Acute Cerebral Haemorrhage Trial Research Articles

Can propensity score matching replace randomized controlled trials?

Randomized controlled trials (RCTs) have long been recognized as the gold standard for establishing causal relationships in clinical research. Despite that, various limitations of RCTs prevent its widespread implementation, ranging from the ethicality of withholding potentially-lifesaving treatment from a group to relatively poor external validity due to stringent inclusion criteria, amongst others. However, with the introduction of propensity score matching (PSM) as a retrospective statistical tool, new frontiers in establishing causation in clinical research were opened up. PSM predicts treatment effects using observational data from existing sources such as registries or electronic health records, to create a matched sample of participants who received or did not receive the intervention based on their propensity scores, which takes into account characteristics such as age, gender and comorbidities. Given its retrospective nature and its use of observational data from existing sources, PSM circumvents the aforementioned ethical issues faced by RCTs. Majority of RCTs exclude elderly, pregnant women and young children; thus, evidence of therapy efficacy is rarely proven by robust clinical research for this population. On the other hand, by matching study patient characteristics to that of the population of interest, including the elderly, pregnant women and young children, PSM allows for generalization of results to the wider population and hence greatly increases the external validity. Instead of replacing RCTs with PSM, the synergistic integration of PSM into RCTs stands to provide better research outcomes with both methods complementing each other. For example, in an RCT investigating the impact of mannitol on outcomes among participants of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial, the baseline characteristics of comorbidities and current medications between treatment and control arms were significantly different despite the randomization protocol. Therefore, PSM was incorporated in its analysis to create samples from the treatment and control arms that were matched in terms of these baseline characteristics, thus providing a fairer comparison for the impact of mannitol. This literature review reports the applications, advantages, and considerations of using PSM with RCTs, illustrating its utility in refining randomization, improving external validity, and accounting for non-compliance to protocol. Future research should consider integrating the use of PSM in RCTs to better generalize outcomes to target populations for clinical practice and thereby benefit a wider range of patients, while maintaining the robustness of randomization offered by RCTs.

The third intensive care bundle with blood pressure reduction in acute cerebral haemorrhage trial (INTERACT3): an interactional, stepped wedge, cluster randomized controlled trial.

The third intensive care bundle with blood pressure reduction in acute cerebral haemorrhage trial (INTERACT3): an interactional, stepped wedge, cluster randomized controlled trial.

Abstract TMP74: Association Between Hematoma Volume After Risk of Subsequent Ischemic Stroke: A MISTIE III and ATACH-2 Analysis

Background: Non-traumatic intracerebral hemorrhage (ICH) is independently associated with long-term increased risk of major arterial ischemic events. Whether hematoma volume influences this risk is poorly understood. Methods: We pooled individual patient data from the MISTIE III (Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation phase 3) and the ATACH-2 (Antihypertensive Treatment of Acute Cerebral Hemorrhage) trials. The exposure was hematoma volume. In the primary analysis, hematoma volume was treated as a continuous measure after natural logarithmic transformation to approximate linearity, and in the secondary analysis, it was dichotomized by the median. The outcome was an ischemic stroke, adjudicated centrally within each trial. We evaluated the association between hematoma volume and the risk of an ischemic stroke using Cox regression analyses after adjustment for demographics, vascular comorbidities, and ICH characteristics. Results: Of 1,499 ICH patients, the mean age was 61.7 (SD, 12.8) years and 574 (38.3%) were female. The median hematoma volume was 17.3 mL (IQR, 7.2-35.7). During a median follow up of 107 days (IQR, 91-140), 30 ischemic strokes occurred of which 22 were in patients with median ICH volume > 17.3 mL with a cumulative incidence of 4.6% (95% CI, 3.1-7.1). Among patients with median ICH volume < 17.3 mL, there were 8 ischemic strokes with a cumulative incidence of 3.1% (95% CI, 1.7-6.0). Using adjusted Cox regression models, log-transformed ICH volume (continuous measure) was associated with an increased risk of ischemic stroke (HR, 1.5 per log-unit increase; 95% CI, 1.1-2.8). Similarly, ICH volume > 17.3 mL was associated with an increased risk of ischemic stroke (HR, 2.5; 95% CI, 1.1-7.2), compared to those with an ICH volume < 17.3 mL. Conclusions: In a heterogeneous cohort of ICH patients, initial hematoma volume was associated with a heightened risk of subsequent ischemic stroke.

