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Aspirin for all? No

Ami Banerjee
Last edited 7th June 2009
Since medical school, I have always been struck by the number of patients of all ages who live life by the “aspirin-a-day” mantra. In people who have had heart attacks or strokes, aspirin reduces further events by 25%. This beneficial effect is known as “secondary prevention”, and outweighs aspirin’s bleeding risk [1, 2]. However, the role of aspirin in primary prevention (i.e. in patients who have not yet had a heart attack or stroke) has been less clear because the risks of heart attacks and stroke are lower in these patients. Therefore, the measurable benefit of aspirin will be less, especially when we consider it against the bleeding risk. However, current guidelines tend to recommend aspirin in people at risk of heart attacks and ignore the bleeding risk [3]. Alternatively, they advocate aspirin for all patients above a certain age, either alone or in combination with other drugs [4, 5]. As an example, for diabetic patients, there is no trial data to suggest use of aspirin in primary prevention of cardiovascular disease, and yet it is widely used [6]. Thankfully, the big guns of meta-analysis (studying overall effects of drugs across different randomised controlled trials), the Antithrombotic Trialists' (ATT) Collaboration in Oxford, have put our doubts to bed. They looked through the individual patient data for an astounding 95 000 patients at low risk of cardiovascular disease, in 22 different trials to answer this question [7]. The main finding was a 12% reduction in serious vascular events per year with a 20% reduction in heart attacks, but no significant reduction in stroke. There was a 54% increased risk of major bleeding in patients taking aspirin compared with no aspirin. Interestingly, the risk factors for coronary heart disease also predicted risk of bleeding complications. Most people were not taking cholesterol-reducing statin therapy during the trials. Statins have been shown to half the risk of cardiovascular disease and are now widely used, so the authors speculate that the actual cardiovascular benefit of aspirin in primary prevention may now be even less. The bottom line is that we should only give aspirin to people after and not before they have had heart attacks or stroke.
  1. Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ. 1994 Jan 8;308(6921):81-106. Antithrombotic Trialists' Collaboration.
  2. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002 Jan 12;324(7329):71-86. Antithrombotic Trialists' Collaboration.
  3. JBS 2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice. Heart. 2005 Dec; 91 Suppl 5:v1-52. British Cardiac Society; British Hypertension Society; Diabetes UK; HEART UK; Primary Care Cardiovascular Society; Stroke Association.
  4. Aspirin for everyone older than 50? For. BMJ. 2005 Jun 18;330(7505):1440-1. Review. Elwood P, Morgan G, Brown G, Pickering J.
  5. A strategy to reduce cardiovascular disease by more than 80%. BMJ. 2003 Jun 28; 326:1419. Wald NJ, Law MR.
  6. Primary prevention of cardiovascular events in diabetes: is there a role for aspirin? Nat Clin Pract Cardiovasc Med. 2009 Mar; 6(3):168-9. Price HC, Holman RR.
  7. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009 May 30; 373:1849-60. Antithrombotic Trialists' (ATT) Collaboration, Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, Buring J, Hennekens C, Kearney P, Meade T, Patrono C, Roncaglioni MC, Zanchetti A.

What about people who may be at higher risk of stroke?

Is there any evidence of aspirin benefit in people who have a known risk factor for stroke, but who haven't had one? For example, I have a slightly dodgy mitral valve, and was told I should be on Warfarin, but I refused as it would interfere with my lifestyle too much (I commute to work by bike, and would have to stop if on Warfarin). So the GP told me to take aspirin instead. Which I do - but now I wonder if it's worth bothering.

Yet more evidence against aspirin in primary prevention

At the European Society for Cardiology Congress this week, we learned about more situations where aspirin is unhelpful. Professor Gerry Fowkes and colleagues from Edinburgh looked at nearly 30000 men and women aged 50 to 80 years who had never had any cardiovascular disease. The ankle brachial index (ABI) is the ratio of the blood pressure in the arm to the blood pressure at the ankle, and is an indicator atherosclerosis that cannot be picked up by doctors. The ABI predicts risk of major vascular events in healthy populations, independently of established cardiovascular risk factors, such as diabetes, smoking and cholesterol. The Edinburgh team recruited over 3000 people with low ABI from their population and randomised them to 100mg aspirin or placebo, with 8 years of follow-up.

There was no difference between aspirin and placebo whether we look at cardiovascular events or all cause mortality, and there were more major bleeds in the aspirin arm of the trial. Same bottom line as before: do not give aspirin to people before they have a vascular event.

Absolute reduction in MI vs absolute increase in bleeding

Many thanks for the comment.

This meta-analysis showed that the patients who you are most likely to give aspirin for primary prevention (those at high risk of coronary heart disease: high cholesterol, diabetes, smoking etc) are precisely the people who are at highest risk of GI bleeding.

The investigators do not report the data stratified by risk factors for bleeding. However, looking through the trials that were included, there is no evidence that there were different proportions of people with high bleeding risk between the aspirin and control arms of the individual trials. Therefore it seems that aspirin is responsible for the difference in bleeding.

The authors state, "Figure 6 suggests that (irrespective of age or sex) the absolute reduction in occlusive events would be only about twice as large as the absolute increase in bleeding". This means that we have to consider the bleeding risk more seriously in primary prevention than we would in secondary prevention, and weigh up the cost and benefit of aspirin in each patient.

Bleed risk should be viewed in context

While I agree that the evidence is unequivocal for secondary prevention and less strong for primary prevention -- the 54% rate of "major bleed" should be viewed in terms comparable to the events prevented. How many people have you seen have had a major GI bleed leading to death or long-term disability from a baby aspirin per day? If you select out the clearly high-risk (e.g. on steroids, past GI-bleeds, etc.) then I challenge you to find even one such patient taking baby aspirin. On the other hand, the 20% reduction in heart attacks and 12% reduction in strokes is life-changing -- these patients might have morbid events from not taking aspirin.

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