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PAPERS: T W Meade and P J Brennan Determination of who may derive most benefit from aspirin in primary prevention: subgroup results from a randomised controlled trial BMJ 2000; 321: 13-17 [Abstract] [Full text]

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Aspirin for Hypertensives under control

Moises S Malowany   (4 July 2000)

Aspirin's risks and benefits

Abdullah Alkhenizan   (4 July 2000)

The aspirin factor

Tom Oommen   (5 July 2000)

Aspirin for primary prevention

Lawrence E Ramsay   (7 July 2000)

Determination of who may derive most benefit from aspirin in primary prevention.

Mark G Watson   (18 July 2000)

Benefit v. Risk of Aspirin in primary prevention.

Brendan Delaney   (19 July 2000)

Aspirin for Hypertensives under control 4 July 2000
Moises S Malowany, Assistant Professor of Clinical Path. Mt. Sinai School of Medicine Send response to journal: Re: Aspirin for Hypertensives under control	Hypertensives patients which are under control will also benefit from Aspirin prophylaxis.
Aspirin's risks and benefits 4 July 2000
Abdullah Alkhenizan, Clinical Fellow, University of Toronto Sunnybrook Hospital Send response to journal: Re: Aspirin's risks and benefits	I will echoe the authers concern that the subgroup findings in this paper must be interpreted with caution. In the HOT trial the use of 75mg of aspirin was associated with the prevention of 1.5 MI(2.5 in patients with diabetes) per 1000 patients treated for one year. It will be interesting if a subgroup analysis of the diabetic patients in Meade et al subgroup results, is possible(1).In the Nurses Health study the reduction in large artery- occlusive infarction was of greater magnitude for older, or hypertensive women(2). 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 randomized controlled clinical trials(3). In He et al meta-analysis, a large meta-analysis of 16 trials, including the British Doctors and the US physicians trials, aspirin treatment was associated with an absolute risk increase in hemorrhagic stroke of 12 events per 1000 persons (95%CI 5-20; P<0.001)(4). The mean dosage of aspirin in this meta-analysis was 273mg and the mean duration of treatment was 37 months. This meta-analysis showed that the increase of the absolute risk of hemorrhagic stroke is not related to patient characteristics, such as age, hypertension and hyperlipidemia. The pooled odds ratio for hematemesis was 1.5 in Rodrick et al overview of 21 randomized controlled trials(5), with 3.85 years average follow up, which is lower than the odds ratio of 3.3 for upper GI bleeding derived from case control studies(6). The Canadian and the US Preventive Services Task Forces do not recommend for or against the use of aspirin in asymptomatic patients for the primary prevention of cardiovascular diseases(7),(8). If aspirin therapy is considered physicians and patients should understand the potential benifits and risks of aspirin therapy before starting it. (1) Hanson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S for the HOT Study Group. Effects of intensive blood pressure lowering and low dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomized trial. Lancet;351:1755-62. (2) Iso H, Hennekens CH, Stampfer MJ, Rexrode KM, Colditz GA, Speizer FE, Willett WC, Manson JE. Prospective study of aspirin use and risk of stroke in women. Stroke. 1999;30:1764-1771. (3) Buring JE, Hennekens CH. The Women’s Health Study: summary of the study design. J Myocardial Ischemia. 1992;4:27-29. (4) He J, Whelton PK, Vu B, Klag MJ. Aspirin and risk of hemorrhagic stroke; A meta-analysis of randomized controlled trials. JAMA 1998;280:1930-1935. (5) Roderick PJ, Wilkes HC, Meade TW. The gastrointestinal toxicity of aspirin: an overview of randomized controlled trials. Br. J. Clin. Pharmac. 1993;35:219-226. (6) Hawkey CJ. Non-steroidal anti-inflammatory drugs and peptic ulcers. Facts and figures multiply but do they add up?. BMJ. 1990;300:278-284. (7) The canadian Task Force on the periodic Health Examination. The Canadian Guide to Clinical Preventive Health Care. Minister of Supply and Services Ottawa, Canada, 1994. P.680-690. (8) Guide to clinical preventive services. Report of the US Preventive Services Task Force, 1996.
The aspirin factor 5 July 2000
