Candice Delcourt

Rapid Blood-Pressure Lowering in Patients with Acute Intracerebral Hemorrhage

BACKGROUND Whether rapid lowering of elevated blood pressure would improve the outcome in patients with intracerebral hemorrhage is not known. METHODS We randomly assigned 2839 patients who had had a spontaneous intracerebral hemorrhage within the previous 6 hours and who had elevated systolic blood pressure to receive intensive treatment to lower their blood pressure (with a target systolic level of <140 mm Hg within 1 hour) or guideline-recommended treatment (with a target systolic level of <180 mm Hg) with the use of agents of the physicians choosing. The primary outcome was death or major disability, which was defined as a score of 3 to 6 on the modified Rankin scale (in which a score of 0 indicates no symptoms, a score of 5 indicates severe disability, and a score of 6 indicates death) at 90 days. A prespecified ordinal analysis of the modified Rankin score was also performed. The rate of serious adverse events was compared between the two groups. RESULTS Among the 2794 participants for whom the primary outcome could be determined, 719 of 1382 participants (52.0%) receiving intensive treatment, as compared with 785 of 1412 (55.6%) receiving guideline-recommended treatment, had a primary outcome event (odds ratio with intensive treatment, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P=0.06). The ordinal analysis showed significantly lower modified Rankin scores with intensive treatment (odds ratio for greater disability, 0.87; 95% CI, 0.77 to 1.00; P=0.04). Mortality was 11.9% in the group receiving intensive treatment and 12.0% in the group receiving guideline-recommended treatment. Nonfatal serious adverse events occurred in 23.3% and 23.6% of the patients in the two groups, respectively. CONCLUSIONS In patients with intracerebral hemorrhage, intensive lowering of blood pressure did not result in a significant reduction in the rate of the primary outcome of death or severe disability. An ordinal analysis of modified Rankin scores indicated improved functional outcomes with intensive lowering of blood pressure. (Funded by the National Health and Medical Research Council of Australia; INTERACT2 ClinicalTrials.gov number, NCT00716079.).

The Second (Main) Phase of an Open, Randomised, Multicentre Study to Investigate the Effectiveness of an Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (Interact2)

Rationale: The INTERACT pilot study demonstrated the feasibility of the protocol, safety of early intensive blood pressure lowering and effects on haematoma expansion within 6h of onset of intracerebral haemorrhage. This article describes the design of the second, main phase, INTERACT2. Aims: To compare the effects of a management strategy of early intensive blood pressure lowering with a more conservative guideline-based blood pressure management policy in patients with acute intracerebral hemorrhage. Design: INTERACT2 is a prospective, randomized, open label, assessor-blinded end-point (PROBE). Patients with a systolic blood pressure greater than 150 mmHg and no definite indication for or contraindication to blood pressure-lowering treatment are centrally randomised to either of two treatment groups within 6h onset of intracerebral haemorrhage. Those allocated to intensive blood pressure lowering will receive primarily intravenous, hypotensive agents to achieve a systolic blood pressure target of <140 mmHg within 1 h of randomisation and to maintain this level for up to 7 days in hospital. The control group will receive blood pressure-lowering treatment to a target systolic blood pressure of < 180 mmHg. Both groups are to receive similar acute stroke unit care, therapy and active management. Oral antihypertensive therapy is recommended in patients before hospital discharge with a long-term systolic blood pressure goal of 140 mmHg according to secondary stroke prevention guidelines. A projected 2800 subjects are to be enrolled from approximately 140 centres worldwide to provide 90% power (α 0·05) to detect a 14% difference in the risk of death and dependency between the groups, which equates to one or more cases of a poor outcome prevented in every 15 patients treated. Study outcomes: The primary outcome is the combined end-point of death and dependency according to the modified Rankin Scale at 90 days. The secondary outcomes are the separate components of the primary end-point in patients treated <4 hours of ICH onset, grades of physical function on the modified Rankin Scale, health-related quality of life on the EuroQoL, recurrent stroke and other vascular events, days of hospitalisation, requirement for permanent residential care and unexpected serious adverse events. The study is registered under NCT00716079, ISRCTN73916115 and ACTRN12608000362392.

