Prevalence and Factors Associated with Carotid Stenosis in Acute Ischemic Stroke Patients with Atrial Fibrillation.

INTRODUCTION: Among stroke patients with atrial fibrillation (AF), it is not uncommon to identify carotid atherosclerosis. This study aimed to estimate the prevalence of, and factors associated with, carotid atherosclerosis among patients with AF and acute ischemic stroke. PATIENTS AND METHODS: Prospectively collected data from consecutive patients with anterior ischemic stroke and AF who underwent carotid imaging from 10 stroke registries were categorized retrospectively according to the degree of stenosis in: no atherosclerosis, stenosis <50%, stenosis ≥50%, and occlusion. Logistic regression analysis was used to identify factors associated with ipsilateral carotid atherosclerosis. RESULTS: Among 2,955 patients with ischemic stroke and AF, carotid atherosclerosis was evident in 1,022 (34.6%) patients, while carotid stenosis ≥50% and occlusion were identified in 204 (6.9%) and 168 (5.7%) patients, respectively. Ipsilateral carotid stenosis ≥50% or occlusion was associated with higher age (OR: 1.15, 95% CI: 1.01-1.32, per decade), previous ischemic stroke or transient ischemic attack (OR: 1.70, 95% CI: 1.29-2.25), peripheral artery disease (OR: 1.85, 95% CI: 1.23-2.78), coronary artery disease (OR: 1.53, 95% CI: 1.16-2.04), and statin treatment on admission (OR: 1.30, 95% CI: 1.01-1.67). Patients with lacunar stroke had a lower likelihood of stenosis ≥50% or occlusion (OR: 0.29, 95% CI: 0.13-0.68). Compared to the absence of atherosclerotic disease, atherosclerosis in one and two arterial beds was associated with the identification of ipsilateral carotid stenosis (OR: 1.49, 95% CI: 1.22-2.98 and OR: 3.18, 95% CI: 1.85-5.49, respectively). CONCLUSION: Among acute ischemic stroke patients with AF, 1 out of 3 had ipsilateral carotid atherosclerosis, and 1 out of 8 had ipsilateral carotid stenosis ≥50% or occlusion. Atherosclerosis in two arterial beds was the most important predictor for the identification of ipsilateral carotid stenosis. Among ischemic stroke patients with AF, carotid atherosclerosis is common, while carotid imaging should not be overlooked, especially in those with coronary or/and peripheral artery disease.

Recommendations for implementing the INTERACT3 care bundle for intracerebral hemorrhage in Latin America: results of a Delphi method.

INTRODUCTION: The third Intensive Care Bundle with Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT3) showed that the implementation of a care bundle improves outcomes after acute intracerebral hemorrhage (ICH). We aimed to establish consensus-based recommendations for the broader integration of the care bundle across Latin American countries (LAC). METHODS: A 3-phase Delphi study allowed a panel of 32 healthcare workers from 14 LAC to sequentially rank statements relevant to 7 domains (training, resources/infrastructure, patient education, blood pressure, temperature, glycemic control, and anticoagulation reversal). Pre-defined consensus threshold was 75%. RESULTS: A total of 43 statements reached consensus by the third round, with 12 new statements emerging through rounds. The highest-ranked statements in each domain emphasized critical aspects but successful implementation requires appropriate resourcing. Key priorities were continuous training of all healthcare workers in ICH management, establishing protocols aligned with available resources, and collaborative interdisciplinary care supported by institutional networks. Statements related to anticoagulation reversal had the highest priority. CONCLUSIONS: Consensus statements are provided to facilitate integration of the INTERACT3 care bundle to reduce disparities in ICH outcomes in LAC.

Gene-Gene Interaction Between Factor-XI and ABO Genes in Cerebral Venous Thrombosis: The BEAST Study.

BACKGROUND AND OBJECTIVES: Gene-gene interactions likely contribute to the etiology of multifactorial diseases such as cerebral venous thrombosis (CVT) and could be one of the main sources of known missing heritability. We explored Factor XI (F11) and ABO gene interactions among patients with CVT. METHODS: Patients with CVT of European ancestry from the large Bio-Repository to Establish the Aetiology of Sinovenous Thrombosis (BEAST) international collaboration were recruited. Codominant modelling was used to determine interactions between genome-wide identified F11 and ABO genes with CVT status. RESULTS: We studied 882 patients with CVT and 1,205 ethnically matched control participants (age: 42 ± 15 vs 43 ± 12 years, p = 0.08: sex: 71% male vs 68% female, p = 0.09, respectively). Individuals heterozygous (AT) for the risk allele (T) at both loci (rs56810541/F11 and rs8176645/ABO) had a 3.9 (95% CI 2.74-5.71, p = 2.75e-13) increase in risk of CVT. Individuals homozygous (TT) for the risk allele at both loci had a 13.9 (95% CI 7.64-26.17, p = 2.0e-15) increase in risk of CVT. The presence of a non-O blood group (A, B, AB) combined with TT/rs56810541/F11 increased CVT risk by OR = 6.8 (95% CI 4.54-10.33, p = 2.00e15), compared with blood group-O combined with AA. DISCUSSION: Interactions between factor XI and ABO genes increase risk of CVT by 4- to 14-fold.

