Cerebral microbleeds and intracranial haemorrhage risk in patients anticoagulated for atrial fibrillation after acute ischaemic stroke or transient ischaemic attack (CROMIS-2): a multicentre observational cohort study

Abstract

SummaryBackgroundCerebral microbleeds are a potential neuroimaging biomarker of cerebral small vessel diseases that are prone to intracranial bleeding. We aimed to determine whether presence of cerebral microbleeds can identify patients at high risk of symptomatic intracranial haemorrhage when anticoagulated for atrial fibrillation after recent ischaemic stroke or transient ischaemic attack.MethodsOur observational, multicentre, prospective inception cohort study recruited adults aged 18 years or older from 79 hospitals in the UK and one in the Netherlands with atrial fibrillation and recent acute ischaemic stroke or transient ischaemic attack, treated with a vitamin K antagonist or direct oral anticoagulant, and followed up for 24 months using general practitioner and patient postal questionnaires, telephone interviews, hospital visits, and National Health Service digital data on hospital admissions or death. We excluded patients if they could not undergo MRI, had a definite contraindication to anticoagulation, or had previously received therapeutic anticoagulation. The primary outcome was symptomatic intracranial haemorrhage occurring at any time before the final follow-up at 24 months. The log-rank test was used to compare rates of intracranial haemorrhage between those with and without cerebral microbleeds. We developed two prediction models using Cox regression: first, including all predictors associated with intracranial haemorrhage at the 20% level in univariable analysis; and second, including cerebral microbleed presence and HAS-BLED score. We then compared these with the HAS-BLED score alone. This study is registered with ClinicalTrials.gov, number NCT02513316.FindingsBetween Aug 4, 2011, and July 31, 2015, we recruited 1490 participants of whom follow-up data were available for 1447 (97%), over a mean period of 850 days (SD 373; 3366 patient-years). The symptomatic intracranial haemorrhage rate in patients with cerebral microbleeds was 9·8 per 1000 patient-years (95% CI 4·0–20·3) compared with 2·6 per 1000 patient-years (95% CI 1·1–5·4) in those without cerebral microbleeds (adjusted hazard ratio 3·67, 95% CI 1·27–10·60). Compared with the HAS-BLED score alone (C-index 0·41, 95% CI 0·29–0·53), models including cerebral microbleeds and HAS-BLED (0·66, 0·53–0·80) and cerebral microbleeds, diabetes, anticoagulant type, and HAS-BLED (0·74, 0·60–0·88) predicted symptomatic intracranial haemorrhage significantly better (difference in C-index 0·25, 95% CI 0·07–0·43, p=0·0065; and 0·33, 0·14–0·51, p=0·00059, respectively).InterpretationIn patients with atrial fibrillation anticoagulated after recent ischaemic stroke or transient ischaemic attack, cerebral microbleed presence is independently associated with symptomatic intracranial haemorrhage risk and could be used to inform anticoagulation decisions. Large-scale collaborative observational cohort analyses are needed to refine and validate intracranial haemorrhage risk scores incorporating cerebral microbleeds to identify patients at risk of net harm from ora...

Direct oral anticoagulants versus vitamin K antagonists after recent ischemic stroke in patients with atrial fibrillation

“…All invited centers agreed to participate. The following studies were included: the single center prospective cohort studies from Verona/Italy, 19 Erlangen/Germany, 20 Basel/Switzerland ("Novel oral anticoagulants in stroke patients"/NOACISP), 23 and the multicenter cohort studies "Early Recurrence and Cerebral Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation" (RAF 21 and RAF-NOAC 22 ; 29 centers in Europe and Asia), "The Clinical Relevance of Microbleeds in Stroke study" (CROMIS-2; 79 centers in the UK and one in the Netherlands), 26,27 and "The Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-Non-Valvular Atrial Fibrillation Study" (SAMURAI-NVAF; 18 centers in Japan). 18,24,28 Details about the participating studies can be obtained from Table 1 (collaborators are listed in Supplementary Table 1).…”

Atrial fibrillation and stroke: a practical guide

“…19 The CROMIS-2 study included 1490 participants with recent ischaemic stroke or transient ischaemic attack and AF; the symptomatic intracranial haemorrhage rate in patients with cerebral microbleeds was 9.8 per 1000 patient-years (95% CI 4.0 to 20.3) compared with 2.6 per 1000 patient-years (95% CI 1.1 to 5.4) in those without cerebral microbleeds (adjusted HR 3.67, 95% CI 1.27 to 10.60). Compared with the HAS-BLED score alone, models including cerebral microbleeds predicted symptomatic intracranial haemorrhage significantly better with a c-statistic of 0.74 (95% CI 0.60 to 0.88).…”

“…Several randomised controlled trials—including SoSTART, APACHE-AF and PRESTIGE-AF—will provide more definitive evidence, and an individual patient data meta-analysis is planned through the COCROACH collaboration. In the interim, we suggest a careful re-evaluation of the bleeding and stroke risks, including location of the intracerebral haemorrhage (as the recurrence risk of lobar haemorrhage is about four times greater than non-lobar haemorrhage107) and MRI markers of cerebral amyloid angiopathy,19 careful control of modifiable risk factors and use of a direct oral anticoagulant in preference to warfarin. We strongly encourage randomisation of eligible patients into ongoing trials, but left atrial appendage occlusion may reasonably be considered if the risk of recurrent intracerebral haemorrhage is judged to be unacceptably high.…”

“…17 CHA2DS2VASc was validated on the Euro Heart Survey on AF population in 1084 patients not taking anticoagulants at baseline; its low-risk category had very few thromboembolic events (none in the initial validation cohort, table 3), and fewer patients categorised as being at intermediate risk (14.9%) than with CHADS2 (table 3). This revised score still has limitations: it does not include several important ischaemic stroke risk factors—notably left atrial remodelling from any cause (detectable on echocardiography), chronic kidney disease (particularly those with chronic kidney disease 3B or greater (estimated glomerular filtration rate <45 mL/min/1.73 m 2 )), obstructive sleep apnoea, circulating cardiac biomarkers (review18) or brain biomarkers of cerebrovascular disease 19. There have been scoring systems developed (and currently being validated) that incorporate one or more of these factors.…”

Risk of intracerebral haemorrhage in Chinese patients with atrial fibrillation on warfarin with cerebral microbleeds: the IPAAC-Warfarin study

“…Hence, larger prospective studies are urgently needed. The recently published CROMIS-2 study, which recruited patients with AF with recent ischaemic stroke or transient ischaemic attack treated with warfarin or DOACs, has shown that presence of CMBs was independently associated with symptomatic ICH (HR 3.67) 17. Unfortunately, as most of the patients were recruited from the UK (only 2% were Asians), the safety of oral anticoagulants in Chinese patients with CMBs, who have higher risk of ICH compared with Caucasians (HR 4.0), remains unknown 18.…”