Individualised prediction of alternate-day aspirin treatment effects on the combined risk of cancer, cardiovascular disease and gastrointestinal bleeding in healthy women

Abstract

Background: The value of aspirin in primary prevention of cancer and cardiovascular disease (CVD) remains unclear. The aim of this study was to identify women who benefit from alternate-day aspirin with regard to all relevant outcomes, including cancer, CVD and major gastrointestinal bleeding.

Methods: Long term follow-up data of 27 939 healthy women with baseline plasma samples in the Women's Health Study, a randomised trial of 100 mg alternate-day aspirin versus placebo, were used to develop competing risks models for individualised prediction of absolute risk reduction of the combination of CVD, cancer and major gastrointestinal bleeding by aspirin.

Results: Although aspirin was associated with a modestly decreased 15-year risk of colorectal cancer, CVD, and in some women non-colorectal cancer, aspirin treatment resulted in a negative treatment effect in the majority of women if gastrointestinal bleeding was also taken into account. The excess risk of major gastrointestinal bleeding by aspirin increased with age, but the benefits for colorectal cancer and CVD risk were also greater at higher age. Decision curves indicated that selective treatment of women ≥65 years may improve net benefit compared to treating all, none and prediction-based treatment. The observed 15-year number needed to treat to prevent one event among women ≥65 years was 29 (95% CI 12 to 102).

Conclusions: Concurrent evaluation of the absolute effects on cancer, CVD and major gastrointestinal bleeding showed that alternate-day use of low-dose aspirin is ineffective or harmful in the majority of women in primary prevention. Selective treatment of women ≥65 years with aspirin may improve net benefit.

Trial registration number: NCT00000479.

Keywords: CORONARY ARTERY DISEASE; MALIGNENCY.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Figures

Figure 1

Distribution of predicted 15-year absolute risk reduction for major cardiovascular events, colorectal cancer, non-colorectal cancer and major gastro-intestinal bleeding with aspirin treatment in the study population. ARR: absolute risk reduction; NNT/NNH: Number needed to treat/harm.

Figure 2

Distribution of predicted 15-year absolute risk reduction for the total of all outcomes (major cardiovascular events, colorectal cancer, non-colorectal cancer and major gastro-intestinal bleeding) applying different weights for gastro-intestinal bleeding, in participants in the Women’s Health Study. ARR: absolute risk reduction; NNT/NNH: Number needed to treat/harm.

Figure 3

Decision curves for different aspirin treatment strategies, with different weights applied to major gastro-intestinal bleeding: A. No weight (one bleeding is equal to one cardiovascular event or cancer diagnosis); B. Weight of 0.5 (two bleedings are equal to one cardiovascular event or cancer diagnosis); C. Weight of 0.25 (four bleedings are equal to one cardiovascular event or cancer diagnosis); D. Weight of 0.1 (ten bleedings are equal to one cardiovascular event or cancer diagnosis). Reading the net benefit plot starts with choosing a treatment threshold, that is the absolute risk reduction (ARR) at which one would opt for treatment, or number-willing-to-treat (NWT). A NWT of 30 implies that one is willing to treat 30 women to prevent at least 1 event. Since major gastro-intestinal bleeding is already incorporated in the total outcome, the treatment threshold is mainly chosen depending on how important one would deem less serious complications, inconvenience of taking pills and costs. Positive net benefit means that the treatment strategy led to a more favourable trade-off between benefits (observed decrease in event rate) and harms (the proportion of patients receiving treatment weighted by the reciprocal of the treatment threshold). For example, when using a weight of 0.25 for bleeding (panel C) and a NWT of 30 (treatment of all women with predicted risk reduction of 3.3% or more, i.e. a threshold of 3.3%), treating only women ≥ 65 years yields a positive net benefit of observed reduction in event rate – (proportion receiving treatment*treatment threshold) = 0.03748 – (0.11*0.033) = 0.12% and would be the optimal treatment strategy, whereas prediction-based treatment gives a net benefit of zero (predicted ARR are below the treatment threshold for all women, so equal to treating none) and treating all worseness clinical outcome (negative net benefit).