The Bloody Scales: Weighing the Risks and Benefits of Long-Term Aspirin

Overwhelming research confirms aspirin’s net benefit for secondary prevention of cardiovascular (CV) events. However, the latest guidelines suggest providers should weigh the risks and benefits of aspirin for primary prevention.

Aspirin prevents first and recurrent myocardial infarction (MI), stroke, and transient ischemic attack (TIA), but it increases the risk of gastrointestinal (GI) bleeding and hemorrhagic stroke. Targeted aspirin use for secondary prevention has more substantial benefits that clearly outweigh the modest bleeding risk, but broad use in patients without a history of cardiovascular (CV) events provides a smaller benefit with the same risk.

Many randomized, controlled trials (RCTs) exclude individuals with high bleed risk. Real-world patients take medications that increase this risk (eg, anticoagulants, NSAIDs), are elderly, or have a history of peptic ulcer disease (PUD). Therefore, clinicians should expect more bleeding in the general populations than study cohorts.

An international team of researchers recently weighed the risks of low-dose aspirin therapy for CV event primary prevention. They curated 39 English-language observational studies (excluding reviews, editorials, comments, clinical trials, high-dose use, and pediatric studies). The studies must have reported odds ratio, relative risk, hazard ratio, incidence rate ratio, or standardized incidence ratio between aspirin use and the risk of major bleeding events.

Aspirin users were 40% more likely to develop any GI bleed and 130% more likely to have an upper GI bleed compared to nonusers. GI bleeds affected primary prevention patients to a greater extent than secondary prevention patients, but the latter had a higher baseline risk. Aspirin use increased intracranial bleeding by 40%, on average, but the study results were variable. The baseline intracranial hemorrhage risk was marginal in patients younger than 70 years regardless of aspirin use.

Two studies illustrated advancing age predisposes patients to aspirin-induced bleeding. The upper GI bleed rates increased by 2 to 3 cases per 1000 patient-year (doubled risk) in older patients compared with those younger than 60 years. This finding is consistent with GI bleed relative risk in RCTs. A 2009 meta-analysis found aspirin-induced bleeding doubles with every decade of advancing age. However, the increasing bleeding risk and CV event preventive benefit with age offset each other.

Aspirin has an additive effect on GI bleed risk independent of Helicobacter pylori infection or history of PUD. The ongoing Helicobacter Eradication Aspirin Trial is determining the impact of H. pylori eradication on aspirin-induced peptic ulcers. Concomitant NSAID use (namely ibuprofen, diclofenac, and mefenamic acid) had no effect on bleed risk except at high doses. The studies split on the impact of SSRIs on bleed-related hospitalization risk.

Any aspirin dose- or duration-dependent effects on bleeds were unclear based on the included literature. In fact, long-term aspirin use produced less bleeding than short-term use. This may be due to self-selection: patients who tolerate aspirin well continue indefinitely, while those liable to adverse effects discontinue over time.

Aspirin has utility in the primary prevention of non-CV conditions like colorectal cancer. The US Preventive Services Task Force recommends aspirin use based on age, bleed risk, life expectancy, and willingness to take a daily medication.

This review clarifies the risks and benefits of low-dose aspirin therapy for primary prevention of CV events. Three ongoing trials (ARRIVE, ASPREE, and ASCEND) are investigating aspirin use in specific populations (moderate CV risk, elderly, and diabetics, respectively). Providers should weigh the bleed risks and CV primary prevention benefits of low-dose aspirin therapy on a patient-specific level.

Reference

García Rodríguez LA, et al. Bleeding risk with long-term low-dose aspirin: a systematic review of observational studies. PLoS One. 2016;11(8):e0160046.