Trial In Intracerebral Hemorrhage Research Articles

Location-Specific Hematoma Volume Cutoff and Clinical Outcomes in Intracerebral Hemorrhage.

Major intracerebral hemorrhage (ICH) trials have largely been unable to demonstrate therapeutic benefit in improving functional outcomes. This may be partly due to the heterogeneity of ICH outcomes based on their location, where a small strategic ICH could be debilitating, thus confounding therapeutic effects. We aimed to determine the ideal hematoma volume cutoff for different ICH locations in predicting ICH outcomes. We retrospectively analyzed consecutive ICH patients enrolled in the University of Hong Kong prospective stroke registry from January 2011 to December 2018. Patients with premorbid modified Rankin Scale score >2 or who underwent neurosurgical intervention were excluded. ICH volume cutoff, sensitivity, and specificity in predicting respective 6-month neurological outcomes (good [modified Rankin Scale score 0-2], poor [modified Rankin Scale score 4-6], and mortality) for specific ICH locations were determined using receiver operating characteristic curves. Separate multivariate logistic regression models were also conducted for each location-specific volume cutoff to determine whether these cutoffs were independently associated with respective outcomes. Among 533 ICHs, the volume cutoff for good outcome according to ICH location was 40.5 mL for lobar, 32.5 mL for putamen/external capsule, 5.5 mL for internal capsule/globus pallidus, 6.5 mL for thalamus, 17 mL for cerebellum, and 3 mL for brainstem. ICH smaller than the cutoff for all supratentorial sites had higher odds of good outcomes (all P<0.05). Volumes exceeding 48 mL for lobar, 41 mL for putamen/external capsule, 6 mL for internal capsule/globus pallidus, 9.5 mL for thalamus, 22 mL for cerebellum, and 7.5 mL for brainstem were at greater risk of poor outcomes (all P<0.05). Mortality risks were significantly higher for volumes that exceeded 89.5 mL for lobar, 42 mL for putamen/external capsule, and 21 mL for internal capsule/globus pallidus (all P<0.001). All receiver operating characteristic models for location-specific cutoffs had good discriminant values (area under the curve >0.8), except in predicting good outcome for cerebellum. ICH outcomes differed with location-specific hematoma size. Location-specific volume cutoff should be considered in patient selection for ICH trials.

Process Evaluation of an Implementation Trial: Design, Rationale, and Early Lessons Learnt From an International Cluster Clinical Trial in Intracerebral Hemorrhage.

BackgroundThe third INTEnsive care bundle with blood pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT3) is an ongoing, international, multicenter, stepped-wedge cluster, prospective, randomized, open, blinded endpoint assessed trial evaluating the effectiveness of a quality improvement “care bundle” for the management of patients with acute spontaneous intracerebral hemorrhage (ICH) in low- and middle-income countries (LMICs). An embedded process evaluation aims to explore the uptake and implementation of the intervention, and understand the context and stakeholder perspectives, for interpreting the trial outcomes.MethodologyThe design was informed by Normalization Process Theory and the UK Medical Research Council process evaluation guidance. Mixed methods are used to evaluate the implementation outcomes of fidelity, reach, dose, acceptability, appropriateness, adoption, sustainability, and relevant contextual factors and mechanisms affecting delivery of the care bundle. Semi-structured interviews and non-participant observations are conducted with the primary implementers (physicians and nurses) and patients/carers to explore how the care bundle was integrated into routine care. Focus group discussions are conducted with investigators and project operational staff to understand challenges and possible solutions in the organization of the trial. Data from observational records, surveys, routine monitoring data, field notes and case report forms, inform contextual factors, and adoption of the intervention. Purposive sampling of sites according to pre-specified criteria is used to achieve sample representativeness.DiscussionImplementation outcomes, and relevant barriers and facilitators to integrating the care bundle into routine practice, will be reported after completion of the process evaluation. The embedded process evaluation will aid understanding of the causal mechanisms between care bundle elements and clinical outcomes within complex health systems across diverse LMIC settings.Trial RegistrationThe INTERACT3 study is registered at ClinicalTrials.gov (NCT03209258).