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

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

Acute spontaneous intracerebral haemorrhage: does a care bundle approach work?

A care bundle is a small but crucial set of treatments that, when implemented together, can improve outcomes. 1 NHS Modernisation Agency10 high impact changes for service improvement and delivery: a guide for NHS leaders. http://www.nursingleadership.org.uk/publications/HIC.pdfDate: 2004 Date accessed: April 24, 2023 Google Scholar Acute spontaneous intracerebral haemorrhage has few effective treatments and intracerebral haemorrhage-specific recommendations for care bundles. 2 Parry-Jones AR Sammut-Powell C Paroutoglou K et al. Intracerebral hemorrhage care bundle is associated with lower case fatality. Ann Neurol. 2019; 86: 495-503 Crossref PubMed Scopus (40) Google Scholar , 3 Middleton S McElduff P Ward J et al. Implementation of evidence-based treatment protocols to manage fever, hyperglycaemia, and swallowing dysfunction in acute stroke (QASC): a cluster randomised controlled trial. Lancet. 2011; 378: 1699-1706 Summary Full Text Full Text PDF PubMed Scopus (266) Google Scholar In clinical practice, intracerebral haemorrhage is often approached with negativity. 4 Willie JT Gross RE Beyond therapeutic nihilism? The neurosurgical treatment of intracerebral hemorrhage. World Neurosurg. 2013; 80: e135-e137 Crossref PubMed Scopus (1) Google Scholar Moreover, the synergistic benefits of specialised nursing care, neurointensive and neurosurgical care, blood pressure control, reversal of coagulopathy, and other interventions have not been ascertained. 5 Greenberg SM Ziai WC Cordonnier C et al. 2022 guideline for the management of patients with spontaneous intracerebral hemorrhage: a guideline from the American Heart Association/American Stroke Association. Stroke. 2022; 53: e282-e361 Crossref PubMed Scopus (107) Google Scholar The third Intensive Care Bundle with Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT3): an international, stepped wedge cluster randomised controlled trialImplementation of a care bundle protocol for intensive blood pressure lowering and other management algorithms for physiological control within several hours of the onset of symptoms resulted in improved functional outcome for patients with acute intracerebral haemorrhage. Hospitals should incorporate this approach into clinical practice as part of active management for this serious condition. Full-Text PDF Open Access

Implementing a Goal-Directed Care Bundle after Acute Intracerebral Haemorrhage: Process Evaluation for the Third INTEnsive Care Bundle with Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial Study in China

Background: The third INTEnsive care bundle with blood pressure Reduction in Acute Cerebral Haemorrhage Trial is an ongoing international, multicentre, stepped wedge, cluster-randomized trial to determine the effectiveness of a goal-directed care bundle (early intensive blood pressure [BP] lowering, glycaemic control, treatment of pyrexia, and reversal of anticoagulation), as compared to standard of care, on patient-centred outcomes after acute intracerebral haemorrhage (ICH). An embedded process evaluation aims to identify factors related to the uptake and implementation of the intervention. Herein, we present the process evaluation results for hospital sites in China. Methods/Design: A mixed methods approach, including surveys, focused group discussions and interviews with clinicians, routine monitoring, and recruitment logs were used to collect data across purposively sampled hospitals. Medical Research Council guidance and normalization process theory were used as theoretical frameworks for design, data analysis, and synthesis. Results: Twenty quantitative surveys were completed with clinicians, and 26 interviews and 2 focus group discussions were conducted during 2019–2020. The care bundle was generally delivered as planned and acceptable by doctors and nurses, but difficulties were reported in achieving the protocol-defined target levels of BP and glycaemic control. Resistance to implementing the care bundle occurred for patients perceived to be at high risk of adverse effects. Common organizational contextual factors that impeded implementation included delayed processes and limited medication supply, while established background care procedures, expertise, and capacity influenced its integration into routine practice. Areas to facilitate implementation included optimizing workflow within available resources, having a dedicated team, and recognizing the potential benefits of the intervention. Conclusions: Varied established care protocols across sites, different levels of background expertise, and lack of staff capacity impeded the integration of goal-directed care bundle into routine practice for ICH patients in China. Ready identification, and efforts to address, these barriers could facilitate uptake of future guideline-recommended interventions for the management of patients with ICH.

