ED I T O R I A L S

Should aspirin be used for the primary prevention of cardiovascular disease in people with diabetes?
Robyn L Woods, Andrew M Tonkin, Mark R Nelson, Helena C Britt and Christopher M Reid

Robust evidence remains to be gathered

henever possible, clinical decision making should be evidence-based. In reality, the evidence may be incomplete and the practitioner must use personal clinical judgement. This should be based on recommendations or guidelines provided by authoritative groups. An example of clinical practice reliant on guidelines with an incomplete evidence base is the use of low-dose aspirin for primary prevention of cardiovascular disease (CVD) events in people with diabetes mellitus. Diabetes Australia, the Royal Australian College of General Practitioners, of Australia ISSN: 0025The Medical Journal and the National Health and Medical Research Council 2009 190 11 as well as numerous associations in 729X 1 June (NHMRC), 614-615 the United States and United of Australia 2009 recommended The Medical Journal Kingdom, have all low-dose aspirin for men and women with diabetes (Box). www.mja.com.au Editorials Until very recently, there were no randomised controlled trials of aspirin use for people with diabetes to provide the evidence for these guidelines. Rather, the recommendations are based on the rationale that low-dose aspirin should benefit people with diabetes because aspirin has proven benefit for secondary prevention of CVD events, and people with diabetes have a risk of CVD events equivalent to the risk found in secondary prevention populations. However, people with diabetes represent a heterogeneous population, and an individual patients risk of CVD events varies according to factors such as age at diagnosis and duration of diabetes.8 Therefore, the guidelines for aspirin use in people with diabetes, based on extrapolation from secondary to primary prevention, may be flawed. Two substudies of the Bettering the Evaluation And Care of Health (BEACH) program, one undertaken in 20069 and the other in 2007,10 generated data about patients with diagnosed type 2 diabetes and allowed us to determine the compliance of Australian general practitioners with the relevant guidelines. Using the BEACH substudy data, we analysed aspirin usage by patients with

and without diagnosed CVD comorbidity. The results indicated that 39% of people with type 2 diabetes were taking aspirin for primary prevention. In late 2008, two randomised controlled trials of low-dose aspirin in people with diabetes were reported.11,12 They showed no significant effect of aspirin on the primary endpoint (CVD events). These studies attracted a good deal of attention, not only in the medical press but the lay press as well (eg, Norman Swans The health report on Radio National13). They also left medical practitioners with a conundrum whether or not to prescribe low-dose aspirin to their patients with diabetes but no overt CVD. In this editorial, we highlight the deficiencies in these trials; suggest that the evidence for the use of aspirin in this context is still lacking; and inform clinicians of ongoing trials that should provide adequate power to address this issue reliably. The two 2008 trials of low-dose aspirin therapy for people with diabetes were substantially underpowered to address the question of aspirin effectiveness for reducing CVD events.14,15 The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) study of low-dose aspirin (100mg daily)11 followed 1276 participants with diabetes and asymptomatic peripheral arterial disease but no CVD events for a median of 6.7 years. The annual CVD event rate was less than 3% in those assigned placebo (lower than the expected rate of 8% per annum). There were 116 primary CVD events in subjects receiving aspirin, compared with 117 in those not receiving aspirin (hazard ratio, 0.98). In the open-label Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) study,12 2539 patients with type 2 diabetes and no history of CVD were treated either with aspirin (81mg or 100mg daily) or with no aspirin. The median follow-up period was 4.37 years. In both groups, actual event rates were about three times lower than

Guidelines for the use of aspirin for primary prevention in people with diabetes
Source Diabetes Australia and Royal Australian College of General Practitioners (guidelines updated annually)1 National Health and Medical Research Council2 United States Preventive Services Task Force3 American Diabetes Association and American Heart Association4 British Cardiac Society, British Hyperlipidaemia Association, British Hypertension Society and British Diabetic Association5,6 International Diabetes Federation7
CHD = coronary heart disease.

Recommendation Prophylactic aspirin (75325 mg/day) for people with diabetes unless contraindicated Prophylactic aspirin (75325 mg/day) should be considered for people with type 2 diabetes unless contraindicated Aspirin (75 mg/day) should be used for primary prevention in people with diabetes who have a 5-year risk 3% of a CHD event Aspirin (75162 mg/day) strongly recommended for people aged > 40 years with diabetes or with an additional risk factor for vascular disease Cardioprotective use of aspirin (75 mg/day) in people with diabetes or other risk factors aged >50 years with an absolute CHD risk 15% over 10 years Low-dose aspirin (75100 mg/day) prophylaxis recommended for people with diabetes

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anticipated rates. A 20% reduction in the primary endpoint of composite CVD events for the group assigned aspirin was not statistically significant because of wide confidence intervals. Nevertheless, the secondary endpoint of CVD mortality was significantly reduced, and, in a sub-analysis of subjects aged 65 years and over at baseline, aspirin significantly reduced CVD events. For both the POPADAD and JPAD trials, there was no significant difference in the occurrence of adverse events among subjects receiving or not receiving aspirin. As a result of the lower than expected event rates (possibly related to effects of more optimal background therapies) and the relatively low numbers of people included in the trials, results of POPADAD and JPAD have not ruled out important benefits or risks of aspirin. Larger trials are needed. A major study (A Study of Cardiovascular Events in Diabetes [ASCEND])16 is underway in Britain to determine whether lowdose aspirin has a benefit for primary prevention of CVD in people with diabetes. About half of its estimated sample size of 10 000 men and women has been recruited. In Australia, our own trial of aspirin therapy for primary prevention in 19 000 people aged 70 years and over, the Aspirin in Reducing Events in the Elderly (A SPREE) study 1 7 ( cl inical tri al reg istration n umber ISRCTN83772183), will also be including participants with diabetes on the basis that equipoise prevails between the benefits and risks of aspirin therapy. In the ASPREE study, a GP co-investigator will help decide whether the patient is a suitable candidate for the placebo-controlled trial. A recent editorial in the Journal of the American Medical Association concluded that
[T]he decision to prescribe aspirin should be made on an individual patient basis after careful evaluation of the balance between the expected benefits and the risk of major bleeding. The issue of aspirin therapy for patients with diabetes is an example of how, in the presence of a long-lasting uncertainty, scientific organizations or governmental bodies should provide the foundation for answering this question by promoting pragmatic, large-scale clinical trials.14