Blood pressure variability and outcome after acute intracerebral haemorrhage: a post-hoc analysis of INTERACT2, a randomised controlled trial

BACKGROUND High blood pressure is a prognostic factor for acute stroke, but blood pressure variability might also independently predict outcome. We assessed the prognostic value of blood pressure variability in participants of INTERACT2, an open-label randomised controlled trial (ClinicalTrials.gov number NCT00716079). METHODS INTERACT2 enrolled 2839 adults with spontaneous intracerebral haemorrhage (ICH) and high systolic blood pressure (150-220 mm Hg) without a definite indication or contraindication to early intensive treatment to reduce blood pressure. Participants were randomly assigned to intensive treatment (target systolic blood pressure <140 mm Hg within 1 h using locally available intravenous drugs) or guideline-recommended treatment (target systolic blood pressure <180 mm Hg) within 6 h of onset of ICH. The primary outcome was death or major disability at 90 days (modified Rankin Scale score ≥3) and the secondary outcome was an ordinal shift in modified Rankin Scale scores at 90 days, assessed by investigators masked to treatment allocation. Blood pressure variability was defined according to standard criteria: five measurements were taken in the first 24 h (hyperacute phase) and 12 over days 2-7 (acute phase). We estimated associations between blood pressure variability and outcomes with logistic and proportional odds regression models. The key parameter for blood pressure variability was standard deviation (SD) of systolic blood pressure, categorised into quintiles. FINDINGS We studied 2645 (93·2%) participants in the hyperacute phase and 2347 (82·7%) in the acute phase. In both treatment cohorts combined, SD of systolic blood pressure had a significant linear association with the primary outcome for both the hyperacute phase (highest quintile adjusted OR 1·41, 95% CI 1·05-1·90; ptrend=0·0167) and the acute phase (highest quintile adjusted OR 1·57, 95% CI 1·14-2·17; ptrend=0·0124). The strongest predictors of outcome were maximum systolic blood pressure in the hyperacute phase and SD of systolic blood pressure in the acute phase. Associations were similar for the secondary outcome (for the hyperacute phase, highest quintile adjusted OR 1·43, 95% CI 1·14-1·80; ptrend=0·0014; for the acute phase OR 1·46, 95% CI 1·13-1·88; ptrend=0·0044). INTERPRETATION Systolic blood pressure variability seems to predict a poor outcome in patients with acute intracerebral haemorrhage. The benefits of early treatment to reduce systolic blood pressure to 140 mm Hg might be enhanced by smooth and sustained control, and particularly by avoiding peaks in systolic blood pressure. FUNDING National Health and Medical Research Council of Australia.

Hematoma growth and outcomes in intracerebral hemorrhage The INTERACT1 study

Objective: Uncertainty exists over the size of potential beneficial effects of medical treatments targeting hematoma growth in intracerebral hemorrhage (ICH). We report associations of hematoma growth parameters on clinical outcomes in the pilot phase, Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT1) (ClinicalTrials.gov NCT00226096). Methods: In randomized patients with both baseline and 24-hour brain CT (n = 335), associations between measures of absolute and relative hematoma growth and 90-day poor outcomes of death and dependency (modified Rankin Scale score 3–5) were assessed in logistic regression models, with data reported as odds ratios (OR) and 95% confidence intervals (CI). Results: A total of 10.7 mL (1 SD) increase in hematoma volume over 24 hours was strongly associated with poor outcome (adjusted OR 1.72, 95% CI 1.19–2.49; p = 0.004). An association was also evident for relative growth (adjusted OR 1.67, 95% 1.22–2.27; p = 0.001 for 1 SD increase). The analyses were adjusted for age, sex, achieved systolic blood pressure, elevated NIH Stroke Scale score (≥14), hematoma location, baseline hematoma volume, intraventricular extension, antithrombotic therapy, baseline glucose, time from ICH to baseline CT scan, and time from baseline to repeat CT scan. A 1 mL increase in hematoma growth was associated with a 5% (95% CI 2%–9%) higher risk of death or dependency. Conclusion: Medical treatments, such as rapid intensive blood pressure lowering, could achieve ∼2–4 mL absolute attenuation of hematoma growth. There is hope that this could translate into modest but still clinically worthwhile (∼10%–20% better chance) outcome from ICH.

