alda I. Inveiss for her expert technical assistance. The authors acknowledge the helpful input and contributions of all members (comprising Sentinel investigators and FDA staff) of the working groups for this project, as well as the constructive comments and suggestions from many additional FDA staff, Sentinel collaborators, and Sentinel Operations Center staff during the planning stages. The authors thank programmers and research staff from the Sentinel collaborators that contributed data to the analyses (Aetna, Harvard Pilgrim Health Care Institute, HealthCore, HealthPartners Institute, Humana Comprehensive Health Insights, Kaiser Permanente Northern California, Kaiser Permanente Washington Health Research Institute, and Optum Epidemiology) and the Sentinel collaborators that did the initial workplans but did not contribute data to the included analyses (Kaiser Permanente Colorado, Kaiser Permanente Georgia, Kaiser Permanente Hawaii, Kaiser Permanente Mid-Atlantic, Kaiser Permanente Northwest, Lovelace Clinic Foundation, Marshfield Clinic Research Foundation, Meyers Primary Care Institute, and Vanderbilt University Medical Center).
Financial Support: The Sentinel Coordinating Center is funded by the FDA through contract HHSF223200910006I from the U.S. Department of Health and Human Services and task order HHSF22301007T from the Center for Drug Evaluation and Research.
Disclosures: Dr. Go reports grants from the FDA during the conduct of the study. Dr. Singer reports grants and personal fees from Boehringer Ingelheim outside the submitted work; personal fees from Johnson & Johnson, Merck, Pfizer, Bristol-Myers Squibb, and CVS Health outside the submitted work; and other support from the Department of Population Medicine of Harvard Medical School during the conduct of the study. Dr. Toh reports grants from the FDA during the conduct of the study. Dr. Cheetham reports grants from Bristol-Myers Squibb outside the submitted work. Dr. Gagne reports grants from the FDA during the conduct of the study, personal fees from Optum and Aetion outside the submitted work, and grants from Novartis outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M16-1157.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement:Study protocol: Available at www.sentinelinitiative.org/sites/default/files/Drugs/Assessments/Mini-Sentinel_Protocol-for-Assessment-of-Dabigatran_0.pdf. Statistical code: Available from Dr. Toh (e-mail, Darren_Toh@harvardpilgrim.org). Data set: Not available.
Requests for Single Reprints: Alan S. Go, MD, Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA 94612; e-mail, Alan.S.Go@kp.org.
Current Author Addresses: Dr. Go and Ms. Sung: Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA 94612.
Dr. Singer: Division of General Internal Medicine, Massachusetts General Hospital, 50 Staniford Street, 9th Floor, Boston, MA 02114.
Dr. Toh: Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Landmark Center, 401 Park Drive, Suite 401 East, Boston, MA 02215.
Dr. Cheetham: Western University College of Pharmacy, 309 East Second Street, Pomona, CA 91766.
Drs. Reichman, Graham, and Goulding and Ms. Mott: Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Building 22, Silver Spring, MD 20993.
Drs. Southworth and Houstoun: Office of New Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Building 22, Suite 4177, Silver Spring, MD 20993.
Drs. Zhang and Izem: Office of Biostatistics, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Building 21, Silver Spring, MD 20993.
Dr. Gagne: Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont Street, Suite 3030, Boston, MA 02120.
Author Contributions: Conception and design: A.S. Go, S. Toh, T.C. Cheetham, M.E. Reichman, D.J. Graham, M.R. Southworth, R. Zhang, M.R. Goulding, M. Houstoun, K. Mott, J.J. Gagne.
Analysis and interpretation of the data: A.S. Go, D.E. Singer, S. Toh, T.C. Cheetham, M.E. Reichman, D.J. Graham, M.R. Southworth, R. Zhang, R. Izem, M.R. Goulding, M. Houstoun, K. Mott, J.J. Gagne.
Drafting of the article: A.S. Go, R. Izem.
