Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 392 (10145), 387-399

Effects of Aspirin on Risks of Vascular Events and Cancer According to Bodyweight and Dose: Analysis of Individual Patient Data From Randomised Trials

Affiliations

Effects of Aspirin on Risks of Vascular Events and Cancer According to Bodyweight and Dose: Analysis of Individual Patient Data From Randomised Trials

Peter M Rothwell et al. Lancet.

Abstract

Background: A one-dose-fits-all approach to use of aspirin has yielded only modest benefits in long-term prevention of cardiovascular events, possibly due to underdosing in patients of large body size and excess dosing in patients of small body size, which might also affect other outcomes.

Methods: Using individual patient data, we analysed the modifying effects of bodyweight (10 kg bands) and height (10 cm bands) on the effects of low doses (≤100 mg) and higher doses (300-325 mg or ≥500 mg) of aspirin in randomised trials of aspirin in primary prevention of cardiovascular events. We stratified the findings by age, sex, and vascular risk factors, and validated them in trials of aspirin in secondary prevention of stroke. Additionally, we assessed whether any weight or height dependence was evident for the effect of aspirin on 20-year risk of colorectal cancer or any in-trial cancer.

Results: Among ten eligible trials of aspirin in primary prevention (including 117 279 participants), bodyweight varied four-fold and trial median weight ranged from 60·0 kg to 81·2 kg (p<0·0001). The ability of 75-100 mg aspirin to reduce cardiovascular events decreased with increasing weight (pinteraction=0·0072), with benefit seen in people weighing 50-69 kg (hazard ratio [HR] 0·75 [95% CI 0·65-0·85]) but not in those weighing 70 kg or more (0·95 [0·86-1·04]; 1·09 [0·93-1·29] for vascular death). Furthermore, the case fatality of a first cardiovascular event was increased by low-dose aspirin in people weighing 70 kg or more (odds ratio 1·33 [95% CI 1·08-1·64], p=0·0082). Higher doses of aspirin (≥325 mg) had the opposite interaction with bodyweight (difference pinteraction=0·0013), reducing cardiovascular events only at higher weight (pinteraction=0·017). Findings were similar in men and women, in people with diabetes, in trials of aspirin in secondary prevention, and in relation to height (pinteraction=0·0025 for cardiovascular events). Aspirin-mediated reductions in long-term risk of colorectal cancer were also weight dependent (pinteraction=0·038). Stratification by body size also revealed harms due to excess dosing: risk of sudden death was increased by aspirin in people at low weight for dose (pinteraction=0·0018) and risk of all-cause death was increased in people weighing less than 50 kg who were receiving 75-100 mg aspirin (HR 1·52 [95% CI 1·04-2·21], p=0·031). In participants aged 70 years or older, the 3-year risk of cancer was also increased by aspirin (1·20 [1·03-1·47], p=0·02), particularly in those weighing less than 70 kg (1·31 [1·07-1·61], p=0·009) and consequently in women (1·44 [1·11-1·87], p=0·0069).

Interpretation: Low doses of aspirin (75-100 mg) were only effective in preventing vascular events in patients weighing less than 70 kg, and had no benefit in the 80% of men and nearly 50% of all women weighing 70 kg or more. By contrast, higher doses of aspirin were only effective in patients weighing 70 kg or more. Given that aspirin's effects on other outcomes, including cancer, also showed interactions with body size, a one-dose-fits-all approach to aspirin is unlikely to be optimal, and a more tailored strategy is required.

Funding: Wellcome Trust and National Institute for Health Research Oxford Biomedical Research Centre.

Figures

Figure 1
Figure 1
Effect of low-dose aspirin versus control on risks of cardiovascular events, death, and major bleeding according to bodyweight in trials of aspirin in primary prevention The size of the circles representing the point estimates of the HRs is proportional to the inverse of the variance of the estimate. BMI=body-mass index. HR=hazard ratio.
Figure 2
Figure 2
Effect of low-dose aspirin versus control on risk of all cardiovascular events and of all cardiovascular events and death in women, stratified by bodyweight The analysis of the six trials of aspirin in primary prevention is shown for all participants (top) and with exclusion of participants who were assigned to vitamin E (middle). The bottom two panels are for aspirin in secondary prevention in the ESPS-2 trial. The size of the circles representing the point estimates of the HRs is proportional to the inverse of the variance of the estimate. HR=hazard ratio.
Figure 3
Figure 3
Effect of higher-dose aspirin versus control, stratified by bodyweight and dose of aspirin The size of the circles representing the point estimates of the HRs is proportional to the inverse of the variance of the estimate. The analysis included all participants in trials of higher-dose aspirin versus control in primary or secondary prevention of cardiovascular events and cardiovascular events or death (analyses confined to trials in primary prevention are in appendix pp 16, 17). HR=hazard ratio.
Figure 4
Figure 4
Effect of aspirin versus control on risk of cardiovascular events in trials in primary prevention, stratified by bodyweight, height, and dose The size of the circles representing the point estimates of the HRs is proportional to the inverse of the variance of the estimate. The analysis was limited to participants who were not obese (body-mass index <30 kg/m2). HR=hazard ratio.
Figure 5
Figure 5
Effect of aspirin versus control on 20-year risk of colorectal cancer, stratified by aspirin dose and age The size of the circles representing the point estimates of the HRs is proportional to the inverse of the variance of the estimate. The analysis included the five trials, , , , with post-trial follow-up data and data on bodyweight. (A) Included participants treated with any dose and of any age. (B) Included participants treated with any dose who were younger than 70 years. (C) Included participants treated with 75–100 mg aspirin who were younger than 70 years. (D) Included participants treated with ≥325 mg aspirin who were younger than 70 years. HR=hazard ratio.
Figure 6
Figure 6
Effect of aspirin (all doses) versus control on early cancer risk in trials of aspirin in primary prevention of vascular events The size of the circles representing the point estimates of the HRs is proportional to the inverse of the variance of the estimate. (A) 3-year risk of cancer stratified by age. (B) 5-year risk of death due to cancer stratified by age. (C) Cancer risk stratified by year of follow-up in participants aged ≥70 years who had low weight for dose received (<70 kg for 75–100 mg and <80 kg for ≥325 mg). (D) Cancer risk stratified by year of follow-up in participants aged ≥70 years who had low height for dose received (1·6 m for 75–100 mg and <1·8 m for ≥325 mg). HR=hazard ratio.

Comment in

Similar articles

See all similar articles

Cited by 35 articles

See all "Cited by" articles

References

    1. Patrono C. The multifaceted clinical readouts of platelet inhibition by low-dose aspirin. J Am Coll Cardiol. 2015;66:74–85. - PubMed
    1. Bibbins-Domingo K. Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med. 2016;164:836–845. - PubMed
    1. Antithrombotic Trialists' (ATT) Collaboration Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373:1849–1860. - PMC - PubMed
    1. Basili S, Pacini G, Guagnano MT. Insulin resistance as a determinant of platelet activation in obese women. J Am Coll Cardiol. 2006;48:2531–2538. - PubMed
    1. Patrono C, Rocca B. Type 2 diabetes, obesity, and aspirin responsiveness. J Am Coll Cardiol. 2017;69:613–615. - PubMed

Publication types

MeSH terms

Feedback