Aspirin Use to Prevent Cardiovascular Disease and Colorectal Cancer: An Evidence Update for the U.S. Preventive Services Task Force

Project Summary Title and Description

Title
Aspirin Use to Prevent Cardiovascular Disease and Colorectal Cancer: An Evidence Update for the U.S. Preventive Services Task Force
Description
Background: Cardiovascular disease (CVD) is the leading cause of death and colorectal cancer (CRC) is the third leading cause of death in the United States. Purpose: To systematically review evidence for the effectiveness of aspirin to prevent myocardial infarction (MI), stroke, cardiovascular death, and all-cause mortality in those without a history of CVD. In addition, to review evidence for CRC incidence and mortality associated with aspirin use in primary and secondary CVD populations. To further review harms associated with aspirin use. Data Sources: We searched MEDLINE, PubMed, and the Cochrane Collaboration Registry of Controlled Trials to identify literature that was published between January 2014 and January 14, 2021. We supplemented our searches with reference lists from the previous review, relevant existing systematic reviews, suggestions from experts, and Clinicaltrials.gov to identify ongoing trials. We conducted ongoing surveillance for relevant literature through January 21, 2022. Study Selection: Two investigators independently reviewed identified abstracts and full text articles against a set of a priori inclusion and quality criteria. Data Analysis: One investigator abstracted data into an evidence table and a second investigator checked these data. We conducted Peto fixed effects meta-analyses to estimate the effect size of aspirin in preventing MI, stroke, CVD-related death and all-cause mortality, CRC incidence and mortality, major bleeding, major gastrointestinal (GI) bleeding, intracranial bleeding, hemorrhagic stroke, and extracranial bleeding. Additionally, we conducted sensitivity analyses using Mantel-Haenszel fixed effects and Restricted Maximum Likelihood random effects. Results: We included 13 fair- to good-quality randomized, controlled trials (RCTs) (N=161,680) examining the effectiveness of aspirin for the primary prevention of CVD. Based on pooled analysis of 11 primary CVD prevention trials using aspirin ≤100 mg/day, low-dose aspirin reduces the risk of major CVD events (total MI, total stroke, CVD mortality) by 10 percent (k=11, N=134,470; Peto odds ratio [OR], 0.90 [95% confidence interval (CI), 0.85 to 0.95]), MI by 11 percent (k=11, N=134,470; Peto OR, 0.89 [95% CI, 0.82 to 0.96]), and ischemic stroke by 18 percent (k=5, N=79,334; Peto OR, 0.82 [95% CI, 0.72 to 0.92]) with no differences in CVD mortality (k=11, N=134,470; Peto OR, 0.95 [95% CI, 0.86 to 1.05]) or all-cause mortality (k=11, N=134,470; Peto OR 0.98 [95% CI, 0.93 to 1.03]). Absolute risk reductions in major CVD events in the trials ranged from 0.08 to 2.5 percent. Aspirin’s benefits were similar when trials of all doses were pooled. Sensitivity analyses restricted to more recent trials where usual care includes aggressive risk factor modification including statin therapy show diminished effects of aspirin for major CVD events and total MI but larger effects for total ischemic stroke compared to older trials. A small subset of the trials reporting CVD outcomes also reported CRC outcomes. Based on 4 low-dose aspirin trials (N=86,137) recruiting primary CVD prevention populations, there was no statistically significant association between aspirin and CRC incidence when analyzing