Advancing the Surgical Treatment of Intracerebral Hemorrhage: Study Design and Research Directions

In this narrative review, we discuss aspects of study design for research in the surgical treatment of patients with spontaneous acute intracerebral hemorrhage (ICH). We emphasize the importance of carefully defining the primary end point relevant to the intervention under investigation, whether this is technical (i.e., residual hematoma volume) or clinical (i.e., mortality or functional outcome), and the timing of its assessment. Compared with patients with acute ischemic stroke, patients with spontaneous acute ICH may take longer to fully recover. Efficient patient recruitment is essential for all research studies and deferred consent is an option to allow disabled and critically ill patients to be included. Although central concealment of the randomization process, often with a method of stratification to ensure that prognostic variables are balanced between groups, it is often appropriate to undertake analysis of the treatment effect adjusted for various predefined covariables. The definition of minimally invasive surgery, and its use and timing in relation to ICH, requires urgent assessment. Future studies could be better designed and executed as part of a large (inter)national ICH trials consortium, consisting of dedicated interdisciplinary teams of neurologists, neurosurgeons, intensivists, and epidemiologists. We advocate studies to be pragmatic and adhere to the IDEAL recommendations and CONSORT guidelines.

Blood Pressure in Acute Stroke and Secondary Stroke Prevention.

Hypertension is common in patients presenting with stroke and is independently associated with unfavorable outcomes. This article reviews current guidelines for early management of blood pressure (BP) and highlights the findings of recent investigative works. Intensive blood pressure reduction after receiving alteplase has not been shown to improve outcomes. Patients with large vessel occlusions may benefit from lower blood pressure targets post-intervention. Retrospective analyses of large intracerebral hemorrhage trials suggest that specific subgroups of patients may disproportionately benefit from or be harmed by intensive BP reduction. Robust data for management of blood pressure in subarachnoid hemorrhage patients is lacking and expert consensus continues to guide decision-making. Despite the impact of hypertension on outcomes, most prospective trials assessing efficacy of blood pressure reduction have yielded neutral or inconclusive results. Further trials are necessary to determine which patient populations are most likely to benefit from blood pressure control.

Use of the Estimand Framework to Manage the Disruptive Effects of COVID-19 on Stroke Clinical Trials.

The coronavirus disease 2019 (COVID-19) pandemic has presented unique challenges to stroke care and research internationally. In particular, clinical trials in stroke are vulnerable to the impacts of the pandemic at multiple stages, including design, recruitment, intervention, follow-up, and interpretation of outcomes. A carefully considered approach is required to ensure the appropriate conduct of stroke trials during the pandemic and to maintain patient and participant safety. This has been recently addressed by the International Council for Harmonisation which, in November 2019, released an addendum to the Statistical Principles for Clinical Trials guidelines entitled Estimands and Sensitivity Analysis in Clinical Trials. In this article, we present the International Council for Harmonisation estimand framework for the design and conduct of clinical trials, with a specific focus on its application to stroke clinical trials. This framework aims to align the clinical and scientific objectives of a trial with its design and end points. It also encourages the prospective consideration of potential postrandomization intercurrent events which may occur during a trial and either impact the ability to measure an end point or its interpretation. We describe the different categories of such events and the proposed strategies for dealing with them, specifically focusing on the COVID-19 pandemic as a source of intercurrent events. We also describe potential practical impacts posed by the COVID-19 pandemic on trials, health systems, study groups, and participants, all of which should be carefully reviewed by investigators to ensure an adequate practical and statistical strategy is in place to protect trial integrity. We provide examples of the implementation of the estimand framework within hypothetical stroke trials in intracerebral hemorrhage and stroke recovery. While the focus of this article is on COVID-19 impacts, the strategies and principles proposed are well suited for other potential events or issues, which may impact clinical trials in the field of stroke.

