Why Are Women Less Represented in Intracerebral Hemorrhage Trials?

BACKGROUND AND PURPOSE: Fewer women than men tend to be enrolled in clinical trials of intracerebral hemorrhage. It is unclear whether this reflects lower prevalence of intracerebral hemorrhage in women, selection bias, or poor recruitment efforts. We undertook this study to examine differences between men and women in the reasons for exclusion from the iDEF trial (Intracerebral Hemorrhage Deferoxamine). METHODS: The screen failure log included 29 different reasons for exclusion. Chi-square statistics were used to evaluate the differences in reasons for exclusion between men and women. RESULTS: A total of 38.2% of participants in iDEF were women. Three thousand nine hundred eighty-two women (45.7%) and 4736 men (54.3%) were screen failures (P<0.0001). Similar proportions of women (1.28%) and men (1.73%) were excluded due to inability to obtain consent (P=0.1). Patients or families declined participation in 1.26% of women versus 1.31% of men (P=0.9). More women than men failed screening because of age>80 (22.40% versus 12.61%; adjusted P=0.0007) and preexisting do-not-resuscitate/do-not-intubate (3.69% versus 2.83%; adjusted P=0.067). CONCLUSIONS: Lower rates of women enrollment in the iDEF trial may be attributed to older age. Inability to obtain consent or declining participation was similar between women and men, arguing against selection bias. Our findings should be confirmed in other intracerebral hemorrhage trials to determine best strategies to improve women's representation in future trials.

A Pooled Analysis of Diffusion-Weighted Imaging Lesions in Patients With Acute Intracerebral Hemorrhage.

Importance: The etiology and significance of diffusion-weighted imaging (DWI) lesions in patients with acute intracerebral hemorrhage (ICH) remain unclear. Objective: To evaluate which factors are associated with DWI lesions, whether associated factors differ by ICH location, and whether DWI lesions are associated with functional outcomes. Design, Setting, and Participants: This analysis pooled individual patient data from 3 randomized clinical trials (Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation phase 3 trial, Antihypertensive Treatment of Acute Cerebral Hemorrhage trial, and Intracerebral Hemorrhage Deferoxamine phase 2 trial) and 1 multicenter prospective study (Ethnic/Racial Variations of Intracerebral Hemorrhage). Patients were enrolled from August 1, 2010, to September 30, 2018. Of the 4782 patients, 1788 who underwent magnetic resonance imaging scans of the brain were included. Data were analyzed from July 1 to December 31, 2019. Main Outcomes and Measures: The primary outcome consisted of factors associated with DWI lesions. Secondary outcomes were poor functional outcome, defined as a modified Rankin score (mRS) of 4 to 6, and mortality, both assessed at 3 months. Mixed-effects logistic regression was used to evaluate the association between exposures and outcomes. Subgroup analyses stratified by hematoma location were performed. Results: After exclusion of 36 patients with missing data on DWI lesions, 1752 patients were included in the analysis (1019 men [58.2%]; mean [SD] age, 60.8 [13.3] years). Diffusion-weighted imaging lesions occurred in 549 patients (31.3%). In mixed-effects regression models, factors associated with DWI lesions included younger age (odds ratio [OR] per year, 0.98; 95% CI, 0.97-0.99), black race (OR, 1.64; 95% CI, 1.17-2.30), admission systolic blood pressure (OR per 10-mm Hg increase, 1.13; 95% CI, 1.08-1.18), baseline hematoma volume (OR per 10-mL increase, 1.12; 95% CI, 1.02-1.22), cerebral microbleeds (OR, 1.85; 95% CI, 1.39-2.46), and leukoaraiosis (OR, 1.59; 95% CI, 1.67-2.17). Diffusion-weighted imaging lesions were independently associated with poor mRS (OR, 1.50; 95% CI, 1.13-2.00), but not with mortality (OR, 1.11; 95% CI, 0.72-1.71). In subgroup analyses, similar factors were associated with DWI lesions in lobar and deep ICH. Diffusion-weighted imaging lesions were associated with poor mRS in deep but not lobar ICH. Conclusions and Relevance: In a large, heterogeneous cohort of prospectively identified patients with ICH, results were consistent with the hypothesis that DWI lesions represent acute sequelae of chronic cerebral small vessel disease, particularly hypertensive vasculopathy. Diffusion-weighted imaging lesions portend a worse prognosis after ICH, mainly deep hemorrhages.

