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Antiplatelet Therapy Is Safe for Secondary Prevention of Stroke—Even with Cerebral Microbleeds

Article In Brief

Two studies report that the risk associated with antiplatelet therapy in people with cerebral microbleeds is much lower than previously believed.

The risk of recurrent intracerebral hemorrhage associated with antiplatelet therapy appears to be too small to outweigh its well-established benefits for secondary prevention of heart attack and stroke, according to reports appearing simultaneously in The Lancet and Lancet Neurology.

And even the presence of cerebral microbleeds need not preclude antiplatelet therapy, the studies found.

Results of The REstart or STop Antithrombotics Randomised Trial (RESTART) trial appear in The Lancet, and a sub-analysis looking specifically at patients who underwent brain imaging, including an analysis of those who had evidence of cerebral microbleeds on magnetic resonance imaging (MRI), appears in Lancet Neurology.

The findings of the sub-analysis suggest that the risk associated with antiplatelet therapy in people with cerebral microbleeds is much lower than previously believed. “Our findings exclude all but a very modest harmful effect of antiplatelet therapy on recurrent intracerebral hemorrhage in the presence of cerebral microbleeds,” Rustam Al-Shahi Salman, PhD, professor of clinical neurology at the University of Edinburgh told Neurology Today. “Therefore, it seems safe for clinicians to use antiplatelet therapy for secondary prevention of occlusive vascular disease after intracerebral hemorrhage (ICH) in patients with microbleeds in general.”

Dr. Salman emphasized that the sub-analysis results need to be replicated and should be viewed in the context of the overall results of the larger RESTART trial, which found half as many recurrent ICHs with antiplatelet therapy as occurred without antiplatelet therapy.

Study Design, Findings

RESTART was a prospective, randomized, open-label, trial at 122 hospitals in the United Kingdom. Researchers recruited adults who were using antiplatelet or anticoagulant therapy for the prevention of occlusive vascular disease, then developed ICH and discontinued therapy and survived for 24 hours. Patients meeting these criteria were randomized to start or avoid antiplatelet therapy and followed for up to five years for recurrent symptomatic ICH and other major vascular events.

In the overall study, a total of 537 participants were enrolled, of whom 268 were assigned to start antiplatelet therapy and 269 assigned to avoid antiplatelet therapy. Antiplatelet therapy was restricted to the use of one or more of oral aspirin, dipyridamole, or clopidogrel, begun within 24 hours of randomization. Twelve (4 percent) of the participants allocated to antiplatelet therapy had recurrence of ICH compared with 23 participants allocated to avoid antiplatelet therapy.

For the sub-analysis, a total of 254 underwent MRI—122 in the start antiplatelet therapy group and 132 in the avoid antiplatelet therapy group.

Antiplatelet therapy in the 93 participants with two or more cerebral microbleeds appeared to reduce the occurrence of the primary outcome of recurrent ICH, with a hazard ratio of 0.3. There were no statistically significant effects related to the other features of the initial ICH found on imaging, or to cerebral small vessel diseases.

Dr. Salman said the results of the sub-analysis should provide some reassurance to clinicians who have assumed that cerebral microbleeds preclude use of antiplatelet therapy. “Our major finding was that for people with cerebral microbleeds, the risk of recurrent ICH in people taking antiplatelet therapy compared to those avoiding it was much lower than expected,” he said. “The presence of cerebral microbleeds on MRI in patients with ICH need not be a contraindication. The risks in people with large numbers of microbleeds, and strictly lobar microbleeds, are less certain.”

Dr. Salman explained that one third of patients in high income countries with a prior history of occlusive vascular disease—either ischemic stroke or ischemic heart disease—are taking antiplatelet drugs at the time they develop stroke due to ICH.

Antiplatelet drugs are well known to be beneficial in reducing the risk of major vascular events after ischemic stroke or ischemic heart disease but can potentially increase the risk of ICH. A small observational study appearing in Neurology in 2010 found that the presence of microbleeds on brain MRI was associated with a higher risk of recurrent ICH in patients who started aspirin after ICH.

Expert Commentary

Experts who reviewed the new findings said they are surprising but do suggest that the risk associated with cerebral microbleeds has been overstated. “This is a very interesting study with a somewhat counterintuitive result,” Steven R. Messe, MD, FAAN, FAHA, associate professor of neurology at the Hospital of the University of Pennsylvania, told Neurology Today.

