Anticoagulation in patients with cerebral amyloid angiopathy

Survivors of intracranial haemorrhage with atrial fibrillation are a population that have a heightened risk of future ischaemic stroke and recurrent intracranial haemorrhage.1Li L Poon MTC Samarasekera NE et al.Risks of recurrent stroke and all serious vascular events after spontaneous intracerebral haemorrhage: pooled analyses of two population-based studies.Lancet Neurol. 2021; 20: 437-447Summary Full Text Full Text PDF PubMed Scopus (46) Google Scholar In the absence of definitive randomised evidence to guide antithrombotic prophylaxis in these patients, current guidelines recommend individualised decisions that weigh a patient's absolute risks of thromboembolism and recurrent haemorrhage.2Shoamanesh A Patrice Lindsay M Castellucci LA et al.Canadian stroke best practice recommendations: management of spontaneous intracerebral hemorrhage, 7th edition update 2020.Int J Stroke. 2021; 16: 321-341Crossref PubMed Scopus (60) Google Scholar Intracranial haemorrhage can occur from different underlying causes, with different rates of disease progression and intracranial haemorrhage recurrence. Lobar intracerebral haemorrhage and spontaneous convexity subarachnoid haemorrhage are likely to result from underlying cerebral amyloid angiopathy in patients aged older than 50 years; these types of haemorrhage carry a two to four times higher risk of recurrence compared with non-lobar intracerebral haemorrhage resulting from arteriolosclerosis.3Charidimou A Imaizumi T Moulin S et al.Brain hemorrhage recurrence, small vessel disease type, and cerebral microbleeds: a meta-analysis.Neurology. 2017; 89: 820-829Crossref PubMed Scopus (176) Google Scholar Although observational data have suggested net benefit from anticoagulation in intracranial haemorrhage survivors with atrial fibrillation, including those with lobar and cerebral amyloid angiopathy-related intracerebral haemorrhage,4Biffi A Kuramatsu JB Leasure A et al.Oral anticoagulation and functional outcome after intracerebral hemorrhage.Ann Neurol. 2017; 82: 755-765Crossref PubMed Scopus (105) Google Scholar the propensity for confounding by indication and immortal time bias limit their interpretation. Three large main-phase randomised trials comparing anticoagulation with no anticoagulation in survivors of intracranial haemorrhage with atrial fibrillation are ongoing (appendix). The Edoxaban for Intracranial Haemorrhage Survivors with Atrial Fibrillation trial (ENRICH-AF; NCT03950076) is assessing standard dosing edoxaban (60 mg daily; dose reduced to 30 mg daily in patients with moderate renal impairment, bodyweight of ≤60 kg, or concomitant use of potent P-glycoprotein inhibitors) compared with non-anticoagulant medical treatment for stroke prevention in survivors of intracranial haemorrhage with atrial fibrillation. ENRICH-AF is currently enrolling patients at 239 hospitals in 20 countries. Following a safety review of the first 699 patients (174 [25%] of 699 with lobar intracranial haemorrhage and 34 [5%] of 699 with convexity subarachnoid haemorrhage), the ENRICH-AF data safety monitoring board (DSMB) recommended that participants with lobar intracranial haemorrhage and convexity subarachnoid haemorrhage stop receiving the drug as soon as possible and that no further patients with these intracranial haemorrhage subtypes be enrolled. The DSMB indicated that these recommendations were based on observations of unacceptably high risks of recurrent haemorrhagic stroke among patients with lobar intracerebral haemorrhage and convexity subarachnoid haemorrhage assigned to the edoxaban arm. The ENRICH-AF steering committee has accepted the DSMB recommendations and remains masked to these results (two members who were unmasked to interact with the DSMB are recused from further participation). The ENRICH-AF trial is continuing to recruit the remainder of the eligible population, and the results for the participants with lobar intracerebral haemorrhage and convexity subarachnoid haemorrhage will not be available until after study completion. In the interim, we write to make physicians aware of these ENRICH-AF DSMB recommendations as survey data indicate that 30–70% of specialists are currently resuming anticoagulation in survivors of lobar and cerebral amyloid angiopathy-related intracerebral haemorrhage with atrial fibrillation.5Xu Y Shoamanesh A Schulman S et al.Oral anticoagulant re-initiation following intracerebral hemorrhage in non-valvular atrial fibrillation: global survey of the practices of neurologists, neurosurgeons and thrombosis experts.PLoS One. 2018; 13e0191137Google Scholar On the basis of emerging information from the ENRICH-AF trial, caution is warranted regarding the use of standard-dose anticoagulation in survivors of lobar intracerebral haemorrhage and convexity subarachnoid haemorrhage with atrial fibrillation outside of ongoing randomised trials until more data become available on the net benefit of anticoagulation in these high-risk subgroups of patients. AS reports research funding from the National Institutes of Health, Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Brain Canada, British Heart Foundation, Medical Research Future Fund, Marta and Owen Boris Foundation, Daiichi Sankyo, Bayer, Servier Canada, and Octapharma; and reports consultancy honoraria from AstraZeneca, Bayer AG, Bioxodes, Daiichi Sankyo, Servier Canada, and Takeda Pharmaceuticals. The ENRICH-AF trial is an investigator initiated study that is supported by an unrestricted grant-in-aid from Daiichi Sankyo Company. *Members of the ENRICH-AF Steering Committee are listed in the appendix. Download .pdf (.15 MB) Help with pdf files Supplementary appendix Understanding and approaching excessive daytime sleepinessExcessive daytime sleepiness (EDS) is a public health issue. However, it remains largely undervalued, scarcely diagnosed, and poorly supported. Variations in the definition of EDS and limitations in clinical assessment lead to difficulties in its epidemiological study, but the relevance of this symptom from a socioeconomic perspective is inarguable. EDS might be a consequence of several behavioural issues leading to insufficient or disrupted sleep, as well as a consequence of sleep disorders including sleep apnoea syndrome, circadian disorders, central hypersomnolence disorders (narcolepsy and idiopathic hypersomnia), other medical or psychiatric conditions, or medications. Full-Text PDF