Lowering blood pressure after acute intracerebral haemorrhage: protocol for a systematic review and meta-analysis using individual patient data from randomised controlled trials participating in the Blood Pressure in Acute Stroke Collaboration (BASC)

INTRODUCTION: Conflicting results from multiple randomised trials indicate that the methods and effects of blood pressure (BP) reduction after acute intracerebral haemorrhage (ICH) are complex. The Blood pressure in Acute Stroke Collaboration is an international collaboration, which aims to determine the optimal management of BP after acute stroke including ICH. METHODS AND ANALYSIS: A systematic review will be undertaken according to the Preferred Reporting Items for Systematic review and Meta-Analysis of Individual Participant Data (IPD) guideline. A search of Cochrane Central Register of Controlled Trials, EMBASE and MEDLINE from inception will be conducted to identify randomised controlled trials of BP management in adults with acute spontaneous (non-traumatic) ICH enrolled within the first 7 days of symptom onset. Authors of studies that meet the inclusion criteria will be invited to share their IPD. The primary outcome will be functional outcome according to the modified Rankin Scale. Safety outcomes will be early neurological deterioration, symptomatic hypotension and serious adverse events. Secondary outcomes will include death and neuroradiological and haemodynamic variables. Meta-analyses of pooled IPD using the intention-to-treat dataset of included trials, including subgroup analyses to assess modification of the effects of BP lowering by time to treatment, treatment strategy and patient's demographic, clinical and prestroke neuroradiological characteristics. ETHICS AND DISSEMINATION: No new patient data will be collected nor is there any deviation from the original purposes of each study where ethical approvals were granted; therefore, further ethical approval is not required. Results will be reported in international peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42019141136

Associations of Early Systolic Blood Pressure Control and Outcome after Thrombolysis-Eligible Acute Ischemic Stroke: Results from the ENCHANTED Study

Background and Purpose: In thrombolysis-eligible patients with acute ischemic stroke, there is uncertainty over the most appropriate systolic blood pressure (SBP) lowering profile that provides an optimal balance of potential benefit (functional recovery) and harm (intracranial hemorrhage). We aimed to determine relationships of SBP parameters and outcomes in thrombolyzed acute ischemic stroke patients. Methods: Post hoc analyzes of the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study), a partial-factorial trial of thrombolysis-eligible and treated acute ischemic stroke patients with high SBP (150-180 mm Hg) assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) alteplase and intensive (target SBP, 130-140 mm Hg) or guideline-recommended (target SBP <180 mm Hg) treatment. All patients were followed up for functional status and serious adverse events to 90 days. Logistic regression models were used to analyze 3 SBP summary measures postrandomization: attained (mean), variability (SD) in 1-24 hours, and magnitude of reduction in 1 hour. The primary outcome was a favorable shift on the modified Rankin Scale. The key safety outcome was any intracranial hemorrhage. Results: Among 4511 included participants (mean age 67 years, 38% female, 65% Asian) lower attained SBP and smaller SBP variability were associated with favorable shift on the modified Rankin Scale (per 10 mm Hg increase: odds ratio, 0.76 [95% CI, 0.71-0.82]; P<0.001 and 0.86 [95% CI, 0.76-0.98]; P=0.025) respectively, but not for magnitude of SBP reduction (0.98, [0.93-1.04]; P=0.564). Odds of intracranial hemorrhage was associated with higher attained SBP and greater SBP variability (1.18 [1.06-1.31]; P=0.002 and 1.34 [1.11-1.62]; P=0.002) but not with magnitude of SBP reduction (1.05 [0.98-1.14]; P=0.184). Conclusions: Attaining early and consistent low levels in SBP <140 mm Hg, even as low as 110 to 120 mm Hg, over 24 hours is associated with better outcomes in thrombolyzed acute ischemic stroke patients. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01422616

Prevention of haematoma progression by tranexamic acid in intracerebral haemorrhage patients with and without spot sign on admission scan: a statistical analysis plan of a pre-specified sub-study of the TICH-2 trial

