IMPORTANCE: Low-dose aspirin is used for primary cardiovascular disease prevention and may have benefits for colorectal cancer prevention.
OBJECTIVE: To review the benefits and harms of aspirin in primary cardiovascular disease prevention and colorectal cancer prevention to inform the US Preventive Services Task Force.
DATA SOURCES: MEDLINE, PubMed, Embase, and the Cochrane Central Register of Controlled Trials through January 2021; literature surveillance through January 21, 2022.
STUDY SELECTION: English-language randomized clinical trials (RCTs) of low-dose aspirin (≤100 mg/d) compared with placebo or no intervention in primary prevention populations.
DATA EXTRACTION AND SYNTHESIS: Single extraction, verified by a second reviewer. Quantitative synthesis using Peto fixed-effects meta-analysis.
MAIN OUTCOMES AND MEASURES: Cardiovascular disease events and mortality, all-cause mortality, colorectal cancer incidence and mortality, major bleeding, and hemorrhagic stroke.
RESULTS: Eleven RCTs (N = 134 470) and 1 pilot trial (N = 400) of low-dose aspirin for primary cardiovascular disease prevention were included. Low-dose aspirin was associated with a significant decrease in major cardiovascular disease events (odds ratio [OR], 0.90 [95% CI, 0.85-0.95]; 11 RCTs [n = 134 470]; I2 = 0%; range in absolute effects, -2.5% to 0.1%). Results for individual cardiovascular disease outcomes were significant, with similar magnitude of benefit. Aspirin was not significantly associated with reductions in cardiovascular disease mortality or all-cause mortality. There was limited trial evidence on benefits for colorectal cancer, with the findings highly variable by length of follow-up and statistically significant only when considering long-term observational follow-up beyond randomized trial periods. Low-dose aspirin was associated with significant increases in total major bleeding (OR, 1.44 [95% CI, 1.32-1.57]; 10 RCTs [n = 133 194]; I2 = 4.7%; range in absolute effects, 0.1% to 1.0%) and in site-specific bleeding, with similar magnitude.
CONCLUSIONS AND RELEVANCE: Low-dose aspirin was associated with small absolute risk reductions in major cardiovascular disease events and small absolute increases in major bleeding. Colorectal cancer results were less robust and highly variable.
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.
Background: Whether aspirin use can decrease or increase cancer risk remains controversial. In this study, a meta-analysis of cohort studies and randomized controlled trials (RCTs) were conducted to evaluate the effect of aspirin use on common cancer risk. Method: Medline and Embase databases were searched to identify relevant studies. Meta-analyses of cohort studies and RCTs were performed to assess the effect of aspirin use on the risk of colorectal, gastric, breast, prostate and lung cancer. Cochran Q test and the I square metric were calculated to detect potential heterogeneity among studies. Subgroup meta-analyses according to exposure categories (frequency and duration) and timing of aspirin use (whether aspirin was used before and after cancer diagnosis) were also performed. A dose-response analysis was carried out to evaluate and quantify the association between aspirin dose and cancer risk. Results: A total of 88 cohort studies and seven RCTs were included in the final analysis. Meta-analyses of cohort studies revealed that regular aspirin use reduced the risk of colorectal cancer (CRC) (RR=0.85, 95%CI: 0.78-0.92), gastric cancer (RR=0.67, 95%CI: 0.52-0.87), breast cancer (RR=0.93, 95%CI: 0.87-0.99) and prostate cancer (RR=0.92, 95%CI: 0.86-0.98), but showed no association with lung cancer risk. Additionally, meta-analyses of RCTs showed that aspirin use had a protective effect on CRC risk (OR=0.74, 95%CI: 0.56-0.97). When combining evidence from meta-analyses of cohorts and RCTs, consistent evidence was found for the protective effect of aspirin use on CRC risk. Subgroup analysis showed that high frequency aspirin use was associated with increased lung cancer risk (RR=1.05, 95%CI: 1.01-1.09). Dose-response analysis revealed that high-dose aspirin use may increase prostate cancer risk. Conclusions: This study provides evidence for low-dose aspirin use for the prevention of CRC, but not other common cancers. High frequency or high dose use of aspirin should be prescribed with caution because of their associations with increased lung and prostate cancer risk, respectively. Further studies are warranted to validate these findings and to find the minimum effective dose required for cancer prevention.