INTEnsive care bundle with blood pressure reduction in acute cerebral hemorrhage trial (INTERACT3): study protocol for a pragmatic stepped-wedge cluster-randomized controlled trial

BackgroundEarly intensive blood pressure (BP) lowering remains the most promising treatment for acute intracerebral hemorrhage (ICH), despite discordant results between clinical trials and potential variation in the treatment effects by approach to control BP. As the third in a series of clinical trials on this topic, the INTEnsive care bundle with blood pressure Reduction in Acute Cerebral hemorrhage Trial (INTERACT3) aims to determine the effectiveness of a goal-directed care bundle protocol of early physiological control (intensive BP lowering, glycemic control, and pyrexia treatment) and reversal of anticoagulation, in acute ICH.MethodsINTERACT3 is a pragmatic, international, multicenter, stepped-wedge (4 phases/3 steps), cluster-randomized controlled trial to determine the effectiveness of a multifaceted care package in adult (age ≥ 18 years) patients (target 8360) with acute ICH (< 6 h of onset) recruited from 110 hospitals (average of 19 consecutive patients per phase) in low- and middle-income countries. After a control phase, each hospital implements the intervention (intensive BP lowering, target systolic < 140 mmHg; glucose control, target 6.1–7.8 mmol/L and 7.8–10.0 mmol/L in those without and with diabetes mellitus, respectively; anti-pyrexia treatment to target body temperature ≤ 37.5 °C; and reversal of anticoagulation, target international normalized ratio < 1.5 within 1 h). Information will be obtained on demographic and baseline clinical characteristics, in-hospital management, and 7-day outcomes. Central trained blinded assessors will conduct telephone interviews to assess physical function and health-related quality of life at 6 months. The primary outcome is the modified Rankin scale (mRS) at 6 months analyzed using ordinal logistic regression. The sample size of 8360 subjects provides 90% power (α = 0.05) to detect a 5.6% absolute improvement (shift) in the primary outcome of the intervention versus control standard care, with various assumptions.DiscussionAs the largest clinical trial in acute ICH, INTERACT3 is on schedule to provide an assessment of the effectiveness of a widely applicable goal-directed care bundle for a serious condition in which a clearly proven treatment has yet to be established.Trial registrationClinicalTrials.gov NCT03209258. Registered on 1 July 2017. Chinese Trial Registry ChiCTR-IOC-17011787. Registered on 28 June 2017

Surgical Evacuation of Intracerebral Hemorrhage: The Potential Importance of Timing.

Surgical Evacuation of Intracerebral Hemorrhage: The Potential Importance of Timing.

Prognostic significance of early pyrexia in acute intracerebral haemorrhage: The INTERACT2 study

