ICH Risk Increased With Low-Dose Aspirin in Primary Prevention

Batya Swift Yasgur, MA, LSW

May 21, 2019

Low-dose aspirin can increase risk of intracranial hemorrhage (ICH) in people without symptomatic cardiovascular disease (CVD), new research suggests.

Investigators did a systematic review and meta-analysis of 13 randomized clinical trials of low-dose aspirin for primary prevention, encompassing over 134,000 patients, and found that the risk of ICH was almost 40% higher in people taking aspirin compared with those taking placebo or no treatment.

There were 2 additional intracranial hemorrhages per 1000 people in those taking aspirin, with potentially the greatest risk increase for subdural or extradural hemorrhage.

People of Asian race/ethnicity and those who were underweight had a heightened risk of ICH if they were taking aspirin rather than placebo or no treatment.

"The benefits of low-dose aspirin for secondary prevention of myocardial infarction and ischemic stroke are well established, with the prevention of recurrent ischemic events outweighing the risk of hemorrhage," study coauthor Meng Lee, MD, associate professor in the Department of Neurology at Chang Gung University College of Medicine in Taiwan, told Medscape Medical News.

"However, the value of aspirin for primary prevention of symptomatic cardiovascular disease is controversial," Lee cautioned, "since the risk of cardiovascular events among event-free individuals is typically lower than those of patients with symptomatic atherosclerotic disease, and the increased bleeding risk may offset the overall benefit of aspirin use."

The study was published online May 13 in JAMA Neurology.

Conflicting Findings

"Of the various major bleeding events related to the use of aspirin, intracranial hemorrhage is a special concern because it is strongly associated with a high risk of mortality and poorer health over a lifetime," the authors write.

Previous research has yielded "conflicting findings" regarding the use of aspirin for primary prevention of symptomatic CVD. Moreover, the possible association between aspirin use in primary prevention and specific subtypes of intracranial hemorrhage, such as intracerebral or subdural hemorrhage, was not previously investigated.

To look at these potential risks, the researchers conducted a systematic review and meta-analysis of randomized clinical trials from 1966 to October 30, 2018 — a span of 52 years.

To qualify for inclusion, a study had to include a comparison of (a) aspirin with placebo or (b) aspirin with no aspirin; have one or more intracerebral hemorrhage type; use an aspirin dosage ≤100 mg once daily; and have a treatment duration of at least 6 months.

Qualified studies could not include participants with preexisting CVD, use of antithrombotic agents other than aspirin in either the active or control group of the study, or aspirin dosage ≥100 mg daily.

The Cochrane risk of bias tool was used to assess the quality of the trials.

Of the 18 studies originally identified, 13 met inclusion criteria, with a median follow-up duration of 2.3 to 8.2 years. These included the most recent large trials — ASPREE, ARRIVE, and ASCEND — that have called into question use of aspirin in the setting of primary prevention.

Patients included in the trials (N = 134,446 total) ranged in age from 42.9 to 74.0 years, with a mean BMI of 24.0 (normal) to 30.7 (slightly obese).

Modest But Clinically Relevant

Pooled results of the random-effects model found that low-dose aspirin was associated with increased risk of any intracranial hemorrhage compared with control (8 trials; 0.63% vs 0.46%; RR, 1.37 [95% confidence interval, 1.13 - 1.66]; I 2 = 0%).

Compared with control, low-dose aspirin would therefore be associated with an additional 2 (1 to 3) intracranial hemorrhages per 1000 people.

The increased risk remained but became nonsignificant, however, after a sensitivity analysis was performed excluding one trial with elderly participants who had more intracranial hemorrhages (RR, 1.28 [95% CI, 0.99 - 1.65]).

Low-dose aspirin also showed a "strong but nonsignificant" association with a higher risk of ICH compared with control (10 trials; 0.30% vs 0.24%; RR, 1.23 [95% CI, 0.98 - 1.54]; I 2 = 0%)

Compared with control, low-dose aspirin was associated with an increased risk of subdural or extradural hemorrhage (4 trials; 0.31% vs 0.20%; RR, 1.53 [95% CI, 1.08 - 2.18]; I 2 = 0%).

This translates into an association of an additional 1 (0–2) subdural or extradural hemorrhage in 1000 people in those taking low-dose aspirin, compared with control.