Perihematomal edema: Implications for intracerebral hemorrhage research and therapeutic advances.

In humans, perihematomal edema (PHE) is considered to be a radiological marker of secondary injury following intracerebral hemorrhage (ICH). There is also evidence that PHE might contribute to poor outcome in ICH patients. Given the rising interest in secondary injury after ICH as a therapeutic target, PHE is becoming increasingly used as a proof-of-concept surrogate measure to assess the potential efficacy of various therapeutic interventions in clinical trials. We review the pathophysiology of PHE and its evolution, its prognostic significance and relationship to clinical outcomes, and variabilities in its detection and measurement methodologies to determine the advantages versus shortcomings of using PHE as a translational target or radiological marker to examine the efficacy of interventions aiming to mitigate secondary injury in ICH.

Deferoxamine mesylate in patients with intracerebral haemorrhage (i-DEF): a multicentre, randomised, placebo-controlled, double-blind phase 2 trial.

BACKGROUND: Iron from haemolysed blood is implicated in secondary injury after intracerebral haemorrhage. We aimed to assess the safety of the iron chelator deferoxamine mesylate in patients with intracerebral haemorrhage and to establish whether the drug merits investigation in a phase 3 trial. METHODS: We did a multicentre, futility-design, randomised, placebo-controlled, double-blind, phase 2 trial at 40 hospitals in Canada and the USA. Adults aged 18-80 years with primary, spontaneous, supratentorial intracerebral haemorrhage were randomly assigned (1:1) to receive deferoxamine mesylate (32 mg/kg per day) or placebo (saline) infusions for 3 consecutive days within 24 h of haemorrhage onset. Randomisation was done via a web-based trial-management system centrally in real time, and treatment allocation was concealed from both participants and investigators. The primary outcome was good clinical outcome, which was defined as a modified Rankin Scale score of 0-2 at day 90. We did a futility analysis: if the 90% upper confidence bound of the absolute risk difference between the two groups in the proportion of participants with a good clinical outcome was less than 12% in favour of deferoxamine mesylate, then to move to a phase 3 efficacy trial would be futile. Primary outcome and safety data were analysed in the modified intention-to-treat population, comprising only participants in whom the study infusions were initiated. This trial is registered with ClinicalTrials.gov, number NCT02175225, and is completed. FINDINGS: We recruited 294 participants between Nov 23, 2014, and Nov 10, 2017. The modified intention-to-treat population consisted of 144 patients assigned to the deferoxamine mesylate group and 147 assigned to the placebo group. At day 90, among patients with available data for the primary outcome, 48 (34%) of 140 participants in the deferoxamine mesylate group, and 47 (33%) of 143 patients in the placebo group, had modified Rankin Scale scores of 0-2 (adjusted absolute risk difference 0·6% [90% upper confidence bound 6·8%]). By day 90, 70 serious adverse events were reported in 39 (27%) of 144 patients in the deferoxamine mesylate group, and 78 serious adverse events were reported in 49 (33%) of 147 patients in the placebo group. Ten (7%) participants in the deferoxamine mesylate and 11 (7%) in the placebo group died. None of the deaths were judged to be treatment related. INTERPRETATION: Deferoxamine mesylate was safe. However, the primary result showed that further study of the efficacy of deferoxamine mesylate with anticipation that the drug would significantly improve the chance of good clinical outcome (ie, mRS score of 0-2) at day 90 would be futile. FUNDING: US National Institutes of Health and US National Institute of Neurological Disorders and Stroke.

Progression of White Matter Injury After Intracerebral Hemorrhage: A Magnetic Resonance Imaging Study.