IntroductionUncertainty exists over the prognostic significance of pyrexia in acute intracerebral haemorrhage (ICH). We aimed to determine the association of elevated body temperature with clinical and imaging outcomes among participants of the main Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT2). MethodsPost-hoc analyses of INTERACT2, an international open, blinded outcome assessed, randomised trial of 2839 patients with spontaneous ICH (<6 h of onset) and elevated systolic blood pressure (SBP, 150–220 mmHg) randomly assigned to intensive (SBP target <140 mmHg) or guideline-recommended (SBP target < 180 mmHg) BP management. Multivariable logistic regression was used to determine associations of elevated baseline body temperature (<37.5 vs. ≥37.5 °C) and 90-day clinical outcome defined on the modified Rankin scale (mRS). Analysis of covariance determined relations of body temperature and haematoma and perihaematomal oedema (PHE) volumes, at baseline and 24 h post-randomisation. ResultsOf 2792 participants with data available at admission, 39 (1.4%) patients had elevated body temperature ≥ 37.5 °C. Elevated body temperature was significantly associated with 90-day mortality (adjusted odds ratio 2.44; 95% confidence interval 1.02–5.82; P = .044) but not with major disability alone (mRS scores 3–5) and combination death or major disability (mRS scores 3–6). Elevated body temperature was also associated with larger PHE volume at baseline (10.89 vs. 3.14 cm3, P < .001;) and 24 h (12.43 vs 5.76 cm3, P = .018) but not with haematoma volumes at these time points. ConclusionEarly pyrexia in mild to moderate ICH is associated with greater mortality and larger PHE volume, suggesting an early inflammatory-mediated reaction. Clinical trial registrationwww.clinicaltrials.gov (NCT00716079).

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

The etiology and significance of diffusion-weighted imaging (DWI) lesions in patients with acute intracerebral hemorrhage (ICH) remain unclear. 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. 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. 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. 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. 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.

Blood pressure control and clinical outcomes in acute intracerebral haemorrhage: a preplanned pooled analysis of individual participant data

Uncertainty persists over the effects of blood pressure lowering in acute intracerebral haemorrhage. We aimed to combine individual patient-level data from the two largest randomised controlled trials of blood pressure lowering strategies in patients with acute intracerebral haemorrhage to determine the strength of associations between key measures of systolic blood pressure control and safety and efficacy outcomes. We did a preplanned pooled analysis of individual patient-level data acquired from the main phase of the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT2) and the second Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH-II) trial. These trials included adult patients aged 19-99 years with spontaneous (non-traumatic) intracerebral haemorrhage and elevated systolic blood pressure, without a clear indication or contraindication to treatment. Patients were excluded if they had a structural cerebral cause for the intracerebral haemorrhage, had a low score (3-5) on the Glasgow Coma Scale, or required immediate neurosurgery. Our primary analysis assessed the independent associations between three post-randomisation systolic blood pressure summary measures-magnitude of reduction in 1 h, mean achieved systolic blood pressure, and variability in systolic blood pressure between 1 h and 24 h-and the primary outcome of functional status, as defined by the distribution of scores on the modified Rankin Scale at 90 days post-randomisation. We analysed the systolic blood pressure measures as continuous variables using generalised linear mixed models, adjusted for baseline covariables and trial. The primary and safety analyses were done in a modified intention-to-treat population, which only included patients with sufficient data on systolic blood pressure. 3829 patients (mean age 63·1 years [SD 12·9], 1429 [37%] women, and 2490 [65%] Asian ethnicity) were randomly assigned in INTERACT2 and ATACH-II, with a median neurological impairment defined by scores on the National Institutes of Health Stroke Scale of 11 (IQR 6-16) and median time from the onset of symptoms of intracerebral haemorrhage to randomisation of 3·6 h (2·7-4·4). We excluded 20 patients with insufficient or no systolic blood pressure data, and we imputed missing systolic blood pressure data in 23 (1%) of the remaining 3809 patients. Overall, the mean magnitude of early systolic blood pressure reduction was 29 mm Hg (SD 22), and subsequent mean systolic blood pressure achieved was 147 mm Hg (15) and variability in systolic blood pressure was 14 mm Hg (8). Achieved systolic blood pressure was continuously associated with functional status (improvement per 10 mm Hg increase adjusted odds ratio [OR] 0·90 [95% CI 0·87-0·94], p<0·0001). Symptomatic hypotension occurred in 28 (1%) patients, renal serious adverse events occurred in 26 (1%) patients, and cardiac serious adverse events occurred in 99 (3%) patients. Our pooled analyses indicate that achieving early and stable systolic blood pressure seems to be safe and associated with favourable outcomes in patients with acute intracerebral haemorrhage of predominantly mild-to-moderate severity. None.

