Association of Antithrombotic Drug Use With Incident Intracerebral Hemorrhage Location.

BACKGROUND AND OBJECTIVES: Few population-based studies have assessed associations between the use of antithrombotic (platelet antiaggregant or anticoagulant) drugs and location-specific risks of spontaneous intracerebral hemorrhage (s-ICH). In this study, we estimated associations between antithrombotic drug use and the risk of lobar vs nonlobar incident s-ICH. METHODS: Using Danish nationwide registries, we identified cases in the Southern Denmark Region of first-ever s-ICH in patients aged 50 years or older between 2009 and 2018. Each verified case was classified as lobar or nonlobar s-ICH and matched to controls in the general population by age, sex, and calendar year. Prior antithrombotic use was ascertained from a nationwide prescription registry. We calculated odds ratios (aORs) for associations between the use of clopidogrel, aspirin, direct oral anticoagulants (DOACs) or vitamin K antagonists (VKA), and lobar and nonlobar ICH in conditional logistic regression analyses that were adjusted for potential confounders. RESULTS: A total of 1,040 cases of lobar (47.9% men, mean age [SD] 75.2 [10.7] years) and 1,263 cases of nonlobar s-ICH (54.2% men, mean age 73.6 [11.4] years) were matched to 41,651 and 50,574 controls, respectively. A stronger association with lobar s-ICH was found for clopidogrel (cases: 7.6%, controls: 3.5%; aOR 3.46 [95% CI 2.45-4.89]) vs aspirin (cases: 22.9%, controls: 20.4%; aOR 2.14 [1.74-2.63; p = 0.019). Corresponding estimates for nonlobar s-ICH were not different between clopidogrel (cases: 5.4%, controls: 3.4%; aOR 2.44 [1.71-3.49]) and aspirin (cases: 20.7%, controls: 19.2%; aOR 1.77 [1.47-2.15]; p = 0.12). VKA use was associated with higher odds of both lobar (cases: 14.3%, controls: 6.1%; aOR 3.66 [2.78-4.80]) and nonlobar (cases: 15.4%, controls: 5.5%; aOR 4.62 [3.67-5.82]) s-ICH. The association of DOAC use with lobar s-ICH (cases: 3.5%, controls: 2.7%; aOR 1.66 [1.02-2.70]) was weaker than that of VKA use (p = 0.006). Corresponding estimates for nonlobar s-ICH were not different between DOACs (cases: 5.1%, controls: 2.4%; aOR 3.44 [2.33-5.08]) and VKAs (p = 0.20). DISCUSSION: Antithrombotics were associated with higher risks of s-ICH, but the strength of the associations varied by s-ICH location and drug, which may reflect differences in the cerebral microangiopathies associated with lobar vs nonlobar hemorrhages and the mechanisms of drug action.

Decompressive craniectomy plus best medical treatment versus best medical treatment alone for spontaneous severe deep supratentorial intracerebral haemorrhage: a randomised controlled clinical trial.

BACKGROUND: It is unknown whether decompressive craniectomy improves clinical outcome for people with spontaneous severe deep intracerebral haemorrhage. The SWITCH trial aimed to assess whether decompressive craniectomy plus best medical treatment in these patients improves outcome at 6 months compared to best medical treatment alone. METHODS: In this multicentre, randomised, open-label, assessor-blinded trial conducted in 42 stroke centres in Austria, Belgium, Finland, France, Germany, the Netherlands, Spain, Sweden, and Switzerland, adults (18-75 years) with a severe intracerebral haemorrhage involving the basal ganglia or thalamus were randomly assigned to receive either decompressive craniectomy plus best medical treatment or best medical treatment alone. The primary outcome was a score of 5-6 on the modified Rankin Scale (mRS) at 180 days, analysed in the intention-to-treat population. This trial is registered with ClincalTrials.gov, NCT02258919, and is completed. FINDINGS: SWITCH had to be stopped early due to lack of funding. Between Oct 6, 2014, and April 4, 2023, 201 individuals were randomly assigned and 197 gave delayed informed consent (96 decompressive craniectomy plus best medical treatment, 101 best medical treatment). 63 (32%) were women and 134 (68%) men, the median age was 61 years (IQR 51-68), and the median haematoma volume 57 mL (IQR 44-74). 42 (44%) of 95 participants assigned to decompressive craniectomy plus best medical treatment and 55 (58%) assigned to best medical treatment alone had an mRS of 5-6 at 180 days (adjusted risk ratio [aRR] 0·77, 95% CI 0·59 to 1·01, adjusted risk difference [aRD] -13%, 95% CI -26 to 0, p=0·057). In the per-protocol analysis, 36 (47%) of 77 participants in the decompressive craniectomy plus best medical treatment group and 44 (60%) of 73 in the best medical treatment alone group had an mRS of 5-6 (aRR 0·76, 95% CI 0·58 to 1·00, aRD -15%, 95% CI -28 to 0). Severe adverse events occurred in 42 (41%) of 103 participants receiving decompressive craniectomy plus best medical treatment and 41 (44%) of 94 receiving best medical treatment. INTERPRETATION: SWITCH provides weak evidence that decompressive craniectomy plus best medical treatment might be superior to best medical treatment alone in people with severe deep intracerebral haemorrhage. The results do not apply to intracerebral haemorrhage in other locations, and survival is associated with severe disability in both groups. FUNDING: Swiss National Science Foundation, Swiss Heart Foundation, Inselspital Stiftung, and Boehringer Ingelheim.

Statin Therapy for Secondary Prevention in Ischemic Stroke Patients With Cerebral Microbleeds.

