The risk of major bleeding in diabetics increased only marginally with the use of low-dose aspirin, according to a population-based cohort study published June 6 is the Journal of the American Medical Association. In nondiabetics, though, the incidence of major bleeding events far outpaced results from controlled randomized clinical trials. Based on those results, the accompanying editorialist encouraged physicians to carefully weigh the cardiovascular (CV) benefits against bleeding risks before prescribing low-dose aspirin.

Antonio Nicolucci, MD, of the clinical pharmacology department at Consorzio Mario Negri Sud in Chieti, Italy, and colleagues noted that low-dose aspirin is recommended as a secondary prevention measure for patients at moderate to high risk of CV disease, and for diabetic patients in the U.S., who have a 10-year risk and no increased risk of bleeding.

But aspirin use also carries a risk of gastrointestinal and hemorrhagic complications. Based on randomized controlled clinical trials, these risks are small but observational studies suggest otherwise. Other studies also question the risk-to-benefit ratio for patients with diabetes, they wrote.

“Randomized controlled trials evaluate selected patient groups and do not necessarily generalize to an entire population,” Nicolucci et al wrote. “They are particularly limited when evaluating relatively rare events.”

To clarify the issues, the researchers used comprehensive data sources that capture pharmaceutical services provided for free or at a minimal cost through Italy’s healthcare system, hospital discharge data and registry data to conduct a population-based cohort study. From a pool of records on 4.1 million citizens, they identified new users of low-dose aspirin who were 30 years or older between the beginning of 2003 and the end of 2008. The final sample included 186,425 patients taking low-dose aspirin and, after propensity-score matching, an equal number of randomly selected patients who did not take aspirin. The cohort covered a total of 1.6 million person years with a median follow-up of 5.7 years.

The researchers found the overall incidence rate for hemorrhagic events was 5.58 per 1,000 person years for those taking aspirin and 3.6 per 1,000 person years for those not taking aspirin. Diabetics had an increased risk of 59 percent for gastrointestinal bleeding and 64 percent for intracranial bleeding.  

But among aspirin takers, the incidence rate for major bleeding was 5.53 per 1,000 person years for those without diabetes compared with 5.83 per 1,000 person-years for diabetics. They found similar estimates for gastrointestinal and intracranial bleeding.

“Our study demonstrated that the incidence of major bleeding events is much higher than that recorded in randomized, prospective clinical trials,” Nicolucci et al wrote. “[T]he use of aspirin was associated with a 55 percent relative risk increase in major bleeding; this translates to two excess cases for 1,000 patients treated per year. In other words, the excess number of major bleeding events associated with the use of aspirin is of the same magnitude of the number of major cardiovascular events avoided in the primary prevention setting for individuals with a 10-year risk of between 10 percent and 20 percent.”

They added that their results showed that low-dose aspirin therapy only marginally increases the risk of bleeding in diabetics. “These results can represent indirect evidence that the efficacy of aspirin in suppressing platelet function is reduced in this population,” they wrote.

The study could not account for variables such as the use of over-the-counter drugs, including aspirin, which are not captured in the healthcare database. But long-term use of aspiring as a therapy for CV protection is covered in the national healthcare system, they wrote, suggesting that few patients would choose to pocket the cost.

In an accompanying editorial, Jolanta M. Siller-Matula, MD, PhD, of the cardiology department at Medical University of Vienna in Austria, commended the study by Nicolucci et al for its large patient sample size taken from a real-world setting and its inclusion of a large number of diabetic patients. The editorialist wrote that the findings reinforce the 2012 European guidelines for the prevention of cardiovascular disease, which do not recommend the use of aspirin for primary prevention. The European guidelines also do not recommend aspirin for cardiovascular disease prevention in patients with diabetes.

These guidelines differ from recommendations in the U.S., where the American Diabetes Association, the American Heart Association and the American College of Cardiology have recommended the use of low-dose aspirin for primary prevention for adult diabetics with a 10-year risk of vascular events of more than 10 percent and who are not at increased risk for bleeding, Siller-Matula wrote.

“The study … underscores that the potential risk of bleeding should be carefully considered in decision making,” Siller-Matula wrote, adding that such assessments should be considered for not only aspirin but also platelet inhibitors and anticoagulants. “[T]here is only a thin line between efficacy and safety, and the reduction in ischemic events comes at the cost of increased major bleedings,” Siller-Matula wrote, concluding that physicians needed more risk-benefit studies to help guide their decisions.