Intracerebral Hemorrhage Volume Reduction and Timing of Intervention Versus Functional Benefit and Survival in the MISTIE III and STICH Trials.

The extent of intracerebral hemorrhage (ICH) removal conferred survival and functional benefits in the minimally invasive surgery with thrombolysis in intracerebral hemorrhage evacuation (MISTIE) III trial. It is unclear whether this similarly impacts outcome with craniotomy (open surgery) or whether timing from ictus to intervention influences outcome with either procedure. To compare volume evacuation and timing of surgery in relation to outcomes in the MISTIE III and STICH (Surgical Trial in Intracerebral Hemorrhage) trials. Postoperative scans were performed in STICH II, but not in STICH I; therefore, surgical MISTIE III cases with lobar hemorrhages (n=84) were compared to STICH II all lobar cases (n=259) for volumetric analyses. All MISTIE III surgical patients (n=240) were compared to both STICH I and II (n=722) surgical patients for timing analyses. These were investigated using cubic spline modeling and multivariate risk adjustment. End-of-treatment ICH volume ≤28.8mL in MISTIE III and ≤30.0mL in STICH II had increased probability of modified Rankin Scale (mRS) 0 to 3 at 180d (P=.01 and P=.003, respectively). The effect in the MISTIE cohort remained significant after multivariate risk adjustments. Earlier surgery within 62 h of ictus had a lower probability of achieving an mRS 0 to 3 at 180d with STICH I and II (P=.0004), but not with MISTIE III. This remained significant with multivariate risk adjustments. There was no impact of timing until intervention on mortality up to 47 h with either procedure. Thresholds of ICH removal influenced outcome with both procedures to a similar extent. There was a similar likelihood of achieving a good outcome with both procedures within a broad therapeutic time window.

Why Are Women Less Represented in Intracerebral Hemorrhage Trials?

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). 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. 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). 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.

Secondary mechanisms of injury and viable pathophysiological targets in intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) can be divided into a primary and secondary phase. In the primary phase, hematoma volume is evaluated and therapies are focused on reducing hematoma expansion. In the secondary, neuroprotective phase, complex systemic inflammatory cascades, direct cellular toxicity, and blood-brain barrier disruption can result in worsening perihematomal edema that can adversely affect functional outcome. To date, all major randomized phase 3 trials for ICH have targeted primary phase hematoma volume and incorporated clot evacuation, intensive blood pressure control, and hemostasis. Reasons for this lack of clinical efficacy in the major ICH trials may be due to the lack of therapeutics involving mitigation of secondary injury and inflexible trial design that favors unilateral mechanisms in a complex pathophysiology. Potential pathophysiological targets for attenuating secondary injury are highlighted in this review and include therapies increasing calcium, antagonizing microglial activation, maintaining macrophage M1 versus M2 balance by decreasing M1 signaling, aquaporin inhibition, NKCCl inhibition, endothelin receptor inhibition, Sur1-TRPM4 inhibition, matrix metalloproteinase inhibition, and sphingosine-1-phosphate receptor modulation. Future clinical trials in ICH focusing on secondary phase injury and, potentially implementing adaptive trial design approaches with multifocal targets, may improve insight into these mechanisms and provide potential therapies that may improve survival and functional outcome.

Comparison of Prognostic Models of Spontaneous Intracerebral Hemorrhage: Potential Tools for Personalized Care and Clinical Trial in ICH