BACKGROUND AND OBJECTIVES: The association between statin use and the risk of intracranial hemorrhage (ICrH) following ischemic stroke (IS) or transient ischemic attack (TIA) in patients with cerebral microbleeds (CMBs) remains uncertain. This study investigated the risk of recurrent IS and ICrH in patients receiving statins based on the presence of CMBs. METHODS: We conducted a pooled analysis of individual patient data from the Microbleeds International Collaborative Network, comprising 32 hospital-based prospective studies fulfilling the following criteria: adult patients with IS or TIA, availability of appropriate baseline MRI for CMB quantification and distribution, registration of statin use after the index stroke, and collection of stroke event data during a follow-up period of ≥3 months. The primary endpoint was the occurrence of recurrent symptomatic stroke (IS or ICrH), while secondary endpoints included IS alone or ICrH alone. We calculated incidence rates and performed Cox regression analyses adjusting for age, sex, hypertension, atrial fibrillation, previous stroke, and use of antiplatelet or anticoagulant drugs to explore the association between statin use and stroke events during follow-up in patients with CMBs. RESULTS: In total, 16,373 patients were included (mean age 70.5 ± 12.8 years; 42.5% female). Among them, 10,812 received statins at discharge, and 4,668 had 1 or more CMBs. The median follow-up duration was 1.34 years (interquartile range: 0.32-2.44). In patients with CMBs, statin users were compared with nonusers. Compared with nonusers, statin therapy was associated with a reduced risk of any stroke (incidence rate [IR] 53 vs 79 per 1,000 patient-years, adjusted hazard ratio [aHR] 0.68 [95% CI 0.56-0.84]), a reduced risk of IS (IR 39 vs 65 per 1,000 patient-years, aHR 0.65 [95% CI 0.51-0.82]), and no association with the risk of ICrH (IR 11 vs 16 per 1,000 patient-years, aHR 0.73 [95% CI 0.46-1.15]). The results in aHR remained consistent when considering anatomical distribution and high burden (≥5) of CMBs. DISCUSSION: These observational data suggest that secondary stroke prevention with statins in patients with IS or TIA and CMBs is associated with a lower risk of any stroke or IS without an increased risk of ICrH. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with IS or TIA and CMBs, statins lower the risk of any stroke or IS without increasing the risk of ICrH.

Long-Term Outcomes in Patients With Spontaneous Cerebellar Hemorrhage: An International Cohort Study.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) in the cerebellum has a poor short-term prognosis, whereas data on the long-term case fatality and recurrent vascular events are sparse. Herewith, we aimed to assess the long-term case fatality and recurrence rate of vascular events after a first cerebellar ICH. METHODS: In this international cohort study, we included patients from 10 hospitals (the United States and Europe from 1997 to 2017) aged ≥18 years with a first spontaneous cerebellar ICH who were discharged alive. Data on long-term case fatality and recurrence of vascular events (recurrent ICH [supratentoria or infratentorial], ischemic stroke, myocardial infarction, or major vascular surgery) were collected for survival analysis and absolute event rate calculation. RESULTS: We included 405 patients with cerebellar ICH (mean age [SD], 72 [13] years, 49% female). The median survival time was 67 months (interquartile range, 23-100 months), with a cumulative survival rate of 34% at 10-year follow-up (median follow-up time per center ranged: 15-80 months). In the 347 patients with data on vascular events 92 events occurred in 78 patients, after initial cerebellar ICH: 31 (8.9%) patients had a recurrent ICH (absolute event rate, 1.8 per 100 patient-years [95% CI, 1.2-2.6]), 39 (11%) had an ischemic stroke (absolute event rate, 2.3 [95% CI, 1.6-3.2]), 13 (3.7%) had a myocardial infarction (absolute event rate, 0.8 [95% CI, 0.4-1.3]), and 5 (1.4%) underwent major vascular surgery (absolute event rate, 0.3 [95% CI, 0.1-0.7]). The median time to a first vascular event during follow-up was 27 months (interquartile range, 8.7-50 months), with a cumulative hazard of 47% at 10 years. CONCLUSIONS: The long-term prognosis of patients who survive a first spontaneous cerebellar ICH is poor and comparable to that of patients who survive a first supratentorial ICH. Further identification of patients at high risk of vascular events following the initial cerebellar ICH is needed. Including patients with cerebellar ICH in randomized controlled trials on secondary prevention of patients with ICH is warranted.

Influence of Time to Achieve Target Systolic Blood Pressure on Outcome After Intracerebral Hemorrhage: The Blood Pressure in Acute Stroke Collaboration.

OBJECTIVE: To investigate whether an earlier time to achieving and maintaining systolic blood pressure (SBP) at 120 to 140 mm Hg is associated with favorable outcomes in a cohort of patients with acute intracerebral hemorrhage. METHODS: We pooled individual patient data from randomized controlled trials registered in the Blood Pressure in Acute Stroke Collaboration. Time was defined as time form symptom onset plus the time (hour) to first achieve and subsequently maintain SBP at 120 to 140 mm Hg over 24 hours. The primary outcome was functional status measured by the modified Rankin Scale at 90 to 180 days. A generalized linear mixed models was used, with adjustment for covariables and trial as a random effect. RESULTS: A total of 5761 patients (mean age, 64.0 [SD, 13.0], 2120 [36.8%] females) were included in analyses. Earlier SBP control was associated with better functional outcomes (modified Rankin Scale score, 3-6; odds ratio, 0.98 [95% CI, 0.97-0.99]) and a significant lower risk of hematoma expansion (0.98, 0.96-1.00). This association was stronger in patients with bigger baseline hematoma volume (>10 mL) compared with those with baseline hematoma volume ≤10 mL (0.006 for interaction). Earlier SBP control was not associated with cardiac or renal adverse events. CONCLUSIONS: Our study confirms a clear time relation between early versus later SBP control (120-140 mm Hg) and outcomes in the one-third of patients with intracerebral hemorrhage who attained sustained SBP levels within this range. These data provide further support for the value of early recognition, rapid transport, and prompt initiation of treatment of patients with intracerebral hemorrhage.

Swiss trial of decompressive craniectomy versus best medical treatment of spontaneous supratentorial intracerebral haemorrhage (SWITCH): an international, multicentre, randomised-controlled, two-arm, assessor-blinded trial.

