Is Low-Dose ASA of Value for Primary Prevention of Atherosclerotic Events in Type 2 Diabetes?
Abstract & Commentary
By Harold L. Karpman, MD, FACC, FACP, Clinical Professor of Medicine, UCLA School of Medicine. Dr. Karpman reports no financial relationship to this field of study.
Synopsis: In a multicenter, prospective, randomized study of Japanese Type 2 diabetic patients, low-dose aspirin as primary prevention did not reduce the risk of cardiovascular events.
Source: Ogawa H, 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.
It has been clearly demonstrated that individuals with diabetes mellitus have a 2- to 4-fold increased risk of developing cardiovascular (CV) events.1 Because numerous investigators have suggested that aspirin therapy is an excellent secondary prevention strategy for CV events,2-4 clinical guidelines have recommended that all individuals with risk factors for coronary heart disease, but especially those with diabetes, should take aspirin not only for secondary prevention, but also for primary prevention unless there are specific contraindications to aspirin therapy.5-10 Although the American Diabetes Association has recommended use of aspirin as a primary prevention strategy in diabetic patients who are at increased CV risk (i.e., older than 40 years of age, family history of coronary heart disease [CAD], hypertensive patients, cigarette smokers, and in patients with dyslipidemia or albuminuria),11 the clinical trial data supporting the use of aspirin for primary prevention have been limited.
The Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial was undertaken to examine the efficacy of low-dose aspirin therapy for the primary prevention of atherosclerotic events in patients with Type 2 diabetes.12 This multicenter, prospective, randomized, open label, blinded trial enrolled 2539 patients with Type 2 diabetes and without a history of atherosclerotic disease at 163 institutions throughout Japan. The patients were followed for a mean period of 4.37 years and the primary endpoints were atherosclerotic events including fatal or nonfatal ischemic heart disease, fatal or nonfatal stroke, and peripheral arterial disease. Despite a large sample size, the event rate in the study was lower than anticipated with only 68 atherosclerotic events occurring in the aspirin group and 86 in the non-aspirin group. In this study of patients with Type 2 diabetes, low-dose aspirin given for primary prevention did not significantly reduce the risk of the primary CV endpoints.
Commentary
As indicated above, the use of aspirin for primary prevention of CV events in individuals with diabetes is widely recommended in existing guidelines, despite the fact that the evidence supporting the efficacy of aspirin for primary prevention of CV events in diabetics is surprisingly quite scanty.13 Many of the recommendations have been extrapolated from data derived from high-risk groups rather than from studies conducted specifically on patients with diabetes and, in fact, an increasing amount of evidence suggests that the efficacy of antiplatelet therapy in patients with diabetes may be lower than in individuals without diabetes.14 It must be recognized that the lack of precision and the low statistical power in the JPAD trial are the consequence of a substantially lower-than-expected event rate in the trial population; in addition, the study was also underpowered to detect differences in the incidence of rare complication events such as hemorrhagic stroke or severe hemorrhage. As a consequence, a much longer follow-up period and/or a larger sample size would have been needed to more reliably estimate benefits and risks related to aspirin therapy. Furthermore, the epidemiology of CV disease in Japan is substantially different from that of non-Japanese Western populations in that Japanese study groups tend to have a relatively higher incidence of cerebrovascular events, particularly hemorrhagic stroke, and a relatively lower incidence of symptomatic CAD.15 In fact, since a meta-analysis of primary prevention randomized controlled trials in Western populations has suggested that aspirin reduced the risk of myocardial infarction but not the risk of ischemic stroke in men, whereas in women aspirin reduced the risk of stroke with no effect on the risk of myocardial infarction,16 it must be recognized that the overall effect of antiplatelet therapy is quite likely to be substantially different in Japanese patients as compared with Western patient populations.
For the many reasons outlined above, the role of antiplatelet therapy in the context of the overall approach to CV risk reduction in individuals with diabetes remains to be elucidated. Fortunately, three large-scale randomized trials are currently investigating the role of aspirin in patients with diabetes. Two of these trials, which have enrolled 15,000 patients overall, will help clarify the role of aspirin for primary prevention of CV disease.17 The third study, which was recently published and included 1276 patients with asymptomatic peripheral arterial disease, found evidence of the benefit of aspirin on the risk of developing CV events and/or mortality.18 Until the results of all three of these studies have been completed and carefully analyzed, the decision to prescribe aspirin to patients with Type 2 diabetes for primary prevention of CV disease should be made on an individual patient basis after careful evaluation of the balance between the expected benefits and the risk of major bleeding episodes. Therefore, it would appear that firm evidence supporting the use of aspirin for primary prevention of CV disease in all Type 2 diabetic patients is not available just yet.
References
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12. Ogawa H, 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.
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17. De Berardis G, et al; ACCEPT-D Study Group. 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;8:21-29.
18. Belch J, et al; Prevention of Progression of Arterial Disease and Diabetes Study Group; Diabetes Registry Group; Royal College of Physicians Edinburgh. The prevention of progression of arterial disease and diabetes (POPADAD) trial: Factorial randomized placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ 2008;337:a1840.
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