BACKGROUND:There is an unmet need for high-quality data from prospective studies on the safety and effectiveness of direct oral anticoagulants (DOACs) for the treatment of cerebral venous thrombosis (CVT). We aimed to compare the safety and effectiveness of DOACs versus vitamin K antagonists (VKAs) for the treatment of CVT in a setting that reflects daily clinical practice. METHODS:DOAC-CVT was an international, prospective, observational cohort study done in 65 hospitals in 23 countries across five continents. Eligible patients were adults (aged ≥18 years) with radiologically confirmed CVT starting oral anticoagulant treatment with either DOACs or VKAs, as per local practice, within 30 days after diagnosis. Exclusion criteria were previous use of anticoagulants at the time of CVT diagnosis or an absolute contraindication to DOACs (eg, pregnancy and lactation, or severe renal or liver disease). Data were collected during routine clinical visits or telephone consultations at CVT diagnosis (baseline) and at 3 months, 6 months, and 12 months after CVT diagnosis. The primary endpoint was a composite of symptomatic venous thromboembolism and major bleeding events (International Society on Thrombosis and Haemostasis criteria) at 6 months. Main outcomes were adjusted for the confounders age, renal function, active cancer, CNS infections, concomitant antiplatelet use, country of inclusion's income status, Glasgow Coma Scale score, intracranial haemorrhage, antiphospholipid antibodies, previous major bleeding, and previous venous thromboembolism using inverse probability-of-treatment weighting. This study is registered at ClinicalTrials.gov (NCT04660747) and is ongoing. FINDINGS:Between Jan 27, 2021, and Jan 15, 2024, 619 patients were included; 401 (65%) patients started DOAC treatment, and 218 (35%) patients started VKA treatment. 390 (63%) of 619 patients were female and 229 (37%) of 619 patients were male. Patients' median age was 41 years (IQR 28-51). 6-month follow-up data were available for 617 (>99%) of 619 patients. 12 (3%) of 401 patients in the DOAC group and seven (3%) of 218 patients in the VKA group had a primary outcome event (weighted odds ratio [OR] 0·99 [95% CI 0·37-3·38]). Three (1%) of 401 patients in the DOAC group died versus three (1%) of 218 patients in the VKA group (weighted OR 0·55 [95% CI 0·11-2·80]). INTERPRETATION:The rate of recurrent thrombosis and major bleeding did not differ between patients with CVT treated with DOACs versus VKAs. This study adds to the increasing evidence that DOACs are a reasonable treatment option for CVT alongside VKAs. FUNDING:Netherlands Thrombosis Foundation.

Importance:Diffusion-weighted imaging (DWI) lesions have been demonstrated in patients with subacute intracerebral hemorrhage (ICH), suggesting ischemic injury, which may be related to blood pressure (BP) reduction. Objective:To test the hypothesis that acute intensive BP lowering is associated with DWI lesions after ICH. Design, Setting, and Participants:The Intracerebral Hemorrhage Acutely Decreasing Arterial Pressure Trial 2 (ICHADAPT-2) was a multicenter, randomized, open-label, blinded-end point trial. Between November 2012 and August 2022, patients with ICH presenting within 6 hours of onset were randomized to a systolic BP (SBP) target of less than 140 mm Hg or less than 180 mm Hg. The trial was conducted at 3 comprehensive stroke centers in Canada and Australia, including 1 telestroke referral hub and 1 community stroke hospital. A total of 162 patients with acute ICH were randomized. The primary analysis population was restricted to those undergoing DWI at 48 hours. Intervention:Patients were randomly assigned to an acute SBP target of less than 140 mm Hg or less than 180 mm Hg. Main Outcome and Measure:The primary end point was the incidence of acute DWI lesions on brain magnetic resonance imaging obtained 48 ± 12 hours after randomization. Results:DWI was obtained in 79 (48% female) patients with a mean (SD) age of 71 (13) years and median baseline ICH volume of 11.2 (range, 0.5-122.2) mL. The median times from onset to randomization and DWI were 3.17 (range, 0.7-14.6) hours and 51.6 (range, 17.0-121.4) hours, respectively. Mean (SD) baseline SBP was 183 (22) mm Hg in the less than 140 mm Hg target group and 181 (28) mm Hg in the less than 180 mm Hg target group. Mean SBP was lower over the 48-hour period after randomization in the less than 140 mm Hg group (mean difference, 18.9 mm Hg [95% CI, 17.6-20.2]; P < .001). DWI lesions were detected in 13 of 42 patients (31%) in the less than 140 mm Hg group and 14 of 37 patients (38%) in the less than 180 mm Hg group (odds ratio, 0.74 [95% CI, 0.12-4.64]; P = .32). The median number of DWI lesions (1 [95% CI, 1-10] vs 1.5 [95% CI, 1-10]; P = .26) and total DWI lesion volume (0.1 [95% CI, 0.01-41.3] mL vs 0.3 [95% CI, 0.02-2.03] mL; P = .17) were not different in the less than 140 mm Hg and less than 180 mm Hg groups. Conclusions and Relevance:DWI lesion frequency and volume were unaffected by intensive antihypertensive therapy. These results support the safety of early BP reduction in acute ICH.

