Aspirin in primary prevention of cardiovascular disease and cancer: a systematic review of the balance of evidence from reviews of randomized trials

Abstract

Background: Aspirin has been recommended for primary prevention of cardiovascular disease (CVD) and cancer, but overall benefits are unclear. We aimed to use novel methods to re-evaluate the balance of benefits and harms of aspirin using evidence from randomised controlled trials, systematic reviews and meta-analyses.

Methods and findings: Data sources included ten electronic bibliographic databases, contact with experts, and scrutiny of reference lists of included studies. Searches were undertaken in September 2012 and restricted to publications since 2008. Of 2,572 potentially relevant papers 27 met the inclusion criteria. Meta-analysis of control arms to estimate event rates, modelling of all-cause mortality and L'Abbé plots to estimate heterogeneity were undertaken. Absolute benefits and harms were low: 60-84 major CVD events and 34-36 colorectal cancer deaths per 100,000 person-years were averted, whereas 46-49 major bleeds and 68-117 gastrointestinal bleeds were incurred. Reductions in all-cause mortality were minor and uncertain (Hazard Ratio 0.96; 95% CI: 0.90-1.02 at 20 years, Relative Risk [RR] 0.94, 95% CI: 0.88-1.00 at 8 years); there was a non-significant change in total CVD (RR 0.85, 95% CI: 0.69-1.06) and change in total cancer mortality ranged from 0.76 (95% CI: 0.66-0.88) to 0.93 (95% CI: 0.84-1.03) depending on follow-up time and studies included. Risks were increased by 37% for gastrointestinal bleeds (RR 1.37, 95% CI: 1.15-1.62), 54%-66% for major bleeds (Rate Ratio from IPD analysis 1.54, 95% CI: 1.30-1.82, and RR 1.62, 95% CI: 1.31-2.00), and 32%-38% for haemorrhagic stroke (Rate Ratio from IPD analysis 1.32; 95% CI: 1.00-1.74; RR 1.38; 95% CI: 1.01-1.82).

Conclusions: Findings indicate small absolute effects of aspirin relative to the burden of these diseases. When aspirin is used for primary prevention of CVD the absolute harms exceed the benefits. Estimates of cancer benefit rely on selective retrospective re-analysis of RCTs and more information is needed.

Figure 1. PRISMA flow diagram.

Key: CVD=Cardiovascular diseases; RCT=Randomised controlled trial; SR=Systematic Review. *Of the 27 included publications: a) CVD, SR=9, RCT=3; b) Cancer, SR=6; and c) Diabetes, SR=7, RCT=2. **One paper was identified from assessment of reference lists of excluded papers, this had been excluded at abstract sift but was not considered relevant until reading the paper in full.

Figure 2. Cumulative random effects meta-analysis of odds ratio for total CHD.

Studies arranged according to recruitment year (data from Seshasai et al., 2012) [38].

Figure 3. Gompertz fit to the ONS data.

Symbols represent the UK ONS survival for 50 year old individuals; the solid line is a Gompertz fit to the ONS data; the dashed line represents the survival of aspirin users based on a ten year OR for all-cause mortality of 0.94 (Seshasai [38] & Berger [19]) and modelled keeping the scale parameter for the Gompertz fit constant. The difference in area under the solid and dashed curves represents the mean gain in life over a life time horizon.