The risk of major bleeding events in Italians taking low-dose aspirin was more than 50% higher than in those not on the regimen in a large population-based cohort study.
However, those with diabetes had showed no increase in bleeding risk.
"Weighing the benefits of aspirin therapy against the potential harms is of particular relevance in the primary prevention setting, in which benefits seem to be lower than expected based on results in high risk populations," concluded Giorgia De Berardis of the department of clinical pharmacology and epidemiology, Consorzio Mario Negri Sud, S. Maria Imbaro, Italy, and her associates. The study was published online on June 6 (JAMA 2012;307:2286-94).
Although low-dose aspirin was associated with an increased risk of major bleeding in people with hypertension and most other subgroups they identified, it was not independently associated with such a risk in people with diabetes, a finding that indicates that "diabetes might represent a different population in terms of both expected benefits and risks associated with antiplatelet therapy," they wrote.
In the study, the investigators used administrative data on people living in 12 local health authorities in Puglia, Italy, which is in the southeastern part of the country, linking data from hospital discharge records, prescription databases (including information on aspirin, which in Italy is prescribed for CV prevention), and the civil registry. They compared hospitalizations for major gastrointestinal bleeding or cerebral hemorrhage among 186,425 users of low-dose aspirin (300 mg or less) during 2003-2008, to matched controls who had never used aspirin. A little over half were women; the mean age was about 69 years.
Over a median follow-up of almost 6 years, 5.58 hemorrhagic events/1,000 person-years occurred in persons on aspirin, compared with 3.60 events/1,000 person-years in those who had never used aspirin, for an increased risk of 55%. Among those on aspirin, the risk of GI bleeding was increased by 55% and the risk of intracranial bleed was increased by 54%, compared with those who had never used aspirin.
Among those on aspirin, the risk of bleeding was increased in most of the subgroups evaluated, and was "particularly high" among those younger than age 50 years(an incidence rate ratio of 1.93 – about a threefold greater risk when compared with people under 50 years who were not on aspirin). It was also increased in aspirin users who had not been treated for hypertension. They pointed out that this increased risk was seen in most of the subgroups they evaluated, except for patients with diabetes and those who had previously been admitted to the hospital for GI or CV problems, which they said could be "partially" attributed to the use of proton pump inhibitors (PPIs).
Those with diabetes who were not taking aspirin had a 59% increased risk for GI bleeding and a 64% increase risk for intracranial bleeding. But among those with diabetes who were on aspirin, the risk of bleeding was only slightly elevated. "Our study shows, for the first time, to our knowledge, that aspirin therapy only marginally increases the risk of bleeding in individuals with diabetes," the authors wrote, adding that these results "can represent indirect evidence that the efficacy of aspirin in suppressing platelet function is reduced in this population."
A notable finding, they said, was that the use of statins was associated with a significant reduction of gastrointestinal bleeding (35%) and intracranial bleeding (31%).
The authors said that the incidence of major bleeding events associated with aspirin identified in their study was "much higher" than reported in randomized prospective studies. The 55% increase in the relative risk of major bleeding, over no aspirin, "translates to 2 excess cases for 1,000 patients treated per year," they said. "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% and 20%."
Limitations of their study include the not being able to adjust for all potential factors that can affect bleeding, including over-the-counter aspirin use, although in Italy, low-dose aspirin for CV prevention in high-risk individuals is available by prescription and is fully covered.
Four of the seven authors, including the lead author, reported no disclosures. One author reported receiving a research grant from Bristol-Myers Squibb, another reported receiving a research grant from Bayer, and another reported receiving a research grant and lecture fees, including service on speakers bureaus from Bayer.
