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Heart Online First, published on December 4, 2014 as 10.1136/heartjnl-2014-306770 Editorial

Aspirin use in women for primary prevention Marco M Ferrario, Giovanni Veronesi At present, there is no consensus on antiplatelet treatments in primary prevention, particularly for women. European guidelines on cardiovascular disease (CVD) prevention1 do not recommend antiplatelet therapy, while the American Heart Association guidelines for primary prevention2 support a daily treatment of low-dose aspirin in women aged >65 years. The US Food and Drug Administration at the beginning of this year stated that the agency “does not believe the evidence supports the general use of aspirin for primary prevention of a heart attack or stroke. In fact, there are serious risks associated with the use of aspirin, including increased risk of bleeding in the stomach and brain, in situations where the benefit of aspirin for primary prevention has not been established”. A meta-analysis including nine controlled and randomised clinical trials (CRCT)3 well-summarised major evidences holding such endorsements: the risk reduction of 20% for non-fatal myocardial infarction in the aspirin treatment group corresponding to a number-needed-to-treat (NNT) of 162 did not balance the 31% increased risk of ‘non-trivial’ bleeding events with a number needed to harm (NNH) equal to 73. For a more comprehensive understanding of the balance between benefits and harms of aspirin treatment, we need to take into account recent scientific reports on the protective effect of acetyl salicylic acid (ASA) with respect to some forms of cancer. Evidences from both CRCT and observational studies lead to conclude that a daily use of low-dose aspirin has a clear protective effect on colorectal and other gastrointestinal cancers in healthy people even if the effect appears generally after 10 years of follow-up.4 OR for all gastrointestinal cancers when comparing aspirin users versus non-users resulted to be 0.62, 95% CI 0.55 to 0.70 in observational

Department of Clinical and Experimental Medicine, University of Insubria at Varese, Varese, Italy Correspondence to Professor Marco M Ferrario, Research Centre for Epidemiology and Preventive Medicine (EPIMED), Department of Clinical and Experimental Medicine, University of Insubria, Via O Rossi 9, Varese I-21100, Italy; [email protected]

studies and 0.54, 95% CI 0.42 to 0.70 in CRCT. It is worth noticing the concordance in the association estimates between clinical trials and epidemiological studies, which usually include unselected subjects with more concomitant comorbidities. A first attempt to estimate the combined balance between benefits and harms of low-dose, daily ASA use was reported in a 2012 meta-analysis of CRCT only.5 In six trials conducted in the primary prevention setting, a daily low-dose treatment was found to reduce the hazard of CVD, cancer or bleeding by 8%; the effects on cumulative risk becoming evident from 6 years on. Interestingly, the reported data showed clear time-dependent effects: the risk of major bleeding concentrated during the first three follow-up years, supporting the hypothesis that the identification of subjects at high risk of bleeding may be crucial. The authors concluded in favour of the ASA treatment after the first 3 years of follow-up and claimed that the results can be applied to men and women even if a gender-specific stratified analysis was not extensively reported. All these evidences paved the road to new research questions: first, whether stratification based on patients’ characteristics can be more effective than unselected drug allocation to maximise the benefits of ASA treatment; and second, since cancer risk reduction seems to be time dependent, to estimate the global or ‘combined’ risks and benefits on longer time periods. The former question requires a specific methodological approach that was addressed by an earlier report from the Women’s Health Study (WHS),6 allowing the authors to conclude that aspirin treatment in women was ineffective or even harmful in the majority of patients when considering the cardiovascular endpoint only. Their assessment is based on the absolute risk reduction (ARR), an index of individualised predicted treatment effect, calculated as the difference between the predicted risk of CVD events without and with the treatment for each studied woman. While medical research often reports on the average effect for the ‘average patient’ of a given treatment (but as we know such patient does not exist in the ‘real word’), the ARR approach allows Ferrario MM, et al. Heart Month 2014 Vol 0 No 0