randomized trial periods (Peto OR 1.07 [95% CI, 0.92 to 1.24]; trial period 5-10 years). Analysis including post-trial observation periods up to 20 years and including trials with high-dose aspirin up to 500 mg/day (k=2; N=45,015) in primary prevention populations show statistically significant reductions in CRC incidence (0.70 [95% CI, 0.50 to 0.98] and 0.82 [95% CI, 0.69 to 0.98]). Two low-dose aspirin RCTs (N=59,020) in primary CVD prevention populations report CRC mortality during the trial period (5-10 years) showing results concerning for possible harm with one trial demonstrating a statistically significant increase in CRC mortality in older adults. At 18 years of followup, including post-trial observational periods, three primary CVD prevention trials with mean daily aspirin doses ranging from 75 to 500 mg showed aspirin was associated with a decreased risk of CRC mortality (Peto OR 0.76 [95% CI, 0.62 to 0.94]). Low-dose aspirin is associated with a 31 percent increase in intracranial bleeding events (k=11; N=134,470; Peto OR, 1.31 [95% CI, 1.11 to 1.54]), and 53 percent increase in extracranial bleeding events (k=10; N=133,194; Peto OR 1.53 [95% CI, 1.39 to 1.70]). The absolute increases ranged from -0.2 to 0.4 percent for intracranial bleeding events and 0.2 to 0.9 percent for extracranial bleeding events. There is no compelling evidence to suggest that aspirin has a different relative CVD benefit or bleeding risk in specific populations defined by age, sex, race and ethnicity, diabetes status, or baseline 10-year CVD risk. Aspirin’s CVD benefits appear to begin within the first 1-2 years of administration and the bleeding harms begin soon after aspirin initiation; there are limited data for more precise time increments or longer durations. Limitations: Primary CVD prevention trials used different aspirin doses in heterogeneous populations with relatively short study followup, with duration mostly ranging from 4-6 years. Trials reporting CRC incidence and mortality outcomes are limited by short trial duration and multiple comparisons; observational followup of trials are limited by heterogeneity of aspirin doses, duration, indications, and populations with risk of biases and confounding. Estimates of rare bleeding harms are imprecise. Conclusions: In primary prevention populations, low-dose aspirin reduces major CVD events, MI and ischemic stroke, but also increases major GI bleeding, extracranial bleeding, and intracranial bleeding. Our evidence suggests aspirin is associated with a possible long-term reduction in CRC incidence and mortality based on post-trial period observation, but the results are limited for low-dose aspirin among primary CVD prevention populations. More precise real-world U.S.-based estimates for bleeding events in the general population and specific populations with elevated CVD risk are necessary to accurately estimate the net benefit. Depending on CVD risk, this absolute CVD benefit in specific populations could potentially outweigh the bleeding risks. Models to identify these populations are needed.
Attribution
N/A
Authors of Report
Janelle M. Guirguis-Blake, MD Corinne V. Evans, MPP Leslie A. Perdue, MPH Sarah I. Bean, MPH Caitlyn A. Senger, MPH
Methodology description
Systematic Review
PROSPERO
NA
DOI
N/A
Notes
AHRQ Publication No. 21-05283-EF-1 April 2022 https://www.uspreventiveservicestaskforce.org/uspstf/document/final-evidence-review/aspirin-to-prevent-cardiovascular-disease-preventive-medication
Funding Source
Agency for Healthcare Research and Quality