Coma in adult cerebral venous thrombosis: The BEAST study.

BACKGROUND AND PURPOSE: Coma is an independent predictor of poor clinical outcomes in cerebral venous thrombosis (CVT). We aimed to describe the association of age, sex, and radiological characteristics of adult coma patients with CVT. METHODS: We used data from the international, multicentre prospective observational BEAST (Biorepository to Establish the Aetiology of Sinovenous Thrombosis) study. Only positively associated variables with coma with <10% missing data in univariate analysis were considered for the multivariate logistic regression model. RESULTS: Of the 596 adult patients with CVT (75.7% women), 53 (8.9%) patients suffered coma. Despite being a female-predominant disease, the prevalence of coma was higher among men than women (13.1% vs. 7.5%, p = 0.04). Transverse sinus thrombosis was least likely to be associated with coma (23.9% vs. 73.3%, p < 0.001). The prevalence of superior sagittal sinus thrombosis was higher among men than women in the coma sample (73.6% vs. 37.5%, p = 0.01). Men were significantly older than women, with a median (interquartile range) age of 51 (38.5-60) versus 40 (33-47) years in the coma (p = 0.04) and 44.5 (34-58) versus 37 (29-48) years in the non-coma sample (p < 0.001), respectively. Furthermore, an age- and superior sagittal sinus-adjusted multivariate logistic regression model found male sex (odds ratio = 1.8, 95% confidence interval [CI] = 1.0-3.4, p = 0.04) to be an independent predictor of coma in CVT, with an area under the receiver operating characteristic curve of 0.61 (95% CI = 0.52-0.68, p = 0.01). CONCLUSIONS: Although CVT is a female-predominant disease, men were older and nearly twice as likely to suffer from coma than women.

Outcomes of Decompressive Surgery for Patients With Severe Cerebral Venous Thrombosis: DECOMPRESS2 Observational Study.

BACKGROUND: Decompressive neurosurgery is recommended for patients with cerebral venous thrombosis (CVT) who have large parenchymal lesions and impending brain herniation. This recommendation is based on limited evidence. We report long-term outcomes of patients with CVT treated by decompressive neurosurgery in an international cohort. METHODS: DECOMPRESS2 (Decompressive Surgery for Patients With Cerebral Venous Thrombosis, Part 2) was a prospective, international cohort study. Consecutive patients with CVT treated by decompressive neurosurgery were evaluated at admission, discharge, 6 months, and 12 months. The primary outcome was death or severe disability (modified Rankin Scale scores, 5-6) at 12 months. The secondary outcomes included patient and caregiver opinions on the benefits of surgery. The association between baseline variables before surgery and the primary outcome was assessed by multivariable logistic regression. RESULTS: A total of 118 patients (80 women; median age, 38 years) were included from 15 centers in 10 countries from December 2011 to December 2019. Surgery (115 craniectomies and 37 hematoma evacuations) was performed within a median of 1 day after diagnosis. At last assessment before surgery, 68 (57.6%) patients were comatose, fixed dilated pupils were found unilaterally in 27 (22.9%) and bilaterally in 9 (7.6%). Twelve-month follow-up data were available for 113 (95.8%) patients. Forty-six (39%) patients were dead or severely disabled (modified Rankin Scale scores, 5-6), of whom 40 (33.9%) patients had died. Forty-two (35.6%) patients were independent (modified Rankin Scale scores, 0-2). Coma (odds ratio, 2.39 [95% CI, 1.03-5.56]) and fixed dilated pupil (odds ratio, 2.22 [95% CI, 0.90-4.92]) were predictors of death or severe disability. Of the survivors, 56 (78.9%) patients and 61 (87.1%) caregivers expressed a positive opinion on surgery. CONCLUSIONS: Two-thirds of patients with severe CVT were alive and more than one-third were independent 1 year after decompressive surgery. Among survivors, surgery was judged as worthwhile by 4 out of 5 patients and caregivers. These results support the recommendation to perform decompressive neurosurgery in patients with CVT with impending brain herniation.

Reducing the global burden of cerebral venous thrombosis: An international research agenda.