RATIONALE: Decompressive craniectomy (DC) is beneficial in people with malignant middle cerebral artery infarction. Whether DC improves outcome in spontaneous intracerebral haemorrhage (ICH) is unknown. AIM: To determine whether DC without haematoma evacuation plus best medical treatment (BMT) in people with ICH decreases the risk of death or dependence at 6 months compared to BMT alone. METHODS AND DESIGN: SWITCH is an international, multicentre, randomised (1:1), two-arm, open-label, assessor-blinded trial. Key inclusion criteria are age ⩽75 years, stroke due to basal ganglia or thalamic ICH that may extend into cerebral lobes, ventricles or subarachnoid space, Glasgow coma scale of 8-13, NIHSS score of 10-30 and ICH volume of 30-100 mL. Randomisation must be performed <66 h after onset and DC <6 h after randomisation. Both groups will receive BMT. Participants randomised to the treatment group will receive DC of at least 12 cm in diameter according to institutional standards. SAMPLE SIZE: A sample of 300 participants randomised 1:1 to DC plus BMT versus BMT alone provides over 85% power at a two-sided alpha-level of 0.05 to detect a relative risk reduction of 33% using a chi-squared test. OUTCOMES: The primary outcome is the composite of death or dependence, defined as modified Rankin scale score 5-6 at 6 months. Secondary outcomes include death, functional status, quality of life and complications at 180 days and 12 months. DISCUSSION: SWITCH will inform physicians about the outcomes of DC plus BMT in people with spontaneous deep ICH, compared to BMT alone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02258919.

Clinical Associations and Prognostic Value of MRI-Visible Perivascular Spaces in Patients With Ischemic Stroke or TIA: A Pooled Analysis

BACKGROUND AND OBJECTIVES: Visible perivascular spaces are an MRI marker of cerebral small vessel disease and might predict future stroke. However, results from existing studies vary. We aimed to clarify this through a large collaborative multicenter analysis. METHODS: We pooled individual patient data from a consortium of prospective cohort studies. Participants had recent ischemic stroke or transient ischemic attack (TIA), underwent baseline MRI, and were followed up for ischemic stroke and symptomatic intracranial hemorrhage (ICH). Perivascular spaces in the basal ganglia (BGPVS) and perivascular spaces in the centrum semiovale (CSOPVS) were rated locally using a validated visual scale. We investigated clinical and radiologic associations cross-sectionally using multinomial logistic regression and prospective associations with ischemic stroke and ICH using Cox regression. RESULTS: We included 7,778 participants (mean age 70.6 years; 42.7% female) from 16 studies, followed up for a median of 1.44 years. Eighty ICH and 424 ischemic strokes occurred. BGPVS were associated with increasing age, hypertension, previous ischemic stroke, previous ICH, lacunes, cerebral microbleeds, and white matter hyperintensities. CSOPVS showed consistently weaker associations. Prospectively, after adjusting for potential confounders including cerebral microbleeds, increasing BGPVS burden was independently associated with future ischemic stroke (versus 0-10 BGPVS, 11-20 BGPVS: HR 1.19, 95% CI 0.93-1.53; 21+ BGPVS: HR 1.50, 95% CI 1.10-2.06; p = 0.040). Higher BGPVS burden was associated with increased ICH risk in univariable analysis, but not in adjusted analyses. CSOPVS were not significantly associated with either outcome. DISCUSSION: In patients with ischemic stroke or TIA, increasing BGPVS burden is associated with more severe cerebral small vessel disease and higher ischemic stroke risk. Neither BGPVS nor CSOPVS were independently associated with future ICH.

Evaluating artificial intelligence software for delineating hemorrhage extent on CT brain imaging in stroke: AI delineation of ICH on CT.

BACKGROUND: The extent and distribution of intracranial hemorrhage (ICH) directly affects clinical management. Artificial intelligence (AI) software can detect and may delineate ICH extent on brain CT. We evaluated e-ASPECTS software (Brainomix Ltd.) performance for ICH delineation. METHODS: We qualitatively assessed software delineation of ICH on CT using patients from six stroke trials. We assessed hemorrhage delineation in five compartments: lobar, deep, posterior fossa, intraventricular, extra-axial. We categorized delineation as excellent, good, moderate, or poor. We assessed quality of software delineation with number of affected compartments in univariate analysis (Kruskall-Wallis test) and ICH location using logistic regression (dependent variable: dichotomous delineation categories 'excellent-good' versus 'moderate-poor'), and report odds ratios (OR) and 95 % confidence intervals (95 %CI). RESULTS: From 651 patients with ICH (median age 75 years, 53 % male), we included 628 with assessable CTs. Software delineation of ICH extent was 'excellent' in 189/628 (30 %), 'good' in 255/628 (41 %), 'moderate' in 127/628 (20 %), and 'poor' in 57/628 cases (9 %). The quality of software delineation of ICH was better when fewer compartments were affected (Z = 3.61-6.27; p = 0.0063). Software delineation of ICH extent was more likely to be 'excellent-good' quality when lobar alone (OR = 1.56, 95 %CI = 0.97-2.53) but 'moderate-poor' with any intraventricular (OR = 0.56, 95 %CI = 0.39-0.81, p = 0.002) or any extra-axial (OR = 0.41, 95 %CI = 0.27-0.62, p<0.001) extension. CONCLUSIONS: Delineation of ICH extent on stroke CT scans by AI software was excellent or good in 71 % of cases but was more likely to over- or under-estimate extent when ICH was either more extensive, intraventricular, or extra-axial.

Association between circulating inflammatory biomarkers and functional outcome or perihaematomal oedema after ICH: a systematic review & meta-analysis.

