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Aspirin Use in Adults: Cancer, All-Cause Mortality, and Harms
Evidence Syntheses, No. 132
Investigators: Evelyn P Whitlock, MD, MPH, Selvi B Williams, MD, MPH, Brittany U Burda, MPH, Alisha Feightner, MPH, and Tracy Beil, MS.
Author Information and AffiliationsStructured Abstract
Background:
Cancer is the second leading cause of death in United States. The net benefit for aspirin (ASA) in cardiovascular disease (CVD) primary prevention is controversial due to increased risks from bleeding alongside relatively modest cardiovascular benefits. Consideration of additional cancer prevention effects might clarify whether long-term, low-dose ASA may offer an overall health benefit for the two top causes of mortality in the United States.
Purpose:
We conducted this review, alongside two companion reviews, to support the U.S. Preventive Services Task Force (USPSTF) in making evidence-based recommendations about the use of ASA for primary prevention in adults and to understand the risks of regular ASA use.
Data Sources:
We used a systematic evidence review published in 2012 for cancer-specific and all-cause mortality outcomes and conducted a bridge search of PubMed, MEDLINE, and the Cochrane Central Register of Controlled Trials from 2011 to October 2013. For bleeding harms, we used four published systematic evidence reviews and conducted a search of PubMed, MEDLINE, and the Cochrane Central Register of Controlled Trials from January 1, 2010 to June 3, 2014 in PubMed and MEDLINE. We also reviewed all studies included and excluded for companion USPSTF reviews on ASA for colorectal cancer and CVD prevention and checked for additional relevant studies by reviewing reference lists of included studies and other published reviews or meta-analyses.
Study Selection:
Two investigators independently reviewed 4,393 abstracts and 336 articles against previously established inclusion and exclusion criteria and critically appraised studies for risk of bias using USPSTF methods, supplemented by the Newcastle-Ottawa Scale for cohort studies and the Assessment of Multiple Systematic Reviews for systematic reviews. We included fair- or good-quality trials evaluating the effect of 75 mg or greater ASA at least every other day for 12 months or longer versus no ASA, in the absence of other antithrombotic medications, on cancer mortality, all-cause mortality, cancer incidence, and harms, primarily related to serious bleeding. We also included cohort studies meeting these criteria to evaluate potential harms of ASA.
Data Extraction and Analysis:
For fair- and good-quality studies, one investigator abstracted study characteristics and outcomes into structured tables and a second verified accuracy. We assessed trials for heterogeneity using I2 statistics and pooled trial-level results when appropriate using Mantel-Haenszel fixed effects to calculate relative risks (RRs) and Peto's odds ratios (OR). We focused on cancer effects and bleeding harms in CVD primary prevention trials, but also assessed results after including secondary CVD and colorectal adenoma prevention trials. Expected outcome rates with ASA intervention were calculated by multiplying simulated control group event rates for benefits as well as harms from the CVD primary prevention trials by the pooled RR estimate (and bounds of 95% confidence interval [CI]). The expected outcome rates were subtracted from the simulated control group rate to calculate the absolute risk reduction with 95% CI. We calculated expected outcomes using the minimum, maximum, and median control group rate for a given outcome to examine the range of results suggested by the primary studies.
