Effect of Aspirin Dose on Mortality and Cardiovascular Events in People with Diabetes: A Meta-Analysis
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Pharmacologic evidence suggests adequate antiplatelet activity in diabetic patients requires >100 mg aspirin daily, yet recent trials have used ≤100 mg daily. This meta-analysis explored the relationship between aspirin dose and prevention of cardiovascular events.
Six electronic databases were searched using database-appropriate terms for aspirin, diabetes, and comparative study from inception until February 2010.
Randomized controlled trials and cohort studies comparing aspirin to no antiplatelet therapy were included if they reported cardiovascular events as pre-specified outcomes, aspirin dose, and number of diabetic patients. Studies were stratified by daily aspirin dose (≤100 mg; 101–325 mg; >325 mg) and pooled risk ratios (RR) were calculated using random effects models. All-cause mortality was the primary outcome of interest. Cardiovascular-related mortality, myocardial infarction, and stroke were secondary outcomes.
Data for diabetic patients were available from 21 studies (n = 17,522). Overall, 1,172 (15.4%) of 7,592 aspirin users and 1,520 (18.4%) of 8,269 controls died (p = 0.31). The pooled RRs were 0.89 (95% CI: 0.72–1.10; p = 0.27) from 13 studies using ≤100 mg (I2 = 64%); 0.89 (95% CI: 0.61–1.30; p = 0.55) from four studies using 101–325 mg (I2 = 83%); and 0.96 (95% CI: 0.85–1.08; p = 0.50) from eight studies using >325 mg (I2 = 0%). Aspirin use was associated with a significantly lower risk of mortality (RR: 0.82; 95% CI: 0.69–0.98; p = 0.03) in 13 secondary prevention studies (I2 = 27%), whereas aspirin use in seven primary prevention studies (I2 = 0%) was not (RR: 1.01; 95% CI 0.85–1.19; p = 0.94). A substantial amount of heterogeneity was observed amongst studies in all outcomes. Although inclusion of cohort studies was a major source of heterogeneity, stratification by study design did not reveal a significant dose-response relationship.
This summary of available data does not support an aspirin dose-response effect for prevention of cardiovascular events in diabetic patients. However, the systematic review identified an important gap in randomized controlled trial evidence for using 101–325 mg aspirin daily in diabetes.
- Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Vascular protection in people with diabetes. Can J Diabetes. 2008;32(suppl 1):S102–S106.
- Buse JB, Ginsberg HN, Bakris GL, et al. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care. 2007;30(1):162–172. CrossRef
- Ryden L, Standl E, Bartnik M, et al. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J. 2007;28(1):88–136. CrossRef
- 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. Antiplatelet Trialists' Collaboration. BMJ 1994;308(6921):81–106.
- Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324(7329):71–86.
- Final report on the aspirin component of the ongoing Physicians' Health Study. Steering Committee of the Physicians' Health Study Research Group. N Engl J Med 1989;321(3):129–135.
- Hansson L, Zanchetti A, Carruthers SG, 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. HOT Study Group. Lancet. 1998;351(9118):1755–1762. CrossRef
- Sacco M, Pellegrini F, Roncaglioni MC, Avanzini F, Tognoni G, Nicolucci A. Primary Prevention of Cardiovascular Events With Low-Dose Aspirin and Vitamin E in Type 2 Diabetic Patients: Results of the Primary Prevention Project (PPP) trial. Diabetes Care. 2003;26(12):3264–3272. CrossRef
- Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report 14. ETDRS Investigators. JAMA 1992;268(10):1292–1300.
- Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285(19):2486–2497.