Objective We present the statistical analysis plan of a prespecified Tranexamic Acid for Hyperacute Primary Intracerebral Haemorrhage (TICH)-2 sub-study aiming to investigate, if tranexamic acid has a different effect in intracerebral haemorrhage patients with the spot sign on admission compared to spot sign negative patients. The TICH-2 trial recruited above 2000 participants with intracerebral haemorrhage arriving in hospital within 8 h after symptom onset. They were included irrespective of radiological signs of on-going haematoma expansion. Participants were randomised to tranexamic acid versus matching placebo. In this subgroup analysis, we will include all participants in TICH-2 with a computed tomography angiography on admission allowing adjudication of the participants’ spot sign status. Results Primary outcome will be the ability of tranexamic acid to limit absolute haematoma volume on computed tomography at 24 h (± 12 h) after randomisation among spot sign positive and spot sign negative participants, respectively. Within all outcome measures, the effect of tranexamic acid in spot sign positive/negative participants will be compared using tests of interaction. This sub-study will investigate the important clinical hypothesis that spot sign positive patients might benefit more from administration of tranexamic acid compared to spot sign negative patients

Blood Pressure Variability and Outcome in Acute Ischemic and Hemorrhagic Stroke: A Post-Hoc Analysis of the HeadPoST Study

The Head Positioning in Acute Stroke Trial (HeadPoST) is a pragmatic, international, cluster crossover randomized trial of 11,093 patients with acute stroke assigned to a lying-flat (0o) or sitting-up (head elevated ≥30o) position. This post-hoc analysis aimed to determine the association between BPV and outcomes for patients from a wide range of international clinical settings and how the association was modified by randomized head position. BPV was defined according to standard criteria with the key parameter considered the coefficient of variation (CV) of systolic BP (SBP) over 24 hours. Outcome was ordinal 90-day modified Rankin Scale (mRS) score. The association was analyzed by ordinal, logistic regression, hierarchical, mixed models with fixed intervention (lying-flat vs. sitting-up), and fixed period, random cluster, and random cluster-period, effects. 9,156 (8,324 AIS and 817 ICH; mean age 68.1 years; 39.2% women) were included in the analysis. CV of SBP had a significant linear association with unfavorable shift of mRS at 90 days (adjusted odds ratio [OR] 1.06, 95% confidence interval [CI] 1.02-1.11; P=0.01). There was no heterogeneity of the association by randomized head positioning. In addition, CV of diastolic BP (DBP) (1.08, 1.03-1.12; P=0.001) over 24 hours post stroke, was significantly associated with 3-month poor outcome. The association was more apparent in sitting-up position (1.12, 1.06-1.19) compared with lying-flat position (1.03, 0.98-1.09) (P interaction = 0.005). BPV was associated with adverse stroke outcome, the magnitude of the association was greater with sitting-up head positioning in terms of DBP variability

Determinants of the high admission blood pressure in mild-to-moderate acute intracerebral hemorrhage

Background and purpose: An early elevation in blood pressure (BP) is common after spontaneous intracerebral hemorrhage (ICH), has various potential causes, and is predictive of poor outcome. We aimed to determine the predictors of this phenomenon, in pooled analyses of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trials [INTERACT1 (n = 404) and INTERACT2 (n = 2829)]. Methods: INTERACT trials were international, open, blinded endpoint, randomized controlled trials of patients with spontaneous ICH (&lt;6 h) and elevated SBP (150–220 mmHg) assigned to intensive (target SBP &lt; 140 mmHg) or guideline-recommended (SBP &lt; 180 mmHg) treatment. Multivariable linear and logistic regression models were used to determine associations between baseline variables and the high admission BP, with continuous and binary SBP measures, respectively. Results: Among 3233 patients (mean age 63 years; 37% female; baseline mean SBP 179 mmHg), both analytic approaches showed significant positive associations of high admission BP with history of hypertension, admission hyperglycemia at least 6.5 mmol/l, elevated heart rate, and greater neurological severity (National Institutes of Health Stroke Scale scores); and significant negative associations with prior use of antithrombotic agents and longer time from onset to randomization. Conclusion: The high admission BP of mild-to-moderate acute ICH is related to autonomic nervous system activated ‘stress’ rather than hematoma location and mass effect

Determinants of the high admission blood pressure in mild-to-moderate acute intracerebral hemorrhage