BACKGROUND: Due to the rarity of cerebral venous thrombosis (CVT), performing high-quality scientific research in this field is challenging. Providing answers to unresolved research questions will improve prevention, diagnosis, and treatment, and ultimately translate to a better outcome of patients with CVT. We present an international research agenda, in which the most important research questions in the field of CVT are prioritized. AIMS: This research agenda has three distinct goals: (1) to provide inspiration and focus to research on CVT for the coming years, (2) to reinforce international collaboration, and (3) to facilitate the acquisition of research funding. SUMMARY OF REVIEW: This international research agenda is the result of a research summit organized by the International Cerebral Venous Thrombosis Consortium in Amsterdam, the Netherlands, in June 2023. The summit brought together 45 participants from 15 countries including clinical researchers from various disciplines, patients who previously suffered from CVT, and delegates from industry and non-profit funding organizations. The research agenda is categorized into six pre-specified themes: (1) epidemiology and clinical features, (2) life after CVT, (3) neuroimaging and diagnosis, (4) pathophysiology, (5) medical treatment, and (6) endovascular treatment. For each theme, we present two to four research questions, followed by a brief substantiation per question. The research questions were prioritized by the participants of the summit through consensus discussion. CONCLUSIONS: This international research agenda provides an overview of the most burning research questions on CVT. Answering these questions will advance our understanding and management of CVT, which will ultimately lead to improved outcomes for CVT patients worldwide.

Antithrombotic Treatment for Stroke Prevention in Cervical Artery Dissection: The STOP-CAD Study.

BACKGROUND: Small, randomized trials of patients with cervical artery dissection showed conflicting results regarding optimal stroke prevention strategies. We aimed to compare outcomes in patients with cervical artery dissection treated with antiplatelets versus anticoagulation. METHODS: This is a multicenter observational retrospective international study (16 countries, 63 sites) that included patients with cervical artery dissection without major trauma. The exposure was antithrombotic treatment type (anticoagulation versus antiplatelets), and outcomes were subsequent ischemic stroke and major hemorrhage (intracranial or extracranial hemorrhage). We used adjusted Cox regression with inverse probability of treatment weighting to determine associations between anticoagulation and study outcomes within 30 and 180 days. The main analysis used an as-treated crossover approach and only included outcomes occurring with the above treatments. RESULTS: The study included 3636 patients (402 [11.1%] received exclusively anticoagulation and 2453 [67.5%] received exclusively antiplatelets). By day 180, there were 162 new ischemic strokes (4.4%) and 28 major hemorrhages (0.8%); 87.0% of ischemic strokes occurred by day 30. In adjusted Cox regression with inverse probability of treatment weighting, compared with antiplatelet therapy, anticoagulation was associated with a nonsignificantly lower risk of subsequent ischemic stroke by day 30 (adjusted hazard ratio [HR], 0.71 [95% CI, 0.45-1.12]; P=0.145) and by day 180 (adjusted HR, 0.80 [95% CI, 0.28-2.24]; P=0.670). Anticoagulation therapy was not associated with a higher risk of major hemorrhage by day 30 (adjusted HR, 1.39 [95% CI, 0.35-5.45]; P=0.637) but was by day 180 (adjusted HR, 5.56 [95% CI, 1.53-20.13]; P=0.009). In interaction analyses, patients with occlusive dissection had significantly lower ischemic stroke risk with anticoagulation (adjusted HR, 0.40 [95% CI, 0.18-0.88]; Pinteraction=0.009). CONCLUSIONS: Our study does not rule out the benefit of anticoagulation in reducing ischemic stroke risk, particularly in patients with occlusive dissection. If anticoagulation is chosen, it seems reasonable to switch to antiplatelet therapy before 180 days to lower the risk of major bleeding. Large prospective studies are needed to validate our findings.

World Stroke Organization Brain & hEart globAl iniTiative Program.

INTRODUCTION: The World Stroke Organization (WSO) Brain & Heart Task Force developed the Brain & hEart globAl iniTiative (BEAT), a pilot feasibility implementation program to establish clinical collaborations between cardiologists and stroke physicians who work at large healthcare facilities. METHODS: The WSO BEAT pilot project focused on atrial fibrillation (AF) and patent foramen ovale (PFO) detection and management, and poststroke cardiovascular complications known as the stroke-heart syndrome. The program included 10 sites from 8 countries: Brazil, China, Egypt, Germany, Japan, Mexico, Romania, and the USA The primary composite feasibility outcome was the achievement of the following 3 implementation metrics (1) developing site-specific clinical pathways for the diagnosis and management of AF, PFO, and the stroke-heart syndrome; (2) establishing regular Neurocardiology rounds (e.g., monthly); and (3) incorporating a cardiologist to the stroke team. The secondary objectives were (1) to identify implementation challenges to guide a larger program and (2) to describe qualitative improvements. RESULTS: The WSO BEAT pilot feasibility program achieved the prespecified primary composite outcome in 9 of 10 (90%) sites. The most common challenges were the limited access to specific medications (e.g., direct oral anticoagulants) and diagnostic (e.g., prolonged cardiac monitoring) or therapeutic (e.g., PFO closure devices) technologies. The most relevant qualitative improvement was the achievement of a more homogeneous diagnostic and therapeutic approach. CONCLUSION: The WSO BEAT pilot program suggests that developing neurocardiology collaborations is feasible. The long-term sustainability of the WSO BEAT program and its impact on quality of stroke care and clinical outcomes needs to be tested in a larger and longer duration program.