Prognostic Significance of Perihematomal Edema in Acute Intracerebral Hemorrhage Pooled Analysis From the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial Studies

Background and Purpose— Controversy exists over the prognostic significance of perihematomal edema (PHE) in intracerebral hemorrhage. We aimed to determine the association of early PHE and clinical outcome among participants of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT) studies. Methods— Pooled analyses of computed tomographic substudies in the pilot phase (INTERACT1) and main phase (INTERACT2), both international, prospective, open, blinded end point, randomized controlled trials, of patients with spontaneous intracerebral hemorrhage (<6 hours) and elevated systolic blood pressure, randomly assigned to intensive (target systolic blood pressure, <140 mm Hg) or guideline-based (systolic blood pressure, <180 mm Hg) blood-pressure management. Substudy participants (n=1310; 346 INTERACT1, 964 INTERACT2) had blinded central analyses of digital images from standardized baseline and 24-hour computed tomography. Predictors of death or dependency (modified Rankin scale scores, ≥3) at 90 days were assessed in logistic regression models and reported with odds ratios and 95% confidence intervals. INTERACT studies are registered at ClinicalTrials.gov (NCT00226096 and NCT00716079). Results— Of 1138 (87%) patients with 2 CTs available for edema analysis and outcome information, time from intracerebral hemorrhage onset to baseline computed tomography, baseline hematoma volume, 24-hour hematoma growth, and intraventricular extension were independent predictors of 24-hour PHE growth. Absolute growth in PHE volume was significantly associated with death or dependency (adjusted odds ratio, 1.17; 95% confidence interval, 1.02–1.33 per 5 mL increase from baseline; P=0.025) at 90 days after adjustment for demographic, clinical, and hematoma parameter prognostic factors. Associations were consistent across various sensitivity analyses. Conclusion— PHE growth is an independent prognostic factor in intracerebral hemorrhage. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00226096 and NCT00716079.

The Spot Sign and Tranexamic Acid on Preventing ICH Growth – AUStralasia Trial (STOP-AUST): Protocol of a Phase II Randomized, Placebo-Controlled, Double-Blind, Multicenter Trial

Rationale No evidence-based acute therapies exist for intracerebral hemorrhage. Intracerebral hemorrhage growth is an important determinant of patient outcome. Tranexamic acid is known to reduce hemorrhage in other conditions. Aim The study aims to test the hypothesis that intracerebral hemorrhage patients selected with computed tomography angiography contrast extravasation ‘spot sign’ will have lower rates of hematoma growth when treated with intravenous tranexamic acid within 4·5-hours of stroke onset compared with placebo. Design The Spot sign and Tranexamic acid On Preventing ICH growth – AUStralasia Trial is a multicenter, prospective, 1:1 randomized, double-blind, placebo-controlled, investigator-initiated, academic Phase II trial. Intracerebral hemorrhage patients fulfilling clinical criteria (e.g. Glasgow Coma Scale >7, intracerebral hemorrhage volume <70 ml, no identified secondary cause of intracerebral hemorrhage, no thrombotic events within the previous 12 months, no planned surgery) and demonstrating contrast extravasation on computed tomography angiography will receive either intravenous tranexamic acid 1 g 10-min bolus followed by 1 g eight-hour infusion or placebo. A second computed tomography will be performed at 24 ± 3 hours to evaluate intracerebral hemorrhage growth and patients followed up for three-months. Study outcomes The primary outcome measure is presence of intracerebral hemorrhage growth by 24 ± 3 hours, defined as either >33% or >6 ml increase from baseline, and will be adjusted for baseline intracerebral hemorrhage volume. Secondary outcome measures include growth as a continuous measure, thromboembolic events, and the three-month modified Rankin Scale score. Discussion This is the first trial to evaluate the efficacy of tranexamic acid in intracerebral hemorrhage patients selected based on an imaging biomarker of high likelihood of hematoma growth. The trial is registered as NCT01702636.

