Cerebral Microbleeds Should Not Deter Antithrombotics in Stroke

May 23, 2019

The presence of cerebral microbleeds should not deter the use of antithrombotic treatment in patients with recent ischemic stroke or transient ischemic attack (TIA), new data from a pooled analysis of cohort studies suggest.

The presence of microbleeds was linked to a greater risk for both future ischemic stroke and intracranial hemorrhage (ICH) in the analysis. Although the number of microbleeds was associated with a greater relative risk for subsequent ICH than for ischemic stroke, the absolute risk for ischemic stroke was consistently higher than the absolute risk for ICH regardless of microbleed burden or anatomic distribution.

The analysis was presented today at the 5th European Stroke Organisation Conference (ESOC) 2019 and was simultaneously published online May 23 in the Lancet Neurology.

"We found that the relative risk of ICH goes up more dramatically with increasing microbleed burden than the relative risk for ischemic stroke," senior author David J. Werring, PhD, UCL Queen Square Institute of Neurology, London, United Kingdom, told Medscape Medical News.

"But — and this is the really key finding — it doesn't matter how many microbleeds there were. The absolute risk of ischemic stroke is always higher than the absolute risk of ICH," Werring said.

"This evidence therefore does not support withholding antithrombotic treatment in patients with a history of stroke/TIA in patients with a high microbleed burden," he said.

Werring explained that new, sophisticated scanning methods that are often used in assessing stroke patients can detect the presence of microbleeds in the cerebral circulation. In radiologic examinations, these microbleeds appear as small, hypointense, ovoid or rounded regions.

"The question we are addressing in this analysis is whether the presence of microbleeds in patients who have had an ischemic stroke or TIA is a signal of an increased risk of ICH, which could have implications for the use of antithrombotic medications," he said. "This is something that has been challenging stroke doctors for several years now and generating considerable anxiety about whether to continue antithrombotic medication.

"Our results show that regardless of the type of antithrombotics/anticoagulants/antiplatelets used and however many microbleeds were present, the risk of ischemic stroke is always higher than the risk of ICH," he added. "This provides reassurance for clinicians and patients that in patients with a previous ischemic stroke or TIA, we do not need to worry too much about the presence of microbleeds on the scan — they should be treated with antithrombotic regardless."

In the Lancet Neurology article, Werring and colleagues note that in previous studies of this issue, the sample sizes were small and there were few ICH outcome events. Thus, these studies could not reliably answer the important clinical question of whether many cerebral microbleeds or patterns of cerebral microbleeds indicate a higher risk for ICH than for recurrent ischemic stroke.

The authors therefore conducted the current pooled analysis. The analysis included data regarding individual patients with ischemic stroke or TIA from 38 cohort studies in which microbleeds and future stroke/ICH events were documented. The analysis included a total of 20,322 patients; the median follow-up was 1.34 years.

During follow-up, 189 ICH events and 1113 ischemic strokes occurred.

Results showed that patients with cerebral microbleeds were at increased risk for ischemic stroke (hazard ratio [HR], 1.23) and ICH (HR, 2.45) in comparison with patients who did not have microbleeds.

Although the HR for ICH increased more with increasing microbleed burden than the HR for ischemic stroke, the rate of ischemic stroke always exceeded that of ICH.

Table. Rate of ICH and Ischemic Stroke With Increasing Microbleed Burden

Number of Microbleeds Symptomatic ICH (Rate/1000 Patient-Years) Symptomatic Ischemic Stroke (Rate/1000 Patient-Years)
0 4 30
1 8 37
2 – 4 9 48
≥5 23 64
≥10 27 64
≥20 39 73

"These microbleeds appear to be a marker of small vessel disease," Werring commented. "The vessels can either get blocked or bleed. The dots on the scan might not all be actual bleeds — they could be red cells that have not been cleared properly or previous ischemic lesions than have transformed into hemorrhage."

Commenting on the study for Medscape Medical News, Alistair Webb, BMBCh, MRCP(Neurol), DPhil FESO, University of Oxford, United Kingdom, said the results were "very interesting."

"This is observational data, so it is not the most reliable data we can have, but it does provide reassurance," Webb said. "It has been a concern that these imaging changes are a risk of future bleeding which we haven't quantified, but this new information shows patients with numerous microbleeds are still much more likely to have an ischemic stroke than an ICH, so antithrombotic treatment is still likely to have more benefit than harm."

Complements RESTART

Webb noted that this study fits in well with the RESTART study, which was also presented at ESOC 2019. That study showed that restarting antithrombotic therapy for patients after an ICH was safe.

"With these two new studies, we have a lot more security that in a patient who has an increased risk of ischemic stroke, we can give antithrombotic therapy and not be deterred by whether they've had an ICH (as in RESTART) or their scan shows the presence of these microbleeds (as in this study)," Webb said.

Werring agreed. "There is a common theme in these two studies — that antithrombotics appear to be safer than we thought."

In a comment that accompanied the article in the Lancet Neurology, Georgios Tsivgoulis, MD, and Aristeidis Katsanos, MD, University of Athens, Greece, point out that the main strengths of the new microbleed analysis are the large sample size, the prospective study design with strict inclusion and exclusion criteria, and the comprehensive, prespecified, robust statistical analysis. They add that the observational study design is prone to confounding and selection and indication biases.

They agree that the findings "suggest that cerebral microbleed presence, burden, and pattern on neuroimaging should not influence the decision to select appropriate antithrombotic therapy for secondary stroke prevention."

But they add that additional research is required to establish whether cerebral microbleeds should be incorporated as a neuroimaging marker in clinical risk prediction scores of recurrent ischemic stroke or ICH in patients with recent cerebral ischemia treated with oral anticoagulants or antiplatelet drugs.

The study was supported by the British Heart Foundation and UK Stroke Association. Werring has received personal fees from Bayer outside the submitted work. Disclosures of relevant financial relationships of the study's coauthors appear in the original article. The editorialists have disclosed no relevant financial relationships.

Lancet Neurol. Published online May 23, 2019. Full text, Comment

5th European Stroke Organisation Conference (ESOC) 2019: Presented May 23, 2019.

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