Aspirin for primary prevention of coronary heart disease: safety and absolute benefit related to coronary risk derived from meta-analysis of randomised trials.

Abstract

Objective--To determine the cardiovascular and coronary risk thresholds at which aspirin for primary prevention of coronary heart disease is safe and worthwhile.

Design--Meta-analysis of four randomised controlled trials of aspirin for primary prevention. The benefit and harm from aspirin treatment were examined to determine: (1) the cardiovascular and coronary risk threshold at which benefit in prevention of myocardial infarction exceeds harm from significant bleeding; and (2) the absolute benefit expressed as number needed to treat (NNT) for aspirin net of cerebral haemorrhage and other bleeding complications at different levels of coronary risk.

Main outcome measures--Benefit from aspirin, expressed as reduction in cardiovascular events, myocardial infarctions, strokes, and total mortality; harm caused by aspirin in relation to significant bleeds and major haemorrhages.

Results--Aspirin for primary prevention significantly reduced all cardiovascular events by 15% (95% confidence interval (CI) 6% to 22%) and myocardial infarctions by 30% (95% CI 21% to 38%), and non-significantly reduced all deaths by 6% (95% CI -4% to 15%). Aspirin non-significantly increased strokes by 6% (95% CI -24% to 9%) and significantly increased bleeding complications by 69% (95% CI 38% to 107%). The risk of major bleeding balanced the reduction in cardiovascular events when cardiovascular event risk was 0.22%/year. The upper 95% CI for this estimate suggests that harm from aspirin is unlikely to outweigh benefit provided the cardiovascular event risk is 0.8%/year, equivalent to a coronary risk of 0.6%/year. At coronary event risk 1.5%/year, the five year NNT was 44 to prevent a myocardial infarction, and 77 to prevent a myocardial infarction net of any important bleeding complication. At coronary event risk 1%/year the NNT was 67 to prevent a myocardial infarction, and 182 to prevent a myocardial in farction net of important bleeding.

Conclusions--Aspirin treatment for primary prevention is safe and worthwhile at coronary event risk [greater than or equal to] 1.5%/year; safe but of limited value at coronary risk 1%/year; and unsafe at coronary event risk 0.5%/year. Advice on aspirin for primary prevention requires formal accurate estimation of absolute coronary event risk.

(Heart 2001;85:265-271)

Keywords: aspirin; coronary heart disease; primary prevention; meta-analysis

Aspirin reduces the risk of non-fatal myocardial infarction by 34%, [1] and in the setting of secondary prevention reduces non-fatal strokes by 31%, cardiovascular events by 27%, and cardiovascular deaths by 18%. [1] The relative risk reduction by aspirin appears constant, [1-3] and absolute benefit is therefore determined by absolute coronary heart disease or cardiovascular risk. [3] Aspirin causes cerebral [2] and other haemorrhages, [4-6] and this risk seems constant and independent of coronary heart disease risk. [3] The balance between benefit and harm is therefore related to absolute coronary heart disease risk. [3] When used for secondary prevention, the benefit from aspirin readily outweighs possible harm from major haemorrhage, [1 3 7] but in primary prevention the balance between benefit and harm is not clear cut. [1 3 7] Benefit will probably exceed harm in those at high risk, [3 7] but a safe threshold of coronary heart disease risk for primary prevention with aspirin has not been defined. [1] The question is important, because aspirin certainly can prevent non-fatal myocardial infarction when used for primary prevention. [4-6] Furthermore, 6-9% of healthy people take aspirin regularly. [8 9] The aims of this analysis were to define the threshold of absolute coronary heart disease risk at which aspirin treatment is safe, and to quantitate benefit and harm from aspirin treatment at different levels of coronary heart disease risk.

Methods

TRIALS

Randomised controlled trials of aspirin for primary prevention were sought by Medline search from 1985 onwards, using the terms cardiovascular disease and aspirin, and by scrutiny of previous meta-analyses and review articles. Additional prespecified criteria were that the studies had to report total cardiovascular events, myocardial infarction, stroke, bleeding complications, and all cause mortality as primary or secondary end points. We found four studies, one of unifactorial design [10] and three of multifactorial design. [4-6] In one factorial for coronary heart disease event risks of 0.5%, 1.0%, and 1.5% a year. The benefit and NNT for preventing myocardial infarction net of cerebral haemorrhage, of cerebral haemorrhage plus major bleed, and of cerebral haemorrhage plus all non-minor bleeds were calculated at these same coronary heart disease event risk levels. The risk of all bleeding complications was assumed constant, independent of coronary heart disease risk. Confidence intervals for estimates of NN T were calculated as described by Altman. [14]

Results

TRIALS OF ASPIRIN FOR PRIMARY PREVENTION

Four randomised controlled trials, the US physicians health study, [4] UK doctors study, [10] thrombosis prevention trial, [5] and the HOT study [6] included 48 540 people, of whom 25 133 were treated with aspirin. …