Importance:Clinical practice guidelines recommend initiation of anticoagulation within 2 weeks after stroke with atrial fibrillation. It is unknown whether there is an optimal starting day within the 14-day period that balances the risks of recurrent embolic events against serious hemorrhagic events. Objective:To determine if there is an optimal delay time to initiate treatment with a direct oral anticoagulant after atrial fibrillation-related stroke that minimizes the risk of a composite outcome of ischemic or hemorrhagic events. Design, Setting, and Participants:This phase 2, pragmatic, response-adaptive randomized clinical trial was conducted between June 2017 and June 2023 at acute care hospitals in Texas and included patients who had a mild to moderate ischemic stroke (minimum lesion diameter of 1.5 cm) with atrial fibrillation and were prescribed a direct oral anticoagulant within 2 weeks from stroke onset. Intervention:Within 3 to 4 days after atrial fibrillation-associated ischemic stroke, patients were randomized to a group for treatment start date (group 1 was day 3 or 4 after stoke onset; group 2 was day 6; group 3 was day 10; and group 4 was day 14) with a direct oral anticoagulant for secondary stroke prevention. Main Outcomes and Measures:The composite primary outcome was an ischemic (stroke or systemic embolism) or hemorrhagic (symptomatic intracranial hemorrhage or major systemic hemorrhage) event observed within 30 days from the index stroke time of onset. Posterior probabilities were used to estimate which timing groups were optimal for treatment initiation and were recalculated at predefined intervals. The randomization allocations were adjusted to favor the groups with higher probabilities. Results:The trial enrolled and randomized 200 patients (50% were female; the median age was 75 years [IQR, 65-81 years]; 17.5% were Asian, Black, or >1 race; 16.5% were Hispanic; the median National Institutes of Health Stroke Scale score was 6.5 [IQR, 4-14]; and the median lesion diameter was 3.1 cm [IQR, 2.0-4.4 cm]). No ischemic events were observed for group 1, 3 events were observed for group 2, 2 events were observed for group 3, and 2 events were observed for group 4. One hemorrhagic event was observed for group 1, 1 event was observed for group 2, 1 event was observed for group 3, and 0 events were observed for group 4. Group 1 had a posterior probability of 0.41 for being the optimal day for treatment initiation and it was 0.26 for group 2, 0.17 for group 3, and 0.15 for group 4. The use of response-adaptive randomization was feasible and favored groups with earlier initiation times for use of a direct oral anticoagulant. Conclusions and Relevance:A clearly superior day to initiate use of a direct oral anticoagulant for secondary stroke prevention in patients with atrial fibrillation was not identified, but the evidence suggests that initiating use of a direct oral anticoagulant earlier is better than at later times within the first 2 weeks after stroke onset. Trial Registration:ClinicalTrials.gov Identifier: NCT03021928.

Preservation of brain health is a worldwide priority. The traditional view is that the major threats to the ageing brain lie within the brain itself. Consequently, therapeutic approaches have focused on protecting the brain from these presumably intrinsic pathogenic processes. However, an increasing body of evidence has unveiled a previously under-recognized contribution of peripheral organs to brain dysfunction and damage. Thus, in addition to the well-known impact of diseases of the heart and endocrine glands on the brain, accumulating data suggest that dysfunction of other organs, such as gut, liver, kidney and lung, substantially affects the development and clinical manifestation of age-related brain pathologies. In this Review, a framework is provided to indicate how organ dysfunction can alter brain homeostasis and promote neurodegeneration, with a focus on dementia. We delineate the associations of subclinical dysfunction in specific organs with dementia risk and provide suggestions for public health promotion and clinical management.