Long term aspirin therapy, even at a low dose, carries a risk of gastrointestinal haemorrhage, with a number needed to harm per year of 248. Although it would be preferable, for the purposes of comparison, to have a number needed to harm and a number needed to treat from the same trial or review, this may not always be feasible. It is possible, however, to obtain some idea of the trade-off between benefit and harm when using aspirin in patients with different cardiovascular risk levels by weighing up the pooled estimate of the number needed to harm against the number needed to treat from individual trials.
In the secondary prevention of stroke, for example, the number needed to treat per year with aspirin to prevent a further event was 106.w5 This means that if aspirin was used in patients with stroke who had similar baseline risks to those above, at least two recurrent strokes could be prevented at the cost of one gastrointestinal haemorrhage. The benefits of aspirin are less marked, however, in primary prevention of myocardial infarction—in the US physicians study, the number needed to treat per year was 555,w9 whereas the number needed to treat per year in hypertensive patients was 794.w3 Aspirin use in primary prevention could, depending on the baseline risks of the patients, cause two or three gastrointestinal haemorrhages for each myocardial infarction prevented.
As there are relatively few deaths after gastrointestinal haemorrhage (estimated death rate 12%10
) compared with myocardial infarction, such a trade-off may be considered worth while. Doctors and patients involved in making decisions about aspirin therapy need to consider carefully whether the inconvenience of long term therapy and the associated risk of gastrointestinal haemorrhage are outweighed by the potential cardiovascular benefits. This is particularly so for those at low absolute risk of cardiovascular events (with correspondingly high numbers needed to treat), in whom the likelihood of harm is greater than that of therapeutic benefit (as shown in the example above for hypertensive patients).
Although doctors have hoped that changes in the dose or formulation of aspirin might reduce the problem of gastrointestinal haemorrhage, the results of this meta-analysis do not suggest that either approach offers clear benefits. Our findings are supported by those of two recent case-control studies, in which aspirin increased the risk of gastrointestinal haemorrhage, despite the use of low dose or modified release formulations.11,12
The results of our meta-regression are compatible with those of a large Dutch trial of transient ischaemic attack in which no significant difference in the rate of gastrointestinal haemorrhage was found between two different doses of aspirin.13
In this study, aspirin was efficacious at a dose of 30 mg a day, but a threshold dose for either the therapeutic or adverse effects of aspirin has yet to be established, and further attempts at dosage reduction might compromise therapeutic efficacy before adverse effects are eliminated completely.
Insufficient evidence exists to support the view that modified release formulations are safer, in terms of gastrointestinal haemorrhage, than standard formulations. Here we have studied the effect of dose and formulation on the incidence of gastrointestinal haemorrhage only; it may be that other symptomatic gastrointestinal adverse effects, such as nausea and epigastric pain, can be significantly reduced.13
The incidence of gastrointestinal haemorrhage with aspirin is relatively low, and to avoid factors that could have led us to underestimate the risk, we set inclusion and exclusion criteria such that only trials of a certain quality, with adequate numbers and follow up, would be selected. Although there is some asymmetry in the funnel plot (see figure on BMJ
's website), suggesting the possibility of selection bias, adjustment for the likely effect of bias using “trim and fill” gave a pooled odds ratio of 1.62, which is only a slight change from our estimate of 1.68.14
Our meta-analysis seems reasonably robust to the asymmetry observed in the funnel plot.
We believe that the findings of our study are relevant to everyday practice. No significant heterogeneity was found, even though the studies we analysed encompassed a broad selection of patients with varying clinical indications. All the trials excluded patients at increased risk of gastrointestinal haemorrhage or with aspirin intolerance, but this is consistent with current advice on the use of aspirin and does not invalidate the relevance of our findings. Nevertheless, aspirin is available over the counter, and the risk of gastrointestinal haemorrhage could be higher in patients who take it without consulting a doctor.