Background: Currently, there are no specific medical treatments for intracerebral haemorrhage (ICH), but the inflammatory response may provide a potential route to treatment. Given the known effects of acute brain injury on peripheral immunity, we hypothesised that inflammatory biomarkers in peripheral blood may be associated with clinical outcome following ICH, as well as perihaematomal oedema (PHO), which is an imaging marker of the neuroinflammatory response. Methods: We searched OVID Medline and EMBASE on 07 April 2021 for studies of humans with ICH measuring an inflammatory biomarker in peripheral blood and PHO or clinical outcome. Risk of bias was assessed both by using a scale comprising features of the Newcastle-Ottawa Assessment Scale, STROBE-ME and REMARK guidelines, and for studies included in meta-analysis, also by the QUIPS tool.We used random effects meta-analysis to pool standardised mean differences (SMD) if ≥1 study quantified the association between identical biomarkers and measures of PHO or functional outcome. Results: Of 8,615 publications, 16 examined associations between 21 inflammatory biomarkers and PHO (n=1,299 participants), and 93 studies examined associations between ≥1 biomarker and clinical outcome (n=17,702 participants). Overall, 20 studies of nine biomarkers (n=3,199) met criteria for meta-analysis of associations between inflammatory biomarkers and clinical outcome. Death or dependency (modified Rankin Scale (mRS) 3‒6) 90 days after ICH was associated with higher levels of fibrinogen (SMD 0.32; 95%CI [0.04, 0.61]; p=0.025), and high mobility group box protein 1 (HMGB1) (SMD 1.67; 95%CI [0.05, 3.30]; p=0.04). Higher WBC was associated with death or dependency at 90 days (pooled SMD 0.27; 95% CI [0.11, 0.44]; p=0.001; but the association was no longer significant when the analysis was restricted to studies with a low risk of bias (pooled SMD 0.22; 95% CI -0.04-0.48). Higher CRP seemed to be associated with death or dependency at 90 days (pooled SMD 0.80; 95% CI [0.44, 1.17]; p<0.0001) but this association was no longer significant when adjusted OR were pooled (OR 0.99 (95% CI 0.98-1.01)). Conclusions: Higher circulating levels of, fibrinogen and HMGB1 are associated with poorer outcomes after ICH. This study highlights the clinical importance of the inflammatory response to ICH and identifies additional research needs in determining if these associations are mediated via PHO and are potential therapeutic targets. Registration: PROSPERO ( CRD42019132628; 28/05/2019).

Antiplatelet Agent Use After Stroke due to Intracerebral Hemorrhage.

This focused update about antiplatelet agents to reduce the high risk of major adverse cardiovascular events after stroke due to spontaneous (nontraumatic) intracerebral hemorrhage (ICH) complements earlier updates about blood pressure-lowering, lipid-lowering, and oral anticoagulation or left atrial appendage occlusion for atrial fibrillation after ICH. When used for secondary prevention in people without ICH, antiplatelet agents reduce the risk of major adverse cardiovascular event (rate ratio, 0.81 [95% CI, 0.75-0.87]) and might increase the risk of ICH (rate ratio, 1.67 [95% CI, 0.97-2.90]). Before 2019, guidance for clinical decisions about antiplatelet agent use after ICH has focused on estimating patients' predicted absolute risks and severities of ischemic and hemorrhagic major adverse cardiovascular event and applying the known effects of these drugs in people without ICH to estimate whether individual ICH survivors in clinical practice might be helped or harmed by antiplatelet agents. In 2019, the main results of the RESTART (Restart or Stop Antithrombotics Randomized Trial) randomized controlled trial including 537 survivors of ICH associated with antithrombotic drug use showed, counterintuitively, that antiplatelet agents might not increase the risk of recurrent ICH compared to antiplatelet agent avoidance over 2 years of follow-up (12/268 [4%] versus 23/268 [9%]; adjusted hazard ratio, 0.51 [95% CI, 0.25-1.03]; P=0.060). Guidelines in the United States, Canada, China, and the United Kingdom and Ireland have classified the level of evidence as B and indicated that antiplatelet agents may be considered/reasonable after ICH associated with antithrombotic agent use. Three subsequent clinical trials have recruited another 174 participants with ICH, but they will not be sufficient to determine the effects of antiplatelet therapy on all major adverse cardiovascular events reliably when pooled with RESTART. Therefore, ASPIRING (Antiplatelet Secondary Prevention International Randomized Study After Intracerebral Hemorrhage) aims to recruit 4148 ICH survivors to determine the effects of antiplatelet agents after ICH definitively overall and in subgroups.

Effects of oral anticoagulation in people with atrial fibrillation after spontaneous intracranial haemorrhage (COCROACH): prospective, individual participant data meta-analysis of randomised trials.

BACKGROUND: The safety and efficacy of oral anticoagulation for prevention of major adverse cardiovascular events in people with atrial fibrillation and spontaneous intracranial haemorrhage are uncertain. We planned to estimate the effects of starting versus avoiding oral anticoagulation in people with spontaneous intracranial haemorrhage and atrial fibrillation. METHODS: In this prospective meta-analysis, we searched bibliographic databases and trial registries using the strategies of a Cochrane systematic review (CD012144) on June 23, 2023. We included clinical trials if they were registered, randomised, and included participants with spontaneous intracranial haemorrhage and atrial fibrillation who were assigned to either start long-term use of any oral anticoagulant agent or avoid oral anticoagulation (ie, placebo, open control, another antithrombotic agent, or another intervention for the prevention of major adverse cardiovascular events). We assessed eligible trials using the Cochrane Risk of Bias tool. We sought data for individual participants who had not opted out of data sharing from chief investigators of completed trials, pending completion of ongoing trials in 2028. The primary outcome was any stroke or cardiovascular death. We used individual participant data to construct a Cox regression model of the time to the first occurrence of outcome events during follow-up in the intention-to-treat dataset supplied by each trial, followed by meta-analysis using a fixed-effect inverse-variance model to generate a pooled estimate of the hazard ratio (HR) with 95% CI. This study is registered with PROSPERO, CRD42021246133. FINDINGS: We identified four eligible trials; three were restricted to participants with atrial fibrillation and intracranial haemorrhage (SoSTART [NCT03153150], with 203 participants) or intracerebral haemorrhage (APACHE-AF [NCT02565693], with 101 participants, and NASPAF-ICH [NCT02998905], with 30 participants), and one included a subgroup of participants with previous intracranial haemorrhage (ELDERCARE-AF [NCT02801669], with 80 participants). After excluding two participants who opted out of data sharing, we included 412 participants (310 [75%] aged 75 years or older, 249 [60%] with CHA2DS2-VASc score ≤4, and 163 [40%] with CHA2DS2-VASc score >4). The intervention was a direct oral anticoagulant in 209 (99%) of 212 participants who were assigned to start oral anticoagulation, and the comparator was antiplatelet monotherapy in 67 (33%) of 200 participants assigned to avoid oral anticoagulation. The primary outcome of any stroke or cardiovascular death occurred in 29 (14%) of 212 participants who started oral anticoagulation versus 43 (22%) of 200 who avoided oral anticoagulation (pooled HR 0·68 [95% CI 0·42-1·10]; I2=0%). Oral anticoagulation reduced the risk of ischaemic major adverse cardiovascular events (nine [4%] of 212 vs 38 [19%] of 200; pooled HR 0·27 [95% CI 0·13-0·56]; I2=0%). There was no significant increase in haemorrhagic major adverse cardiovascular events (15 [7%] of 212 vs nine [5%] of 200; pooled HR 1·80 [95% CI 0·77-4·21]; I2=0%), death from any cause (38 [18%] of 212 vs 29 [15%] of 200; 1·29 [0·78-2·11]; I2=50%), or death or dependence after 1 year (78 [53%] of 147 vs 74 [51%] of 145; pooled odds ratio 1·12 [95% CI 0·70-1·79]; I2=0%). INTERPRETATION: For people with atrial fibrillation and intracranial haemorrhage, oral anticoagulation had uncertain effects on the risk of any stroke or cardiovascular death (both overall and in subgroups), haemorrhagic major adverse cardiovascular events, and functional outcome. Oral anticoagulation reduced the risk of ischaemic major adverse cardiovascular events, which can inform clinical practice. These findings should encourage recruitment to, and completion of, ongoing trials. FUNDING: British Heart Foundation.