Background and purpose: An early elevation in blood pressure (BP) is common after spontaneous intracerebral hemorrhage (ICH), has various potential causes, and is predictive of poor outcome. We aimed to determine the predictors of this phenomenon, in pooled analyses of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trials [INTERACT1 (n = 404) and INTERACT2 (n = 2829)]. Methods: INTERACT trials were international, open, blinded endpoint, randomized controlled trials of patients with spontaneous ICH (<6 h) and elevated SBP (150–220 mmHg) assigned to intensive (target SBP < 140 mmHg) or guideline-recommended (SBP < 180 mmHg) treatment. Multivariable linear and logistic regression models were used to determine associations between baseline variables and the high admission BP, with continuous and binary SBP measures, respectively. Results: Among 3233 patients (mean age 63 years; 37% female; baseline mean SBP 179 mmHg), both analytic approaches showed significant positive associations of high admission BP with history of hypertension, admission hyperglycemia at least 6.5 mmol/l, elevated heart rate, and greater neurological severity (National Institutes of Health Stroke Scale scores); and significant negative associations with prior use of antithrombotic agents and longer time from onset to randomization. Conclusion: The high admission BP of mild-to-moderate acute ICH is related to autonomic nervous system activated ‘stress’ rather than hematoma location and mass effect

Risks of recurrent stroke and all serious vascular events after spontaneous intracerebral haemorrhage: pooled analyses of two population-based studies

Background Patients with stroke due to spontaneous (non-traumatic) intracerebral haemorrhage (ICH) are at risk of recurrent ICH, ischaemic stroke, and other serious vascular events. We aimed to analyse these risks in population-based studies and compare them with the risks in RESTART, which assessed antiplatelet therapy after ICH. Methods We pooled individual patient data from two prospective, population-based inception cohort studies of all patients with an incident firs-in-a-lifetime ICH in Oxfordshire, England (Oxford Vascular Study; April 1, 2002, to Sept 28, 2018) and Lothian, Scotland, UK (Lothian Audit of the Treatment of Cerebral Haemorrhage; June 1, 2010, to May 31, 2013). We quantified the absolute and relative risks of recurrent ICH, ischaemic stroke, or any serious vascular event (non-fatal stroke, non-fatal myocardial infarction, or vascular death), stratified by ICH location (lobar vs non-lobar) and comorbid atrial fibrillation (AF). We compared pooled event rates with those after allocation to avoid antiplatelet therapy in RESTART. Findings Among 674 patients (mean age 74·7 years [SD 12·6], 320 [47%] men) with 1553 person-years of follow-up, 46 recurrent ICHs (event rate 3·2 per 100 patient-years, 95% CI 2·0–5·1) and 25 ischaemic strokes (1·7 per 100 patient-years, 0·8–3·3) were reported. Patients with lobar ICH (n=317) had higher risk of recurrent ICH (5·1 per 100 patient-years, 95% CI 3·6–7·2) than patients with non-lobar ICH (n=355; 1·8 per 100 patient-years, 1·0–3·3; hazard ratio [HR] 3·2, 95% CI 1·6–6·3; p=0·0010), but there was no evidence of a difference in the risk of ischaemic stroke (1·8 per 100 patient-years, 1·0–3·2, vs 1·6 per 100 patient-years, 0·6–4·4; HR 1·1, 95% CI 0·5–2·8). Conversely, there was no evidence of a difference in recurrent ICH rate in patients with AF (n=147; 3·3 per 100 patient-years, 95% CI 1·0–10·7) compared with those without (n=526; 3·2 per 100 patient-years, 2·2–4·7; HR 0·9, 95% CI 0·4–2·1), but the risk of ischaemic stroke was higher with AF (6·3 per 100 patient-years, 3·7–10·9, vs 0·7 per 100 patient-years, 0·1–5·6; HR 8·2, 3·3–20·3; p<0·0001), resulting in patients with AF having a higher risk of all serious vascular events than patients without AF (15·5 per 100 patient-years, 10·0–24·1, vs 6·8 per 100 patient-years, 3·6–12·5; HR 1·78, 95% CI 1·16–2·74; p=0·0090). Only for patients with lobar ICH without comorbid AF was the risk of recurrent ICH greater than the risk of ischaemic stroke (5·2 per 100 patient-years, 95% CI 3·6–7·5, vs 0·9 per 100 patient-years, 0·2–4·8; p=0·00034). Comparing data from the pooled population-based studies with that from patients allocated to not receive antiplatelet therapy in RESTART, there was no evidence of a difference in the rate of recurrent ICH (3·5 per 100 patient-years, 95% CI 1·9–6·0, vs 4·4 per 100 patient-years, 2·6–6·1) or ischaemic stroke (3·4 per 100 patient-years, 1·9–5·9, vs 5·3 per 100 patient-years, 3·3–7·2). Interpretation The risks of recurrent ICH, ischaemic stroke, and all serious vascular events after ICH differ by ICH location and comorbid AF. These data enable risk stratification of patients in clinical practice and ongoing randomised trials

Influence of Including Patients with Premorbid Disability in Acute Stroke Trials: The HeadPoST Experience.

