Tuesday, 7 June 2011

Mark Nelson, risk of bleeding with Asprin, Peter Rothwell reply

reposted from:
crabsallover highlightskey pointscomments / links.

Mark Nelson

Although Peter Rothwell and colleagues 1 provide the strongest evidence to date for the effect of aspirin in cancer prevention, they do not consider the well known adverse effects of aspirin, and focused on one potential benefit of aspirin in a study largely confined to middle-aged men.

Risk and benefit increase with age.2 Although the results look impressive when presented in proportional reduction terms, they are less so in “real” terms (14 000 people took aspirin for at least 4 years for a saving of about 100 cancer deaths). It is important, therefore, to be aware that a small proportion of those who develop serious adverse events, such as haemorrhagic stroke and major gastrointestinal bleeding, could reduce or reverse the benefi t.2–4

In older people, for whom serious adverse events are much more common and their consequences potentially more serious, the risk/benefi t equation will probably be different. The ASPirin in Reducing Events in the Elderly (ASPREE) trial5 examines whether the benefits of daily aspirin outweigh the risks in people aged 70 years or older. The ASPREE primary endpoint is extension of life free from dementia and disability. The trial will be able to show the true overall benefi t of routine use of aspirin in older people for primary prevention beyond simply counting individual adverse events.

I have received travel support from Bayer Healthcare—a manufacturer of aspirin. This company is also providing aspirin for ASPREE, of which I am a principal investigator. Mark Nelson Menzies Research Institute/University of Tasmania, Private Bag 23, Hobart, Tasmania 7001, Australia

1 Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 2011; 377: 31–41.
2 Hernandez-Diaz S, Rodriguez LA. Incidence of serious upper gastrointestinal bleeding/ perforation in the general population: review of epidemiologic studies. J Clin Epidemiol 2002; 55: 157–63.
3 He J, Whelton PK, Vu B, Klag MJ. Aspirin and risk of hemorrhagic stroke: a meta-analysis of randomized controlled trials. JAMA 1998; 280: 1930–35

Peter Rothwell Reply
Mark Nelson raises the issue of the risk of bleeding on aspirin. We deliberately made no specific recommendations about the widespread use of aspirin in healthy individuals, but we did discuss the issue of bleeding in some detail. Our analyses showed that taking aspirin daily for 5–10 years would reduce all-cause mortality (including any fatal bleeds) during that time by about 10% in relative terms. Subsequently, there would be further delayed reductions in risk of cancer death even if aspirin was stopped. In healthy middle-aged individuals, the risk of major bleeding on aspirin is relatively low (about 0·2 per 1000 patients per year—only a small proportion of which are fatal),3 and is already off set in many groups by the small reduction in risk of ischaemic vascular events.3 The reduction in risk of cancer is therefore additional to this existing balance in which the bleeding risk is already taken into account. However, the risk of bleeding on aspirin increases steeply with age and so we did not comment on use of aspirin in healthy individuals older than 75 years. The results of the ASPREE trial will be of great importance in this respect.

We agree with L H Opie that, in individuals without previous vascular events, both the relative and absolute reductions in risk of death due to cancer on aspirin versus control are larger than the equivalent reductions in risk of fatal vascular events, and that eff ects on cancer outcomes will dominate the overall risk/benefi t equation, particularly when the delayed eff ects on cancer death beyond the end of the trials is also factored in.

I have received honoraria for talks, advisory boards, and clinical trial committees from several pharmaceutical companies with an interest in antiplatelet agents, including AstraZeneca, Bayer, Boehringer Ingelheim, Sanofi -Aventis/ Bristol-Myers Squibb, and Servier.
Peter M Rothwell, on behalf of all authors Stroke Prevention Research Unit, University Department of Clinical Neurology, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK

1 Medical Research Council’s General Practice Research Framework. Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. Lancet 1998; 351: 233–41.
2 Peto R, Gray R, Collins R, et al. Randomised trial of prophylactic daily aspirin in British male doctors. BMJ 1988; 296: 313–31.
3 Antithrombotic Trialists’ (ATT) 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.

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