Endovascular treatment of cerebral sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia.

INTRODUCTION: There is little data on the role of endovascular treatment (EVT) of cerebral venous sinus thrombosis (CVST) due to vaccine-induced immune thrombotic thrombocytopenia (VITT). Here, we describe clinical characteristics and outcomes of CVST-VITT patients who were treated with EVT. PATIENTS AND METHODS: We report data from an international registry of patients who developed CVST within 28 days of SARS-CoV-2 vaccination, reported between 29 March 2021 and 6 March 2023. VITT was defined according to the Pavord criteria. RESULTS: EVT was performed in 18/136 (13%) patients with CVST-VITT (92% aspiration and/or stent retrieval, 8% local thrombolysis). Most common indications were extensive thrombosis and clinical or radiological deterioration. Compared to non-EVT patients, those receiving EVT had a higher median thrombus load (4.5 vs 3). Following EVT, local blood flow was improved in 83% (10/12, 95% confidence interval [CI] 54-96). One (6%) asymptomatic sinus perforation occurred. Eight (44%) patients treated with EVT also underwent decompressive surgery. Mortality was 50% (9/18, 95% CI 29-71) and 88% (8/9, 95% CI 25-66) of surviving EVT patients achieved functional independence with a modified Rankin Scale score of 0-2 at follow-up. In multivariable analysis, EVT was not associated with increased mortality (adjusted odds ratio, 0.66, 95% CI 0.16-2.58). DISCUSSION AND CONCLUSION: We describe the largest cohort of CVST-VITT patients receiving EVT. Half of the patients receiving EVT died during hospital admission, but most survivors achieved functional independence.

Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial.

BACKGROUND: People with factor XI deficiency have lower rates of ischaemic stroke than the general population and infrequent spontaneous bleeding, suggesting that factor XI has a more important role in thrombosis than in haemostasis. Milvexian, an oral small-molecule inhibitor of activated factor XI, added to standard antiplatelet therapy, might reduce the risk of non-cardioembolic ischaemic stroke without increasing the risk of bleeding. We aimed to estimate the dose-response of milvexian for recurrent ischaemic cerebral events and major bleeding in patients with recent ischaemic stroke or transient ischaemic attack (TIA). METHODS: AXIOMATIC-SSP was a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial done at 367 hospitals in 27 countries. Eligible participants aged 40 years or older, with acute (<48 h) ischaemic stroke or high-risk TIA, were randomly assigned by a web-based interactive response system in a 1:1:1:1:1:2 ratio to receive one of five doses of milvexian (25 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, or 200 mg twice daily) or matching placebo twice daily for 90 days. All participants received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg daily for the first 90 days. Investigators, site staff, and participants were masked to treatment assignment. The primary efficacy endpoint was the composite of ischaemic stroke or incident covert brain infarct on MRI at 90 days, assessed in all participants allocated to treatment who completed a follow-up MRI brain scan, and the primary analysis assessed the dose-response relationship with Multiple Comparison Procedure-Modelling (MCP-MOD). The main safety outcome was major bleeding at 90 days, assessed in all participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT03766581) and the EU Clinical Trials Register (2017-005029-19). FINDINGS: Between Jan 27, 2019, and Dec 24, 2021, 2366 participants were randomly allocated to placebo (n=691); milvexian 25 mg once daily (n=328); or twice-daily doses of milvexian 25 mg (n=318), 50 mg (n=328), 100 mg (n=310), or 200 mg (n=351). The median age of participants was 71 (IQR 62-77) years and 859 (36%) were female. At 90 days, the estimates of the percentage of participants with either symptomatic ischaemic stroke or covert brain infarcts were 16·8 (90·2% CI 14·5-19·1) for placebo, 16·7 (14·8-18·6) for 25 mg milvexian once daily, 16·6 (14·8-18·3) for 25 mg twice daily, 15·6 (13·9-17·5) for 50 mg twice daily, 15·4 (13·4-17·6) for 100 mg twice daily, and 15·3 (12·8-19·7) for 200 mg twice daily. No significant dose-response was observed among the five milvexian doses for the primary composite efficacy outcome. Model-based estimates of the relative risk with milvexian compared with placebo were 0·99 (90·2% CI 0·91-1·05) for 25 mg once daily, 0·99 (0·87-1·11) for 25 mg twice daily, 0·93 (0·78-1·11) for 50 mg twice daily, 0·92 (0·75-1·13) for 100 mg twice daily, and 0·91 (0·72-1·26) for 200 mg twice daily. No apparent dose-response was observed for major bleeding (four [1%] of 682 participants with placebo, two [1%] of 325 with milvexian 25 mg once daily, two [1%] of 313 with 25 mg twice daily, five [2%] of 325 with 50 mg twice daily, five [2%] of 306 with 100 mg twice daily, and five [1%] of 344 with 200 mg twice daily). Five treatment-emergent deaths occurred, four of which were considered unrelated to the study drug by the investigator. INTERPRETATION: Factor XIa inhibition with milvexian, added to dual antiplatelet therapy, did not substantially reduce the composite outcome of symptomatic ischaemic stroke or covert brain infarction and did not meaningfully increase the risk of major bleeding. Findings from our study have informed the design of a phase 3 trial of milvexian for the prevention of ischaemic stroke in patients with acute ischaemic stroke or TIA. FUNDING: Bristol Myers Squibb and Janssen Research & Development.

