Risk, Clinical Course, and Outcome of Ischemic Stroke in Patients Hospitalized With COVID-19: A Multicenter Cohort Study.

BACKGROUND AND PURPOSE: The frequency of ischemic stroke in patients with coronavirus disease 2019 (COVID-19) varies in the current literature, and risk factors are unknown. We assessed the incidence, risk factors, and outcomes of acute ischemic stroke in hospitalized patients with COVID-19. METHODS: We included patients with a laboratory-confirmed SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) infection admitted in 16 Dutch hospitals participating in the international CAPACITY-COVID registry between March 1 and August 1, 2020. Patients were screened for the occurrence of acute ischemic stroke. We calculated the cumulative incidence of ischemic stroke and compared risk factors, cardiovascular complications, and in-hospital mortality in patients with and without ischemic stroke. RESULTS: We included 2147 patients with COVID-19, of whom 586 (27.3%) needed treatment at an intensive care unit. Thirty-eight patients (1.8%) had an ischemic stroke. Patients with stroke were older but did not differ in sex or cardiovascular risk factors. Median time between the onset of COVID-19 symptoms and diagnosis of stroke was 2 weeks. The incidence of ischemic stroke was higher among patients who were treated at an intensive care unit (16/586; 2.7% versus nonintensive care unit, 22/1561; 1.4%; P=0.039). Pulmonary embolism was more common in patients with (8/38; 21.1%) than in those without stroke (160/2109; 7.6%; adjusted risk ratio, 2.08 [95% CI, 1.52-2.84]). Twenty-seven patients with ischemic stroke (71.1%) died during admission or were functionally dependent at discharge. Patients with ischemic stroke were at a higher risk of in-hospital mortality (adjusted risk ratio, 1.56 [95% CI, 1.13-2.15]) than patients without stroke. CONCLUSIONS: In this multicenter cohort study, the cumulative incidence of acute ischemic stroke in hospitalized patients with COVID-19 was ≈2%, with a higher risk in patients treated at an intensive care unit. The majority of stroke patients had a poor outcome. The association between ischemic stroke and pulmonary embolism warrants further investigation.

Apixaban versus no anticoagulation after anticoagulation-associated intracerebral haemorrhage in patients with atrial fibrillation in the Netherlands (APACHE-AF): a randomised, open-label, phase 2 trial.

BACKGROUND: In patients with atrial fibrillation who survive an anticoagulation-associated intracerebral haemorrhage, a decision must be made as to whether restarting or permanently avoiding anticoagulation is the best long-term strategy to prevent recurrent stroke and other vascular events. In APACHE-AF, we aimed to estimate the rates of non-fatal stroke or vascular death in such patients when treated with apixaban compared with when anticoagulation was avoided, to inform the design of a larger trial. METHODS: APACHE-AF was a prospective, randomised, open-label, phase 2 trial with masked endpoint assessment, done at 16 hospitals in the Netherlands. Patients who survived intracerebral haemorrhage while treated with anticoagulation for atrial fibrillation were eligible for inclusion 7-90 days after the haemorrhage. Participants also had a CHA2DS2-VASc score of at least 2 and a score on the modified Rankin scale (mRS) of 4 or less. Participants were randomly assigned (1:1) to receive oral apixaban (5 mg twice daily or a reduced dose of 2·5 mg twice daily) or to avoid anticoagulation (oral antiplatelet agents could be prescribed at the discretion of the treating physician) by a central computerised randomisation system, stratified by the intention to start or withhold antiplatelet therapy in participants randomised to avoiding anticoagulation, and minimised for age and intracerebral haemorrhage location. The primary outcome was a composite of non-fatal stroke or vascular death, whichever came first, during a minimum follow-up of 6 months, analysed using Cox proportional hazards modelling in the intention-to-treat population. APACHE-AF is registered with ClinicalTrials.gov (NCT02565693) and the Netherlands Trial Register (NL4395), and the trial is closed to enrolment at all participating sites. FINDINGS: Between Jan 15, 2015, and July 6, 2020, we recruited 101 patients (median age 78 years [IQR 73-83]; 55 [54%] were men and 46 [46%] were women; 100 [99%] were White and one [1%] was Black) a median of 46 days (IQR 21-74) after intracerebral haemorrhage. 50 were assigned to apixaban and 51 to avoid anticoagulation (of whom 26 [51%] started antiplatelet therapy). None were lost to follow-up. Over a median follow-up of 1·9 years (IQR 1·0-3·1; 222 person-years), non-fatal stroke or vascular death occurred in 13 (26%) participants allocated to apixaban (annual event rate 12·6% [95% CI 6·7-21·5]) and in 12 (24%) allocated to avoid anticoagulation (11·9% [95% CI 6·2-20·8]; adjusted hazard ratio 1·05 [95% CI 0·48-2·31]; p=0·90). Serious adverse events that were not outcome events occurred in 29 (58%) of 50 participants assigned to apixaban and 29 (57%) of 51 assigned to avoid anticoagulation. INTERPRETATION: Patients with atrial fibrillation who had an intracerebral haemorrhage while taking anticoagulants have a high subsequent annual risk of non-fatal stroke or vascular death, whether allocated to apixaban or to avoid anticoagulation. Our data underline the need for randomised controlled trials large enough to allow identification of subgroups in whom restarting anticoagulation might be either beneficial or hazardous. FUNDING: Dutch Heart Foundation (grant 2012T077).