There were no significant differences, but rather a similar risk of subarachnoid hemorrhage, between low-dose aspirin and control (5 trials; 0.14% vs 0.12%; RR, 1.13 [95% CI, 0.70 - 1.83]; P = .83 for heterogeneity; I 2 = 0%).

None of the trials showed evidence of publication bias when subjected to funnel plot analysis.

Two analyses showed higher levels of risk in particular subgroups, including race/ethnicity and BMI.

Low-dose aspirin, compared with control, was associated with a magnified risk of ICH in the trials enrolling only Asian populations vs the trials with preponderantly non-Asian populations (I 2 = 56%; RR, 1.84 [95% CI, 1.04 - 3.27], 2 trials and 1.14 [95% CI, 0.89 - 1.46], 8 trials, respectively).

Moreover, low-dose aspirin was associated with a magnified risk of ICH, compared with control, in populations with a mean BMI <25 vs populations with a mean BMI ≥25 (I 2 = 62%; RR, 1.84 [95% CI, 1.04-3.27], 2 trials, and 1.08 [95% CI, 0.79 - 1.46], 5 trials, respectively).

"The absolute magnitude of these adverse events is modest, but clinically relevant," the authors state.

"Given that the many individuals in the general population have a very low risk of atherosclerotic events, if low-dose aspirin is given universally, adverse outcomes from intracranial hemorrhage may outweigh the beneficial effects of low-dose aspirin," they comment.

"For people without heart disease or ischemic stroke — ie, primary prevention — there are numerous things needed to do, such as keeping blood pressure below 130/80 mmHg, keeping LDL-cholesterol below 130 mg/dL, or even below 100 mg/dL, blood glucose control, avoiding tobacco use, and adequate exercise," Lee commented.

"All these things are more important than taking low-dose aspirin to prevent future heart disease or ischemic stroke," he emphasized.

"Definite Risks"

Commenting on the study for Medscape Medical News, Brian Silver, MD, interim chair and professor of neurology, UMass Memorial Medical Center in Worcester, said it "confirms that there are definite risks, even with use of low-dose aspirin, including several bleeding episodes, such as intracranial hemorrhage."

However, he raised several cautionary notes, including the fact that the analysis was done at the study level, rather than with individual patient data, and therefore multivariable analyses could not be performed.

Furthermore, "there is no information on the rate of fatal intracranial hemorrhage, and the comparison of the prevention of cardiovascular/cerebrovascular events, relative to the risk of intracranial benefits, is not presented," said Silver, who was not involved with the study.

Nevertheless, the study has some important take-home messages, he said, noting that "there are definite risks to the use of low-dose aspirin and its use in primary prevention should be weighed very carefully against perceived benefits."

Silver added that studies adjusting the dose of aspirin based on body weight should be considered in the future and cited a study published in The Lancet last summer examining this issue.

Also commenting on the study for Medscape Medical News, Lauren Birmingham, PhD, health services scientist at Akron Children's Hospital in Ohio, called it a "very helpful contribution to the literature for a lot of reasons, not the least of which is that it comments on an age-old debacle" and that it looked at the "gamut of head bleeds."

Birmingham, who was not associated with the study, said that the "perception that aspirin can prevent heart attacks with limited side effects has made self-initiated daily aspirin use bit of a public health issue, given how debilitating an intracranial hemorrhage can be."

The findings have important messages for practicing clinicians, she said. "As a public health person, I think one of the messages is counseling about using aspirin off-label for heart attack prevention [since] there are guidelines for when physicians should recommend daily low-dose aspirin use."

Birmingham, who is also an adjunct faculty member at Kent State University's College of Public Health, suggested that clinicians should ask patients if they are engaging in daily aspirin use, since some patients "self-initiate use without a physician’s order."

However, she added, "I do think we need to be a little careful not to scare away patients who have been prescribed low-dose aspirin [since] you can't extrapolate the data of this study to those with symptomatic CVD."

The study was supported by a grant from the Ministry of Science and Technology in Taiwan and grants from Chang Gung Memorial Hospital in Taiwan. Lee, Birmingham, Silver, and study coauthors have disclosed no relevant financial relationships.

JAMA Neurology. Published online May 13, 2019. Abstract

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