Higher Risk of Intracranial Hemorrhage With Aspirin in Primary Prevention

Results from a new meta-analysis provide yet more support against the routine use of aspirin for the primary prevention of atherosclerotic cardiovascular disease (ASCVD).

Low-dose aspirin use in individuals without symptomatic cardiovascular disease increased the risk of intracranial hemorrhage (ICH), and this risk was particularly pronounced in Asian individuals and those with a low body mass index (BMI), report investigators.

“The absolute magnitude of these adverse effects is modest, but clinically relevant,” write Wen-Yi Huang, MD, PhD (Chang Gung University College of Medicine, Taiwan), and colleagues in a study published online May 13, 2019, ahead of print in JAMA Neurology. “Among every 1,000 people treated with low-dose aspirin instead of control, two more had intracranial hemorrhage events. Intracranial hemorrhage events are generally associated with higher mortality and greater disability than ischemic events associated with atherosclerotic cardiovascular disease, such as ischemic stroke.”

Steven Nissen, MD (Cleveland Clinic, OH), a longtime, outspoken critic on the use of aspirin for primary prevention of cardiovascular events, said these latest results support the new primary prevention guidelines that no longer recommend widespread aspirin use. “Frankly, the lower risk you are, the more the risk of aspirin is likely to exceed the benefits,” he told TCTMD. “One of the harms is gastrointestinal hemorrhage and the other is intracranial hemorrhage. We now have additional data that points out there is a real hazard and that people at low risk should not be taking aspirin.”

New Guidelines from ACC/AHA

In March, the American College of Cardiology and American Heart Association (ACC/AHA) released their primary prevention guidelines that largely relegated aspirin to the bench. Aspirin is not recommended in older individuals (> 70 years) and those with an increased risk of bleeding (class III recommendation). For middle-aged adults, those 40 to 70 years old, aspirin might be considered for primary prevention if they are at higher risk for CVD but do not have an excessive risk of bleeding (class IIb recommendation). On the whole, though, aspirin should be used infrequently for primary prevention, according to the ACC/AHA experts.

Three contemporary randomized clinical trials, ASPREE, ARRIVE, and ASCEND, which were published before the new guidelines and contributed to the decision to axe aspirin in primary prevention, showed the risks of aspirin outweighed its potential benefits.

Frankly, the lower risk you are, the more the risk of aspirin is likely to exceed the benefits. Steven Nissen

The new meta-analysis includes these randomized controlled trials, as well as 10 others, comparing low-dose aspirin versus a control therapy in 134,446 individuals without ASCVD. The researchers focused on ICH because the results from previous meta-analyses, as well as the individual trials, have yielded conflicting findings regarding the effect of aspirin therapy on this “devastating” adverse event.

In eight randomized trials, aspirin use was associated with a 37% higher relative risk of any ICH (0.63% versus 0.46%; RR 1.37; 95% CI 1.13-1.66). When investigators excluded the ASPREE trial, which included a large number of elderly patients with a high rate of ICH, aspirin use was associated with a nonsignificant higher risk of ICH (RR 1.28; 95% 0.99-1.65). The higher risk of intracerebral hemorrhage in 10 trials also came up short of statistical significance (RR 1.23; 95% CI 0.98-1.54), but the risk of subdural or extradural hemorrhage was a relative 53% higher among aspirin-treated patients compared with controls in four randomized trials (RR 1.53; 95% CI 1.08-2.18).

In a subgroup analysis, the relative risk of ICH in aspirin-treated patients was higher in two clinical trials that included only Asian populations (RR 1.84; 94% CI 1.04-3.27). Similarly, when the results were stratified by body mass to include only patients with a BMI of 25 kg/m2 or less, the risk of ICH was heightened (RR 1.84; 95% CI 1.04-3.27) compared with studies that included heavier patients.

Occasionally, Selectively, But Not Routinely

Erin Michos, MD (Johns Hopkins University School of Medicine, Baltimore, MD), one of the authors of the 2019 primary prevention guidelines, agreed that this newest study lends further support to their recommendations that aspirin not be used routinely for primary prevention. For the high-risk patients, those with a 10-year risk of ASCVD exceeding 20%, aspirin should be used only “occasionally and selectively.”

“For example, I might personally consider aspirin in my patients who have high coronary artery calcium scores (> 100) suggestive of significant subclinical atherosclerosis if they were at low risk for bleeding,” said Michos in an email. “In other words, for aspirin in primary prevention, ‘yes’ for some, but for most ‘no.’ This decision should be made as part of shared decision-making with the patient, considering their overall ASCVD risk factors, their bleeding risks, and patient preferences.”

Michos added that in contemporary practice, which includes patients who smoke less and are more likely to be taking statins and blood pressure-lowering medications, the relative benefits of aspirin are modest, if there any, and not worth the risks. In adults older than 70 years without cardiovascular disease, aspirin shouldn’t be used because ASPREE not only showed an increased risk of bleeding, but also a higher risk of death, she noted. “So I have actually been de-prescribing aspirin for my patients older than 70, after a discussion with them,” said Michos. “Most patients are happy to stop medications.”     

Nissen also stressed the importance of a careful discussion between the physician and high-risk patient to discuss the relative merits and downsides of treatment. For the low-risk patient, or the worried well, aspirin shouldn’t be considered. Individualized care is critical, added Nissen, noting that risk factors for ICH, such as Asian ethnicity and low BMI, should factor into decision-making.

Nissen frequently sees low-risk patients without ASCVD who are taking aspirin because they think it’s good for their health. “The come into the office all the time, with less than 5% risk, and they’re on aspirin because they think everybody should take it,” he said. “These are the worried well and it’s a really big problem.” Nissen added that he’ll take these patients off aspirin.

Michos pointed out that many patients start themselves on aspirin without an indication for it because it is available over-the-counter (OTC). There is a perception, she said, that OTC medications are safer than those without a prescription.