PURPOSE: Evidence of differences in the etiology of, and poorer survival from, proximal colon compared to the distal colorectum, necessitates research into its risk factors. This systematic review summarizes the evidence on medication use and proximal colon cancer risk.
METHODS: MEDLINE and EMBASE were searched for prospective studies investigating nine medication groups, namely non-steroidal anti-inflammatory drugs (NSAIDs), exogenous hormones, i.e., hormone replacement therapy (HRT) or oral contraceptives (OCs), statins, proton pump inhibitors, anti-hypertensives, metformin (an antidiabetic), antidiarrheals or laxatives, and the risk of proximal colon cancer. Narrative synthesis and meta-analyses, using random effects models to estimate risk ratios (RRs) and 95% confidence intervals (CIs), were conducted.
RESULTS: Twenty nine publications investigating NSAIDs (n = 13), exogenous hormones [HRT (n = 9) or OCs (n = 4)] statins (n = 5), anti-hypertensives (n = 1), and metformin (n = 1) were included. Summary RRs reported a protective effect of aspirin use (RR 0.80, 95% CI 0.73-0.89) but no associations between HRT (RR 0.92, 95% CI 0.83-1.02), OC (RR 1.06, 95% CI 0.98-1.14) or statin use (RR 0.94, 95% CI 0.67-1.31), and proximal colon cancer incidence compared to never/non-use. One study on metformin and one on anti-hypertensives reported no association. Sources of between-study heterogeneity included study design, period of exposure ascertainment, exposure source, and exposure comparison, but this exploration was hindered by the small numbers of studies.
CONCLUSION: Despite some studies on NSAID or HRT use, evidence on the impact of a range of medications on proximal colon cancer risk is limited. This highlights the need for more research to inform chemoprevention strategies.
BACKGROUND: Colorectal cancer (CRC) is the third most common diagnosed cancer and the third leading cause of all cancer deaths in the USA. Some evidences are shown that aspirin can reduce the morbidity and mortality of different cancers, including CRC. Aspirin has become a new focus of cancer prevention and treatment research so far; clinical studies, however, found conflicting conclusions of its anti-cancer characteristics. This study is to summarize the latest evidence of correlation between aspirin use and CRC and/or colorectal adenomas.
METHODS: Databases were searched to identify randomized controlled trials (RCTs) in the salvage setting. The pooled relative risk (RR) with 95% confidence interval (CI) was used to estimate the effect of aspirin on colorectal cancer and/or colorectal adenomas. Subgroup analysis and sensitivity analysis were also conducted.
RESULTS: The result showed that aspirin use was not associated with incidence of CRC (RR 0.97; 95% CI 0.84-1.12; P = 0.66; I2 = 34%), aspirin use was found to be associated with reduced recurrence of colorectal adenomas (RR 0.83; 95% CI 0.72-0.95; P = 0.006; I2 = 63%) and reduced mortality of CRC (RR 0.79; 95% CI 0.64-0.97; P = 0.02; I2 = 14%). Subgroup analysis found a statistically significant association in low dose with a pooled RR of 0.85 (95% CI 0.74-0.99; P = 0.03; I2 = 31%).
CONCLUSIONS: This meta-analysis of randomized controlled trial data indicates that aspirin reduces the overall risk of recurrence and mortality of CRC and/or colorectal adenomas. Incidence of CRC was also reduced with low-dose aspirin. The emerging evidence on aspirin's cancer protection role highlights an exciting time for cancer prevention through low-cost interventions.
TRIAL REGISTRATION: Clinicaltrials.gov no: CRD42020208852; August 18, 2020; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020208852 ).
