Evelyn P. Whitlock, MD, MPH; Brittany U. Burda, MPH; Selvi B. Williams, MD, MPH; Janelle M. Guirguis-Blake, MD; Corinne V. Evans, MPP
Note: This review was conducted by the Kaiser Permanente Research Affiliates Evidence-based Practice Center under contract to the Agency for Healthcare Research and Quality (AHRQ). The staff of AHRQ provided oversight for the project and assisted in the external review of the companion draft evidence synthesis.
Acknowledgment: The authors thank the following persons for their contributions to this project: AHRQ staff; the U.S. Preventive Services Task Force; Luis Alberto Garcia Rodriguez, MD, MS, Barnett Kramer, MD, MPH, Diana Petitti, MD, MPH, Peter Rothwell, MD, Steven Teutsch, MD, MPH, and Asad Umar, DVM, PhD, for providing expert review of the report; and Elizabeth O'Connor, PhD, Smyth Lai, MLS, Kevin Lutz, MFA, Elizabeth L. Hess, ELS(D), and Keshia Bigler, BS, at the Kaiser Permanente Center for Health Research at the Kaiser Permanente Center for Health Research.
Financial Support: By contract HHS-290-2012-00151-I from AHRQ.
Disclosures: The authors report a contract with AHRQ during the conduct of the study. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-2112.
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.uspreventiveservicestaskforce.org/Page/Document/final-research-plan-aspirin-to-prevent-cancer/aspirin-to-prevent-cardiovascular-disease-and-cancer. Statistical code: Not available. Data set: Available at www.uspreventiveservicestaskforce.org/Page/Document/final-evidence-review-aspirin-to-prevent-cancer-and-harms-of/aspirin-to-prevent-cardiovascular-disease-and-cancer.
Requests for Single Reprints: Reprints are available from the AHRQ Web site (www.ahrq.gov).
Current Author Addresses: Dr. Whitlock: Patient-Centered Outcomes Research Institute, 1828 L Street, Northwest, Suite 900, Washington, DC 20036.
Dr. Williams, Ms. Burda, and Ms. Evans: Kaiser Permanente Center for Health Research, 3800 North Interstate Avenue, Portland, OR 97227.
Dr. Guirguis-Blake: University of Washington, Department of Family Medicine, Tacoma Family Medicine Residency Program, 521 Martin Luther King Jr. Way, Tacoma, WA 98405.
Author Contributions: Conception and design: E.P. Whitlock, B.U. Burda, J.M. Guirguis-Blake, C.V. Evans.
Analysis and interpretation of the data: E.P. Whitlock, B.U. Burda, S.B. Williams, C.V. Evans.
Drafting of the article: E.P. Whitlock, B.U. Burda, S.B. Williams, C.V. Evans.
Critical revision of the article for important intellectual content: E.P. Whitlock, B.U. Burda, S.B. Williams, J.M. Guirguis-Blake, C.V. Evans.
Final approval of the article: E.P. Whitlock, B.U. Burda, S.B. Williams, J.M. Guirguis-Blake, C.V. Evans.
Statistical expertise: E.P. Whitlock.
Obtaining of funding: E.P. Whitlock.
Administrative, technical, or logistic support: B.U. Burda, C.V. Evans.
Collection and assembly of data: E.P. Whitlock, B.U. Burda, S.B. Williams, C.V. Evans.
The balance between potential aspirin-related risks and benefits is critical in primary prevention.
To evaluate the risk for serious bleeding with regular aspirin use in cardiovascular disease (CVD) primary prevention.
PubMed, MEDLINE, Cochrane Central Register of Controlled Trials (2010 through 6 January 2015), and relevant references from other reviews.
Randomized, controlled trials; cohort studies; and meta-analyses comparing aspirin with placebo or no treatment to prevent CVD or cancer in adults.
One investigator abstracted data, another checked for accuracy, and 2 assessed study quality.
In CVD primary prevention studies, very-low-dose aspirin use (≤100 mg daily or every other day) increased major gastrointestinal (GI) bleeding risk by 58% (odds ratio [OR], 1.58 [95% CI, 1.29 to 1.95]) and hemorrhagic stroke risk by 27% (OR, 1.27 [CI, 0.96 to 1.68]). Projected excess bleeding events with aspirin depend on baseline assumptions. Estimated excess major bleeding events were 1.39 (CI, 0.70 to 2.28) for GI bleeding and 0.32 (CI, −0.05 to 0.82) for hemorrhagic stroke per 1000 person-years of aspirin exposure using baseline bleeding rates from a community-based observational sample. Such events could be greater among older persons, men, and those with CVD risk factors that also increase bleeding risk.
Power to detect effects on hemorrhagic stroke was limited. Harms other than serious bleeding were not examined.
Consideration of the safety of primary prevention with aspirin requires an individualized assessment of aspirin's effects on bleeding risks and expected benefits because absolute bleeding risk may vary considerably by patient.
Agency for Healthcare Research and Quality.
Appendix Table 1. Comparison of Different Meta-analytic Approaches: CVD Primary Prevention Trials
Appendix Table 2. Brief Description of Included Cohort Studies and IPD Meta-analysis
Major GI bleeding in CVD primary prevention trials.
AAA = Aspirin for Asymptomatic Atherosclerosis; ABI = ankle brachial index; BMD = British Doctor's Trial; CVD = cardiovascular disease; GI = gastrointestinal; HOT = Hypertension Optimal Treatment; IHD = ischemic heart disease; JPAD = Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes; OR = odds ratio; PHS = Physicians' Health Study; TPT = Thrombosis Prevention Trial; WHS = Women's Health Study.
Table 1. Sensitivity Analyses for Bleeding in CVD Primary Prevention Trials
Hemorrhagic stroke in CVD primary prevention trials.
AAA = Aspirin for Asymptomatic Atherosclerosis; ABI = ankle brachial index; BMD = British Doctor's Trial; CVD = cardiovascular disease; HOT = Hypertension Optimal Treatment; IHD = ischemic heart disease; JPAD = Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes; JPPP = Japanese Primary Prevention Project; OR = odds ratio; PHS = Physicians' Health Study; PPP = Primary Prevention Project; TPT = Thrombosis Prevention Trial; WHS = Women's Health Study.
Table 2. Absolute Bleeding Rates Among Nonaspirin Control Groups, Overall and by Subpopulations*
Table 3. Absolute Events Caused or Prevented With Very-Low-Dose Aspirin Use for ≤10 y*
Table 4. Relative Rate Ratios for Bleeding Among Subpopulations From Trials and Cohort Studies
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Whitlock EP, Burda BU, Williams SB, et al. Bleeding Risks With Aspirin Use for Primary Prevention in Adults: A Systematic Review for the U.S. Preventive Services Task Force. Ann Intern Med. [Epub ahead of print 12 April 2016]164:826–835. doi: 10.7326/M15-2112
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Published: Ann Intern Med. 2016;164(12):826-835.
Published at www.annals.org on 12 April 2016
Cardiology, Gastroenterology/Hepatology, Neurology, Prevention/Screening.
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