Assessing the Evidence of Aspirin for Primary Prevention in Diabetes
The substantial burden of cardiovascular disease in patients with diabetes has led to the exploration of various cardiovascular disease prevention strategies, including the use of aspirin.
The substantial burden of cardiovascular disease (CVD) in patients with diabetes has led to the exploration of various CVD prevention strategies, including the use of aspirin in patients with diabetes but without documented CVD (primary prevention). The efficacy of aspirin for preventing CV events in patients with a CV history, for secondary prevention of cardiovascular disease, is well-supported by clinical data, but the clinical benefit of aspirin for primary prevention has not been fully determined.
Diabetes represents a major risk factor for CVD. The rate of CV events, including myocardial infarction and stroke, is significantly increased in persons with diabetes, contributing to a CV mortality rate that is up to 4 times higher than that in the general population.1 In patients with diabetes older than 65 years, 68% of deaths are a result of coronary heart disease (CHD), and 16% are caused by a stroke.2 Because of the magnitude of CVD risk imparted by diabetes, diabetes was deemed a CHD risk equivalent by the National Cholesterol Education Program Adult Treatment Panel III guidelines in 2001.3 Classifying patients with diabetes as being in the same risk category as patients with established CVD raises the question of whether the well-supported strategy of using aspirin as preventive therapy in patients with a CV history should also be applied in patients with diabetes. However, the status of diabetes as a CHD risk equivalent has been disputed, and the evidence for aspirin as a primary prevention strategy in patients both with and without diabetes has not been persuasively demonstrated.3
The antithrombotic effects of aspirin are believed to result from its ability to block the production of thromboxane A2, a potent promoter of platelet aggregation, through the irreversible inhibition of cyclooxygenase-1. Cyclooxygenase-1 is an enzyme necessary for thromboxane A2 synthesis, as well as a factor in the production of prostaglandins. However, this effect is accompanied by an elevated risk for bleeding complications.4 A systematic review prepared for the US Preventive Services Task Force concluded that on the basis of available evidence, aspirin does not appear to differ in its effects based on a patient's diabetes status.5
"Although early studies showed benefits in primary prevention, recent studies have not," stated Vijay Nambi, MD, PhD, staff cardiologist at Michael E. DeBakey Veterans Affairs hospital and associate professor of medicine at Baylor College of Medicine, Houston, Texas, in an interview with Endocrinology Advisor. "The thought is that the advent of therapies such as statins, which were not used in early studies, and better efforts on modulating other risk factors including smoking may be some of the reasons why the more recent studies have not shown benefit."
In a recent commentary published in Endocrine Practice,6 Jennifer G. Foster, MD, MBA, assistant professor of medicine at Florida Atlantic University's Schmidt College of Medicine, Boca Raton, and colleagues noted that only 3 trials have specifically evaluated aspirin for primary prevention in type 2 diabetes. The Early Treatment of Diabetic Retinopathy Study evaluated the effects of aspirin vs placebo in patients with type 1 or type 2 diabetes and retinopathy. Approximately 49% of participants had a prior history of cardiovascular disease. Although a reduction in the relative risk for myocardial infarction was demonstrated for patients receiving aspirin, the effects did not substantially differ from those in other studies that primarily enrolled patients without diabetes.7,8
The Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes trial found that low-dose aspirin did not affect the risk for cardiovascular events (fatal or nonfatal ischemic heart disease, fatal or nonfatal stroke, and peripheral arterial disease), but did increase risk for gastrointestinal bleeding.9,10 Findings from the Prevention of Progression of Arterial Disease and Diabetes trials, which evaluated the use of antioxidants and aspirin for primary prevention in a cohort of patients with diabetes and asymptomatic peripheral arterial disease, failed to demonstrate a statistically significant prophylactic effect for either agent.11 "In the primary prevention trials completed to date, over 90% of the patients have a 10-year risk for a first coronary event less than 10%. That is generally the threshold at which clinicians begin to prescribe aspirin in primary prevention, because the benefits on occlusion will outweigh the risks for bleeding," Dr. Foster told Endocrinology Advisor.