Haemostatic therapies for stroke due to acute, spontaneous intracerebral haemorrhage.

BACKGROUND: Outcome after acute spontaneous (non-traumatic) intracerebral haemorrhage (ICH) is influenced by haematoma volume. ICH expansion occurs in about 20% of people with acute ICH. Early haemostatic therapy might improve outcome by limiting ICH expansion. This is an update of a Cochrane Review first published in 2006, and last updated in 2018. OBJECTIVES: To examine 1. the effects of individual classes of haemostatic therapies, compared with placebo or open control, in adults with acute spontaneous ICH, and 2. the effects of each class of haemostatic therapy according to the use and type of antithrombotic drug before ICH onset. SEARCH METHODS: We searched the Cochrane Stroke Trials Register, CENTRAL (2022, Issue 8), MEDLINE Ovid, and Embase Ovid on 12 September 2022. To identify further published, ongoing, and unpublished randomised controlled trials (RCTs), we scanned bibliographies of relevant articles and searched international registers of RCTs in September 2022. SELECTION CRITERIA: We included RCTs of any haemostatic intervention (i.e. procoagulant treatments such as clotting factor concentrates, antifibrinolytic drugs, platelet transfusion, or agents to reverse the action of antithrombotic drugs) for acute spontaneous ICH, compared with placebo, open control, or an active comparator. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcome was death/dependence (modified Rankin Scale (mRS) 4 to 6) by day 90. Secondary outcomes were ICH expansion on brain imaging after 24 hours, all serious adverse events, thromboembolic adverse events, death from any cause, quality of life, mood, cognitive function, Barthel Index score, and death or dependence measured on the Extended Glasgow Outcome Scale by day 90. MAIN RESULTS: We included 20 RCTs involving 4652 participants: nine RCTs of recombinant activated factor VII (rFVIIa) versus placebo/open control (1549 participants), eight RCTs of antifibrinolytic drugs versus placebo/open control (2866 participants), one RCT of platelet transfusion versus open control (190 participants), and two RCTs of prothrombin complex concentrates (PCC) versus fresh frozen plasma (FFP) (47 participants). Four (20%) RCTs were at low risk of bias in all criteria. For rFVIIa versus placebo/open control for spontaneous ICH with or without surgery there was little to no difference in death/dependence by day 90 (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.74 to 1.05; 7 RCTs, 1454 participants; low-certainty evidence). We found little to no difference in ICH expansion between groups (RR 0.81, 95% CI 0.56 to 1.16; 4 RCTs, 220 participants; low-certainty evidence). There was little to no difference in all serious adverse events and death from any cause between groups (all serious adverse events: RR 0.81, 95% CI 0.30 to 2.22; 2 RCTs, 87 participants; very low-certainty evidence; death from any cause: RR 0.78, 95% CI 0.56 to 1.08; 8 RCTs, 1544 participants; moderate-certainty evidence). For antifibrinolytic drugs versus placebo/open control for spontaneous ICH, there was no difference in death/dependence by day 90 (RR 1.00, 95% CI 0.93 to 1.07; 5 RCTs, 2683 participants; high-certainty evidence). We found a slight reduction in ICH expansion with antifibrinolytic drugs for spontaneous ICH compared to placebo/open control (RR 0.86, 95% CI 0.76 to 0.96; 8 RCTs, 2866 participants; high-certainty evidence). There was little to no difference in all serious adverse events and death from any cause between groups (all serious adverse events: RR 1.02, 95% CI 0.75 to 1.39; 4 RCTs, 2599 participants; high-certainty evidence; death from any cause: RR 1.02, 95% CI 0.89 to 1.18; 8 RCTs, 2866 participants; high-certainty evidence). There was little to no difference in quality of life, mood, or cognitive function (quality of life: mean difference (MD) 0, 95% CI -0.03 to 0.03; 2 RCTs, 2349 participants; mood: MD 0.30, 95% CI -1.98 to 2.57; 2 RCTs, 2349 participants; cognitive function: MD -0.37, 95% CI -1.40 to 0.66; 1 RCTs, 2325 participants; all high-certainty evidence). Platelet transfusion likely increases death/dependence by day 90 compared to open control for antiplatelet-associated ICH (RR 1.29, 95% CI 1.04 to 1.61; 1 RCT, 190 participants; moderate-certainty evidence). We found little to no difference in ICH expansion between groups (RR 1.32, 95% CI 0.91 to 1.92; 1 RCT, 153 participants; moderate-certainty evidence). There was little to no difference in all serious adverse events and death from any cause between groups (all serious adverse events: RR 1.46, 95% CI 0.98 to 2.16; 1 RCT, 190 participants; death from any cause: RR 1.42, 95% CI 0.88 to 2.28; 1 RCT, 190 participants; both moderate-certainty evidence). For PCC versus FFP for anticoagulant-associated ICH, the evidence was very uncertain about the effect on death/dependence by day 90, ICH expansion, all serious adverse events, and death from any cause between groups (death/dependence by day 90: RR 1.21, 95% CI 0.76 to 1.90; 1 RCT, 37 participants; ICH expansion: RR 0.54, 95% CI 0.23 to 1.22; 1 RCT, 36 participants; all serious adverse events: RR 0.27, 95% CI 0.02 to 3.74; 1 RCT, 5 participants; death from any cause: RR 0.49, 95% CI 0.16 to 1.56; 2 RCTs, 42 participants; all very low-certainty evidence). AUTHORS' CONCLUSIONS: In this updated Cochrane Review including 20 RCTs involving 4652 participants, rFVIIa likely results in little to no difference in reducing death or dependence after spontaneous ICH with or without surgery; antifibrinolytic drugs result in little to no difference in reducing death or dependence after spontaneous ICH, but result in a slight reduction in ICH expansion within 24 hours; platelet transfusion likely increases death or dependence after antiplatelet-associated ICH; and the evidence is very uncertain about the effect of PCC compared to FFP on death or dependence after anticoagulant-associated ICH. Thirteen RCTs are ongoing and are likely to increase the certainty of the estimates of treatment effect.