Background: Several prognostic models have been developed for spontaneous intracerebral hemorrhage (ICH); however, none of them have been consistently used in routine clinical practice or clinical research. In the study, we systematically compared 27 ICH models with regard to mortality and functional outcome at 1-month, 3-month and 1-year after ICH. Methods: The validation cohort was derived from the Beijing Registration of Intracerebral Hemorrhage. Poor functional outcome was defined as modified Rankin Scale score (mRS) > 3 at 1-month, 3-month and 1-year after ICH, respectively. The area under the receiver operating characteristic curve (AUROC) and Hosmer-Lemeshow goodness-of-fit test were used to assess model discrimination and calibration. Moderate, good, excellent and outstanding discrimination were predefined as AUROC of 0.75-0.79, 0.80-0.84, 0.85-0.89 and above 0.90, respectively. Findings: A total number of 1575 patients were included. The mean age was 57.2±14.3 and 67.2% were male. The median NIHSS score on admission was 11 (IQR: 3-21). For predicting mortality at 3-month after ICH, AUROC of 27 ICH models ranged from 0.604 to 0.856. One model showed excellent discrimination; fifteen models demonstrated good discrimination; and seven models demonstrated moderate discrimination. In pairwise comparison, the ICH-FOS (0.856, 95%CI=0.835-0.878, P 3) at 3-month after ICH, AUROC of 27 ICH models ranged from 0.602 to 0.880. Five models showed excellent discrimination; six models demonstrated good discrimination; and ten models demonstrated moderate discrimination. In pairwise comparison with other prediction models, the ICH-FOS was superior in predicting poor functional outcome at 3-month after ICH (all P 0.05) for mortality and poor functional outcome at 3-month after ICH, however, the ICH-FOS showed the largest Cox and Snell R-square. Similar results were verified for mortality and poor functional outcome at 1-month and 1-year after ICH. Interpretation: Several risk models are externally validated to be effective for risk stratification and outcome prediction after ICH, which would be useful tools for personalized care and clinical trial in ICH. Funding Statement: Beijing Municipal Science & Technology Commission (Z131107002213009). Declaration of Interests: Dr. Ruijun Ji reports no disclosures. Dr. Wenjuan Wang reports no disclosures. Dr. Xinyu Liu reports no disclosures. Dr. Linlin Wang reports no disclosures. Dr. Ruixuan Jiang reports no disclosures. Dr. Runhua Zhang reports no disclosures. Dr. Dandan Wang reports no disclosures. Dr. Jiaokun Jia reports no disclosures. Dr. Hao Feng reports no disclosures. Dr. Zeyu Ding reports no disclosures. Dr. Yanfang Liu reports no disclosures. Dr. Gaifen Liu reports no disclosures. Dr. Jingjing Lu reports no disclosures. Dr. Yi Ju reports no disclosures. Dr. Xingquan Zhao reports no disclosures. Ethics Approval Statement: The study protocol was approved by the Institutional Review Board (IRB) of the Beijing Tiantan Hospital.

Abstract WMP106: Why Are Women Less Represented in ICH Trials?

Background: Fewer women than men tend to be enrolled in clinical trials of intracerebral hemorrhage (ICH). It is unclear whether this reflects lower prevalence of ICH in women, selection bias, poor recruitment efforts, or other factors. We undertook this study to examine differences between women and men in the reasons for exclusion from the iDEF (Intracerebral hemorrhage Deferoxamine) trial. Methods: The screen failure log included 29 different reasons for exclusion. Chi square statistics and p-values were used to evaluate whether women and men differed with regard to reason for screen failure. Findings: The iDEF trial enrolled 294 subjects; 38.5% were women. A total of 8776 subjects were screen failures. Sex was missing in 58. The remaining 8718 were included in this analysis; 3982 women (45.7%) and 4736 men (54.3%) (p&lt;0.0001). The enrollment rates were 2.8% in women vs. 3.7% in men (p=0.01). We were unable to obtain consent in 1.3% of women vs 1.7% of men (p=0.1), and patients/families declined participation in 1.3% of women vs. 1.3% of men (p=0.9). More women than men failed screening because of age &gt;80 (22.4% vs 12.6%) and pre-existing DNR/DNI (3.7% vs. 2.8%). Conversely, fewer women than men failed screening because inability to administer study drug within 24 hour due to late presentation (6.6% vs 7.8%), admission NIHSS score &lt;6 (10.2% vs 13.2%), coagulopathy (5.3% vs 7.5%), inability to comply with the protocol (0.7% vs 1.3%), abnormal renal function (1.9% vs 2.9%), drug/alcohol abuse (1.7% vs 3.7%), and presentation with confirmed aspiration or pneumonia (1.1% vs 1.8%).These differences were statistically significant. Interpretation: Results from this multi-center, prospective, ICH trial indicate that lower rates of women enrollment may be attributed to older age and higher rates of pre-existing DNR/DNI orders. Inability to obtain consent or declining participation was similar between women and men, arguing against selection bias. Our findings should be confirmed in other ICH trials to determine if additional efforts are needed to improve women’s participation in future studies. Funding: US National Institutes of Health and US National Institute of Neurological Disorders and Stroke (U01NS074425)

