17 February, 2014

Once in a while the question whether or not low-dose aspirin should be recommended for primary prevention of cardiovascular disease is put on the table, analyzed and debated, but still there is no clear-cut recommendation. Patrono has recently provided another overview on this topic [1]. Low-dose aspirin has been shown to be effective in preventing about one-fifth of atherothrombotic vascular complications (non-fatal myocardial infarction, non-fatal stroke, or vascular death) in a meta-analysis of 16 secondary prevention trials in patients with previous myocardial infarction, stroke, or transient cerebral ischemia. This corresponds to an absolute reduction of about 10-20 per 1000 patients in the yearly incidence of non-fatal events, and to a smaller, but still definite, reduction in vascular death. Against this benefit, the absolute increase in major extracranial bleeding complications (mostly, gastrointestinal) is 20- to 50-fold smaller, depending on age and sex. Hence, for secondary prevention, the benefits of antiplatelet therapy substantially exceed the risks. For primary prevention, the balance between vascular events avoided and major bleeds caused by aspirin is substantially uncertain because the risks without aspirin, and hence the absolute benefits of antiplatelet prophylaxis, are at least an order of magnitude lower than in secondary prevention. For many people without pre-existing vascular disease, the cardiovascular benefits of adding long-term aspirin to other, safer, forms of primary prevention (e.g. statins and antihypertensive drugs) are likely to be of similar magnitude as the hazards [2].

Comment

In 2009, the US Preventive Services Task Force published its recommendations on the use of aspirin for primary prevention of cardiovascular disease [3]. It acknowledged the contribution of age and gender to the benefit–risk assessment by stating 'Encourage men age 45–79 years to use aspirin when the potential benefit of a reduction in myocardial infarctions outweighs the potential harm of an increase in gastrointestinal hemorrhage. Encourage women age 55–79 years to use aspirin when the potential benefit of a reduction in ischemic strokes outweighs the potential harm of an increase in gastrointestinal hemorrhage. Do not encourage aspirin use for prevention in women younger than 55 years and in men younger than 45 years.' The report included some instructions on how to calculate the cardiovascular risks according to the individual case scenario, but in fact left many vague edges. The latest, 2012 version of the European Guidelines on cardiovascular disease prevention, a joint project by the European Society of Cardiology and the European Association for Cardiovascular Prevention & Rehabilitation addressed the role of aspirin in a very short statement [4]: 'Aspirin cannot be recommended in individuals without overt cardiovascular disease risk due to its increased risk of major bleeding.'

For the lay physician and the patients measuring the benefit–risk balance is much easier when absolute numbers are used, rather than percentage changes or hazard ratio values. In the set-up of primary prevention, the use of aspirin was associated with 12% proportional reduction in serious vascular events (0.51% aspirin vs. 0.57% control per year, p = 0.0001) [2]. Puhan and colleagues published recently an update on this issue and discussed various aspects of presenting the benefits and risks as numbers needed to treat (NNT) and numbers needed to harm (NNH) [5]. These numbers for aspirin decline with increasing age because of the increase in baseline incidence rates for all outcomes across age categories. For example, in women aged 45–54, the NNT was 5953 person-years of treatment to prevent one myocardial infarction (MI), and the NNH was 404 person-years of treatment to induce one major gastrointestinal (GI) bleed. However, for women aged 65–74, the NNT was 1520 to prevent one MI and the NNH was 108 to induce one major GI bleed. This balance in women was rightly interpreted as pointing against the use of aspirin to prevent MI. The figures for stroke within the age range 65–74 were totally different, with NNT of 2137 for ischemic stroke, but NNH for hemorrhagic stroke being only 5715, thus favoring its use for primary prevention of ischemic stroke. For men the situation was vice versa, with more benefit over risk in regard to MI, but more risk than benefit in regard to ischemic stroke. Puhan and colleagues also stressed the fact that 'The assessment of benefits and harms requires careful selection and integration of data from disparate sources, including baseline risks of events without treatment, the effects of treatments on various outcomes, and relative weights of these outcomes' [5]. It seems therefore that aspirin is used relatively liberally but without a solid clinical basis for primary prevention of cardiovascular diseases in women. In addition, the current guidelines are derived from information retrieved from a relatively small number of large-scale studies. This is well known to experts and policy makers, who wait for the results of further, ongoing studies, which will hopefully close the gaps and provide additional information to cover the outcomes of low-dose aspirin in patients with a higher cardiovascular risk, such as elderly patients, patients with diabetes mellitus, or with a cluster of risk factors. In the meantime, generalized decisions in this respect may not be appropriate, and a personalized approach based on current data and clinical judgment is warranted.

Amos Pines
Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

References

1. Patrono C. Low-dose aspirin in primary prevention: cardioprotection, chemoprevention, both, or neither? Eur Heart J 2013;34:3403-11
http://www.ncbi.nlm.nih.gov/pubmed/23771843 

2. Baigent C, Blackwell L, Collins R, et al. 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
http://www.ncbi.nlm.nih.gov/pubmed/19482214 

3. US Preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: US Preventive Services Task Force Recommendation Statement. Ann Intern Med 2009;150:396–404 
http://www.ncbi.nlm.nih.gov/pubmed/19293072 

4. Perk J, De Backer G, Gohlke H, et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). Eur Heart J 2012;33:1635-701
http://www.ncbi.nlm.nih.gov/pubmed/22555213 

5. Puhan MA, Singh S, Weiss CO, et al. Evaluation of the benefits and harms of aspirin for primary prevention of cardiovascular events: A comparison of quantitative approaches. Rockville (MD): Agency for Healthcare Research and Quality (US); 2013 Nov
http://www.ncbi.nlm.nih.gov/books/NBK179079/