Primum non nocere: An updated meta-analysis on aspirin use in primary prevention of cardiovascular disease in patients with diabetes

Individuals with diabetes have a two- to four-fold increased risk of vascular events.1 A pivotal role in this setting is played by an exaggerated platelet activation. This has led to increasing interest over recent decades in developing interventions aimed at reducing cardiovascular risk in this population. Although the effectiveness of aspirin in secondary prevention of cardiovascular disease (CVD) in diabetes is established, its use in primary prevention is still controversial2 and current European Society of Cardiology guidelines on CVD prevention do not provide a clear recommendation.3 A number of randomized trials have reported on the role of aspirin in primary prevention of CVD in people with diabetes, but the majority of these studies were poorly powered with regard to the number of people with diabetes and reported results from subgroups.4 The recently published ASCEND trial provided new evidences specifically assessing this issue in a large population of diabetic patients.5 We performed an updated study-level meta-analysis to evaluate the efficacy and safety of aspirin in primary prevention of CVD in diabetic patients. Electronic databases were searched for clinical trials that randomized diabetic patients without previous cardiovascular events to aspirin or placebo. The process was performed according to the PRISMA statement.6 Two authors extracted data on patient characteristics and outcomes. Efficacy outcomes were major adverse cardiovascular event (MACE), myocardial infarction (MI), stroke, and cardiovascular and all-cause mortality. Safety endpoints were major bleedings and malignancies. Net adverse clinical events (NACEs) were computed as the unweighted sum of haemorrhagic stroke, major extracranial bleeding, ischaemic stroke and MI and as weighted sum of fatal equivalent of the above events using weights and methods previously reported.7 Random-effects risk ratios (RRs) were estimated using a Mantel–Haenszel method with a person-year approach. Heterogeneity was calculated using the I2 test and publication bias was visually assessed with funnel plots. Univariate meta-regression for unadjusted log-RR was performed to explore the potential moderator effect of mean age, aspirin dose, smoking status, hypertension, gender, type of diabetes, concomitant statin therapy and compliance to study treatment on MACE. Statistical analyses were conducted using Review Manager version 5.3 and OpenMeta-Analyst. Five trials met our inclusion criteria and were included in the analyses (N = 24,037; mean follow-up 5.43 ± 1.56 years; Table 1). Aspirin reduced the risk of MACE compared with placebo (1.5% vs. 1.7% person-year; RR: 0.90; 95% confidence interval (CI): 0.83–0.97; p = 0.004; number needed to treat (NNT) over the mean follow-up = 88). As shown in Figure 1 the risk of MI, stroke, and cardiovascular and all-cause mortality did not differ between the two groups. Aspirin significantly increased the risk of major bleedings compared with placebo (0.53% vs. 0.43% person-year; RR: 1.24; 95% CI: 1.06–1.45; p = 0.03; number needed to harm (NNH) over the mean follow-up = 141). The risk of malignancies and of NACE did not differ between the two groups. No publication bias was detected, both for efficacy and safety outcomes. These results were confirmed also after excluding the Early Treatment Diabetic Retinopathy Study, which included 26% of patients with a previous cardiovascular event.8 The univariate meta-regression did not show any moderator effect on MACE of the variables considered. Efficacy and safety outcomes: aspirin versus placebo in primary prevention. CI: confidence interval; CV: cardiovascular; MACE: major adverse cardiovascular event; MI: myocardial infarction; NACE: net adverse clinical event Study characteristics. ASCEND: A Study of Cardiovascular Events iN Diabetes; BMI: body mass index; ETDRS: Early Treatment Diabetic Retinopathy Study; FU: follow-up; JAPD: Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes; NA: not available; POPADAD: Prevention Of Progression of Arterial Disease And Diabetes; PPP: Primary Prevention Project Study characteristics. ASCEND: A Study of Cardiovascular Events iN Diabetes; BMI: body mass index; ETDRS: Early Treatment Diabetic Retinopathy Study; FU: follow-up; JAPD: Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes; NA: not available; POPADAD: Prevention Of Progression of Arterial Disease And Diabetes; PPP: Primary Prevention Project We must acknowledge some limitations. The definition of major bleedings was not consistent across the trials; however, we carefully revised and included specific major haemorrhagic events in the NACE computation. The absence of any moderator effect in the meta-regression may be due to a type two error related to the limited number of studies included in the analyses. Aspirin significantly reduced by 10% the risk of MACE compared with placebo, whereas the reduction in the risk of individual hard efficacy endpoints did not reach statistical significance. This modest benefit was accompanied by a 24% increased risk of major bleedings and no net clinical benefit was detected. Although the NNT to reduce a MACE in diabetic patients is inferior to the NNH to induce a major bleeding, this updated meta-analysis suggests that aspirin does not provide a clear and significant net clinical benefit when indistinctly used in primary prevention of CVD in patients with diabetes. GC is responsible for the study rationale, manuscript drafting and final review. VG and AMM performed the literature search. FF and VG assessed the selected articles and collected the data of interest. FF drafted the manuscript and performed the statistical analyses. All authors were involved in conception and the design of the study and interpretation of the data, revised the manuscript critically for important intellectual content and finally approved the manuscript submitted. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) received no financial support for the research, authorship, and/or publication of this article.