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Aspirin Use and Bleeding in Patients with and without Diabetes
Patients with multiple risk factors for cardiovascular disease, including hypertension, dyslipidemia, obesity, diabetes, and a family history of ischemic heart disease, are at moderate to high risk of cardiovascular events. For adults with diabetes and no history of vascular disease, but who have a 10-year risk of cardiovascular disease events >10% and no risk of increased bleeding, the American Diabetes Association recommends low-dose (75-162 mg/d) aspirin use.
However, the benefits of a low-dose aspirin regimen for the primary prevention of cardiovascular events are modest, and may be offset by the risk of major bleeding. Previous randomized controlled trials of low-dose aspirin use have evaluated specific groups of patients, raising the possibility that the results do not generalize to an entire population.
A meta-analysis by the Antithrombotic Trialists’ Collaboration suggested that “diabetes, in addition to being an independent risk factor for cardiovascular disease, also increases the risk of extracranial hemorrhage,” according to researchers who cautioned that the estimates “were derived from a limited number of events within randomized trials.” To clarify the risk-to-benefit ratio for the use of low-dose aspirin in patients with diabetes, the researchers increased the number of observations by conducting a population-based cohort study to determine the incidence of major gastrointestinal and intracranial bleeding episodes in individuals with and without diabetes who were on a regimen of daily low-dose aspirin. Results were reported in the Journal of the American Medical Association [2012;307(21):2286-2294].
The researchers utilized administrative data from 4.1 million citizens in 12 local health authorities in Puglia, Italy. During the study period, which was from January 1, 2003, through December 31, 2008, there were 214,844 new users of low-dose (≤300 mg) aspirin. The outcomes of interest in this analysis were hospitalization for major gastrointestinal bleeding or cerebral hemorrhage occurring following initiation of antiplatelet therapy. All diagnoses were identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes.
After applying inclusion and exclusion criteria, the final study cohort included 186,425 individuals treated with low-dose aspirin and 186,425 individuals not treated with low-dose aspirin (controls). Median follow-up was 5.7 years, a total of 1.6 million person-years of observation. Mean age in both cohorts was 69, 53% of participants were female, 57% were affected by hypertension, 15% were treated with antidiabetic agents, 2.0% had been hospitalized previously for gastrointestinal problems, and 0.9% had experienced a previous hospitalization for a cardiovascular problem.
The overall incidence rate (IR) among those in the aspirin group for total hemorrhagic events was 5.58 (95% confidence interval [CI], 5.39-5.77) per 1000 person-years and 3.60 (95% CI, 1.48-1.63) per 100 person-years among those in the control group. Aspirin use was associated with an excess risk of gastrointestinal (IR ratio [IRR] 1.55; 95% CI, 1.46-1.65) and intracranial (IRR, 1.54; 95% CI, 1.43-1.67) bleeding.
In the subgroups in the analysis, the use of aspirin was associated with a greater risk of major bleeding; however, there was no increase in risk among individuals with diabetes (IRR, 1.09; 95% CI, 0.97-1.22). The researchers noted that the “baseline risk of bleeding in the absence of aspirin use was higher among individuals with diabetes compared to those without diabetes, whereas the use of aspirin was associated with a higher bleeding risk only among individuals without diabetes.”
In those treated with antihypertension medications, nonsteroidal anti-inflammatory drugs, other antiplatelet and antithrombotic agents, and in those with previous hospitalization for gastrointestinal and cardiovascular problems, the risk of bleeding increased in age and was higher in men. A reduction in the risk of hemorrhagic events was associated with the use of proton pump inhibitors and statins.