Direct oral anticoagulants for the treatment of cerebral venous thrombosis - a protocol of an international phase IV study.

Introduction: Current guidelines recommend that patients with cerebral venous thrombosis (CVT) should be treated with vitamin K antagonists (VKAs) for 3-12 months. Direct oral anticoagulants (DOACs), however, are increasingly used in clinical practice. An exploratory randomized controlled trial including 120 patients with CVT suggested that the efficacy and safety profile of dabigatran (a DOAC) is similar to VKAs for the treatment of CVT, but large-scale prospective studies from a real-world setting are lacking. Methods: DOAC-CVT is an international, prospective, observational cohort study comparing DOACs to VKAs for the prevention of recurrent venous thrombotic events after acute CVT. Patients are eligible if they are 18 years or older, have a radiologically confirmed CVT, and have started oral anticoagulant treatment (DOAC or VKA) within 30 days of CVT diagnosis. Patients with an absolute contra-indication for DOACs, such as pregnancy or severe renal insufficiency, are excluded from the study. We aim to recruit at least 500 patients within a three-year recruitment period. The primary endpoint is a composite of recurrent venous thrombosis and major bleeding at 6 months of follow-up. We will calculate an adjusted odds ratio for the primary endpoint using propensity score inverse probability treatment weighting. Discussion: DOAC-CVT will provide real-world data on the comparative efficacy and safety of DOACs versus VKAs for the treatment of CVT. Clinical trial registration: ClinicalTrials.gov, NCT04660747.

Sex differences in cerebral venous sinus thrombosis after adenoviral vaccination against COVID-19.

INTRODUCTION: Cerebral venous sinus thrombosis associated with vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) is a severe disease with high mortality. There are few data on sex differences in CVST-VITT. The aim of our study was to investigate the differences in presentation, treatment, clinical course, complications, and outcome of CVST-VITT between women and men. PATIENTS AND METHODS: We used data from an ongoing international registry on CVST-VITT. VITT was diagnosed according to the Pavord criteria. We compared the characteristics of CVST-VITT in women and men. RESULTS: Of 133 patients with possible, probable, or definite CVST-VITT, 102 (77%) were women. Women were slightly younger [median age 42 (IQR 28-54) vs 45 (28-56)], presented more often with coma (26% vs 10%) and had a lower platelet count at presentation [median (IQR) 50x109/L (28-79) vs 68 (30-125)] than men. The nadir platelet count was lower in women [median (IQR) 34 (19-62) vs 53 (20-92)]. More women received endovascular treatment than men (15% vs 6%). Rates of treatment with intravenous immunoglobulins were similar (63% vs 66%), as were new venous thromboembolic events (14% vs 14%) and major bleeding complications (30% vs 20%). Rates of good functional outcome (modified Rankin Scale 0-2, 42% vs 45%) and in-hospital death (39% vs 41%) did not differ. DISCUSSION AND CONCLUSIONS: Three quarters of CVST-VITT patients in this study were women. Women were more severely affected at presentation, but clinical course and outcome did not differ between women and men. VITT-specific treatments were overall similar, but more women received endovascular treatment.

Cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia in middle-income countries.