Critical revision of the article for important intellectual content: A.S. Go, D.E. Singer, S. Toh, T.C. Cheetham, M.E. Reichman, D.J. Graham, M.R. Southworth, R. Zhang, R. Izem, M.R. Goulding, M. Houstoun, K. Mott, J.J. Gagne.
Final approval of the article: A.S. Go, D.E. Singer, S. Toh, T.C. Cheetham, M.E. Reichman, D.J. Graham, M.R. Southworth, R. Zhang, R. Izem, M.R. Goulding, M. Houstoun, K. Mott, S.H. Sung, J.J. Gagne.
Provision of study materials or patients: A.S. Go.
Statistical expertise: A.S. Go, S. Toh, M.E. Reichman, R. Zhang, R. Izem, J.J. Gagne.
Obtaining of funding: A.S. Go, S. Toh, M.E. Reichman, J.J. Gagne.
Administrative, technical, or logistic support: A.S. Go, S. Toh, M.E. Reichman, M. Houstoun, K. Mott, S.H. Sung.
Collection and assembly of data: A.S. Go, S. Toh, M.R. Southworth, M. Houstoun, J.J. Gagne.
This article has been corrected. The original version (PDF) is appended to this article as a Supplement.
Dabigatran (150 mg twice daily) has been associated with lower rates of stroke than warfarin in trials of atrial fibrillation, but large-scale evaluations in clinical practice are limited.
To compare incidence of stroke, bleeding, and myocardial infarction in patients receiving dabigatran versus warfarin in practice.
National U.S. Food and Drug Administration Sentinel network.
Adults with atrial fibrillation initiating dabigatran or warfarin therapy between November 2010 and May 2014.
Ischemic stroke, intracranial hemorrhage, extracranial bleeding, and myocardial infarction identified from hospital claims among propensity score–matched patients starting treatment with dabigatran or warfarin.
Among 25 289 patients starting dabigatran therapy and 25 289 propensity score–matched patients starting warfarin therapy, those receiving dabigatran did not have significantly different rates of ischemic stroke (0.80 vs. 0.94 events per 100 person-years; hazard ratio [HR], 0.92 [95% CI, 0.65 to 1.28]) or extracranial hemorrhage (2.12 vs. 2.63 events per 100 person-years; HR, 0.89 [CI, 0.72 to 1.09]) but were less likely to have intracranial bleeding (0.39 vs. 0.77 events per 100 person-years; HR, 0.51 [CI, 0.33 to 0.79]) and more likely to have myocardial infarction (0.77 vs. 0.43 events per 100 person-years; HR, 1.88 [CI, 1.22 to 2.90]). However, the strength and significance of the association between dabigatran use and myocardial infarction varied in sensitivity analyses and by exposure definition (HR range, 1.13 [CI, 0.78 to 1.64] to 1.43 [CI, 0.99 to 2.08]). Older patients and those with kidney disease had higher gastrointestinal bleeding rates with dabigatran.
Inability to examine outcomes by dabigatran dose (unacceptable covariate balance between matched patients) or quality of warfarin anticoagulation (few patients receiving warfarin had available international normalized ratio values).
In matched adults with atrial fibrillation treated in practice, the incidences of stroke and bleeding with dabigatran versus warfarin were consistent with those seen in trials. The possible relationship between dabigatran and myocardial infarction warrants further investigation.
U.S. Food and Drug Administration.
Go AS, Singer DE, Toh S, Cheetham TC, Reichman ME, Graham DJ, et al. Outcomes of Dabigatran and Warfarin for Atrial Fibrillation in Contemporary Practice: A Retrospective Cohort Study. Ann Intern Med. ;167:845–854. doi: 10.7326/M16-1157
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Published: Ann Intern Med. 2017;167(12):845-854.
Published at www.annals.org on 14 November 2017
Cardiology, Emergency Medicine, Rhythm Disorders and Devices.
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