Key Questions

1. KQ1: Does Regular Aspirin Use in Patients Without Known CVD Reduce CVD and CRC Incidence and Mortality, or All-Cause Mortality? KQ2: Does Regular Aspirin Use Increase Major Gastrointestinal Bleeding, Intracranial Bleeding, or Other Serious Harms?

Associated Extraction Forms

Type
Standard

Associated Studies (each link opens a new tab)

Title Authors Year
Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus Ascend Study Collaborative Group; L. Bowman; M. Mafham; K. Wallendszus; W. Stevens; G. Buck; J. Barton; K. Murphy; T. Aung; R. Haynes; J. Cox; A. Murawska; A. Young; M. Lay; F. Chen; E. Sammons; E. Waters; A. Adler; J. Bodansky; A. Farmer; R. McPherson; A. Neil; D. Simpson; R. Peto; C. Baigent; R. Collins; S. Parish; J. Armitage
Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial J. M. Gaziano; C. Brotons; R. Coppolecchia; C. Cricelli; H. Darius; P. B. Gorelick; G. Howard; T. A. Pearson; P. M. Rothwell; L. M. Ruilope; M. Tendera; G. Tognoni; Arrive Executive Committee
Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council's General Practice Research Framework
Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group Hansson; L.; Zanchetti; A.; Carruthers; S.G.; Dahlof; B.; Elmfeldt; D.; Julius; S.; Menard; J.; Rahn; K.H.; Wedel; H.; Westerling; S.
Randomised trial of prophylactic daily aspirin in British male doctors Peto; R.; Gray; R.; Collins; R.; Wheatley; K.; Hennekens; C.; Jamrozik; K.; Warlow; C.; Hafner; B.; Thompson; E.; Norton; S.; . 1988
A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women Ridker; P.M.; Cook; N.R.; Lee; I.M.; Gordon; D.; Gaziano; J.M.; Manson; J.E.; Hennekens; C.H.; Buring; J.E.
Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly J. J. McNeil; R. Wolfe; R. L. Woods; A. M. Tonkin; G. A. Donnan; M. R. Nelson; C. M. Reid; J. E. Lockery; B. Kirpach; E. Storey; R. C. Shah; J. D. Williamson; K. L. Margolis; M. E. Ernst; W. P. Abhayaratna; N. Stocks; S. M. Fitzgerald; S. G. Orchard; R. E. Trevaks; L. J. Beilin; C. I. Johnston; J. Ryan; B. Radziszewska; M. Jelinek; M. Malik; C. B. Eaton; D. Brauer; G. Cloud; E. M. Wood; S. E. Mahady; S. Satterfield; R. Grimm; A. M. Murray; Aspree Investigator Group
Efficacy of Aspirin in the Primary Prevention of Cardiovascular Diseases and Cancer in the Elderly: A Population-Based Cohort Study in Korea M. Jung; S. Lee
A prospective study of aspirin use and the risk of gastrointestinal bleeding in men Huang; E.S.; Strate; L.L.; Ho; W.W.; Lee; S.S.; Chan; A.T.
Long-term use of aspirin and the risk of gastrointestinal bleeding Huang; E.S.; Strate; L.L.; Ho; W.W.; Lee; S.S.; Chan; A.T.
The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease Belch; J.; MacCuish; A.; Campbell; I.; Cobbe; S.; Taylor; R.; Prescott; R.; Lee; R.; Bancroft; J.; MacEwan; S.; Shepherd; J.; Macfarlane; P.; Morris; A.; Jung; R.; Kelly; C.; Connacher; A.; Peden; N.; Jamieson; A.; Matthews; D.; Leese; G.; McKnight; J.; O'Brien; I.; Semple; C.; Petrie; J.; Gordon; D.; Pringle; S.; MacWalter; R.
Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial.[Erratum appears in JAMA. 2009 May 13;301(18):1882] Ogawa; H.; Nakayama; M.; Morimoto; T.; Uemura; S.; Kanauchi; M.; Doi; N.; Jinnouchi; H.; Sugiyama; S.; Saito; Y.; Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial Investigators
Low-dose aspirin for primary prevention of cardiovascular events in Japanese patients 60 years or older with atherosclerotic risk factors: a randomized clinical trial Ando, K.; Ikeda, Y.; Ishizuka, N.; Murata, M.; Oikawa, S.; Shimada, K.; Sugawara, M.; Teramoto, T.; Uchiyama, S.; Yamazaki, T.; Yokoyama, K.
Adverse effects of low-dose aspirin in a healthy elderly population Silagy; C.A.; McNeil; J.J.; Donnan; G.A.; Tonkin; A.M.; Worsam; B.; Campion; K. 1993
Association of aspirin use with major bleeding in patients with and without diabetes de Berardis; G.; Lucisano; G.; D'Ettorre; A.; Pellegrini; F.; Lepore; V.; Tognoni; G.; Nicolucci; A.
Final report on the aspirin component of the ongoing Physicians' Health Study. Steering Committee of the Physicians' Health Study Research Group 1989
Aspirin treatment and risk of first incident cardiovascular diseases in patients with type 2 diabetes: an observational study from the Swedish National Diabetes Register Ekstrom; N.; Cederholm; J.; Zethelius; B.; Eliasson; B.; Fharm; E.; Rolandsson; O.; Miftaraj; M.; Svensson; A.M.; Gudbjornsdottir; S.
Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general Practice de Gaetano; G; Collaborative Group of the Primary Prevention Project
Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial Fowkes; F.G.; Price; J.F.; Stewart; M.C.; Butcher; I.; Leng; G.C.; Pell; A.C.; Sandercock; P.A.; Fox; K.A.; Lowe; G.D.; Murray; G.D.
The risk of lower gastrointestinal bleeding in low-dose aspirin users W. C. Chen; K. H. Lin; Y. T. Huang; T. J. Tsai; W. C. Sun; S. K. Chuah; D. C. Wu; P. I. Hsu
Risk factors for upper gastrointestinal bleeding among aspirin users: An old issue with new findings from a population-based cohort study P. J. Luo; X. H. Lin; C. C. Lin; J. C. Luo; H. Y. Hu; P. H. Ting; M. C. Hou
The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: Final results Warlow 1991//
Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. The SALT Collaborative Group The SALT Collaborative Group 1991

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