Selective outcome reporting in randomised controlled trials including participants with stroke or transient ischaemic attack: A systematic review.

INTRODUCTION: The prevalence of outcome reporting bias (ORB, i.e. selective reporting according to the results observed) across primary outcomes in randomised controlled trials (RCTs) including participants with stroke or transient ischaemic attack (TIA) is unknown. MATERIALS AND METHODS: We searched the Cochrane Database of Systematic Reviews on 3 February 2021 for reviews published 2008-2020 with at least one RCT of a therapeutic intervention, for participants with stroke or TIA, and a safety or efficacy outcome. We took a random sample of these RCTs and included those with a trial registry record or protocol published before reporting results. Two reviewers assessed discrepancies in outcome reporting across the trial registry record, protocol, statistical analysis plan, and publication for each RCT, using the classification system designed by the Outcome Reporting Bias in Trials group. RESULTS: Of 600 RCTs, we identified a trial registry record in 120 (20%), a protocol in 28 (5%), and a statistical analysis plan in 5 (1%) with 123 (21%) distinct RCTs being eligible for assessment: 110 (89%, 95% CI 83-94) were at no risk, 7 (6%, 95% CI 3-11) RCTs were at low risk, and 6 (5%, 95% CI 2-10) were at high risk of ORB. DISCUSSION: The prevalence of ORB in primary outcomes was low in stroke/TIA RCTs that were included in Cochrane reviews and had an identifiable trial registry record or protocol. Concerningly, we were unable to identify a trial registry record or protocol in most of our sample. CONCLUSION: Work is needed to further reduce ORB in stroke/TIA RCTs and explore the generalisability of these findings to RCTs outside of Cochrane reviews or without a registry record or protocol, as well as to secondary outcomes.

Current practice and attitudes of stroke physicians towards rhythm-control therapy for stroke prevention: results of an international survey.

BACKGROUND: Patients with ischemic stroke and atrial fibrillation (AF) are at particularly high risk for recurrent stroke and cardiovascular events. Early rhythm control has been shown to be superior to usual care for the prevention of stroke and cardiovascular events for people with early AF. There are no data on the willingness to use rhythm control for patients with AF and acute ischemic stroke in clinical practice. METHODS: An online survey was carried out among stroke physicians to assess current practice and attitudes toward rhythm control in patients with AF and acute ischemic stroke between December 22nd 2021 and March 24th 2022. RESULTS: The survey was completed by 277 physicians including 237 from 15 known countries and 40 from unspecified countries. 79% (210/266) reported that they do not regularly apply treatment for rhythm control by ablation or antiarrhythmic drugs at all or only in small numbers (≤ 10%) of patients with AF and acute ischemic stroke. In those patients treated with rhythm-control therapy, antiarrhythmic drugs were used by the majority of respondents (89%), while only a minority reported using AF ablation (11%). 88% of respondents (221/250) stated that they would be willing to randomize patients with AF after acute ischemic stroke to either early rhythm control or usual care in a clinical trial. CONCLUSION: Despite its potential benefit, few patients with AF and acute ischemic stroke appear to be treated with rhythm control, which may result from uncertainty regarding potential complications of antiarrhythmic therapy in patients with acute stroke. Together with recent data on the effectiveness of early rhythm control in patients with a history of stroke, these results call for a randomized clinical trial to assess the efficacy of early rhythm control in patients with acute ischemic stroke and AF.

Effects of blood pressure and tranexamic acid in spontaneous intracerebral haemorrhage: a secondary analysis of a large randomised controlled trial.