BACKGROUND: Adenovirus-based COVID-19 vaccines are extensively used in low- and middle-income countries (LMICs). Remarkably, cases of cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) have rarely been reported from LMICs. AIMS: We studied the frequency, manifestations, treatment, and outcomes of CVST-VITT in LMICs. METHODS: We report data from an international registry on CVST after COVID-19 vaccination. VITT was classified according to the Pavord criteria. We compared CVST-VITT cases from LMICs to cases from high-income countries (HICs). RESULTS: Until August 2022, 228 CVST cases were reported, of which 63 were from LMICs (all middle-income countries [MICs]: Brazil, China, India, Iran, Mexico, Pakistan, Turkey). Of these 63, 32 (51%) met the VITT criteria, compared to 103 of 165 (62%) from HICs. Only 5 of the 32 (16%) CVST-VITT cases from MICs had definite VITT, mostly because anti-platelet factor 4 antibodies were often not tested. The median age was 26 (interquartile range [IQR] 20-37) versus 47 (IQR 32-58) years, and the proportion of women was 25 of 32 (78%) versus 77 of 103 (75%) in MICs versus HICs, respectively. Patients from MICs were diagnosed later than patients from HICs (1/32 [3%] vs. 65/103 [63%] diagnosed before May 2021). Clinical manifestations, including intracranial hemorrhage, were largely similar as was intravenous immunoglobulin use. In-hospital mortality was lower in MICs (7/31 [23%, 95% confidence interval (CI) 11-40]) than in HICs (44/102 [43%, 95% CI 34-53], p = 0.039). CONCLUSIONS: The number of CVST-VITT cases reported from LMICs was small despite the widespread use of adenoviral vaccines. Clinical manifestations and treatment of CVST-VITT cases were largely similar in MICs and HICs, while mortality was lower in patients from MICs.

The third Intensive Care Bundle with Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT3): an international, stepped wedge cluster randomised controlled trial.

BACKGROUND: Early control of elevated blood pressure is the most promising treatment for acute intracerebral haemorrhage. We aimed to establish whether implementing a goal-directed care bundle incorporating protocols for early intensive blood pressure lowering and management algorithms for hyperglycaemia, pyrexia, and abnormal anticoagulation, implemented in a hospital setting, could improve outcomes for patients with acute spontaneous intracerebral haemorrhage. METHODS: We performed a pragmatic, international, multicentre, blinded endpoint, stepped wedge cluster randomised controlled trial at hospitals in nine low-income and middle-income countries (Brazil, China, India, Mexico, Nigeria, Pakistan, Peru, Sri Lanka, and Viet Nam) and one high-income country (Chile). Hospitals were eligible if they had no or inconsistent relevant, disease-specific protocols, and were willing to implement the care bundle to consecutive patients (aged ≥18 years) with imaging-confirmed spontaneous intracerebral haemorrhage presenting within 6 h of the onset of symptoms, had a local champion, and could provide the required study data. Hospitals were centrally randomly allocated using permuted blocks to three sequences of implementation, stratified by country and the projected number of patients to be recruited over the 12 months of the study period. These sequences had four periods that dictated the order in which the hospitals were to switch from the control usual care procedure to the intervention implementation of the care bundle procedure to different clusters of patients in a stepped manner. To avoid contamination, details of the intervention, sequence, and allocation periods were concealed from sites until they had completed the usual care control periods. The care bundle protocol included the early intensive lowering of systolic blood pressure (target <140 mm Hg), strict glucose control (target 6·1-7·8 mmol/L in those without diabetes and 7·8-10·0 mmol/L in those with diabetes), antipyrexia treatment (target body temperature ≤37·5°C), and rapid reversal of warfarin-related anticoagulation (target international normalised ratio <1·5) within 1 h of treatment, in patients where these variables were abnormal. Analyses were performed according to a modified intention-to-treat population with available outcome data (ie, excluding sites that withdrew during the study). The primary outcome was functional recovery, measured with the modified Rankin scale (mRS; range 0 [no symptoms] to 6 [death]) at 6 months by masked research staff, analysed using proportional ordinal logistic regression to assess the distribution in scores on the mRS, with adjustments for cluster (hospital site), group assignment of cluster per period, and time (6-month periods from Dec 12, 2017). This trial is registered at Clinicaltrials.gov (NCT03209258) and the Chinese Clinical Trial Registry (ChiCTR-IOC-17011787) and is completed. FINDINGS: Between May 27, 2017, and July 8, 2021, 206 hospitals were assessed for eligibility, of which 144 hospitals in ten countries agreed to join and were randomly assigned in the trial, but 22 hospitals withdrew before starting to enrol patients and another hospital was withdrawn and their data on enrolled patients was deleted because regulatory approval was not obtained. Between Dec 12, 2017, and Dec 31, 2021, 10 857 patients were screened but 3821 were excluded. Overall, the modified intention-to-treat population included 7036 patients enrolled at 121 hospitals, with 3221 assigned to the care bundle group and 3815 to the usual care group, with primary outcome data available in 2892 patients in the care bundle group and 3363 patients in the usual care group. The likelihood of a poor functional outcome was lower in the care bundle group (common odds ratio 0·86; 95% CI 0·76-0·97; p=0·015). The favourable shift in mRS scores in the care bundle group was generally consistent across a range of sensitivity analyses that included additional adjustments for country and patient variables (0·84; 0·73-0·97; p=0·017), and with different approaches to the use of multiple imputations for missing data. Patients in the care bundle group had fewer serious adverse events than those in the usual care group (16·0% vs 20·1%; p=0·0098). INTERPRETATION: Implementation of a care bundle protocol for intensive blood pressure lowering and other management algorithms for physiological control within several hours of the onset of symptoms resulted in improved functional outcome for patients with acute intracerebral haemorrhage. Hospitals should incorporate this approach into clinical practice as part of active management for this serious condition. FUNDING: Joint Global Health Trials scheme from the Department of Health and Social Care, the Foreign, Commonwealth & Development Office, and the Medical Research Council and Wellcome Trust; West China Hospital; the National Health and Medical Research Council of Australia; Sichuan Credit Pharmaceutic and Takeda China.

