Letters

Aspirin for primary prevention

Treatment policy should be based on all trial evidence, not subgroup analysis

Doctors and patients should understand potential benefits and risks of aspirin treatment

Treatment policy should be based on all trial evidence, not subgroup analysis

EDITORWe have suggested that aspirin for primary prevention is safe and worthwhile when the estimated 10 year coronary risk is >15%, provided that any hypertension is controlled.¹ This conclusion comes from conservative interpretation of a meta-analysis examining the balance of benefit and risk in four large randomised controlled trials of aspirin for primary prevention, and fully supports recommendations in the Joint British Societies and British Hypertension Society guidelines.² One assumption central to this analysis, and to these guidelines, is that relative risk reduction by aspirin is constant, so that the magnitude of benefit from aspirin is determined by pretreatment coronary risk.

Unfortunately, Meade et al did not examine this assumption in their subgroup analysis of the thrombosis prevention trial.³ Rather, they present subgroup analyses according to individual risk factors (systolic blood pressure, age, and cholesterol concentration). These analyses are not really apposite to the guidelines and may even be misleading. For example, their results suggest little benefit (6% reduction in coronary heart disease) or even harm (8% increase in all cardiovascular events) from aspirin when systolic blood pressure exceeds 145 mm Hg. In the physicians' study in the United States there was a substantial (35%) reduction in coronary events at systolic blood pressure >150 mm Hg.⁴ In the hypertension optimal treatment study, men with hypertension that was controlled from 168/106 mm Hg to an average of 140/83 mm Hg, which is still "high normal," had a coronary reduction of 42% (P=0.001) and a 13% reduction in all cardiovascular events.⁵ The important point is that subgroup analysis of the thrombosis prevention trial is certainly not representative of all the trial evidence available.

Similar discrepancies are present in the findings for age. At age 65 and over this subgroup analysis suggests a 29% increase in coronary heart disease, but a 41% reduction in stroke, with aspirin. As the authors note, this is totally inconsistent with the physicians' study, which showed coronary reductions of 44% at ages 60-69 and 41% at ages 70-84.⁴ In the hypertension optimal treatment study, treated hypertensive patients aged 65 and over had reductions in coronary heart disease of 38% and all cardiovascular events by 21%.⁵

The treatment policy for aspirin for primary prevention should be based on all the trial evidence and estimation of absolute risk of coronary heart disease,² not on subgroup analysis of a single trial or on a single coronary risk factor.

Lawrence E Ramsay, professor of clinical pharmacology and therapeutics. 
a.lee{at}sheffield.ac.uk

Philemon S Sanmuganathan, lecturer. 
Erica J Wallis, research fellow. 
Peter R Jackson, reader. 
Department of Clinical Pharmacology and Therapeutics, Royal Hallamshire Hospital, Sheffield S10 2JF

Doctors and patients should understand potential benefits and risks of aspirin treatment

EDITORI echo Meade et al's concern that the subgroup findings in their paper must be interpreted with caution.¹ In the hypertension optimal treatment trial the use of 75 mg aspirin was associated with the prevention of 1.5 myocardial infarctions (2.5 in patients with diabetes) per 1000 patients treated for one year.² It will be interesting to learn if a subgroup analysis of the diabetic patients in Meade et al's study is possible. In the nurses' health study the reduction in occlusive infarction of a large artery was greater for older or hypertensive women.³

Although the nurses' health study is a prospective cohort study, it is the best available evidence for the use of aspirin in primary prevention of stroke and coronary artery diseases in women. Confirmatory data on the role of aspirin in primary prevention in women await results of ongoing randomised controlled clinical trials.

In He et al's meta-analysisa large meta-analysis of 16 trials, including the British doctors' and the United States physicians' trialsaspirin treatment was associated with an absolute increase in risk of haemorrhagic stroke of 12 events per 1000 people (95% confidence interval 5 to 20; P<0.001).⁴ The mean dose of aspirin in this meta-analysis was 273 mg and the mean duration of treatment 37 months.

The meta-analysis showed that the increase in the absolute risk of haemorrhagic stroke is not related to patient characteristics, such as age, hypertension, and hyperlipidaemia. The pooled odds ratio for haematemesis was 1.5 in Roderick et al's overview of 21 randomised controlled trials, with average follow up of 3.85 years.⁵

The Canadian and the United States Preventive Services Task Forces do not make recommendations for or against the use of aspirin in asymptomatic patients for the primary prevention of cardiovascular diseases. If aspirin treatment is considered, doctors and patients should understand the potential benefits and risks of the treatment before starting it.

Abdullah Alkhenizan, clinical fellow, University of Toronto, Sunnybrook Hospital. 
211 St Patrick Street, Apt#506C, M5T 2Y9, Toronto, Ontario, Canada alkhenizan{at}sprint.ca