Objective: The objective of this review was to systematically review and synthesize evidence regarding benefits of using nonsteroidal anti-inflammatory drugs (NSAIDs) for the treatment of colorectal cancer (CRC). Data Sources: The data sources were MEDLINE, PubMed, NEJM, Google Scholar, and Google searches of references from relevant and eligible trials. Review Methods: We screened abstracts and full-text articles of identified references for eligibility and reviewed randomized controlled trials, cohort studies, and meta-analysis for evidence on benefits of using NSAIDs in CRC treatments. For all extracted data, completeness and relevance were checked. Results: The risk of any adenoma among frequent NSAID users was 26.8% vs 39.9% among placebo subjects who later used NSAIDs sporadically (adjusted relative risk = 0.62, 95% confidence interval [CI] = 0.39-0.98; P trend with NSAID use frequency =.03). Long-term use of aspirin reduces the risk of CRC. Aspirin also reduces the incidence of colon adenomas and mortality, especially when used for >10 years. Rofecoxib is associated with the reduction of CRC; however, it was associated with cardiovascular risk (with an overall unadjusted relative risk of 1.50 [95% CI = 0.76-2.94; P =.24]). Adenoma Prevention with Celecoxib trial shows that, for patients of all genotypes, the estimated cumulative incidence of one or more adenomas by year 3 was 59.8% for those randomized to placebo as compared with 43.3% for those randomized to low-dose (200 mg, twice daily) celecoxib (relative risk [RR] = 0.68; 95% CI = 0.59-0.79; P <.001) and 36.8% for those randomized to high-dose (400 mg, twice daily) celecoxib and 60.7% in placebo group (RR = 0.54; 95% CI = 0.46-0.64; P <.001). Conclusions: The use of COX-2 inhibitors both prior to and after diagnosis of CRC seemed to be mildly associated with the reduction in mortality of patients with CRC. Some literatures state that COX-2 inhibitors might play a synergistic role in adjuvant chemotherapy of FOLFOX regimen. Celecoxib was found to increase the radiosensitization of colon cancer cells.
Background: Various interventions have been tested as primary prevention of colorectal cancers (CRC), but comprehensive evidence comparing them is absent. We examined the effects of various chemopreventive agents (CPAs) on CRC incidence and mortality. Methods: We did a network meta-analysis based on a systematic review of randomized controlled trials (RCTs) that compared at least one CPA (aspirin, antioxidants, folic acid, vitamin B6, vitamin B12, calcium, vitamin D, alone or in combination) to placebo or other CPA in persons without history of CRC. Several databases were searched from inception up to March 2017. Primary outcomes were early and long-term CRC incidence and mortality. Results: Twenty-one RCTs comprising 281,063 participants, 9 RCTS comprising 160,101 participants, and 7 RCTs comprising 24,001 participants were included in the network meta-analysis for early risk of CRC incidence, long-term risk of CRC incidence and mortality, respectively. For early CRC incidence, no CPAs were found to be effective. For long-term CRC incidence and mortality, aspirin was the only intervention that showed protective effects with potential dose-dependent effects (risk ratio [RR], 0.74 [95% CI, 0.57–0.97] for high-dose [≥325 mg/day] and RR, 0.81 [95% CI, 0.67–0.98] for very-low-dose [≤100 mg/day]). Similar trend was found for mortality (RR, 0.43 [95% CI, 0.23–0.81] for low-dose [>100–325 mg/day] and RR, 0.65 [95% CI, 0.45–0.94] for very-low-dose). However, in net clinical benefit analysis, when combining risk estimates on mortality from CRC, cardiovascular disease, and pooled risk estimates of major gastrointestinal bleeding, low-dose aspirin provided the highest net survival gain (%) of 1.736 [95% CI, 1.010–2.434]. Conclusion: Aspirin at the dose range of 75–325 mg/day is a safe and effective primary prevention for long-term CRC among people at average risk. None of the other CPAs were found to be effective. There may potentially be differential effects among various doses of aspirin that needs further investigation.