“This separate analysis of patients who received MRI at baseline shows that presence of microbleeds does not meaningfully increase the risk of bleeding when aspirin is restarted, and some patients, like those with non-lobar ICH may even have reduced recurrence of ICH on aspirin.”

Dr. Messe pointed out that there was a high consent failure rate: In the overall study just one in twelve eligible patients consented to participate. “It is unknown whether this will generalize to all or even most patients,” Dr. Messe said. “Presumably, those patients who agreed to participate were going to be most motivated to be healthy, take prescribed medication, control their blood pressure, and follow up with physicians.”

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“The presence of cerebral microbleeds on MRI in patients with ICH need not be a contraindication. The risks in people with large numbers of microbleeds, and strictly lobar microbleeds, are less certain.”—DR. RUSTAM AL-SHAHI SALMAN

Two other reviewers agreed the sub-analysis provides at least tentative evidence of the safety of using antiplatelet therapy in cases where clinicians have tended to be wary.

“We always get nervous that patients who are taking antiplatelet agents—aspirin, clopidogrel, or dipyridamole—who have an intracranial hemorrhage are a set-up for having more intracranial hemorrhages,” said Claiborne Johnston, MD, PhD, dean of the Dell Medical School at the University of Texas, Austin. “Many doctors follow the ‘do no harm’ dictate and stop the antiplatelet agent even when there is a known indication for it in reducing major ischemic events such as ischemic stroke or MI [myocardial infarction].

“The findings are mostly convincing, but the trial is small and unblinded. The authors did not show a benefit in reduction of ischemic events, which were more common than intracranial hemorrhages, but we know from other trials that antiplatelet agents reduce this risk.

“Overall, this is new evidence that it is safe to restart antiplatelet therapy after an intracranial hemorrhage in patients with an indication for reducing major ischemic events,” Dr. Johnston said. “Given prior observational studies and trials of patients with ischemic stroke, this tips the scales toward restarting.”

Jose Merino, MD, FAAN, associate professor of neurology at the University of Maryland, agreed, noting the continued uncertainty about subgroups of patients with numerous bleeds and exclusively lobar ICHs.

“This is a well-designed clinical trial,” he said in comments to Neurology Today. “The point estimate of effect is suggestive that antiplatelets are not harmful in patients with ICH and microbleeds, but the confidence estimates are wide. Most patients had four or fewer microbleeds and this is important to consider. We do not know the effect of antiplatelets in patients with ICH and very numerous microbleeds. As the authors themselves acknowledge, caution is needed when interpreting non-significant differences between small subgroups. The study may not have sufficient power to answer the question definitively.”

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“The findings are mostly convincing, but the trial is small and unblinded. The authors did not show a benefit in reduction of ischemic events, which were more common than intracranial hemorrhages, but we know from other trials that antiplatelet agents reduce this risk.”—DR. S. CLAIBORNE JOHNSTON

Dr. Merino said the results will be important in the design of future studies. “And they may provide some reassurance to patients who had an ICH and a very high risk of ischemic stroke or heart disease who have to take antiplatelets,” he said.

What is a take-home message for clinicians?

“At this point, given that it was a small study and the results are somewhat counterintuitive, I do not think that we should be routinely placing all patients with ICH on aspirin,” said Dr. Messe. “Additional studies are needed, and some are ongoing including a randomized study of anticoagulation for patients with atrial fibrillation and recent ICH. However, if there is a compelling indication for an antiplatelet agent, such as severe or recent coronary artery disease or a stent placed, I think this study provides some comfort in recommending that ICH patients restart an antiplatelet medication. The presence of microbleeds would not be a compelling reason to not do that.”

Disclosures

Drs. Al-Shahi Salman had no disclosures. Dr. Merino receives salary support from British Medical Journal for his services as US research editor. Dr. Messe receives fees from Claret Medical Inc., for consulting on an embolic protection device used in transcatheter aortic valve replacement.

Link Up for More Information

• RESTART Collaboration. Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): A randomized, open-label trial https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)30840-2/fulltext. Lancet 2019; Epub 2019 May 22.
    • Al-Shahi Salman R, Minks DP, Mitra Dipayan M, et al; on behalf of the RESTART Collaboration. Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: Subgroup analyses of the RESTART randomized, open-label trial https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(19)30184-X/fulltext. Lancet Neurol 2019; Epub 2019 May 22.