Aspirin for Heart Disease Prevention in Persons With Diabetes: Is There Proof?
Aspirin has been used clinically since 1899, and its role for the secondary prevention of cardiovascular (CV) disease is well established. The antiplatelet effects of aspirin have been shown to reduce the risk for subsequent vascular events on the order of 25%. Given the efficacy of aspirin for secondary prevention, it is often used for primary prevention in people with a high risk for vascular events. Given the high risk for CV complications associated with diabetes, many guidelines and national organizations recommend that these patients be started on aspirin for the primary prevention of CV events. Is the evidence for the use of aspirin in this population clear and convincing enough to warrant the widespread recommendation to use aspirin in most persons with diabetes?
Case Report
A 66-year-old woman has a history of type 2 diabetes mellitus, hypertension, and dyslipidemia. She takes 500 mg of metformin twice daily for her diabetes, 20 mg of lisinopril daily for her hypertension, and 40 mg of simvastatin daily for her dyslipidemia and diabetes.
She presents for routine follow-up after having undergone yearly laboratory tests a week ago, which revealed the following values: hemoglobin A1c, 6.9%; low-density lipoprotein, 115 mg/dL; high-density lipoprotein, 44 mg/dL; total cholesterol, 200 mg/dL; triglycerides, 155 mg/dL; serum creatinine, 0.9 mg/dL; estimated glomerular filtration rate, greater than 60 mL/min; and potassium, 4.1 mEq/L.
Her vital signs at presentation include blood pressure of 143/88 mm Hg, height of 162.5 cm, and weight of 84 kg.
She is willing to take medication but only that which is absolutely necessary. She has worked very hard on losing weight, dieting, and exercising to help manage her comorbidities. One of her friends told her that she should be taking aspirin, because all patients with diabetes should take an aspirin. But given her hesitation with medications unless they are absolutely necessary, she wanted to check with you first before starting an aspirin regimen. Does the available evidence support a beneficial role of aspirin for this patient?
The Evidence
The American Diabetes Association recommends the use of aspirin therapy for the primary prevention of CV disease in patients with diabetes and with a 10-year atherosclerotic CV disease (ASCVD) risk greater than 10%.1 The guidelines further state that this includes most men or women with diabetes aged 50 years or older who have at least 1 additional major risk factor (a family history of premature ASCVD, hypertension, smoking, dyslipidemia, or albuminuria) and are not at increased risk of bleeding. However, direct evidence supporting the use of aspirin in this patient population is lacking.
Only 2 randomized, controlled clinical trials have evaluated the use of aspirin for primary prevention in patients with diabetes. The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial2 evaluated the use of aspirin, antioxidant therapy, the combination of the 2, or placebo in patients in Scotland aged 40 years and older with diabetes and an ankle brachial index of less than 0.99. Researchers found that aspirin did not significantly reduce the rate of the primary outcome, which included a composite of death from stroke or coronary heart disease, nonfatal stroke or myocardial infarction, or above-the-knee amputation for critical limb ischemia (18.2% vs 18.3%, P = .16). The authors concluded that aspirin was not an effective agent for primary prevention of CV disease in patients with diabetes. Bleeding rates were not reported.
The second randomized, controlled trial evaluating aspirin for primary prevention in diabetes was the Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) trial.3 This study evaluated the use of 100 mg or 81 mg of aspirin vs placebo in Japanese patients aged 30 to 85 years with no prior history of CV disease. Similar to the POPADAD trial results, aspirin was not found to be associated with a significant reduction in atherosclerotic events, which included fatal and nonfatal coronary heart disease, stroke, and peripheral arterial disease. However, the patients enrolled in the study had a lower than anticipated event rate. As a result, the study did not meet the prespecified event rate and therefore was underpowered. Interestingly, the JPAD researchers found a significant reduction in the rate of atherosclerotic events in patients older than 65 years of age (6.3% vs 9.2%, P = .047), but because the primary outcome was not statistically significant, this secondary outcome should be considered hypothesis-generating only. Bleeding rates, including gastrointestinal tract bleeding, were not different between the groups.
In contrast to the guidelines’ recommendations, the currently available high-quality evidence (ie, randomized, controlled trials) does not support the widespread use of aspirin in diabetic patients. Although the POPADAD and JPAD trials may have limitations, several subgroup analyses from separate studies also demonstrate a lack of benefit of aspirin in these patients. One analysis of the Primary Prevention Project4 found that the benefit of aspirin in reducing CV events in nondiabetic patients was not maintained in patients with diabetes (relative risk, 0.90; 95% confidence interval, 0.50-1.62). Researchers go on to state that the lack of benefit may be due to aspirin-insensitive mechanisms of platelet activation and thrombus formation.
Clinical Application
Based on the available evidence, the role of aspirin for the primary prevention of CV events in patients with diabetes is equivocal. Studies of aspirin in diabetics have not shown a substantial or consistent benefit compared with placebo; fortunately the risk for bleeding does not appear to be increased. While the diabetes guidelines recommend aspirin for those with an ASCVD risk greater than 10% or at least 1 risk factor, the clinical trials included patients with a significantly higher baseline risk and still showed no benefit. Furthermore, 1 of the clinical trials was in exclusively Asian patients, calling into question the generalizability to non-Asian populations. Even in studies that demonstrate an overall benefit of aspirin in primary prevention when diabetic and nondiabetic patients are grouped together, subgroup analyses of only the diabetic patients suggests that the benefit may be insignificant.
Therefore, results of the available primary prevention studies do not support the widespread use of aspirin for the primary prevention of CV events in patients with diabetes. In order to optimize CV risk reduction in patients with diabetes, efforts should be made to ensure that patients are receiving well-established medications such as statins and angiotensin-converting enzyme inhibitors, that they abstain from tobacco and do not consume excessive amounts of alcohol, that they maintain a healthy weight by exercising and consuming a proper diet, and that blood pressure control is achieved and maintained.
While the clinical evidence does not appear to support a strong benefit of aspirin, quality reporting metrics (ie, PQRS) still may require the use of aspirin in diabetic patients, since the metrics often lag behind the clinical evidence.
Outcome of the Case
Given the equivocal study results and the patient’s hesitation to take medication unless absolutely necessary, she would be counseled best to avoid starting an aspirin at this time. She would be counseled to continue dieting and exercising to lower her body weight and to continue controlling her blood pressure and blood glucose level.
Eric A. Dietrich, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy and completed a 2-year fellowship in family medicine where he was in charge of an anticoagulation clinic. He works for the College of Pharmacy and the College of Medicine at the University of Florida in Gainesville.
Kyle Davis, PharmD, BCPS, is a graduate of the University of Florida College of Pharmacy in Gainesville and completed a 2-year residency in internal medicine at Indiana University in Indianapolis. He is an internal medicine specialist at Ochsner Medical Center in Jefferson, Louisiana.
References:
- American Diabetes Association. 8. Cardiovascular disease and risk management. Diabetes Care. 2016;39(suppl 1):S60-S71.
- Belch J, MacCuish A, Campbell I, et al; Prevention of Progression of Arterial Disease and Diabetes Study Group, Diabetes Registry Group, and Royal College of Physicians Edinburgh. 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 Oct 16; 337:a1840.
- Ogawa H, Nakayama M, Morimoto T, et al; Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial Investigators. 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.
- Sacco M, Pellegrini F, Roncaglioni MC, Avanzini F, Tognoni G, Nicolucci A; PPP Collaborative Group. 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.