Based on evidence that aspirin modestly reduces the risk of cardiovascular events, a 2010 position statement jointly issued by the American Diabetes Association, the American Heart Association, and the American College of Cardiology Foundation stated that low-dose (75-162 mg/day) aspirin use for prevention is reasonable for adults with diabetes with no previous history of vascular disease at increased risk for CVD (10-year risk of CVD events >10%) who are not at increased risk for bleeding. Aspirin was not recommended for men younger than 50 years or women younger than 60 years with type 2 diabetes whose 10-year risk is less than 5%, based on its unfavorable risk/benefit ratio. Aspirin might be considered in younger patients with 1 or more risk factors, older patients with no risk factors, or patients with an intermediate 10-year CVD risk of 5% to 10%.2
Anticipated results from 2 large, long-term trials may help elucidate the role of aspirin for primary prevention in patients with diabetes. The ACCEPT-D is an open-label trial to determine whether 100 mg/day aspirin prevents cardiovascular events in simvastatin-treated patients who do not have clinically manifest vascular disease. Overall, 5170 patients will be enrolled.12 ASCEND is an ongoing randomized trial involving more than 15,000 participants designed to determine whether aspirin and/or supplementation with omega-3 fatty acids reduce the risk for serious vascular events in individuals with diabetes without clinical evidence of occlusive arterial disease, and whether the benefits of treatment outweigh any potential risks.13,14
Dr. Nambi stated that understanding a patient's baseline CVD risk and then weighing it against potential harms is key to the decision of whether or not to use aspirin for primary prevention in patients with diabetes. "Ultimately, the higher the baseline risk, the more likely that the benefit is greater. Decisions should be individualized and discussed with [the] patient. Not only CVD benefit but prevention of colon cancer could be factored into the decision as well. In situations that are not clear, additional risk stratification with approaches such as calcium scoring can be considered to help physician and patient come up with a decision."
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2. Pignone M, Alberts MJ, Colwell JA, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: a position statement of the American Diabetes Association, a scientific statement of the American Heart Association, and an expert consensus document of the American College of Cardiology Foundation. Circulation. 2010;121(24):2694-2701.
3. Saely CH, Drexel H. Is type 2 diabetes really a coronary heart disease risk equivalent? Vascular Pharmacology. 2013;59(1-2):11-18.
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6. Foster JG, Wood SK, Pfeffer MA, DeMets DL, Garber A, Hennekens CH. Aspirin for primary prevention in patients with type 2 diabetes [published online July 5, 2018]. Endocr Pract. doi: 10.4158/EP-2018-0073
7. Kassoff A, Buzney SM, McMeel JW MD, et al. Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report 14. JAMA. 1992;268(10):1292-1300.
8. Desai D, Ahmed HM, Michos ED. Preventing cardiovascular disease in patients with diabetes: use of aspirin for primary prevention. Curr Cardiol Rep. 2015;17(3):566.
9. 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.
10. Saito Y, Okada S, Ogawa H, et al. Low-dose aspirin for primary prevention of cardiovascular events in patients with type 2 diabetes mellitus: 10-year follow-up of a randomized controlled trial. Circulation. 2017;135(7):659-670.
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. Berardis GD, Sacco M, Evangelista V, et al. Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D): design of a randomized study of the efficacy of low-dose aspirin in the prevention of cardiovascular events in subjects with diabetes mellitus treated with statins. Trials. 2007;8(1):21.
13. Bowman L, Mafham M, Stevens W, et al. ASCEND: A Study of Cardiovascular Events iN Diabetes: characteristics of a randomized trial of aspirin and of omega-3 fatty acid supplementation in 15,480 people with diabetes. Am Heart J. 2018;198:135-144.
14. A study of cardiovascular events in diabetes. https://ascend.medsci.ox.ac.uk/. Accessed August 23, 2018.