Surgical management of spontaneous intracerebral hemorrhage: insights from randomized controlled trials.

Spontaneous intracerebral hemorrhages (ICH) are a major cause of neurologic morbidity and mortality. The optimal management strategy of ICH remains controversial. We examine the available randomized controlled trial (RCT) data regarding neurosurgical evacuation of ICHs. A systematic literature review on surgical evacuation of spontaneous ICHs was performed to identify pertinent RCT data published between 1980 and 2019. We identified five RCTs that assessed the clinical impact of evacuation of spontaneous ICHs. Data from two high-quality RCTs randomizing 1033 and 601 patients with spontaneous ICHs (Surgical Trial in Intracerebral Hemorrhage (STICH) I and II) (1) failed to demonstrate a significant clinical benefit of routine open surgical evacuation of spontaneous cortical ICHs and (2) reinforced the high morbidity and mortality associated with ICH. These trials were nonetheless limited by high (> 20%) crossover from the medical to surgical arms. Data from three smaller RCTs on minimally invasive (stereotactic and endoscopic) surgical approaches randomizing 377, 242, and 100 patients with spontaneous ICHs suggest potential benefits relating to mortality and functional outcomes in patients with subcortical ICHs. While these RCTs do not clearly define the role of surgical resection for ICHs, they provide insights into opportunities for patient advocacy, clinical trial design, and future research studies. Ongoing studies building upon the potential for minimally invasive approaches for ICH evacuation may expand the surgical indications for ICH.

Independent Validation of the Hematoma Expansion Prediction Score: A Non-contrast Score Equivalent in Accuracy to the Spot Sign.

The computed tomography angiography (CTA) spot sign is widely used to assess the risk of hematoma expansion following acute intracerebral hemorrhage (ICH). However, not all patients can receive intravenous contrast nor are all hospital systems equipped with this technology. We aimed to independently validate the Hematoma Expansion Prediction (HEP) Score, an 18-point non-contrast prediction scale, in an external cohort and compare its diagnostic capability to the CTA spot sign. We performed a retrospective analysis of the predicting hematoma growth and outcome in intracerebral hemorrhage using contrast bolus CT (PREDICT) Cohort Study. Primary outcome was significant hematoma expansion (≥ 6mL or ≥ 33%). We generated a receiver operating characteristic (ROC) curve comparing the HEP score to significant expansion. We calculated sensitivity, specificity, positive and negative predictive values (PPV/NPV) for each score point. We determined independent predictors of significant hematoma expansion via logistic regression. A total of 292 patients were included in primary analysis. Hematoma growth of ≥ 6mL or ≥ 33% occurred in 94 patients (32%). The HEP score was associated with significant expansion (adjusted odds ratio [aOR] 1.14, 95% confidence interval [CI] 1.01-1.30). ROC curves comparing HEP score to significant expansion had an area under the curve of 0.64 (95% CI 0.57-0.71). Youden's method showed an optimum score of 4. HEP Scores ≥ 4 (n = 100, sensitivity 49%, specificity 73%, PPV 46%, NPV 75%, aOR 1.99, 95% CI 1.09-3.64) accurately predicted significant expansion. PPV increased with higher HEP scores, but at the cost of lower sensitivity. The diagnostic characteristics of the spot sign (n = 82, Sensitivity 49%, Specificity 81%, PPV 55%, NPV 76%, aOR 2.95, 95% CI 1.61-5.42) were similar to HEP scores ≥ 4. The HEP score is predictive of significant expansion (≥ 6mL or ≥ 33%) and is comparable to the spot sign in diagnostic accuracy. Non-contrast prediction tools may have a potential role in the recruitment of patients in future intracerebral hemorrhage trials.