Oedema extension distance in intracerebral haemorrhage: Association with baseline characteristics and long-term outcome.

Oedema extension distance is a derived parameter that may reduce sample size requirements to demonstrate reduction in perihaematomal oedema in early phase acute intracerebral haemorrhage trials. We aimed to identify baseline predictors of oedema extension distance and its association with clinical outcomes. Using Virtual International Stroke Trials Archive-Intracerebral Haemorrhage, first Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial, and Minimally Invasive Surgery and rtPA for Intracerebral Hemorrhage Evacuation II datasets, we calculated oedema extension distance at baseline and at 72h measured using computed tomography. Using linear regression, we tested for associations between baseline characteristics and oedema extension distance at 72h. Ordinal regression (underlying assumptions validated) was used to test for associations between oedema extension distance at baseline and 72h and oedema extension distance change between baseline and 72h, and modified Rankin scale scores at 90 days, adjusted for baseline and 72h prognostic factors. There were 1028 intracerebral haemorrhage cases with outcome data for analyses. Mean (standard deviation, SD) oedema extension distance at 72h was 0.54 (0.26)cm, and mean oedema extension distance difference from baseline (EED72-0) was 0.24 (0.18)cm. Oedema extension distance at 72h was greater with increasing baseline haematoma volume and baseline oedema extension distance. Increasing age, lobar haemorrhage, and intraventricular haemorrhage were independently associated with EED72-0. In multifactorial ordinal regression analysis, EED72-0 was associated with worse modified Rankin scale scores at 90 days (odds ratio 1.96, 95% confidence interval 1.00-3.82). Increase in oedema extension distance over 72h is independently associated with decreasing functional outcome at 90 days. Oedema extension distance may be a useful surrogate outcome measure in early phase trials of anti-oedema or anti-inflammatory treatments in intracerebral haemorrhage.

Infratentorial Intracerebral Hemorrhage.

Background and Purpose- Infratentorial intracerebral hemorrhage (ICH) has a poor outcome but is rarely analyzed by cerebellar versus brain stem location. We evaluated this relationship and clinical outcomes among participants of the INTERACT 1 and 2 (Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trials). Methods- Participants with brain stem and cerebellar ICH were compared. Logistic regression models were used to compare outcomes of death or major disability and quality of life. Results- Of 195 included patients, 92 (47%) and 103 (53%) had brain stem and cerebellar ICH, respectively. Patients with brain stem ICH were younger (mean [SD] age, 59±13 versus 70±11 years), less female (28.3% versus 50.5%), with higher admission National Institutes of Health Stroke Scale scores (median [interquartile range], 6 [4-10) versus 3 [2-8]), less prior ICH (3% versus 17%), smaller ICH volumes (1.6 mL [1.0-2.8 mL] versus 5.1 mL [2.6-10.7 mL]), and less intraventricular extension (3% versus 39%) than those with cerebellar ICH. Brain stem ICH had higher mortality (odds ratio, 37.1; 95% CI, 1.99-692.27) and worse scores in the European Quality of Life Scale (EQ-5D) pain domain (odds ratio, 3.36; 95% CI, 1.38-8.20). Conclusions- Cerebellar and brain stem ICH differ in their clinical characteristics and prognosis, with the latter being associated with higher case fatality and worse EQ-5D scores in the pain domain. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifiers: NCT00226096 and NCT00716079.

The systolic blood pressure sweet spot after intracerebral hemorrhage

Acute spontaneous intracerebral hemorrhage (ICH), the most severely disabling type of stroke, has few proven therapies. The mainstay of care remains acute blood pressure (BP)–lowering treatment, in order to mitigate hematoma expansion, perihematomal edema, and the attendant mass effects, each linked to early neurologic deterioration (END), death, and major disability.1,2 More than 5 randomized clinical trials (RCTs) have proven the safety and support the efficacy of early intensive BP-lowering treatment, as opposed to conservative BP control. These trials include the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2 (INTERACT-2) and Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH-2) trials, which were recently compared3 and compiled in a large meta-analysis.4 Mounting evidence,1 particularly ad hoc analyses of INTERACT-2,5,6 suggests that the earlier the treatment, the steeper the drop, and the lower the BP achieved, the better the outcome,1,6 halting radiologic or clinical deterioration2 and, more importantly, improving quality of life and shifting toward better functional physical outcome at 3 months.4–6 Furthermore, INTERACT-2 data revealed a dose effect with linear relationship between achieved systolic BP (SBP) and reducing hematoma growth5 and improved functional outcome.6