Results:
When restricting analyses to 10 CVD primary prevention trials with a median of 6.0 years of followup, we found a nonsignificantly reduced mortality due to cancer among 103,787 individuals randomized to ASA or no ASA over 3.7 to 10.1 years (RR, 0.96 [95% CI, 0.87 to 1.06]), corresponding to 0.14 fewer cancer deaths (95% CI, 0.21 more to 0.45 fewer) per 1,000 person-years. Effects on all cancer mortality remained nonstatistically significant in sensitivity analyses exploring the effect of excluding trials of greater than 100 mg per day, of average length of scheduled treatment less than 5 years, or of every other day dosing. Only when including trials of both primary and secondary CVD prevention with doses up to 1,200 mg per day and requiring daily dosing within a scheduled treatment duration of 4 years or more could we find a statistically significant cancer mortality benefit (RR, 0.83 [95% CI, 0.70 to 0.98]) as reported by others. All-cause mortality in 10 CVD primary prevention trials was statistically significantly reduced (RR, 0.94 [95% CI, 0.88 to 0.99]), corresponding to 0.57 fewer deaths (95% CI, 0.10 fewer to 1.15 fewer) per 1,000 person-years, but was sensitive to including longer-term followup results from one trial and some other changes in inclusion or exclusion criteria. When also including CVD secondary prevention trials, all-cause mortality was similarly reduced and remained statistically significant when requiring daily dosing, dosages of 100 mg or less, or at least 4 years of followup, but not when substituting longer-term followup results. Few reduced deaths were cardiovascular and reduced nonvascular noncancer deaths appeared to play a prominent role, but this deserves further exploration. Among 72,926 participants in six CVD primary prevention trials, cancer incidence was similar between ASA and no ASA groups (RR, 0.98 [95% CI, 0.93 to 1.04]), corresponding to 0.20 fewer incident cases (95% CI, 0.39 more to 0.69 fewer) per 1,000 person-years, and was only statistically significantly reduced when including both primary and secondary CVD prevention trials and restricting to daily dose interventions with at least 4 years of followup with doses ranging from 75 to 500 mg per day (RR, 0.86 [95% CI, 0.74 to 0.99]). Data from primary prevention populations are currently too sparse to robustly examine cancer incidence or mortality for any cancer type other than colorectal cancer, which is examined in a companion report. Among 10 CVD primary prevention trials, the risk of major GI bleeding was increased (OR, 1.59 [95% CI, 1.32 to 1.91]), corresponding to 0.29 more cases of bleeding (95% CI, 0.44 more to 0.16 more) per 1,000 person-years. Sensitivity analyses showed little variation, except nonsignificantly increased risk with daily dosing and nonsignificantly decreased risk with alternate-day dosing. Risk of hemorrhagic stroke or other intracranial bleeding tended to be increased in primary prevention trials (OR, 1.27 [95% CI, 0.98 to 1.66]), corresponding to 0.11 more cases (95% CI, 0.28 more to 0.01 fewer) per 1,000 person-years, with statistically significant effects only when both primary and secondary prevention trials were combined (OR, 1.43 [95% CI, 1.12 to 1.81]). When restricted to all trials of 100 mg or less, the risk tended to decrease (OR, 1.32 [95% CI, 1.00 to 1.75]). Relatively rare events limited analyses. Data from cohort studies indicated that baseline rates of serious bleeding are higher than suggested from trials, and data from trials as well as cohorts indicated considerable baseline bleeding rate variation according to age, sex, diabetes, hypertension, and perhaps other selected cardiovascular risk factors. Comedications such as nonsteroidal anti-inflammatory drugs appeared to modify baseline rates in cohort studies, as well as bleeding risks with low-dose ASA, although data adjusted for other risk factors suggested a more modest combined effect than earlier estimates. These and other bleeding risk factors could potentially have a large impact on the absolute number of excess cases of bleeding and therefore net benefit considerations.
Limitations:
Data on cancer benefits were limited by few trials—particularly of low-dose ASA and in CVD primary prevention populations—with adequate length of followup, which also limited analyses for cancer site-specific effects. Few analyses adjusted for combined impact of risk factors on bleeding risks; intracranial bleeding/hemorrhagic strokes are relatively rare and thus incompletely studied, and other potential risks of long-term ASA use are also understudied. Most currently available trial data are from older studies not specifically designed for outcomes beyond CVD and major bleeding, and not considering contemporary medications such as statins. In-progress research will be very valuable in updating these findings.