Elevated Pulse Pressure Levels Are Associated With Increased In-Hospital Mortality in Acute Spontaneous Intracerebral Hemorrhage.

Clinical outcome after intracerebral hemorrhage (ICH) remains poor. Definitive phase-3 trials in ICH have failed to demonstrate improved outcomes with intensive systolic blood pressure (SBP) lowering. We sought to determine whether other BP parameters-diastolic BP (DBP), pulse pressure (PP), and mean arterial pressure (MAP)-showed an association with clinical outcome in ICH. We retrospectively analyzed a prospective cohort of 672 patients with spontaneous ICH and documented demographic characteristics, stroke severity, and neuroimaging parameters. Consecutive hourly BP recordings allowed for computation of SBP, DBP, PP, and MAP. Threshold BP values that transitioned patients from survival to death were determined from ROC curves. Using in-hospital mortality as outcome, BP parameters were evaluated with multivariable logistic regression analysis. Patients who died during hospitalization had higher mean PP compared to survivors (68.5 ± 16.4 mm Hg vs. 65.4 ± 12.4 mm Hg; P = 0.032). The following admission variables were associated with significantly higher in-hospital mortality (P < 0.001): poorer admission clinical condition, intraventricular hemorrhage, and increased admission normalized hematoma volume. ROC analysis showed that mean PP dichotomized at 72.17 mm Hg, provided a transition point that maximized sensitivity and specific for mortality. The association of this increased dichotomized PP with higher in-hospital mortality was maintained in multivariable logistic regression analysis (odds ratio, 3.0; 95% confidence interval, 1.7-5.3; P < 0.001) adjusting for potential confounders. Widened PP may be an independent predictor for higher mortality in ICH. This association requires further study.

Abstract 148: Evaluation of Sex, Racial and Geographic Demographics and Outcomes in Clinical Trials of Spontaneous Intracerebral Hemorrhage

Introduction: As large clinical trials for spontaneous intracerebral hemorrhage (ICH) increasingly influence management, recruitment of diverse populations must be ensured to fully understand the disease process and benefit of interventions to the general public. There is little data on sex, race and outcomes in ICH trials. We hypothesize that women and geographic minorities are underrepresented in ICH clinical trials and that there exist population specific differences in mortality, functional outcomes and response to interventions. Methods: Pooled analysis of 5456 subjects from the following clinical trials: VISTA (985), INTERACT I (404) and II (2829), STICH II (597), MISTIE II (141) and CLEAR III (500). Patients were grouped by sex, race, and geographic location. Modified Rankin Scale [mRS] was obtained at 30 days and 3 months. Results: More men than women participated in ICH trials (61.9% vs. 38.1%); women were older and more likely to have hypertension; men had more coronary artery disease. Women presented with lower Glasgow Coma scale, higher ICH score and more intraventricular hemorrhage. Day 90 mortality was 13.9% in women and 16.6 % in men (p=0.01); 90 day poor outcome (mRS 3-5) was 57.2% in women and 51.0% in men (p&lt;0.001). Only mortality was significantly different between sexes after adjustment for ICH score. Race representation varied in these clinical trials: 1.5% Hispanic; 6.6% black; 14% Arabic; 31% white and 43.4% Asian. Day 90 mortality and mRS 3-5 were highest in Hispanics (22.1%, 78.3%, respectively) and lowest in Asians (9.5%, 43.8%). Hispanics had higher ICH score, but blacks and Hispanics had lower day 90 mortality compared to whites in adjusted models. Asians had both lower mortality and less day 90 mRS 3-5 vs. whites while Arabics and blacks were more likely to have day 90 mRS 3-5. Study interventions were well balanced by sex and race. Conclusions: Sex and race representation in ICH clinical trials only partially equate to current understanding of epidemiology of ICH. There is a lack of trial evidence from Africa and South America and under-representation of women, Hispanics and blacks. Despite higher ICH severity, Hispanics had lower adjusted mortality risk while males had higher risk and Arabics and blacks had worse adjusted poor outcomes.