Author response: Blood pressure reduction and noncontrast CT markers of intracerebral hemorrhage expansion.

We thank Drs. Lattanzi and Silvestrini for their interest in our article.1 Increased blood pressure variability may lead to poor outcome after acute intracerebral hemorrhage (ICH) but a post hoc analysis of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2 (INTERACT2) showed that this association was not mediated by an increased risk of ICH growth.2 Hematoma expansion is a very early event in the natural history of ICH and, therefore, we agree that time is a key factor. Ischemic stroke treatment in mobile stroke units reduces the time from symptom onset to treatment.3 Early identification and treatment of patients with ICH at high risk of hematoma growth may become feasible in the prehospital setting using mobile stroke units equipped with noncontrast CT (NCCT). In a previous analysis, we showed that intrahematoma hypodensities, timing of baseline NCCT, and presence of the CT angiography spot sign predicted ICH expansion independently from each other.4 Further studies are needed to investigate whether the integration of different imaging markers provides additional value in the identification of ICH patients at high risk of hemorrhage growth.

Practice Patterns for Neurosurgical Utilization and Outcome in Acute Intracerebral Hemorrhage: Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trials 1 and 2 Studies.

The prognosis in acute spontaneous intracerebral hemorrhage (ICH) is related to hematoma volume, where >30 mL is commonly used to define large ICH as a threshold for neurosurgical decompression but without clear supporting evidence. To determine the factors associated with large ICH and neurosurgical intervention among participants of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trials (INTERACT). We performed pooled analysis of the pilot INTERACT1 (n = 404) and main INTERACT2 (n = 2839) studies of ICH patients (<6 h of onset) with elevated systolic blood pressure (SBP, 150-220 mm Hg) who were randomized to intensive (target SBP < 140 mm Hg) or contemporaneous guideline-recommended (target SBP < 180 mm Hg) management. Neurosurgical intervention data were collected at 7 d postrandomization. Multivariable logistic regression was used to determine associations. There were 372 (13%) patients with large ICH volume (>30 mL), which was associated with nonresiding in China, nondiabetic status, severe neurological deficit (National Institutes of Health stroke scale [NIHSS] score ≥ 15), lobar location, intraventricular hemorrhage extension, raised leucocyte count, and hyponatremia. Significant predictors of those patients who underwent surgery (226 of 3233 patients overall; 83 of 372 patients with large ICH) were younger age, severe neurological deficit (lower Glasgow coma scale score, and NIHSS score ≥ 15), baseline ICH volume > 30 mL, and intraventricular hemorrhage. Early identification of severe ICH, based on age and clinical and imaging parameters, may facilitate neurosurgery and intensive monitoring of patients.

Management of Acute Hypertensive Response in Intracerebral Hemorrhage Patients After ATACH-2 Trial.

Acute hypertensive response is elevation of systolic blood pressure (SBP) in the first 24h after symptom onset which is highly prevalent in patients with intracerebral hemorrhage (ICH). Observational studies suggested association between acute hypertensive response and hematoma expansion, peri-hematoma edema and death and disability, and possible reduction in these adverse outcomes with treatment of acute hypertensive response. Recent clinical trials have focused on determining the clinical efficacy of early intensive SBP reduction in ICH patients. The Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH-2) trial was the latest phase 3 randomized controlled multicenter clinical trial aimed to study the efficacy of early intensive reduction of SBP in ICH patients. In this review article, we summarize the results of recent clinical trials, treatment principles based on the latest guidelines, and the anticipated interpretation and incorporation of ATACH-2 trial results in clinical practice.