Tom Oommen, Associate Professor in Pharmacology Fr. Muller's Medical College, Mangalore, India Send response to journal: Re: The aspirin factor	To state that the cardioprotective value of aspirin in primary prevention of coronary artery disease is greater the lower the blood pressure is to state the obvious. Even in the absence of aspirin the risk of coronary artery disease is lower with lower blood pressure. But to state that the use of aspirin often self-prescribed, in those who have not experienced heart attacks requires careful consideration as only a few episodes will be prevented and even low dose aspirin may carry an appreciable risk of potentially serious bleeding (1) is really going off the cliff. The number of patients who are reported to have faced the risk of potentially serious bleed after low dose aspirin is so low that they are absolutely no comparison with the number of patients in whom the primary event of the coronary artery disease has been prevented. Any potentially serious bleed is always dose-related and reversible and is rarely, if ever, idiosyncratic or a manifestation of aspirin allergy. If only a few episodes will be prevented (1) is this not a significant minority? If the quality of life of any patient can be improved by an inexpensive modality and if the risk of morbidity or mortality of a disease can be reduced even in a single patient the physician must hold onto the sanctity of human life and the individual's right to a healthy life. If we go by statistics alone we will spend more time analysing numerals than treating individuals. Reference 1. T W Meade and P J Brennan. Determination of who may derive most benefit from aspirin in primary prevention: subgroup results from a randomised controlled trial. BMJ 2000; 321: 13-17
Aspirin for primary prevention 7 July 2000
Lawrence E Ramsay, Professor of Clinical Pharmacolgy University of Sheffield Send response to journal: Re: Aspirin for primary prevention	Editor, - We have suggested that aspirin for primary prevention is safe and worthwhile when the estimated 10-year coronary (CHD) risk is >15%, provided that any hypertension is controlled (1). This conclusion comes from very 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 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 CHD 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 (SBP, age, and cholesterol). These analyses are not really apposite to the guidelines and may even be misleading. For example their results suggest little benefit (6% CHD reduction) or even harm (8% increase in all CVS events) from aspirin when SBP exceeds 145 mmHg. In the US Physicians’ study (4) there was a substantial 35% reduction in CHD events at SBP >150 mmHg. In the HOT study (5) men with hypertension controlled from 168/106 to an average of 140/83 mmHg, which is still “high normal”, had CHD reduction of 42% (p = 0.001) and a 13% reduction in all CVS events. The important point is that subgroup analysis of the thrombosis prevention trial (3) is certainly not representative of all the trial evidence available. Similar discrepancies are present in the findings for age. At age >65 years this subgroup analysis suggests a 29% increase in CHD, but a 41% reduction in stroke, with aspirin. As the authors note this is totally inconsistent with the US Physicians’ study (4), which showed CHD reductions of 44% at ages 60-69 and 41% at ages 70-84 years. In the HOT study (5) treated hypertensive patients aged ³65 years had reductions in CHD by 38% and all CVS events by 21%. The treatment policy for aspirin for primary prevention should be based on all the trial evidence and estimation of absolute CHD risk (2), not on subgroup analysis of a single trial or on single CHD risk factor (3). Authors: Lawrence E. Ramsay Philemon S. Sanmuganathan Erica J. Wallis Peter R. Jackson Department of Clinical Pharmacology and Therapeutics, Floor L , Royal Hallamshire Hospital, Sheffield S10 2JF. E-mail : a.lee@sheffield.ac.uk References 1. Sanmuganathan PS, Ghahramani P, Jackson PR, Wallis EJ, Ramsay LE. Prescribing aspirin safely for primary prevention of cardiovascular disease and the need for absolute cardiovascular risk estimation. Br J Clin Pharmacol 2000; 49:498 P (abstract). 2. Ramsay LE, Williams B, Johnston GD, MacGregor GA, Poston L, et al. British Hypertension Society guidelines for hypertension management 1999: summary. BMJ 1999; 319:630-5. 3. Meade TW, Brennan PJ, on behalf of the MRC General Practice Research framework. Determination of who may derive the most benefit from aspirin in primary prevention; subgroup results from a randomised controlled trial. BMJ 2000; 321:13-7. 4. Steering Committee of the Physicians’ Health Study Research Group. Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 1989; 321:129-35. 5. Kjeldsen SE, Kolloch RE, Leonetti G, Mallion J-M, Zanchetti A, et al for the HOT Study Group. Influence of gender and age on preventing cardiovascular disease by antihypertensive treatment and acetylsalicylic acid. The HOT Study. J Hypertens 2000; 18:629-642.