BACKGROUND: Patients with premorbid functional impairment are generally excluded from acute stroke trials. We aimed to determine the impact of including such patients in the Head Positioning in acute Stroke Trial (HeadPoST) and early additional impairment on outcomes. METHODS: Post hoc analyses of HeadPoST, an international, cluster-randomized crossover trial of lying-flat versus sitting-up head positioning in acute stroke. Associations of early additional impairment, defined as change in modified Rankin scale (mRS) scores from premorbid levels (estimated at baseline) to Day 7 ("early ΔmRS"), and poor outcome (mRS score 3-6) at Day 90 were determined with generalized linear mixed model. Heterogeneity of the trial treatment effect was tested according to premorbid mRS scores 0-1 versus 2-5. RESULTS: Of 8,285 patients (38.9% female, mean age 68 ± 13 years) with complete data, there were 1,984 (23.9%) with premorbid functional impairment (mRS 2-5). A significant linear association was evident for early ∆mRS and poor outcome (per 1-point increase in ΔmRS, adjusted odds ratio 1.20, 95% confidence interval 1.14-1.27; p < 0.0001). Patients with greater premorbid functional impairment were less likely to develop additional impairment, but their risk of poor 90-day outcome significantly increased with increasing (worse) premorbid mRS scores (linear trend p < 0.0001). There was no heterogeneity of the trial treatment effect by level of premorbid function. CONCLUSIONS: Early poststroke functional impairment that exceeded premorbid levels was associated with worse 90-day outcome, and this association increased with greater premorbid functional impairment. Yet, including premorbid impaired patients in the HeadPoST did not materially affect the subsequent treatment effect. CLINICAL TRIAL REGISTRATION: HeadPoST is registered at http://www.ClinicalTrials.gov (NCT02162017)

The Magnitude of Blood Pressure Reduction Predicts Poor In-Hospital Outcome in Acute Intracerebral Hemorrhage

BACKGROUND: Early systolic blood pressure (SBP) reduction is believed to improve outcome after spontaneous intracerebral hemorrhage (ICH), but there has been a limited assessment of SBP trajectories in individual patients. We aimed to determine the prognostic significance of SBP trajectories in ICH. METHODS: We collected routine data on spontaneous ICH patients from two healthcare systems over 10 years. Unsupervised functional principal components analysis (FPCA) was used to characterize SBP trajectories over first 24 h and their relationship to the primary outcome of unfavorable shift on modified Rankin scale (mRS) at hospital discharge, categorized as an ordinal trichotomous variable (mRS 0-2, 3-4, and 5-6 defined as good, poor, and severe, respectively). Ordinal logistic regression models adjusted for baseline SBP and ICH volume were used to determine the prognostic significance of SBP trajectories. RESULTS: The 757 patients included in the study were 65 ± 23 years old, 56% were men, with a median (IQR) Glasgow come scale of 14 (8). FPCA revealed that mean SBP over 24 h and SBP reduction within the first 6 h accounted for 76.8% of the variation in SBP trajectories. An increase in SBP reduction (per 10 mmHg) was significantly associated with unfavorable outcomes defined as mRS \u3e 2 (adjusted-OR = 1.134; 95% CI 1.044-1.233, P = 0.003). Compared with SBP reduction \u3c 20 mmHg, worse outcomes were observed for SBP reduction = 40-60 mmHg (adjusted-OR = 1.940, 95% CI 1.129-3.353, P = 0.017) and \u3e 60 mmHg, (adjusted-OR = 1.965, 95% CI 1.011, 3.846, P = 0.047). Furthermore, the association of SBP reduction and outcome varied according to initial hematoma volume. Smaller SBP reduction was associated with good outcome (mRS 0-2) in small (\u3c 7.42 mL) and medium-size (≥ 7.42 and \u3c 30.47 mL) hematomas. Furthermore, while the likelihood of good outcome was low in those with large hematomas (≥ 30.47 mL), smaller SBP reduction was associated with decreasing probability of severe outcome (mRS 5-6). CONCLUSION: Our analyses suggest that in the first 6 h SBP reduction is significantly associated with the in-hospital outcome that varies with initial hematoma volume, and early SBP reduction \u3e 40 mmHg may be harmful in ICH patients. For early SBP reduction to have an effective therapeutic effect, both target levels and optimum SBP reduction goals vis-à-vis hematoma volume should be considered