Acute Blood Pressure Management in Intracerebral Hemorrhage: Equipoise Resists an Attack.

There are 2 competing rationales for acute blood pressure (BP) management in primary intracerebral hemorrhage (ICH). A conservative approach is predicated on the possibility that cerebral blood flow is passively dependent on perfusion pressure, whereas an aggressive approach has been hypothesized to improve outcomes via a reduction in early hematoma expansion. Although the latter is a biologically plausible hypothesis, this relationship has not been consistently demonstrated in retrospective or prospective studies, likely reflecting the fact that hematoma expansion is dependent on multiple factors, in particular the time from symptom onset to diagnostic scan, and baseline volume.1 The most effective way to address this clinical equipoise is, therefore, a randomized controlled trial of the 2 different BP management strategies. In the ATACH-II trial (Antihypertensive Treatment of Acute Cerebral Hemorrhage II), 1000 patients were randomized to a systolic BP (SBP) target of 110 to 139 mm Hg or 140 to 179 mm Hg, after the Data Safety Monitoring Board–recommended trial suspension on the basis of a futility analysis.2 Despite a robust and early difference in achieved BP between the 2 groups, the 90-day mortality and disability rate was unaffected (38.7% versus 37.7%; P =0.84). The reasons for this lack of treatment effect are not clear. There was no effect on the frequency of hematoma expansion, although the trend was in favor …

Withdrawal of active treatment after intracerebral haemorrhage in the INTERACT2 study.

in the second Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT2), a minority of patients received withdrawal of active treatment (WAT). We wished to determine the characteristics of these patients, and the relation of this decision-making to subsequent management and final outcome. the INTERACT2 cohort of acute intracerebral haemorrhage (ICH) patients had a decision of WAT within 7 days after hospital admission recorded. Multivariable logistic regression was used to identify the determinants of WAT and poor outcome at 90 days, defined by modified Rankin scale (mRS) scores 3-6. of 2,779 participants with available data, WAT occurred in 121 (4%) and this was significantly associated with increasing age, greater neurological severity, larger haematoma volume, intraventricular extension and randomisation to intensive BP lowering. Compared to other patients, those with WAT had greater mortality (81/121 [67%] versus 205/2624 [8%]; P < 0.001) and survivors were more likely to be severely disabled (mRS score 4-5, 19/39 [49%] versus 695/2419 [29%]; P = 0.006). WAT was undertaken in patients with recognised predictors of poor prognosis, who subsequently were more likely to die or be left with severe disability. Improved understanding of specific factors determining WAT in ICH patients might improve care delivery and outcomes. the INTERACT2 study is registered with ClinicalTrials.gov (NCT00716079).

Early Blood Pressure Lowering Does Not Reduce Growth of Intraventricular Hemorrhage following Acute Intracerebral Hemorrhage: Results of the INTERACT Studies

Background: Intraventricular hemorrhage (IVH) extension is common following acute intracerebral hemorrhage (ICH) and is associated with poor prognosis. Aim: To determine whether intensive blood pressure (BP)-lowering therapy reduces IVH growth. Methods: Pooled analyses of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trials (INTERACT1 and INTERACT2) computed tomography (CT) substudies; multicenter, open, controlled, randomized trials of patients with acute spontaneous ICH and elevated systolic BP, randomly assigned to intensive (<140 mm Hg) or guideline-based (<180 mm Hg) BP management. Participants had blinded central analyses of baseline and 24-hour CT. Association of BP lowering to IVH growth was assessed in analysis of covariance. Results: There was no significant difference in adjusted mean IVH growth following intensive (n = 228) compared to guideline-recommended (n = 228) BP treatment (1.6 versus 2.2 ml, respectively; p = 0.56). Adjusted mean IVH growth was nonsignificantly greater in patients with a mean achieved systolic BP ≥160 mm Hg over 24 h (3.94 ml; p trend = 0.26). Conclusions: Early intensive BP-lowering treatment had no clear effect on IVH in acute ICH.