Determination of who may derive most benefit from aspirin in primary prevention. 18 July 2000
Mark G Watson Send response to journal: Re: Determination of who may derive most benefit from aspirin in primary prevention.	Dear Sir - Meade and Brennan point out the risks of haemorrhage in patients taking aspirin at prophylactic doses (1). They mention the risks of cerebral and gastrointestinal bleeding, but it should be remembered that aspirin is a major factor in causing epistaxis in older patients (2,3). Epistaxis is one of the commonest emergencies in ENT, often requiring admission to hospital for nasal packing, blood transfusion or surgical intervention. As well as raising general medical awareness of the link between aspirin and nose bleeds, information needs to be provided to the public as many bleeds are the result of self- administered medication (4). Mark G. Watson Consultant Otolaryngologist / Head & Neck Surgeon Doncaster Royal Infirmary Doncaster DN2 5LT 1) Meade TW, Brennan PJ. Determination of who may derive most benefit from aspirin in primary prevention: subgroup results from a randomised controlled trial. BMJ 2000;321:13-17. 2) Watson MG, Shenoi PM. Drug-induced epistaxis? J Roy Soc Med 1990;83:162-164. 3) Livesey JR, Watson MG, Kelly PJ, Kesteven PJ. Do patients with epistaxis have drug-induced platelet dysfunction? Clin Otolaryngol 1995;20:407-410. 4) McGarry GW. Drug-induced epistaxis? (letter). J Roy Soc Med 1990;83:812.
Benefit v. Risk of Aspirin in primary prevention. 19 July 2000
Brendan Delaney, Senior Lecturer in General Practice The University of Birmingham, UK Send response to journal: Re: Benefit v. Risk of Aspirin in primary prevention.	Editor, The 1999 British Hypertension Society Guidelines recommended Aspirin 75mg to reduce the risk of cardiovascular events in patients of age 50 and over with a 10 year risk of cardiovascular disease of more than 15% and blood pressure controlled to 150/90 or below (1). The principal support for this recommendation comes from the HOT study (2). Meade and Brennan (3) have questioned this recommendation on the basis that, in a subgroup analysis of the MRC Thrombosis Prevention Trial (4), the beneficial effect of aspirin was limited to those patients with systolic blood pressure less than 145mmHg. Many General Practitioners will be considering using Aspirin for primary prevention in line with the BHS guidelines. A recent audit in our practice indicated that whilst 75% of patients eligible to receive aspirin for secondary prevention of cardiovascular disease were receiving it, only 23% of hypertensives above age 50 years were receiving it. Steps were taken to address this gap, revising practice protocols and producing a list of eligible patients. The debate raised by Meade and Brennan prompted us to examine the HOT study in detail, with particular reference to the risk:benefit ratio for aspirin in this context. In the HOT study the principal benefit of aspirin was a 15% reduction in major cardiovascular events. However the absolute reduction in risk was only 1.6 per 1000 patients at risk over 3.8 years, an NNT of 625 to prevent one major event over 4 years. The principal risk of low dose aspirin therapy is of upper gastrointestinal bleeding. Although the risk of fatal bleeding was very low (15 events in 18,790 patients) the absolute risk of a major non-fatal bleed was 6.5 per 1000, representing an number need to harm of 154. General practitioners and their patients may feel less enthusiastic about the role of aspirin in primary prevention when confronted with four patients with a major aspirin-related bleed for every cardiovascular event avoided. Dr Brendan Delaney, Senior Lecturer in General Practice, Department of Primary Care and General Practice, The University of Birmingham, Edgbaston, Birmingham, B15 2TT Dr Sheena Kulshrestha, GP Registrar, Laurie Pike Health Centre, 95 Birchfield Rd, Handsworth, Birmingham B19 1LH. References 1. Ramsay LE, Williams B, Johnston GD, MacGregor GA, Poston L, et al. British Hypertension Society guidelines for hypertension management 1999: summary. BMJ 1999; 319: 630-635. 2. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the hypertension optimal treatment (HOT) randomised trial. Lancet 1998; 351: 1755-1762. 3. T W Meade and P J Brennan. Determination of who may derive most benefit from aspirin in primary prevention: subgroup results from a randomised controlled trial. BMJ 2000; 321: 13-17. 4. 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. A report from the MRC's general practice research framework. Lancet 1998; 351: 233-241.