Applicability of Clinical Trials in an Unselected Cohort of Patients With Intracerebral Hemorrhage.

Patient selection in clinical trials on intracerebral hemorrhage (ICH) affects overall applicability of results. We estimated eligibility for completed, ongoing, and planned clinical trials in an unselected cohort of patients with ICH. Large clinical ICH trials were identified using trial registration databases. Each trial's inclusion criteria were applied to a consecutive group of patients with ICH from the prospective hospital-based Lund Stroke Register. Survival status was obtained from the National Census Office and 90-day poor functional outcome (modified Rankin Scale ≥4) from the Swedish Stroke Register or medical files. Among 253 patients with ICH, estimated eligibility proportions ranged between 2% and 36% for the 11 identified clinical trials. Patients not eligible for any trial (n=96) had more intraventricular hemorrhage, lower baseline level of consciousness, higher rates of cerebellar ICH, and lower rates of lobar ICH (P≤0.001). Thirty-day case fatality for noneligible patients was 54% versus 18% among patients eligible in ≥1 trial (95% confidence interval, 44%-64% versus 13%-25%; P<0.001). Noneligible ICH patients more frequently had poor functional outcome (75% versus 48%; 95% confidence interval, 65%-83% versus 40%-56%; P<0.001). There is large variation in proportions of patients with ICH eligible for inclusion in clinical trials and over a third of patients with ICH are not eligible for any trial.

Treatment of intracerebral hemorrhage: a selective review and future directions.

Intracerebral hemorrhage (ICH) is a devastating disease. Sixty percent of survivors do not function independently at one year. Treatment of ICH costs approximately US$ 12.7 billion annually. To date no intervention has demonstrated clear efficacy in improving outcomes. The goal of this selective review is to provide an understanding of current treatment and discuss future directions. After a discussion of pathophysiology and societal impact, a synopsis of treatment options is reviewed, including: 1) open craniotomy; 2) catheter-based thrombolytic therapy; 3) endoscopic evacuation; and 4) ultrasonic lysis. Amongst other studies, we will discuss the results of STICH (International Surgical Trial in ICH) and MISTIE (Minimally Invasive Surgery plus Recombinant Tissue-type Plasminogen Activator for ICH Evacuation). We hope to provide a succinct, pragmatic review for the neurosurgical community on the current state of therapy and encourage novel ways to aggressively treat this burdensome disease.

Abstract WP356: Eligibility Criteria in Clinical Trials on Intracerebral Hemorrhage Applied to an Unselected Cohort: The Lund Stroke Register

Introduction: Strict patient selection in medical or surgical trials on intracerebral hemorrhage (ICH) is needed to optimize therapeutic benefit but limits trial enrolment as well as overall applicability of results. We studied the applicability of previous, current, and planned large interventional ICH trials by applying each trial’s defined inclusion criteria to an unselected cohort of ICH patients. Methods: Large interventional ICH trials were identified via trial registration databases. To estimate eligibility rates, each trial’s inclusion criteria were applied on an unselected consecutive group of first-ever ICH patients from the prospective hospital-based Lund Stroke Register. Subsequently, 30 day survival status was obtained from the National Census Office and 90 day poor functional outcome (modified Rankin Scale ≥4 or death) from the Swedish Stroke Register or medical files. Results: Among 253 included ICH patients, estimated eligibility rates ranged from 2-38% for the identified 11 large interventional ICH trials (Figure 1). Patients not eligible for any of the trials (N=91, 36%) had: more extensive intraventricular hemorrhage (p&lt;0.001); lower baseline level of consciousness (p&lt;0.001); higher rate of cerebellar ICH and lower rates of lobar ICH (p&lt;0.001). No significant age, sex, or ICH volume differences were observed. The 30 day mortality rates among eligible patients were 0-33% depending on selected trial. The mortality rate for patients not eligible for any trial was 55% vs 19% for patients eligible in ≥1 trial (95% CI: 45-65% vs 13-25%; p&lt;0.001). Non-eligible ICH patients more frequently had poor functional outcome (75% vs 49%; 95% CI: 65-85% vs 41-57%; p&lt;0.001). Conclusions: There is great variation in proportions of unselected ICH patients eligible for inclusion in treatment trials. Even in trials with broad entry criteria only a minority is eligible, which need to be considered when translating ICH-trial results into clinical practice.

