200,000 high-risk individuals and 95,000 low-risk participants

High risk individuals:

• 2002 analyses

• BMJ 2002; 324: 71-86

Low risk individuals:

• 2009 analyses

• Lancet 2009; 373: 1849-60

(PDF of the main article and web materials at The Lancet website)

• Press release: Aspirin in primary prevention: overall benefit is uncertain (PDF) (29 May 2009)

Publications

Funders

Objectives

The ATT was set up to provide reliable updated information about the benefits and hazards, among particular types of patients, of anti-thrombotic therapy.

Results

2002 analysis: 200,000 high-risk individuals in 287 studies

In 2002, the ATT published analyses of all unconfounded randomised trials of antiplatelet therapy among patients with occlusive vascular disease. Data on vascular events were available from 195 trials comparing an antiplatelet regimen versus control, and 89 trials comparing one antiplatelet regimen versus another antiplatelet regimen. Overall, allocation to antiplatelet therapy reduced vascular events by about one quarter in a wide range of patients (figure). Non-fatal MI was reduced by one third, non-fatal stroke by one quarter, and vascular mortality by one sixth (with no apparent adverse effect on other deaths). There were substantial reductions in the absolute risk of a serious vascular event, with 10-20 such events avoided for each year of treatment among people with a history of occlusive vascular disease, and similar reductions within around a month of treatment among people with acute occlusive disease (figure). In each of these high-risk categories, the absolute reductions in vascular events were 10-20 times greater than the absolute risks of major extracranial bleeding. There were also separately significant reductions in serious vascular events among the “other high risk” patients with stable angina (p=0.0005), peripheral arterial disease (p=0.004), and atrial fibrillation (p=0.01).

Aspirin was the most widely studied antiplatelet drug. Indirect and direct comparisons suggested that doses of 75-150mg daily were at least as effective as higher daily doses, and were associated with a lower risk of major extracranial bleeding (figure, figure, figure). The effects of doses lower than 75 mg daily were less certain. Clopidogrel produced a proportional reduction of around 10% in serious vascular events as compared to aspirin, which was similar to the 12% reduction observed with its thienopyridine analogue ticlopidine. Addition of dipyridamole to aspirin produced no significant further reduction in vascular events compared with aspirin alone. Among patients at high risk of immediate coronary occlusion, short term addition of an intravenous glycoprotein IIb/IIIa antagonist to aspirin prevented a further 20 vascular events per 1000 (p<0.0001), but caused 23 major (but rarely fatal) extracranial bleeds per 1000.

Press release: Over 40,000 Lives Lost Worldwide Every Year Because Aspirin is Underused (11 January 2002)

Collaborators

The names of collaborators can be found in the supplementary web materials of the BMJ paper.

2009 analyses: 95,000 low-risk individuals in 6 primary prevention trials

The 2002 ATT analyses showed that aspirin, or some other antiplatelet regimen, was of clear net benefit for those who already have occlusive vascular disease. For primary prevention, however, the balance between risks and benefits was less clear.

In an attempt to assess whether aspirin was of net benefit to individuals without previous disease, we undertook meta-analyses of serious vascular events (myocardial infarction, stroke, or vascular death) and major bleeds in six primary prevention trials (95 000 individuals at low average risk, 660 000 person-years, 3554 serious vascular events) and, by way of comparison, in 16 secondary prevention trials (17 000 individuals at high average risk, 43 000 person-years, 3306 serious vascular events) that compared long-term aspirin versus control.

In the primary prevention trials, aspirin allocation yielded a 12% proportional reduction in serious vascular events (0·51% aspirin vs 0·57% control per year, p=0·0001), due mainly to a reduction of about a fifth in non-fatal myocardial infarction (0·18% vs 0·23% per year, p<0·0001) (figure). The net effect on stroke was not significant (0·20% vs 0·21% per year, p=0·4: haemorrhagic stroke 0·04% vs 0·03%, p=0·05; other stroke 0·16% vs 0·18% per year, p=0·08) (figure,figure,figure,figure,figure). Vascular mortality did not differ significantly (0·19% vs 0·19% per year, p=0·7) (figure). Aspirin allocation increased major gastrointestinal and extracranial bleeds (0·10% vs 0·07% per year, p<0·0001) (figure), and the main risk factors for coronary disease were also risk factors for bleeding (table). In the secondary prevention trials, aspirin allocation yielded a greater absolute reduction in serious vascular events (6·7% vs 8·2% per year, p<0.0001), with a non-significant increase in haemorrhagic stroke but reductions of about a fifth in total stroke (2·08% vs 2·54% per year, p=0·002) and in coronary events (4·3% vs 5·3% per year, p<0·0001). In both primary and secondary prevention trials, the proportional reductions in the aggregate of all serious vascular events seemed similar for men and women (figure).

