Risk of Cerebrovascular Events, All-Cause Mortality High in Intracerebral Hemorrhage With Atrial Fibrillation

After 1 year of follow-up, the cumulative incidences of recurrent intracerebral hemorrhage, cerebrovascular ischemic events, and all-cause death were 2.8%, 3.2%, and 22.0%, respectively, for those initiating or resuming oral anticoagulant therapy.

Recently published data in Stroke from an observational cohort study showed a high risk of cerebrovascular events and all-cause death 1 year in patients with incident intracerebral hemorrhage (ICH) and prevalent atrial fibrillation (AF). Investigators concluded that prospective randomized trials are needed to determine optimal stroke prevention among this patient group.1

Led by Peter B. Nielsen, MD, associate professor, Department of Cardiology, Aalborg University Hospital, the findings also showed that these patients had a greater number of cerebrovascular ischemic events than recurrent ICH events. Cerebrovascular outcomes were highest among those initiating or resuming oral anticoagulant (OAC) during follow-up, but with lower risk of all-cause death.

Using the Danish Stroke Registry, a total of 1885 patients with incident ICH and prevalent AF between 2003 and 2018 were analyzed. The study’s inclusion and exclusion criteria matched that of the PRESTIGE-AF trial (NCT03996772), and patients were stratified by levels of CHA2-DS2-VASc score. For reference, OAC has a class 1a guideline recommendation in patients with AF with a CHA2-DS2-VASc score greater than at least 2 in males and 3 in females to prevent thromboembolic events. Nielsen et al noted that despite this, the optimal prevention strategy for patients with AF who suffered from ICH has been debated.

Demographically, patients were generally elderly (median age range, 78-83 years), and the percentage of females ranged between 29.9% and 71.2% in the 3 CHA2-DS2-VASc score categories. Across all categories, hypertension and prior stroke/heart failure were the most prevalent cardiovascular risk factors.

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At 1 year, there were 841 outcome events in the study population: 40 recurrent ICH, 63 cerebrovascular ischemic events, and 650 all-cause deaths. Risks of cerebrovascular outcomes after 1 year were 2.2% for recurrent ICH and 3.4% for cerebrovascular ischemic events, and all-cause mortality was 34.8%. Higher risk of all-cause death and recurrent ICH trended with increases in CHA2-DS2-VASc score category at 1 year following the incident ICH, but the risks were largely similar across the categories.

For the subgroup of those who did not initiate or resume OAC during follow-up, there was a 2.4% to 2.8% risk of cerebrovascular events, 1.2% to 1.8% risk of recurrent ICH, and a 24.8% to 40.7% risk of all-cause death at 1 year after the incident ICH. The median follow-up in this subgroup was 4.8 months (IQR, 1.1-12.0), with risk difference scores (risk difference, 1.3; 95% CI, –0.1 to 2.8) that indicated a higher risk for ischemic events than for recurrent ICH.

In total, 526 patients initiated/resumed OAC during the first year after ICH, of whom 184 redeemed a warfarin prescription and 342 redeemed a NOAC prescription. The median follow-up time among this group was 9.2 months (IQR, 6.0-10.9) after initiation/resumption of OAC. Investigators recorded a risk of 2.6% to 3.7% for cerebrovascular ischemic events, 2.2% to 3.6% for recurrent ICH, and 12.7% to 28.6% of all-cause death at 1 year after the incident ICH. The risk difference for patients with a CHA2-DS2-VASc score level of 4 to 6 was 1.5 (95% CI, –2.6 to 5.5) while the risk difference in the highest score group (>6 points) displayed higher risk for recurrent ICH (risk difference, –1.2; 95% CI, –6.2 to 3.7).

"In the subpopulation of patients initiating/resuming OAC, we have no clear evidence of accurate timing of initiation or resumption of OAC, as we relied on the date for pharmacy dispense medication," Nielsen et al wrote in their strengths and limitations. "Our risk estimates were merely descriptive in these stratified analyses and cannot be compared with guide risk of the outcomes according to initiate/resume OAC treatment versus no treatment."

There are several ongoing trials aimed at investigating antithrombotic treatments for patients with ICH with prevalent AF, as well as 2 trials—the phase 2 APACHE-AF trial (NCT02565693) and pilot-phase, open-label SoSTART study (NCT03153150)—which have now been concluded and reported.2,3

REFERENCES
1. Nielsen PB, Melgaard L, Overvad TF, et al. Risk of cerebrovascular events in intracerebral hemorrhage survivors with atrial fibrillation: a nationwide cohort study. Stroke. Published online April 13, 2022. doi:10.1161/STROKEAHA.121.038331
2. Schreuder FHBM, van Nieuwenhuizen KM, Hofmeijer J, et al. Apixaban versus no antico-agulation after anticoagulation-associatedintracerebral haemorrhage in patients with atrial fibrillation in the Netherlands (APACHE-AF): a randomised,open-label, phase 2 trial. Lancet Neurol. 2021;20:907–916. doi:10.1016/S1474-4422(21)00298-2
3. Al-Shahi Salman R, Keerie C,Stephen J, et al. Effects of oral anticoagulation for atrial fibrillation after spontaneous intracranial haemorrhage in the UK: a randomised, open-label, assessor-masked, pilot-phase, non-inferiority trial. Lancet Neurol. 2021;20:842–853. doi:10.1016/S1474-4422(21)00264-7