BACKGROUND: White matter injury (WMI) has been observed after experimental intracerebral hemorrhage (ICH). The supporting clinical data have been sparse. We assessed the presence, extent, and progression of WMI in patients with ICH. METHODS: We performed a retrospective review of data from 65 consecutive patients with spontaneous supratentorial ICH who had undergone baseline brain magnetic resonance imaging (MRI) within 7 days of ICH onset and repeat MRI afterward. We used the Fazekas scale (FZKS) to grade the severity of WMI. The clinical and imaging characteristics of the patients with and without WMI progression (WMIP) were compared using uni- and multivariate logistic regression analyses. RESULTS: We observed WMIP in 23 patients (35.4%). WMIP was noted in both hemispheres but more commonly ipsilateral to the ICH (33% vs. 21%). The mean total FZKS score had increased from 3 (interquartile range [IQR], 1-4) at baseline to 4 (IQR, 2-5) on repeat MRI (P < 0.0001). Patients with lobar ICH had a greater median FZKS score than those with deep ICH (median, 3; IQR, 2-4; vs. 1.5, IQR, 1-3.25; P = 0.027). The baseline parenchymal ICH volume (odds ratio [OR], 1.067; 95% confidence interval [CI], 1.018-1.119; P = 0.007) and ventricular volume on baseline MRI (OR, 1.073; 95% CI, 1.019-1.130; P = 0.007) were predictors of WMIP after adjustment. Multivariate analyses showed an independent association between WMIP and unfavorable 3-month outcomes (OR, 5.196; 95% CI, 1.059-25.483; P = 0.042). CONCLUSIONS: WMI will progress over time in patients with ICH, and WMIP has been associated with worse outcomes. This novel finding could represent a potential therapeutic target. Future prospective larger studies are needed to confirm our findings.

Cerebral small vessel disease burden and functional and radiographic outcomes in intracerebral hemorrhage.

OBJECTIVE: To examine the effect of individual cerebral small vessel disease (CSVD) markers and cumulative CSVD burden on functional independence, ambulation and hematoma expansion in spontaneous intracerebral hemorrhage (ICH). METHODS: Retrospective analysis of prospectively collected data from an observational study of consecutive patients with spontaneous ICH, brain MRI within 1 month from ictus, premorbid modified Rankin Scale (mRS) score ≤ 2, available imaging data and 90-day functional status in a tertiary academic center. Functional outcomes included 90-day functional independence (mRS ≤ 2) and independent ambulation; radiographic outcome was hematoma expansion (> 12.5 ml absolute or > 33% relative increase in ICH volume). We identified the presence and burden of individual CSVD markers (cerebral microbleeds (CMBs), enlarged perivascular spaces, lacunes, white matter hyperintensities) and composite CSVD burden score and explored their association with outcomes of interest in multivariable models adjusting for well-established confounders. RESULTS: 111 patients were included, 65% lobar ICH, with a median volume 20.8 ml. 43 (38.7%) achieved functional independence and 71 (64%) independent ambulation. In multivariable adjusted models, there was higher total CSVD burden (OR 0.61, 95% CI 0.37-0.96, p = 0.03) and CMBs presence (OR 0.32, 95% CI 0.1-0.88, p = 0.04) remained independently inversely associated with functional independence. Individual CSVD markers or total CSVD score had no significant relation with ambulation and ICH expansion. Larger ICH volume and deep ICH location were the major determinants of lack of independent ambulation. CONCLUSIONS: Our findings suggest that in ICH patients without previous functional dependence, total CSVD burden and particularly presence of CMBs significantly affect functional recovery. The latter is a novel finding and merits further exploration.

The Risk of Hemorrhagic Transformation After Thrombolysis for Acute Ischemic Stroke in Chinese Versus North Americans: A Comparative Study.

BACKGROUND: There is a widespread belief that Asians are more susceptible to hemorrhagic transformation (HT) after receiving recombinant tissue-type plasminogen activator (rt-PA) for acute ischemic stroke (AIS). However, this has not been examined in clinical practice. This study aims to compare the incidence of symptomatic hemorrhagic transformation (SHT) among thrombolysis-treated AIS patients in China and in the United States. METHODS: We compared 212 consecutive patients receiving thrombolysis within 4.5 hours of onset ± endovascular therapy from an American (n = 86) and a Chinese Stroke Center (n = 126). SHT was defined using various definitions based on the National Institute for Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator (NINDS rt-PA) trials, European-Australian Cooperative Acute Stroke Study 2 (ECASS2), and a modified version of Safe Implementation of Thrombolysis in Stroke-Monitoring Study (mSITS-MOST) study criteria. We used Firth logistic regression to adjust for confounding variables and to identify potential predictors. RESULTS: American patients were older, and had higher prevalence of diabetes, hypertension, cardiac disease, and prestroke use of antithrombotics. They also had higher baseline serum glucose, shorter onset-to-treatment time, and fewer endovascular treatments. The rates of SHT were higher in the American cohort compared to the Chinese cohort: 18.6% versus 14.3% based on NINDS definition of SHT; 15.1% versus 12.7% based on ECASS2; and 11.6% versus 7.2% based on mSITS-MOST. However, none of these differences were significant (unadjusted and adjusted P values > .05). Fatal HT was comparable in Americans versus Chinese (8.1% versus 8.7%). Serum glucose emerged as an independent predictor of SHT (P = .024). CONCLUSIONS: In our cohorts, the rate of SHT after thrombolysis is equivalent between Chinese and North American stroke patients.