identifying subgroups of subjects who would more likely experience higher-than-average treatment net effect. Then the net benefit, as a balance between favourable and harmful effects, for different treatment strategies—in addition to treat no one and treat everyone— can be estimated and compared. This paper did not consider the ASA protective effect on long-term colorectal cancer incidence. In their Heart paper Rod van Kruijsdijk and colleagues7 from WHS extended the methodology to estimate the 15-year ARRs for CVD, cancer and bleeding outcomes in a competing risk setting. This approach allows them to estimate a combined ARR, as the sum of single outcome ARRs, and to attribute to bleeding different weights, acknowledging the relative importance with respect to the two other outcomes. Major results are summarised in table 2 of the paper, where a positive ARR value corresponds to an individualised NNT (iNNT) and a negative value to an individualised NNH (iNNH). ARR of 0.27% for major cardiovascular event in the entire population corresponds to an iNNT of 371 women to be treated to prevent an event, with a lower and upper limit of 116 and >1000, respectively. ARR of major gastrointestinal bleeding is −0.75%, corresponding to an iNNH of 133, which means that one adverse event is expected to occur every 133 treatments. The overall ARR of −0.42% corresponds to 1 adverse outcome every 238 treated women, supporting authors’ conclusion of no indication for treatment in the healthy women population, as the protective effect on CVD and colorectal cancer is completely outweighed by an increased risk of major bleeding and non-colorectal cancers. Conversely, in the subgroup of women aged 65 or more, the overall ARR rose to +3.39%, corresponding to an iNNT of 29. The decision curve analysis helps translating this finding into a public health perspective, identifying the number willing to treat, as the maximum number of healthy women physicians is ready to treat in order to prevent one combined event (CVD or cancer net of bleedings) during a certain time span. When the harmful effects of bleedings are weighted one-fourth and one-tenth with respect to the other outcomes, there would still be the need to treat 703 and 393 women to prevent one event, respectively, with an upper bound of the confidence interval for the iNNT of >1000. The weighted analysis fills in a gap in knowledge on the controversial topic of the relative importance of bleedings with 1

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Editorial respect to CVD and cancer. Moreover, from these last findings, one can also argue that a personalised treatment approach based on pharmacogenomics aiming to a better identification of women more prone to bleedings will probably not end up with sensible advantages. In conclusion, when balancing combined long-period ASA benefits on CVD and cancer with its harmful effects, taking into account the individual risk profile for each investigated outcome, these WHS results support no treatment indications with alternate-day low-dose aspirin in healthy women. In women aged 65 years or more, the question becomes whether it is meaningful to treat more than 32 healthy subjects for 15 years at least in order to prevent one combined event during the same time span. Despite the results of some clinical trials not showing a reduction in clinical outcome in patients with diabetes attributable to ASA treatment, further evidences are needed for subjects at high CVD risk or with metabolic syndrome as this last condition seems to be characterised by a reduction in the protective effect of high-density lipoprotein cholesterol,8 which plays a relevant role in women. Another path


of future research is to improve risk estimation through new biomarkers that could help identify men and women at high risk more accurately.


Contributors MMF wrote the editorial and GV provided support for the interpretation of the statistical analysis and helped in writing.


Competing interests None. Provenance and peer review Commissioned; internally peer reviewed.


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societies and by invited experts). Eur Heart J 2012;33:1635–701. Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women–2011 update: a guideline from the American Heart Association. Circulation 2011;123:1243–62. Seshasai SR, Wijesuriya S, Sivakumaran R, et al. Effect of aspirin on vascular and nonvascular outcomes. Meta-analysis of Randomized Controlled Trials. Arch Intern Med 2012;172:209–16. Algra AM, Rothwell PM. Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. Lancet Oncol 2012;13:518–27. Rothwell PM, Price JF, Fowkes FG, et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet 2012;379:1602–12. Dorresteijn JA, Visseren FL, Ridker PM, et al. Aspirin for primary prevention of vascular events in women: individualized prediction of treatment effects. Eur Heart J 2011;32:2962–9. van Kruijsdijk R, Visseren F, Ridker P, et al. Individualized prediction of alternate-day aspirin treatment effects on the combined risk of cancer, cardiovascular disease and gastro-intestinal bleeding in healthy women. Heart 2014, 10.1136/heartjnl2014-306342 Gianfagna F, Veronesi G, Guasti L, et al. Do apolipoproteins improve coronary risk prediction in subjects with metabolic syndrome? Insights from the North Italian Brianza cohort study. Atherosclerosis 2014;236:175–81.

Ferrario MM, et al. Heart Month 2014 Vol 0 No 0

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Aspirin use in women for primary prevention Marco M Ferrario and Giovanni Veronesi Heart published online December 4, 2014

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