Conclusions:
Low-dose ASA use may eventually be shown to provide modest cancer mortality benefits in CVD primary prevention populations, but effects are not clearly established since current estimates are imprecise and relatively unstable. Modest reductions in all-cause mortality effect are more stable, but cannot be completely explained through cancer and/or CVD mortality reduction. Rates of serious bleeding, with and without ASA, are higher than previously suggested in clinical trial populations, and are very important when assessing the likely net benefit of low-dose ASA use as a chemopreventive agent in a more individualized or subpopulation-specific manner.
Contents
- [Preface]
- Abbreviations
- 1. Introduction
- 2. Methods
- 3. Results
- Literature Search and Included Studies
- KQ 1 Does Regular Aspirin Use Reduce Total Cancer Mortality or All-Cause Mortality in Adults Taking (or Eligible for) Aspirin for Primary Prevention?
- KQ 2 Does Regular Aspirin Use Reduce the Incidence of Cancers in Adults Taking (or Eligible for) Aspirin for Primary Prevention?
- KQs 1a and 2a Does the Effect of Aspirin Vary by a Priori Subgroups: Age, Sex, Race/Ethnicity, Baseline Cancer Risk, and Comorbidities?
- KQs 1b and 2b Does the Effect of Aspirin Vary by Delivery of Intervention (e.g., Dose, Frequency, Duration, Formulation, and Recency of Use)?
- KQ 6 What Are the Serious Harms of Regular Aspirin Use for the Primary Prevention of Cancer (i.e., at the Dosage and Duration Required to Achieve a Preventive Health Effect) in Adults Appropriate for Aspirin Chemoprevention?
- KQ 6a Does the Effect of Aspirin Vary by a Priori Subgroups (Age, Sex, Race/Ethnicity, Baseline Cancer Risk, Comorbid Conditions, or Concomitant Medication Use)?
- KQ 6b Does the Effect of Aspirin Vary by Delivery of Intervention (e.g., Dose, Frequency, Duration, Formulation, and Recency of Use)?
- 4. Discussion
- References
- Appendix A Detailed Methods
- Appendix B Excluded Studies
- Appendix C Control Group Rates
- Appendix D Study Details
- Appendix E Evidence Tables
- Appendix F Subgroup Results
- Appendix G Benefits of ASA Use in Cancer Prevention From Other Meta-Analyses
- Appendix H Ongoing Studies
Acknowledgments: The authors acknowledge the following individuals for their contributions to this project: Robert McNellis, PA, MPH, at AHRQ; current and former members of the U.S. Preventive Services Task Force who contributed to topic deliberations; 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; and Elizabeth O'Connor, PhD, Smyth Lai, MLS, Kevin Lutz, MFA, and Keshia Bigler, BS, at the Kaiser Permanente Center for Health Research.
Prepared for: Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services1, . Contract No. HHSA-290-2012-00151-I, Task Order No. 4. Prepared by: Kaiser Permanente Research Affiliates Evidence-based Practice Center2,
Suggested citation:
Whitlock EP, Williams SB, Burda BU, Feightner A, Beil T. Aspirin Use in Adults: Cancer, All-Cause Mortality, and Harms. A Systematic Evidence Review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 132. AHRQ Publication No. 13-05193-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; September 2015.
This report is based on research conducted by the Kaiser Permanente Research Affiliates Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. HHSA-290-2012-00151-I, Task Order No. 4). The findings and conclusions in this document are those of the authors, who are responsible for its contents, and do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services.
The information in this report is intended to help health care decisionmakers—patients and clinicians, health system leaders, and policymakers, among others—make well-informed decisions and thereby improve the quality of health care services. This report is not intended to be a substitute for the application of clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information, i.e., in the context of available resources and circumstances presented by individual patients.
This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.
None of the investigators has any affiliations or financial involvement that conflicts with the material presented in this report.
- 1
540 Gaither Road, Rockville, MD 20850; www
.ahrq.gov - 2
Kaiser Permanente Center for Health Research, Portland, OR
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