Bleeding risk with aspirin therapy

MARIA IMBARO, ITALY. While there is substantial evidence that taking aspirin daily reduces the incidence of heart attack, ischemic stroke, and cardiovascular death amongst people with existing heart disease or a prior stroke (secondary prevention), there is no convincing evidence that the daily “aspirin ritual” reduces the risk of heart attack and stroke in those without cardiovascular disease (primary prevention). Thus, the Food and Drug Administration (FDA) in the US has not approved aspirin for primary prevention and European guidelines advise against its use for primary prevention in healthy individuals since the risks (major bleedings and hemorrhagic stroke) outweigh its benefits (protection against stroke and heart attack).

A recent Dutch study involved 27,939 initially healthy women who were randomized to receive either placebos or 100 mg of aspirin every second day. During 10 years of follow-up, 340 major cardiovascular events (heart attack, stroke and cardiovascular death) were observed in the placebo group (0.24%/year) as compared to 312 events (0.22%/year) in the aspirin-treated group. However, aspirin therapy was of no net benefit when taking into account its associated increased risk of major bleeding, in particular, gastrointestinal bleeding. Especially noteworthy was the finding that aspirin treatment of women with a 10% or greater 10-year risk for coronary heart disease, as advocated by most guidelines, was not associated with a net benefit.[1]

Another study carried out by researchers at Oxford University involved 95,000 persons with low risk for cardiovascular disease. Amongst participants who took aspirin every day, the incidence of stroke, heart attack, and cardiovascular death was 0.51%/year as compared to 0.57%/year amongst those who did not. On the other hand, 0.10%/year of those on aspirin experienced a major gastrointestinal or intracranial bleed as compared to only 0.07%/year of those not using aspirin. Of particular interest is the finding that aspirin on a daily basis did not reduce the risk of an ischemic or hemorrhagic stroke in those at low average risk for cardiovascular disease.

The Oxford researchers conclude that their observations “do not seem to justify general guidelines advocating the routine use of aspirin in all apparently healthy individuals above a moderate level of risk of coronary heart disease.”[2]

Now a group of Italian researchers report that the daily use of low-dose aspirin (300 mg/day or less) is associated with a significantly increased risk of major gastrointestinal and cerebral bleeding episodes. Their study involved 186,425 individuals being treated with low-dose aspirin and 186,425 matched controls not on aspirin. During an average follow-up of 5.7 years (1.6 million person-years) the incidence of major bleeding events was found to be 0.56%/year in the aspirin group versus 0.36%/year in the control group. This corresponds to a 55% relative risk increase in the aspirin group. The risk increase was similar for major gastrointestinal bleeding and cerebral bleeding.

The following factors were associated with a higher than average incidence of major bleeding amongst aspirin users – female sex, age below 50 years, previous hospitalization for cardiovascular or gastrointestinal problems, and use of oral anticoagulants and other antiplatelet agents. Protective effects were observed from the use of proton pump inhibitors (PPIs) and anti-hypertensive drugs. Multivariate analysis of factors associated with hospitalization for major bleeding events indicated that men were more likely to be hospitalized than women. Other factors associated with an increased risk of hospitalization were the use of aspirin, oral anticoagulants (warfarin), other antiplatelet agents (clopidogrel), anti-hypertensive medications, and previous hospital admittances for cardiovascular or gastrointestinal problems. A reduced risk of admittance was observed for those on PPIs and statin drugs.

Included in the study group were 56,000 patients with type 2 diabetes of which 27,000 were on daily aspirin. Amongst diabetics not on aspirin the incidence of major bleeding was 0.54%/year as compared to 0.33%/year amongst non-diabetics not on aspirin. Thus, it is clear that diabetes, by itself, is a strong risk factor for major bleedings (61% relative risk increase). However, being on aspirin did not significantly increase the risk of bleeding (0.58%/year). The Italian researchers conclude that daily use of low-dose aspirin is associated with a significantly increased risk of major gastrointestinal or cerebral bleeding episodes in non-diabetics. The use of aspirin was not found to increase the already elevated bleeding risk amongst diabetics.
De Berardis, G, et al. Association of aspirin use with major bleeding in patients with and without diabetes. Journal of the American Medical Association (JAMA), Vol. 307, June 6, 2012, pp. 2286-94

Editor’s comment: Aspirin is often prescribed for stroke prevention in lone atrial fibrillation, even in cases where the patients have few, if any, risk factors for stroke. There is evidence that this approach is actually detrimental. In a 2005 study of 871 low-risk AF patients Japanese researchers conclude that daily aspirin therapy (150-200 mg/day) in this group is neither effective nor safe. They actually observed more cardiovascular deaths, strokes and TIAs in the aspirin group than in the placebo group. In addition, fatal or major bleeding was found to be more frequent in the aspirin group than in the placebo group. Overall, the incidence of strokes, deaths and other adverse events was 42% greater in the aspirin group than in the placebo group. The trial was discontinued prematurely since the probability that aspirin would prove superior to placebo in stroke prevention, if it continued, was deemed to be vanishingly small.[3]

[1] Dorresteijn, JAN, et al. Aspirin for primary prevention of vascular events in women: individualized prediction of treatment effects. European Heart Journal, Vol. 32, 2011, pp. 2962-69
[2] Baaigent, C, et al. Aspirin in the primary and secondary prevention of vascular disease. The Lancet, Vol. 373, May 30, 2009, pp. 1849-60
[3] Sato, H, et al. Low-dose aspirin for prevention of stroke in low-risk patients with atrial fibrillation. Stroke, Vol. 37, February 2006, pp. 447-51