References
1 Diabetes Australia and Royal Australian College of General Practitioners. Diabetes management in general practice. Guidelines for type 2 diabetes 2008/9. Canberra: Diabetes Australia, 2008. (Diabetes Australia Publication NP 1055.) http://www.racgp.org.au/Content/NavigationMenu/ C l i ni cal R eso u rces /R AC GP Gu i del i ne s/ Di abe te sm an age me nt / 2008DiabetesManagementInGeneralPractice.pdf (accessed Apr 2009). 2 National Health and Medical Research Council. National evidence based guidelines for the management of type 2 diabetes mellitus. Part 5. Prevention and detection of macrovascular disease in type 2 diabetes. Canberra: NHMRC, 2004. http://www.nhmrc.gov.au/publications/synopses/_files/di11.pdf (accessed Apr 2009). 3 Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the US Preventive Services Task Force. Ann Intern Med 2002; 136: 161-172. 4 Colwell JA, American Diabetes Association. Aspirin therapy in diabetes. Diabetes Care 2004; 27 Suppl 1: 72-73. 5 British Cardiac Society, British Hyperlipidaemia Association, British Hypertension Society, endorsed by the British Diabetic Association. Joint British recommendations on prevention of coronary heart disease in clinical practice. Heart 1998; 80 Suppl 2: 1-9. 6 British Cardiac Society, British Hyperlipidaemia Association, British Hypertension Society, British Diabetic Association. Joint British recommendations on prevention of coronary heart disease in clinical practice: summary. BMJ 2000; 320: 705-708. 7 International Diabetes Federation. Global guideline for type 2 diabetes. Brussels: IDF, 2005. http://www.idf.org/home/index.cfm?node=1457 (accessed Apr 2009). 8 Donnan PT, Donnelly L, New JP, Morris AD. Derivation and validation of a prediction score for major coronary heart disease events in a UK type 2 diabetic population. Diabetes Care 2006; 29: 1231-1236. 9 Britt H, Miller GC, Henderson J, Bayram C. Patient-based substudies from BEACH: abstracts and research tools 19992006. General practice series no. 20. Canberra: Australian Institute of Health and Welfare, 2007. (AIHW Cat. No. GEP 20; abstract item 94.) http://www.aihw.gov.au/ publications/index.cfm/title/10473 (accessed Apr 2009). 10 Britt H, Miller GC, Charles J, et al. General practice activity in Australia 200708. General practice series no. 22. Canberra: Australian Institute of Health and Welfare, 2008. (AIHW Cat. No. GEP 22; abstract item 115.) http://www.aihw.gov.au/publications/index.cfm/title/10651 (accessed Apr 2009). 11 Belch J, MacCuish A, Campbell I, et al. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ 2008; 337: a1840. 12 Ogawa H, Nakayama M, Morimoto T, et al. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA 2008; 300: 2134-2141. 13 Swan N. Aspirin for the prevention of heart attack [radio transcript]. The health report. Radio National. Australian Broadcasting Corporation. 27 October 2008. http://www.abc.net.au/rn/healthreport/stories/2008/ 2399279.htm (accessed Apr 2009). 14 Nicolucci A. Aspirin for primary prevention of cardiovascular events in diabetes [editorial]. JAMA 2008; 300: 2180-2181. 15 Farkouh ME, Fuster V. Diabetes and aspirin: beware of underpowered negative trials [editorial]. Nat Clin Pract Cardiovasc Med 2009; 6: 1. 16 ASCEND: A Study of Cardiovascular Events iN Diabetes. http://clinicaltrials.gov/ct2/show/NCT00135226?spons=%22University+of+Oxford %22&spons_ex=Y&rank=8 (accessed Apr 2009). 17 Nelson MR, Reid CM, Ames DA, et al. Feasibility of conducting a primary prevention trial of low-dose aspirin for major adverse cardiovascular events in older people in Australia: results from the ASPirin in Reducing Events in the Elderly (ASPREE) pilot study. Med J Aust 2008; 189: 105-109.

We concur that an enhanced evidence base can inform a more rational approach to therapy. Competing interests
Andrew Tonkin, Mark Nelson and Christopher Reid have received support from Bayer HealthCare (a manufacturer of aspirin) for their ongoing NHMRCsupported ASPREE trial. Bayer HealthCare provided an educational grant (US$250 000) and is now supplying aspirin and placebo for ASPREE.

Author details
Robyn L Woods, BSc(Hons), PhD, Senior Research Fellow1 Andrew M Tonkin, MB BS, MRACP, FRACP, Professor1 Mark R Nelson, MB BS, MFM, PhD, Professor2 Helena C Britt, BA, PhD, Associate Professor3 Christopher M Reid, BA, MSc, PhD, Associate Professor1 1 Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC. 2 Menzies Research Institute, University of Tasmania, Hobart, TAS. 3 Australian General Practice Statistics and Classification Centre, School of Public Health, University of Sydney, Sydney, NSW. Correspondence: robyn.woods@med.monash.edu.au

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