A scoring tool to predict mortality and dependency after cerebral venous thrombosis.

BACKGROUND AND PURPOSE: A prognostic score was developed to predict dependency and death after cerebral venous thrombosis (CVT) to identify patients for targeted therapy in future clinical trials. METHODS: Data from the International CVT Consortium were used. Patients with pre-existent functional dependency were excluded. Logistic regression was used to predict poor outcome (modified Rankin Scale score 3-6) at 6 months and Cox regression to predict 30-day and 1-year all-cause mortality. Potential predictors derived from previous studies were selected with backward stepwise selection. Coefficients were shrunk using ridge regression to adjust for optimism in internal validation. RESULTS: Of 1454 patients with CVT, the cumulative number of deaths was 44 (3%) and 70 (5%) for 30 days and 1 year, respectively. Of 1126 patients evaluated regarding functional outcome, 137 (12%) were dependent or dead at 6 months. From the retained predictors for both models, the SI2 NCAL2 C score was derived utilizing the following components: absence of female-sex-specific risk factor, intracerebral hemorrhage, infection of the central nervous system, neurological focal deficits, coma, age, lower level of hemoglobin (g/l), higher level of glucose (mmol/l) at admission, and cancer. C-statistics were 0.80 (95% confidence interval [CI] 0.75-0.84), 0.84 (95% CI 0.80-0.88) and 0.84 (95% CI 0.80-0.88) for the poor outcome, 30-day and 1-year mortality model, respectively. Calibration plots indicated a good model fit between predicted and observed values. The SI2 NCAL2 C score calculator is freely available at www.cerebralvenousthrombosis.com. CONCLUSIONS: The SI2 NCAL2 C score shows adequate performance for estimating individual risk of mortality and dependency after CVT but external validation of the score is warranted.

Age of onset of cerebral venous thrombosis: the BEAST study.

Background: Cerebral venous thrombosis (CVT) is an uncommon cause of stroke in young adults. We aimed to determine the impact of age, gender and risk factors (including sex-specific) on CVT onset. Methods: We used data from the BEAST (Biorepository to Establish the Aetiology of Sinovenous Thrombosis), a multicentre multinational prospective observational study on CVT. Composite factors analysis (CFA) was performed to determine the impact on the age of CVT onset in males and females. Results: A total of 1309 CVT patients (75.3% females) aged ⩾18 years were recruited. The overall median (IQR-interquartile range) age for males and females was 46 (35-58) years and 37 (28-47) years (p < 0.001), respectively. However, the presence of antibiotic-requiring sepsis (p = 0.03, 95% CI 27-47 years) among males and gender-specific risk factors like pregnancy (p < 0.001, 95% CI 29-34 years), puerperium (p < 0.001, 95% CI 26-34 years) and oral contraceptive use (p < 0.001, 95% CI 33-36 years) were significantly associated with earlier onset of CVT among females. CFA demonstrated a significantly earlier onset of CVT in females, ~12 years younger, in those with multiple (⩾1) compared to '0' risk factors (p < 0.001, 95% CI 32-35 years). Conclusions: Women suffer CVT 9 years earlier in comparison to men. Female patients with multiple (⩾1) risk factors suffer CVT ~12 years earlier compared to those with no identifiable risk factors.

Decompressive surgery in cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia.

