CROMIS-2: Microbleeds on MRI May Flag Higher ICH Risk

Damian McNamara

May 18, 2018

GOTHENBURG, Sweden — Patients with atrial fibrillation (AF) who are receiving anticoagulation after a recent ischemic stroke or transient ischemic attack (TIA) are at increased risk for symptomatic intracranial hemorrhage (sICH) when MRI shows cerebral microbleeds, an observational study suggests.  

Based on 2 years of follow-up in 1447 patients, the symptomatic intracranial hemorrhage rate was 9.8 per 1000 patient-years among those with microbleeds vs 2.6 among those without microbleeds, the primary outcome of the Clinical Relevance of Microbleeds in Stroke (CROMIS-2) trial.

Results were published online May 16 in Lancet Neurology to coincide with a presentation here at the 4th European Stroke Organisation Conference (ESOC) 2018.

"This is an increasingly common clinical dilemma —  we have a patient with ischemic stroke or transient ischemic attack who has atrial fibrillation. We take an MRI scan with blood-sensitive imaging, and this shows cerebral microbleeds," David Werring, MBBs, PhD, lead researcher at the Stroke Research Centre and professor of neurology at the University College London Institute of Neurology, United Kingdom, said.

"The priority is to reduce the risk of ischemic stroke," he said. Oral anticoagulants are extremely effective, with a relative risk reduction of about 70%, "but this is at the cost of a rare and unpredictable consequence, which is intracranial hemorrhage," added Werring.

The inability to foresee this outcome adds to the challenge, he said. "We don't have good instruments to predict this devastating complication."

Cerebral microbleeds have been shown in previous smaller studies to be associated with increased sICH in patients with stroke or TIA treated with anticoagulation for AF. To see whether such microbleeds might provide a biomarker for sICH risk, researchers enrolled participants at 79 centers in the United Kingdom and 1 in the Netherlands.

The mean age was 76 years; 42% of participants were women, and all were exposed to anticoagulation (warfarin or a direct oral anticoagulant) for the first time. They were assessed with standardized MRI to detect markers of cerebrovascular disease and with validated scales, such as the Microbleed Anatomical Rating Scale. At baseline, the median National Institutes of Health Stroke Scale score was 5 and direct oral anticoagulant use was reported in 38% of patients.

Microbleeds were detected in 311 (21%) of the 1477 participants, representing 3366 patient-years of follow-up.

There were 14 symptomatic intracranial hemorrhages: 11 intracerebral, 2 subdural, and 1 subarachnoid hemorrhage.

The relative adjusted risk for intracranial hemorrhage was 3.67 among patients with microbleeds (95% CI, 1.27 - 10.60).

Interestingly, the authors also found an increased prevalence of diabetes in patients who experienced a hemorrhage, a significant difference compared with those who did not (P = .0086).

Compared with the HAS-BLED (Hypertension, Abnormal renal and liver function, Stroke, Bleeding, Labile international normalized ratio, Elderly and Drugs or alcohol) risk score alone (C-index, 0.41), adding the presence of microbleeds (C-index, 0.66), and diabetes and use of oral anticoagulation (C-index, 0.74) predicted sICH risk significantly better, with a difference in C-index of 0.25 (P = .0065) and 0.33 (P = .00059), respectively.

There were 56 recurrent ischemic strokes in the study. Cerebral microbleed presence was not associated with recurrent ischemic stroke in univariable or multivariable analyses, however.

"We know microbleeds are prevalent in older people exposed to anticoagulants, and we know they evolve over time," Werring said. "It's plausible that a microbleed that would be sealed off normally  in the presence of anticoagulation could instead enlarge to form a symptomatic, macroscopic intracranial hemorrhage."

The study demonstrates a proof-of-concept that adding microbleeds as a neuroimaging marker improves the predictive value of commonly used risk scores.  

"Cerebral microbleeds are associated with an increased rate of symptomatic intracranial hemorrhage but not recurrent ischemic stroke. This could be used to inform anticoagulation decisions," Werring said.

Larger, international individual-patient data analyses are warranted to validate the risk scores including microbleeds, in particular looking at those with a heavy microbleed burden who were underrepresented in the current study. "This should help us establish if microbleeds help us identify patients who might be at risk for net harm from oral anticoagulants," he said.

During the presentation, session moderator Kennedy Lees, MD, from the University of Glasgow in the United Kingdom, summarized the findings. "We can probably identify patients at who are at some increased risk of bleeding, but not necessarily at the moment those who should not be treated with anticoagulants, particularly not with the novel anticoagulants, right?"

"That would be fair," Werring replied. "If we were able to look at more participants with a large number of microbleeds, it might tip the balance, but not now based on these data."

Asked to comment on the study by Medscape Medical News, Valeria Caso, MD, PhD, a stroke neurologist with the Stroke Unit at the University of Perugia in Italy and president of the European Stroke Organisation, said, "This is an extremely well conducted, practice-oriented trial. I think the findings of the CROMIS-2 study are interesting, but I still won't change my clinical attitude towards anticoagulation."

She plans to continue using such therapy as warranted because "I think anticoagulation reduces risk. I am being cautious because I have to prevent ischemic stroke, which still remains my most important goal."

She added that more research in this area is indicated.

The Stroke Association and the British Heart Foundation funded this study. Werring, Lees, and Caso have disclosed no relevant financial relationships.

4th European Stroke Organisation Conference (ESOC) 2018. Presented May 16, 2018.

Lancet Neurol. Published online May 16, 2018. Abstract

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