Direct oral anticoagulant- vs vitamin K antagonist-related nontraumatic intracerebral hemorrhage.

OBJECTIVE: To compare the neuroimaging profile and clinical outcomes among patients with intracerebral hemorrhage (ICH) related to use of vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) for nonvalvular atrial fibrillation (NVAF). METHODS: We evaluated consecutive patients with NVAF with nontraumatic, anticoagulant-related ICH admitted at 13 tertiary stroke care centers over a 12-month period. We also performed a systematic review and meta-analysis of eligible observational studies reporting baseline characteristics and outcomes among patients with VKA- or DOAC-related ICH. RESULTS: We prospectively evaluated 161 patients with anticoagulation-related ICH (mean age 75.6 ± 9.8 years, 57.8% men, median admission NIH Stroke Scale [NIHSSadm] score 13 points, interquartile range 6-21). DOAC-related (n = 47) and VKA-related (n = 114) ICH did not differ in demographics, vascular risk factors, HAS-BLED and CHA2DS2-VASc scores, and antiplatelet pretreatment except for a higher prevalence of chronic kidney disease in VKA-related ICH. Patients with DOAC-related ICH had lower median NIHSSadm scores (8 [3-14] vs 15 [7-25] points, p = 0.003), median baseline hematoma volume (12.8 [4-40] vs 24.3 [11-58.8] cm3, p = 0.007), and median ICH score (1 [0-2] vs 2 [1-3] points, p = 0.049). Severe ICH (>2 points) was less prevalent in DOAC-related ICH (17.0% vs 36.8%, p = 0.013). In multivariable analyses, DOAC-related ICH was independently associated with lower baseline hematoma volume (p = 0.006), lower NIHSSadm scores (p = 0.022), and lower likelihood of severe ICH (odds ratio [OR] 0.34, 95% confidence interval [CI] 0.13-0.87, p = 0.025). In meta-analysis of eligible studies, DOAC-related ICH was associated with lower baseline hematoma volumes on admission CT (standardized mean difference = -0.57, 95% CI -1.02 to -0.12, p = 0.010) and lower in-hospital mortality rates (OR = 0.44, 95% CI 0.21-0.91, p = 0.030). CONCLUSIONS: DOAC-related ICH is associated with smaller baseline hematoma volume and lesser neurologic deficit at hospital admission compared to VKA-related ICH.

Local Fibrinolytic Therapy for Intraventricular Hemorrhage: A Meta-Analysis of Randomized Controlled trials.

BACKGROUND: The safety and efficacy of intraventricular fibrinolysis (IVF) in patients with intraventricular hemorrhage (IVH) are unclear. We aimed to determine these issues and to evaluate whether there are differences between recombinant tissue-plasminogen activator (rt-PA) and urokinase according to subgroup analyses. METHODS: A meta-analysis was undertaken of randomized controlled trials in patients with IVH that compared the administration of rt-PA or urokinase through extraventricular drainage (EVD) with normal saline through EVD or EVD placement alone. RESULTS: Six randomized controlled trials involving 607 patients with IVH were included; 2 trials investigated urokinase and 4 rt-PA. IVF reduced death from any cause at the end of follow-up (risk ratio [RR] 0.63, 95% confidence interval [CI] 0.47-0.83), which was driven mostly by rt-PA (RR 0.65, 95% CI 0.48-0.86). Urokinase did not reduce mortality (RR 0.30, 95% CI 0.06-1.53). However, rt-PA did not reduce the proportion of survivors with poor functional outcome (RR 1.36, 95% CI 1.04-1.77), or the composite endpoint of death and poor functional outcome (RR 0.96, 95% CI 0.83-1.11). IVF neither reduced the need for shunt placement (RR 1.06, 95% CI 0.75-1.49) nor increased ventriculitis (RR 0.57, 95% CI 0.35-0.93) and rebleeding (RR 1.65, 95% CI 0.79-3.45). CONCLUSIONS: Although the use of IVF in patients with IVH appears generally safe, its benefit is limited to a reduction in mortality at the expense of an increased number of survivors with moderately-severe to severe disability. Subgroup analyses do not suggest an advantage of IVF with urokinase over rt-PA.