Background
Both aspirin use and screening with flexible sigmoidoscopy or guaiac faecal occult
blood testing (FOBT) may reduce mortality from colorectal cancer, but comparative
effectiveness of these interventions is unknown.
Aim
To compare aspirin to guaiac FOBT screening with regard to incidence and mortality
of colorectal cancer in a network meta-analysis.
Methods
We searched Medline, EMBASE and the COCHRANE central register (CENTRAL) for
relevant randomised trials identified until 31 October 2015. Randomised trials in average-risk populations that reported colorectal cancer mortality, colorectal cancer incidence, or both, with a minimum follow-up of 2 years, and more than 100 randomised
individuals were included.
Three investigators independently extracted data. We calculated relative risks [RR with
95% predictive intervals (PrIs)] for the comparison of the interventions by frequentist
network meta-analyses.
Results
The effect of aspirin on colorectal cancer mortality was similar to FOBT (RR 1.03; 95%
PrI 0.76–1.39) and flexible sigmoidoscopy (RR 1.16; 95% PrI 0.84–1.60). Aspirin was
more effective than FOBT (RR 0.36; 95% PrI 0.22–0.59) and flexible sigmoidoscopy
(RR 0.37; 95% PrI 0.22–0.62) in preventing death from or cancer in the proximal colon.
Aspirin was equally effective as screening in reducing colorectal cancer incidence, while
flexible sigmoidoscopy was superior to FOBT (RR 0.84; 95% PrI 0.72–0.97).
Conclusions
Low-dose aspirin seems to be equally effective as flexible sigmoidoscopy or guaiac
FOBT screening to reduce colorectal cancer incidence and mortality, and more effective
for cancers in the proximal colon. A randomised comparative effectiveness trial of
aspirin vs. screening is warranted
Low-dose aspirin is used for primary cardiovascular disease prevention and may have benefits for colorectal cancer prevention.
OBJECTIVE:
To review the benefits and harms of aspirin in primary cardiovascular disease prevention and colorectal cancer prevention to inform the US Preventive Services Task Force.
DATA SOURCES:
MEDLINE, PubMed, Embase, and the Cochrane Central Register of Controlled Trials through January 2021; literature surveillance through January 21, 2022.
STUDY SELECTION:
English-language randomized clinical trials (RCTs) of low-dose aspirin (≤100 mg/d) compared with placebo or no intervention in primary prevention populations.
DATA EXTRACTION AND SYNTHESIS:
Single extraction, verified by a second reviewer. Quantitative synthesis using Peto fixed-effects meta-analysis.
MAIN OUTCOMES AND MEASURES:
Cardiovascular disease events and mortality, all-cause mortality, colorectal cancer incidence and mortality, major bleeding, and hemorrhagic stroke.
RESULTS:
Eleven RCTs (N = 134 470) and 1 pilot trial (N = 400) of low-dose aspirin for primary cardiovascular disease prevention were included. Low-dose aspirin was associated with a significant decrease in major cardiovascular disease events (odds ratio [OR], 0.90 [95% CI, 0.85-0.95]; 11 RCTs [n = 134 470]; I2 = 0%; range in absolute effects, -2.5% to 0.1%). Results for individual cardiovascular disease outcomes were significant, with similar magnitude of benefit. Aspirin was not significantly associated with reductions in cardiovascular disease mortality or all-cause mortality. There was limited trial evidence on benefits for colorectal cancer, with the findings highly variable by length of follow-up and statistically significant only when considering long-term observational follow-up beyond randomized trial periods. Low-dose aspirin was associated with significant increases in total major bleeding (OR, 1.44 [95% CI, 1.32-1.57]; 10 RCTs [n = 133 194]; I2 = 4.7%; range in absolute effects, 0.1% to 1.0%) and in site-specific bleeding, with similar magnitude.
CONCLUSIONS AND RELEVANCE:
Low-dose aspirin was associated with small absolute risk reductions in major cardiovascular disease events and small absolute increases in major bleeding. Colorectal cancer results were less robust and highly variable.