Background: Tranexamic acid reduced haematoma expansion and early death, but did not improve functional outcome in the tranexamic acid for hyperacute spontaneous intracerebral haemorrhage-2 (TICH-2) trial. In a predefined subgroup, there was a statistically significant interaction between prerandomisation baseline systolic blood pressure (SBP) and the effect of tranexamic acid on functional outcome (p=0.019). Methods: TICH-2 was an international prospective double-blind placebo-controlled randomised trial evaluating intravenous tranexamic acid in patients with acute spontaneous intracerebral haemorrhage (ICH). Prerandomisation baseline SBP was split into predefined ≤170 and >170 mm Hg groups. The primary outcome at day 90 was the modified Rankin Scale (mRS), a measure of dependency, analysed using ordinal logistic regression. Haematoma expansion was defined as an increase in haematoma volume of >33% or >6 mL from baseline to 24 hours. Data are OR or common OR (cOR) with 95% CIs, with significance at p<0.05. Results: Of 2325 participants in TICH-2, 1152 had baseline SBP≤170 mm Hg and were older, had larger lobar haematomas and were randomised later than 1173 with baseline SBP>170 mm Hg. Tranexamic acid was associated with a favourable shift in mRS at day 90 in those with baseline SBP≤170 mm Hg (cOR 0.73, 95% CI 0.59 to 0.91, p=0.005), but not in those with baseline SBP>170 mm Hg (cOR 1.05, 95% CI 0.85 to 1.30, p=0.63). In those with baseline SBP≤170 mm Hg, tranexamic acid reduced haematoma expansion (OR 0.62, 95% CI 0.47 to 0.82, p=0.001), but not in those with baseline SBP>170 mm Hg (OR 1.02, 95% CI 0.77 to 1.35, p=0.90). Conclusions: Tranexamic acid was associated with improved clinical and radiological outcomes in ICH patients with baseline SBP≤170 mm Hg. Further research is needed to establish whether certain subgroups may benefit from tranexamic acid in acute ICH. Trial registration number: ISRCTN93732214.

Desmopressin for patients with spontaneous intracerebral haemorrhage taking antiplatelet drugs (DASH): a UK-based, phase 2, randomised, placebo-controlled, multicentre feasibility trial.

BACKGROUND: The risk of death from spontaneous intracerebral haemorrhage is increased for people taking antiplatelet drugs. We aimed to assess the feasibility of randomising patients on antiplatelet drug therapy with spontaneous intracerebral haemorrhage to desmopressin or placebo to reduce the antiplatelet drug effect. METHODS: DASH was a phase 2, randomised, placebo-controlled, multicentre feasibility trial. Patients were recruited from ten acute stroke centres in the UK and were eligible if they had an intracerebral haemorrhage with stroke symptom onset within 24 h of randomisation, were aged 18 years or older, and were taking an antiplatelet drug. Participants were randomly assigned (1:1) to a single dose of intravenous desmopressin 20 µg or matching placebo. Treatment allocation was concealed from all staff and patients involved in the trial. The primary outcome was feasibility, which was measured as the number of eligible patients randomised and the proportion of eligible patients approached, and analysis was by intention to treat. The trial was prospectively registered with ISRCTN (reference ISRCTN67038373), and it is closed to recruitment. FINDINGS: Between April 1, 2019, and March 31, 2022, 1380 potential participants were screened for eligibility. 176 (13%) participants were potentially eligible, of whom 57 (32%) were approached, and 54 (31%) consented and were subsequently recruited and randomly assigned to receive desmopressin (n=27) or placebo (n=27). The main reason for eligible patients not being recruited was the patient arriving out of hours (74 [61%] of 122 participants). The recruitment rate increased after the enrolment period was extended from 12 h to 24 h, but it was then impaired due to the COVID-19 pandemic. Of the 54 participants included in the analysis (mean age 76·4 years [SD 11·3]), most were male (36 [67%]) and White (50 [93%]). 53 (98%) of 54 participants received all of their allocated treatment (one participant assigned desmopressin only received part of the infusion). No participants were lost to follow-up or withdrew from the trial. Death or dependency on others for daily activities at day 90 (modified Rankin Scale score >4) occurred in six (22%) of 27 participants in the desmopressin group and ten (37%) of 27 participants in the placebo group. Serious adverse events occurred in 12 (44%) participants in the desmopressin group and 13 (48%) participants in the placebo group. The most common adverse events were expansion of the haemorrhagic stroke (four [15%] of 27 participants in the desmopressin group and six [22%] of 27 participants in the placebo group) and pneumonia (one [4%] of 27 participants in the desmopressin group and six [22%] of 27 participants in the placebo group). INTERPRETATION: Our results show it is feasible to randomise patients with spontaneous intracerebral haemorrhage who are taking antiplatelet drugs to desmopressin or placebo. Our findings support the need for a definitive trial to determine if desmopressin improves outcomes in patients with intracerebral haemorrhage on antiplatelet drug therapy. FUNDING: National Institute for Health Research.

Neuroimaging standards for research into small vessel disease-advances since 2013.

Cerebral small vessel disease (SVD) is common during ageing and can present as stroke, cognitive decline, neurobehavioural symptoms, or functional impairment. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive and other symptoms and affect activities of daily living. Standards for Reporting Vascular Changes on Neuroimaging 1 (STRIVE-1) categorised and standardised the diverse features of SVD that are visible on structural MRI. Since then, new information on these established SVD markers and novel MRI sequences and imaging features have emerged. As the effect of combined SVD imaging features becomes clearer, a key role for quantitative imaging biomarkers to determine sub-visible tissue damage, subtle abnormalities visible at high-field strength MRI, and lesion-symptom patterns, is also apparent. Together with rapidly emerging machine learning methods, these metrics can more comprehensively capture the effect of SVD on the brain than the structural MRI features alone and serve as intermediary outcomes in clinical trials and future routine practice. Using a similar approach to that adopted in STRIVE-1, we updated the guidance on neuroimaging of vascular changes in studies of ageing and neurodegeneration to create STRIVE-2.

The association between perihaematomal oedema and functional outcome after spontaneous intracerebral haemorrhage: A systematic review and meta-analysis.