Advances in minimally invasive treatment of hemorrhagic and ischemic stroke.

Advances in minimally invasive treatment of hemorrhagic and ischemic stroke.

Rethinking the roles of inflammation in the intracerebral hemorrhage.

Blood in the vessels bleeds into the brain parenchyma resulting in the intracerebral hemorrhage (ICH) [1]. The direct mass effect of the rapidly formed hematoma causes the brain damage, which leads to neurologic deficit. Thus, clearing the hematoma may be beneficial to the patient with ICH. However, the Surgical Trial in Intracerebral Hemorrhage (STICH) trial showed no overall benefit from early hematoma evacuation compared to initial conservative treatment [2]. Therefore, the secondary brain injury caused by the metabolic products or the components of hematoma attracted more researchers’ attention [3]. Converging evidence shows that both central and peripheral inflammation play critical roles in the ICH-induced secondary brain injury [3–8]. Previously, most studies concentrated on the downstream inflammatory events, such as proinflammatory cytokines, showed that inflammatory responses contribute to the secondary brain injury after ICH, while no direct clinical effects on targeting these downstream events have been achieved [7]. Hence, it is worth thinking about why this kind of therapeutic strategies has no direct clinical effects and rethinking the roles of inflammation in the ICH.

Time course and predictors of neurological deterioration after intracerebral hemorrhage.

Neurological deterioration (ND) is a devastating complication after intracerebral hemorrhage but little is known about time course and predictors. We performed a retrospective cohort study of placebo patients in intracerebral hemorrhage trials. We performed computed tomographic scans within 3 hours of symptoms and at 24 and 72 hours; and clinical evaluations at baseline, 1-hour, and days 1, 2, 3, and 15. Timing of ND was predefined as follows: hyperacute (within 1 hour), acute (1-24 hours), subacute (1-3 days), and delayed (3-15 days). We enrolled 376 patients and 176 (47%) had ND within 15 days. In multivariate analyses of ND by category, hyperacute ND was associated with hematoma expansion (odds ratio [OR], 3.6; 95% confidence interval [CI], 1.7-7.6) and baseline intracerebral hemorrhage volume (OR, 1.04 per mL; 95% CI 1.02-1.06); acute ND with hematoma expansion (OR, 7.59; 95% CI, 3.91-14.74), baseline intracerebral hemorrhage volume (OR, 1.02 per mL; 95% CI, 1.01-1.04), admission Glasgow Coma Scale (OR, 0.77 per point; 95% CI, 0.65-0.91), and interventricular hemorrhage (OR, 2.14; 95% CI, 1.05-4.35); subacute ND with 72-hour edema (OR, 1.03 per mL; 95% CI, 1.02-1.05) and fever (OR, 2.49; 95% CI, 1.01-6.14); and delayed ND with age (OR, 1.11 per year; 95% CI, 1.04-1.18), troponin (OR, 4.30 per point; 95% CI, 1.71-10.77), and infections (OR, 3.69; 95% CI, 1.11-12.23). Patients with ND had worse 90-day modified Rankin scores (5 versus 3; P<0.001). ND occurs frequently and predicts poor outcomes. Our results implicate hematoma expansion and interventricular hemorrhage in early ND, and cerebral edema, fever, and medical complications in later ND.