- 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(18):2134–2141. CrossRef
- 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. CrossRef
- Welin L, Wilhelmsen L, Bjornberg A, Oden A. Aspirin increases mortality in diabetic patients without cardiovascular disease: a Swedish record linkage study. Pharmacoepidemiol Drug Saf. 2009;18(12):1143–1149. CrossRef
- Leung WY, So WY, Stewart D, et al. Lack of benefits for prevention of cardiovascular disease with aspirin therapy in type 2 diabetic patients–a longitudinal observational study. Cardiovascular Diabetology. 2009;8:57. CrossRef
- Colwell JA. Does aspirin use reduce cardiovascular risk in diabetes? Nat Rev Endocrinol. 2009;5(4):188–190. CrossRef
- Pignone M, Alberts MJ, Colwell JA, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes. Diabetes Care. 2010;33(6):1395–1402. CrossRef
- De Berardis G, Sacco M, Strippoli GF, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials. BMJ. 2009;339:b4531. CrossRef
- Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373(9678):1849–1860. CrossRef
- Zhang C, Sun A, Zhang P, et al. Aspirin for primary prevention of cardiovascular events in patients with diabetes: A meta-analysis. Diabetes Res Clin Pract. 2010;87(2):211–218. CrossRef
- Younis N, Williams S, Ammori B, Soran H. Role of aspirin in the primary prevention of cardiovascular disease in diabetes mellitus: a meta-analysis. Expert Opin Pharmacother. 2010;11(9):1459–1466. CrossRef
- Stavrakis S, Stoner JA, Azar M, Wayangankar S, Thadani U. Low-dose aspirin for primary prevention of cardiovascular events in patients with diabetes: a meta-analysis. Am J Med Sci. 2011;341(1):1–9. CrossRef
- Krasopoulos G, Brister SJ, Beattie WS, Buchanan MR. Aspirin "resistance" and risk of cardiovascular morbidity: systematic review and meta-analysis. BMJ. 2008;336(7637):195–198. CrossRef
- Tantry US, Mahla E, Gurbel PA. Aspirin resistance. Prog Cardiovasc Dis. 2009;52(2):141–152. CrossRef
- Ajjan R, Storey RF, Grant PJ. Aspirin resistance and diabetes mellitus. Diabetologia. 2008;51(3):385–390. CrossRef
- Hovens MM, Snoep JD, Eikenboom JC, van der Bom JG, Mertens BJ, Huisman MV. Prevalence of persistent platelet reactivity despite use of aspirin: a systematic review. Am Heart J. 2007;153(2):175–181. CrossRef
- Mehta SS, Silver RJ, Aaronson A, Abrahamson M, Goldfine AB. Comparison of aspirin resistance in type 1 versus type 2 diabetes mellitus. Am J Cardiol. 2006;97(4):567–570. CrossRef
- Fateh-Moghadam S, Plockinger U, Cabeza N, et al. Prevalence of aspirin resistance in patients with type 2 diabetes. Acta Diabetol. 2005;42(2):99–103. CrossRef
- Dichiara J, Bliden KP, Tantry US, et al. The effect of aspirin dosing on platelet function in diabetic and nondiabetic patients: an analysis from the aspirin-induced platelet effect (ASPECT) study. Diabetes. 2007;56(12):3014–3019. CrossRef
- Law EH, Simpson SH. Aspirin use rates in diabetes: a systematic review and cross-sectional study. Can J Diabetes. 2010;34(3):211–217.
- Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health. 1998;52(6):377–384. CrossRef
- DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–188. CrossRef
- Serebruany VL, Malinin AI, Eisert RM, Sane DC. Risk of bleeding complications with antiplatelet agents: meta-analysis of 338,191 patients enrolled in 50 randomized controlled trials. Am J Hematol. 2004;75(1):40–47. CrossRef
- Serebruany VL, Steinhubl SR, Berger PB, et al. Analysis of risk of bleeding complications after different doses of aspirin in 192,036 patients enrolled in 31 randomized controlled trials. Am J Cardiol. 2005;95(10):1218–1222. CrossRef
- Ray WA. Observational studies of drugs and mortality. N Engl J Med. 2005;353(22):2319–2321. CrossRef
- Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H. Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes. Diabetologia. 2001;44(Suppl 2):S14–S21. CrossRef
- Jansson SP, Andersson DK, Svardsudd K. Mortality trends in subjects with and without diabetes during 33 years of follow-up. Diabetes Care. 2010;33(3):551–556. CrossRef
- Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143(1–2):1–13. CrossRef
- Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005;352(13):1293–1304. CrossRef
- Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. The SALT Collaborative Group. Lancet 1991;338(8779):1345–1349.
- Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study. Lancet. 1989;1(8631):175–179. CrossRef
- Catalano M, Born G, Peto R. Prevention of serious vascular events by aspirin amongst patients with peripheral arterial disease: randomized, double-blind trial. J Intern Med. 2007;261(3):276–284. CrossRef
- Fowkes FG, Price JF, Stewart MC, et al. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial. JAMA. 2010;303(9):841–848. CrossRef
- Farrell B, Godwin J, Richards S, Warlow C. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry. 1991;54(12):1044–1054. CrossRef
- Peto R, Gray R, Collins R, et al. Randomised trial of prophylactic daily aspirin in British male doctors. Br Med J (Clin Res Ed). 1988;296(6618):313–316. CrossRef
- Elwood PC, Sweetnam PM. Aspirin and secondary mortality after myocardial infarction. Lancet. 1979;2(8156–8157):1313–1315. CrossRef
- Aspirin in coronary heart disease. The Coronary Drug Project Research Group. J Chronic Dis. 1976;29(10):625–642. CrossRef
- Cairns JA, Gent M, Singer J, et al. Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter trial. N Engl J Med. 1985;313(22):1369–1375. CrossRef
- Feringa HH, Bax JJ, Karagiannis SE, et al. Elderly patients undergoing major vascular surgery: risk factors and medication associated with risk reduction. Arch Gerontol Geriatr. 2009;48(1):116–120. CrossRef
- McAlister FA, Ghali WA, Gong Y, Fang J, Armstrong PW, Tu JV. Aspirin use and outcomes in a community-based cohort of 7352 patients discharged after first hospitalization for heart failure. Circulation. 2006;113(22):2572–2578. CrossRef
- Cubbon RM, Gale CP, Rajwani A, et al. Aspirin and mortality in patients with diabetes sustaining acute coronary syndrome. Diabetes Care. 2008;31(2):363–365. CrossRef
- Ong G, Davis TM, Davis WA. Aspirin is associated with reduced cardiovascular and all-cause mortality in type 2 diabetes in a primary prevention setting: the Fremantle Diabetes study. Diabetes Care. 2010;33(2):317–321. CrossRef
- Zanchetti A. Aspirin and Antiplatelet Drugs in the Prevention of Cardiovascular Complications of Diabetes. In: Morgensen CE, ed. Pharmacotherapy of diabetes: new developments. New York: Springer; 2007:211–218. CrossRef
- Cochrane Handbook for Systematic Reviews of Interventions. 5.0.2 [updated September 2009] ed. The Cochrane Collaboration; 2008.
- 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. The Medical Research Council's General Practice Research Framework. Lancet 1998;351(9098):233–241.
- Lambert PC, Sutton AJ, Abrams KR, Jones DR. A comparison of summary patient-level covariates in meta-regression with individual patient data meta-analysis. J Clin Epidemiol. 2002;55(1):86–94. CrossRef
- Effect of Aspirin Dose on Mortality and Cardiovascular Events in People with Diabetes: A Meta-Analysis
Journal of General Internal Medicine
Volume 26, Issue 11 , pp 1336-1344
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- 1. Faculty of Pharmacy & Pharmaceutical Sciences, 3126 Dentistry / Pharmacy Centre, University of Alberta, Edmonton, AB, Canada, T6G 2N8
- 2. School of Public Health, University of Alberta, Edmonton, AB, Canada
- 3. Faculty of Medicine & Dentistry, University of Alberta, Edmonton, AB, Canada
- 4. University of Alberta Library Services, Edmonton, AB, Canada