In secondary prevention trials, aspirin is of substantial net benefit (irrespective of age or gender), it reduces non-fatal vascular events by much more than it would increase major extracranial bleeds, and—despite any adverse effects on cerebral haemorrhage—it reduces overall vascular mortality (figure). Nowadays, however, patients with a history of occlusive stroke or MI would probably have their risks of recurrence reduced substantially by statins, other modern drugs, and, where appropriate, vascular procedures. For occlusive vascular events, the relative risks produced by these other interventions and by aspirin may well be approximately multiplicative. If so, and if the other interventions approximately halve the recurrence risk, then the absolute benefit of adding aspirin to these other methods might only be about half as great as that of giving aspirin alone. Still, for secondary prevention, the net benefits of adding aspirin would substantially exceed the bleeding hazards, irrespective of age or gender.

In the primary prevention trials, however, the absolute risk of a serious vascular event was an order of magnitude less than in the secondary prevention trials, and the absolute reduction in occlusive events only about twice as large as the absolute increase in bleeding. Moreover, these trials of aspirin were mainly in people who were not taking statin therapy, which would have reduced both MI and stroke with little hazard. Generic statins are now widely available at low cost so—because of their efficacy and safety—primary prevention by a statin is likely to be preferred to primary prevention just by aspirin. If so, then one of the main questions for aspirin in primary prevention is whether it is worthwhile to add it to a statin (or to some statin-based combination of measures). If the risk of occlusive vascular disease is already approximately halved by statins and/or other measures then the further absolute benefit of adding aspirin could well be only about half as big as was suggested by these primary prevention trials, but the main bleeding hazards would remain (figure). In that case, the benefits and hazards of adding long-term aspirin in people without pre-existing disease might be of approximately similar magnitude.

Most current guidelines assume that the absolute risk of bleeding remains approximately constant irrespective of CHD risk, whereas the present analyses found that the main risk factors for CHD are also risk factors for bleeding (figure). Even for those at moderately elevated risk of CHD , the absolute benefits and hazards of adding aspirin to a statin-based primary prevention regimen could still be approximately evenly balanced (figure).

A nonfatal stroke or heart attack is more likely to result in long-term disability than a non-fatal gastrointestinal (or other extracranial) bleed, but the net reduction in disabling or fatal occlusive events is likely to be small, and at least partially offset by an increase in intracerebral bleeds. Hence, although the currently available trial results could well help inform personally appropriate judgements by individuals about their own use of long-term aspirin, they do not appear to justify general guidelines advocating the routine use of aspirin among all apparently healthy individuals above a moderate level of CHD risk.

Press releases

• University of Oxford press release

• MRC press release

Writing Committee

• Colin Baigent (CTSU, University of Oxford)
• Lisa Blackwell (CTSU, University of Oxford)
• Rory Collins (CTSU, University of Oxford)
• Jonathan Emberson (CTSU, University of Oxford)
• Jon Godwin (CTSU, University of Oxford)
• Richard Peto (CTSU, University of Oxford)
• Julie Buring (Brigham and Women's Hospital, Harvard University, Boston)
• Charles Hennekens (Charles E Schmidt College of Biomedical Science and Center of Excellence, Florida Atlantic University, Boca Raton, Florida)
• Patricia Kearney (Department of Medical Gerontology, Trinity College Dublin)
• Tom Meade (London School of Hygiene and Tropical Medicine)
• Carlo Patrono (Catholic University School of Medicine, Rome)
• Maria Carla Roncaglioni (Mario Negri Institute, Milan)
• Alberto Zanchetti (Istituto Auxologico Italiano, University of Milan)

Publications

• Antithrombotic Trialists' Collaboration: Collaborative meta-analysis of randomised trials for prevention of death, myocardial infarction, and stroke in high risk patients BMJ 2002; 324: 71-86.

• Antithrombotic Trialists' Collaboration: Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials Lancet 2009; 373: 1849-60.

Funders

Sources of funding of each individual trial are described in its publications. The CTSU is supported by a core grant from the UK MRC, the BHF, and Cancer Research UK, and has previously received funding from the European Community Biomed Programme. CB is supported by the MRC, RC by a BHF Personal Chair, and JE by a BHF Intermediate Research Fellowship awarded through the University of Oxford 's BHF Centre for Research Excellence.