BACKGROUND AND PURPOSE: Cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) is an adverse drug reaction occurring after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. CVST-VITT patients often present with large intracerebral haemorrhages and a high proportion undergoes decompressive surgery. Clinical characteristics, therapeutic management and outcomes of CVST-VITT patients who underwent decompressive surgery are described and predictors of in-hospital mortality in these patients are explored. METHODS: Data from an ongoing international registry of patients who developed CVST within 28 days of SARS-CoV-2 vaccination, reported between 29 March 2021 and 10 May 2022, were used. Definite, probable and possible VITT cases, as defined by Pavord et al. (N Engl J Med 2021; 385: 1680-1689), were included. RESULTS: Decompressive surgery was performed in 34/128 (27%) patients with CVST-VITT. In-hospital mortality was 22/34 (65%) in the surgical and 27/94 (29%) in the non-surgical group (p < 0.001). In all surgical cases, the cause of death was brain herniation. The highest mortality rates were found amongst patients with preoperative coma (17/18, 94% vs. 4/14, 29% in the non-comatose; p < 0.001) and bilaterally absent pupillary reflexes (7/7, 100% vs. 6/9, 67% with unilaterally reactive pupil, and 4/11, 36% with bilaterally reactive pupils; p = 0.023). Postoperative imaging revealed worsening of index haemorrhagic lesion in 19 (70%) patients and new haemorrhagic lesions in 16 (59%) patients. At a median follow-up of 6 months, 8/10 of surgical CVST-VITT who survived admission were functionally independent. CONCLUSIONS: Almost two-thirds of surgical CVST-VITT patients died during hospital admission. Preoperative coma and bilateral absence of pupillary responses were associated with higher mortality rates. Survivors often achieved functional independence.

Predictors of Mortality and Functional Outcome in Pregnancy and Puerperium-Related Cerebral Venous Thrombosis.

INTRODUCTION: Cerebral venous thrombosis (CVT) associated with pregnancy and puerperium has long been recognized, with poor information in terms of functional outcomes. Our objective was to analyze risk factors, clinical, imaging, and laboratory variables to predict functional outcome and death in this population. METHODS: CVT registries from three referral centers from Pakistan, Turkey, and Mexico, recruiting prospective cases, were combined for CVT associated with pregnancy or puerperium. Datasets and variables were standardized. Demographic characteristics, presentation, risk factors, and functional outcomes in pregnancy/puerperium-related CVT were analyzed. Binary logistic regression was used to assess predictors of outcome. The main outcome was modified Rankin score >2 at 30 days and mortality at 30 days. RESULTS: Five hundred fifty-three cases (median age 28 years [IQR 23-34]) of CVT associated with pregnancy and puerperium were included; 439 cases (79.4%) happened in the puerperium and 20.6% during pregnancy (53.5% occurred during the first trimester). Anemia (36.7%) and dehydration (22.9%) were the commonest obstetric risk factors identified. Predictors of poor outcome (mRS >2) were encephalopathy (OR 12.8, p < 0.001), cases from Mexican origin (OR 3.1, p = 0.004), fever/puerperal infection (OR 2.7, p = 0.02), and anemia (OR 2.2, p = 0.01). Cases from Mexican origin (OR 12.0, p = 0.003) and Encephalopathy (OR 7.7, p < 0.001), presented with the highest mortality association in the final adjusted model. DISCUSSION/CONCLUSION: In CVT associated with pregnancy and puerperium, encephalopathy, fever/puerperal infection, and anemia are associated with bad functional outcomes, meanwhile encephalopathy and cases from Mexican origin with higher mortality in the acute (30-days) of CVT onset. Anemia and infection are potential reversible predictors of poor outcome that clinicians should be aware of in order to prevent poor outcomes in these patients.

Impact of the Mexican education system and age on basic knowledge about ischemic heart disease in the pre-COVID-19 era.

BACKGROUND AND OBJECTIVE: To assess general population's knowledge about ischemic heart disease (IHD) and its relationship to years of schooling in Mexico. METHOD: Analysis of surveys designed to measure knowledge about IHD applied in Mexico City. RESULTS: 530 surveys were analyzed. 51.7% were women. The median age was 43 years (IQR: 15-92) and the median of schooling was 18 years (IQR: 15-18). 64.5% of respondents scored less than 50% of correct answers. A slight increase in the knowledge level and years of study (p < 0.001) and age (p = 0.101) was observed, but with low correlation indexes (r = 0.215 and r = 0.071, respectively). CONCLUSIONS: Knowledge about IHD in general population is deficient and doesn't increase adequately neither with age nor academic studies. It is necessary to review our health education strategies.

ANTECEDENTES Y OBJETIVO: Evaluar los conocimientos sobre cardiopatía isquémica (CI) de la población general y relacionarlos con los años de escolaridad y la edad. MÉTODO: Análisis de encuestas diseñadas para medir conocimientos sobre CI aplicadas en Ciudad de México. RESULTADOS: Se analizaron 530 encuestas. El 51.7% fueron mujeres. La mediana de edad fue 43 años (RIC: 15 a 92) y la de años de estudio fue de 18 años (RIC: 15-18). El 64.5% de los encuestados obtuvo menos del 50% de aciertos. Se documentó un ligero incremento en el nivel de conocimiento con los años de estudio (p < 0.001) y con la edad (p = 0.101), pero con bajos índices de correlación (r = 0.215 y r = 0.071, respectivamente). CONCLUSIONES: Los conocimientos sobre CI en la población general son deficientes y no se incrementan adecuadamente con la edad ni con los años de estudios académicos. Es necesario revisar nuestras estrategias de educación en salud.