PURPOSE: Perihaematomal oedema (PHO) formation has gained increasing interest as a therapeutic target after spontaneous intracerebral haemorrhage (ICH). Whether PHO contributes to poor outcome is unclear. We aimed to determine the association between PHO and outcome in patients with spontaneous ICH. METHOD: We searched five databases up to 17 November 2021 for studies of ⩾10 adults with ICH reporting the presence of PHO and outcome. We assessed risk of bias, extracted aggregate data and used random effects meta-analysis to pool studies that reported odds ratios (OR) with 95% confidence intervals (CI). Primary outcome was poor functional outcome defined as modified Rankin Scale score of 3-6 at 3 months. Additionally, we assessed PHO growth and poor outcome at any time of follow-up. We prospectively registered the protocol in PROSPERO (CRD42020157088). FINDINGS: We identified 12,968 articles, of which we included 27 studies (n = 9534). Eighteen studies reported an association between larger PHO volume and poor outcome, six a neutral result and three an inverse relationship. Larger absolute PHO volume was associated with poor functional outcome at 3 months (OR per mL increase of absolute PHO 1.03, 95% CI 1.00-1.06, I2 44%, four studies). Additionally, PHO growth was associated with poor outcome (OR 1.04, 95% CI 1.02-1.06, I2 0%, seven studies). DISCUSSION: In patients with spontaneous ICH, larger PHO volume is associated with poor functional outcome at 3 months. These findings support the development and investigation of new therapeutic interventions targeting PHO formation to evaluate if reduction of PHO improves outcome after ICH.

Major Cardiovascular Events After Spontaneous Intracerebral Hemorrhage by Hematoma Location.

Importance: Survivors of spontaneous (ie, nontraumatic and with no known structural cause) intracerebral hemorrhage (ICH) have an increased risk of major cardiovascular events (MACEs), including recurrent ICH, ischemic stroke (IS), and myocardial infarction (MI). Only limited data are available from large, unselected population studies assessing the risk of MACEs according to index hematoma location. Objective: To examine the risk of MACEs (ie, the composite of ICH, IS, spontaneous intracranial extra-axial hemorrhage, MI, systemic embolism, or vascular death) after ICH based on ICH location (lobar vs nonlobar). Design, Setting, and Participants: This cohort study identified 2819 patients in southern Denmark (population of 1.2 million) 50 years or older hospitalized with first-ever spontaneous ICH from January 1, 2009, to December 31, 2018. Intracerebral hemorrhage was categorized as lobar or nonlobar, and the cohorts were linked to registry data until the end of 2018 to identify the occurrence of MACEs and separately recurrent ICH, IS, and MI. Outcome events were validated using medical records. Associations were adjusted for potential confounders using inverse probability weighting. Exposure: Location of ICH (lobar vs nonlobar). Main Outcomes and Measures: The main outcomes were MACEs and separately recurrent ICH, IS, and MI. Crude absolute event rates per 100 person-years and adjusted hazard ratios (aHRs) with 95% CIs were calculated. Data were analyzed from February to September 2022. Results: Compared with patients with nonlobar ICH (n = 1255; 680 [54.2%] men and 575 [45.8%] women; mean [SD] age, 73.5 [11.4] years), those with lobar ICH (n = 1034; 495 [47.9%] men and 539 [52.1%] women, mean [SD] age, 75.2 [10.7] years) had higher rates of MACEs per 100 person-years (10.84 [95% CI, 9.51-12.37] vs 7.91 [95% CI, 6.93-9.03]; aHR, 1.26; 95% CI, 1.10-1.44) and recurrent ICH (3.74 [95% CI, 3.01-4.66] vs 1.24 [95% CI, 0.89-1.73]; aHR, 2.63; 95% CI, 1.97-3.49) but not IS (1.45 [95% CI, 1.02-2.06] vs 1.77 [95% CI, 1.34-2.34]; aHR, 0.81; 95% CI, 0.60-1.10) or MI (0.42 [95% CI, 0.22-0.81] vs 0.64 [95% CI, 0.40-1.01]; aHR, 0.64; 95% CI, 0.38-1.09). Conclusions and Relevance: In this cohort study, spontaneous lobar ICH was associated with a higher rate of subsequent MACEs than nonlobar ICH, primarily due to a higher rate of recurrent ICH. This study highlights the importance of secondary ICH prevention strategies in patients with lobar ICH.

Association Between Statin Use and Intracerebral Hemorrhage Location: A Nested Case-Control Registry Study.

BACKGROUND AND OBJECTIVES: A causal relationship between statin use and intracerebral hemorrhage (ICH) is uncertain. We hypothesized that an association between long-term statin exposure and ICH risk might vary for different ICH locations. METHODS: We conducted this analysis using linked Danish nationwide registries. Within the Southern Denmark Region (population 1.2 million), we identified all first-ever cases of ICH between 2009 and 2018 in persons aged ≥55 years. Patients with medical record-verified diagnoses were classified as having a lobar or nonlobar ICH and matched for age, sex, and calendar year to general population controls. We used a nationwide prescription registry to ascertain prior statin and other medication use that we classified for recency, duration, and intensity. Using conditional logistic regression adjusted for potential confounders, we calculated adjusted ORs (aORs) and corresponding 95% CIs for the risk of lobar and nonlobar ICH. RESULTS: We identified 989 patients with lobar ICH (52.2% women, mean age 76.3 years) who we matched to 39,500 controls and 1,175 patients with nonlobar ICH (46.5% women, mean age 75.1 years) who we matched to 46,755 controls. Current statin use was associated with a lower risk of lobar (aOR 0.83; 95% CI, 0.70-0.98) and nonlobar ICH (aOR 0.84; 95% CI, 0.72-0.98). Longer duration of statin use was also associated with a lower risk of lobar (<1 year: aOR 0.89; 95% CI, 0.69-1.14; ≥1 year to <5 years aOR 0.89; 95% CI 0.73-1.09; ≥5 years aOR 0.67; 95% CI, 0.51-0.87; p for trend 0.040) and nonlobar ICH (<1 year: aOR 1.00; 95% CI, 0.80-1.25; ≥1 year to <5 years aOR 0.88; 95% CI 0.73-1.06; ≥5 years aOR 0.62; 95% CI, 0.48-0.80; p for trend <0.001). Estimates stratified by statin intensity were similar to the main estimates for low-medium intensity therapy (lobar aOR 0.82; nonlobar aOR 0.84); the association with high-intensity therapy was neutral. DISCUSSION: We found that statin use was associated with a lower risk of ICH, particularly with longer treatment duration. This association did not vary by hematoma location.