• Research Review
• Journal Summary

Authors: M Pignone, M Alberts, J Colwell, M Cushman, et al.

Reference: Circulation 2010; 121(24): 2694-701 (open access)
http://circ.ahajournals.org/cgi/content/extract/121/24/2694

Summarized by: Vikram Rangan, third year medical student, Duke University School of Medicine, Durham, North Carolina, USA

Summary: This paper presents a joint scientific statement by the American Diabetes Association, the American Heart Association, and the American College of Cardiology Foundation. It seeks to provide guidelines for the appropriate use of Aspirin therapy in the prevention of cardiovascular (CV) events in patients with diabetes. Indeed, diabetic patients are noted to have a two-to-four-fold increased risk of adverse CV events compared to similar individuals without the disease. The conclusions from this paper are supported by data from nine prior clinical trials, three of which enrolled diabetic patients only, and six others that enrolled both diabetic and non diabetic patients. The authors of this paper performed a meta-analysis by examining data from diabetic patients in the latter six studies, and combining it with the data from the three trials focusing exclusively on diabetic patients.

The authors begin, however, by noting a prior meta-analysis of the six trials that enrolled both diabetic and non diabetic patients (combined, these trials examined data from 95,000 patients, including nearly 4000 with diabetes). This prior meta-analysis had concluded that Aspirin therapy reduces the risk of vascular events by 12%, but has little effect on rates of death from coronary heart disease (CHD), or on rates of stroke (it found a relative reduction in the risk of ischemic stroke, but an increase in the risk of hemorrhagic stroke). Potential gender related effects of Aspirin are mentioned as well; it is suggested that a reduction in the risk of CHD events (such as myocardial infarction) is seen in men but not women, but conversely a reduction in the risk of stroke is seen in women but not men (these results, however, are only of borderline statistical significance).

The authors of this paper then report on the results of their own meta-analysis focusing on diabetic patients only. In this population, they find that Aspirin is associated with a 9% decrease in the risk of CHD events, and a 15% reduction in the risk of stroke, though neither of these effects is statistically significant. Based on these results, the authors conclude that a modest reduction in the risk of cardiovascular events likely exists with Aspirin therapy, but that there is an insufficient amount of data to provide a specific estimate of risk reduction. Similarly, there is insufficient data in this analysis to estimate the specific dose or gender dependent effects of Aspirin.

This paper proceeds to discuss the potential harms of Aspirin therapy. The two most prominent adverse events noted are hemorrhagic stroke (bleeding within the skull capsule, possibly within brain tissue itself) and gastrointestinal (GI) bleeding. The authors cite a study indicating that approximately one in 10,000 Aspirin users (including both diabetic and non diabetic patients) each year experiences a hemorrhagic stroke. Using meta-analysis data, they also report that use of Aspirin is associated with a 54% increased risk of a GI bleed (corresponding to approximately an additional three in 10,000 patients per year). Diabetes is an additional risk factor for bleeding complications with Aspirin; diabetics are 55% more likely to experience an extracranial bleed (bleeding from a location other than the skull capsule, such as a GI bleed) compared to patients without diabetes. The authors note that the use of proton-pump inhibitors (a class of medication frequently used to treat peptic ulcer disease and gastroesophageal reflux disease) may decrease the risk of GI bleeds associated with Aspirin, but may not be cost effective in this role.

In prior studies, higher doses of Aspirin were not shown to produce any greater risk reduction for cardiovascular events. Thus, lower doses (75-162 mg/d) appear to be sufficient for triggering all the protective effects of Aspirin. The authors note patients with diabetes may have higher resistance to the actions of Aspirin, but that there is currently insufficient evidence to recommend higher doses of it for diabetic patients.

The following recommendations are made for the use of Aspirin in preventing cardiovascular events: - For diabetic adults who have additional CVD risk factors (such as smoking history, hypertension, abnormal lipid profile, family history of premature cardiovascular disease, and albuminuria), and no increased bleeding risk (no prior history of GI bleeding, and no use of medications that may increase the bleeding risk): Low dose (75-162 mg/day) Aspirin is recommended. The authors note that this recommendation does not represent a uniform consensus opinion, but that the majority of evidence supports the use of Aspirin in this case. - For diabetic adults at low CVD risk (under age 50 years for men or age 60 years for women, with none of the additional CVD risk factors listed above), Aspirin is not recommended by the authors. For this population the consensus opinion of experts holds that Aspirin is not effective, and may in some cases be harmful. - For diabetics adults at intermediate risk (under age 50 years for men or age 60 years for women, but with one or more of the CVD risk factors listed above; or older than age 50 years for men or age 60 years for women, but with none of the CVD risk factors listed above), no definitive recommendation is made. The efficacy of Aspirin in this population is not well established by existing evidence, and further research is needed.

The authors emphasize that it should not necessarily be assumed that all diabetics have high cardiovascular risk, particularly those being specifically medicated for one or more risk factors. Three online tools are provided to help clinicians better identify those patients who may be at increased cardiovascular risk (links are directly available in full-text version of article). All three seek to quantify a given patient's cardiovascular risk, and are based on data from large clinical, such as the UK Prospective Diabetes Study, and the Atherosclerosis Risk in Communities (ARIC) study in the United States.

The authors conclude by describing two ongoing trials examining gender and age dependent effects of Aspirin use, as well as the use of Aspirin in diabetic patients over age 40 years with no prior vascular events. They note, however, that even these studies may not have a large enough number of subjects to definitively answer the question of whether Aspirin truly is effective for preventing CHD in specific subgroups of diabetic patients.