Optimal achieved blood pressure in acute intracerebral hemorrhage INTERACT2

Objectives: To investigate the effects of intensive blood pressure (BP) lowering according to baseline BP levels and optimal achieved BP levels in patients with acute intracerebral hemorrhage (ICH). Methods: INTERACT2 was an open, blinded endpoint, randomized controlled trial in 2,839 patients with ICH within 6 hours of onset and elevated systolic BP (SBP) (150–220 mm Hg) who were allocated to receive intensive (target SBP <140 mm Hg within 1 hour, with lower limit of 130 mm Hg for treatment cessation) or guideline-recommended (target SBP <180 mm Hg) BP-lowering treatment. Outcome was physical function across all 7 levels of the modified Rankin Scale at 90 days. Results: Analysis of the randomized comparisons showed that intensive BP lowering produced comparable benefits on physical function at 90 days in 5 subgroups defined by baseline SBP of <160, 160–169, 170–179, 180–189, and ≥190 mm Hg (p homogeneity = 0.790). Analyses of achieved BP showed linear increases in the risk of physical dysfunction for achieved SBP above 130 mm Hg for both hyperacute (1–24 hours) and acute (2–7 days) phases while modest increases were also observed for achieved SBP below 130 mm Hg. Conclusions: Intensive BP lowering appears beneficial across a wide range of baseline SBP levels, and target SBP level of 130–139 mm Hg is likely to provide maximum benefit in acute ICH. Classification of evidence: This study provides Class I evidence that the effect of intensive BP lowering on physical function is not influenced by baseline BP.

Clinical Prediction Algorithm (BRAIN) to Determine Risk of Hematoma Growth in Acute Intracerebral Hemorrhage

Background and Purpose— We developed and validated a simple algorithm to predict the risk of hematoma growth in acute spontaneous intracerebral hemorrhage (ICH) to better inform clinicians and researchers in their efforts to improve outcomes for patients. Methods— We analyzed data from the computed tomography substudies of the pilot and main phases of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trials (INTERACT1 and 2, respectively). The study group was divided into a derivation cohort (INTERACT2, n=964) and a validation cohort (INTERACT1, n=346). Multivariable logistic regression was used to identify factors associated with clinically significant (≥6 mL) increase in hematoma volume at 24 hours after symptom onset. A parsimonious risk score was developed on the basis of regression coefficients derived from the logistic model. Results— A 24-point BRAIN score was derived from INTERACT2 (C-statistic, 0.73) based on baseline ICH volume (mL per score, ⩽10=0, 10–20=5, >20=7), recurrent ICH (yes=4), anticoagulation with warfarin at symptom onset (yes=6), intraventricular extension (yes=2), and number of hours to baseline computed tomography from symptom onset (⩽1=5, 1–2=4, 2–3=3, 3–4=2, 4–5=1, >5=0) predicted the probability of ICH growth (ranging from 3.4% for 0 point to 85.8% for 24 points) with good discrimination (C-statistic, 0.73) and calibration (Hosmer–Lemeshow P=0.82) in INTERACT1. Conclusions— The simple BRAIN score predicts the probability of hematoma growth in ICH. This could be used to improve risk stratification for research and clinical practice. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00226096 and NCT00716079.

Earlier Blood Pressure-Lowering and Greater Attenuation of Hematoma Growth in Acute Intracerebral Hemorrhage INTERACT Pilot Phase

Background and Purpose— The INTEnsive blood pressure Reduction in Acute Cerebral hemorrhage Trial (INTERACT) pilot study showed that early intensive blood pressure-lowering can attenuate hematoma growth in acute intracerebral hemorrhage. The present analysis aimed to determine the treatment effects on hematoma growth by time from intracerebral hemorrhage onset to randomization. Methods— Patients (N=404) with acute intracerebral hemorrhage and elevated systolic blood pressure were randomly assigned to intensive or guideline-based blood pressure management. Baseline and repeat CT (24 and 72 hours) were performed and changes in hematoma volume were assessed using generalized estimating equations. Results— Among 296 patients with all 3 CT scans available for analysis, reductions in proportional hematoma growth produced by randomized intensive blood pressure-lowering treatment over 72 hours decreased progressively with delays in initiation of study treatment: 22%, 17%, 9%, and 3% for quartile groups defined by time from onset to randomization of <2.9, 2.9 to 3.6, 3.7 to 4.8, and ≥4.9 hours, respectively (P trend=0.001). There were also smaller absolute reductions in hematoma growth with delays in initiation of study treatment (6.5 mL, 3.3 mL, 0.9 mL, and 0.6 mL), although the trend did not reach statistical significance (P trend=0.12). Conclusions— Earlier initiation of intensive blood pressure-lowering treatment is likely to provide greater protection against hematoma growth in acute intracerebral hemorrhage. Clinical Trial Registration Information— http://www.clinicaltrials.gov, NCT002226096.

Determinants of quality of life after stroke in China: the ChinaQUEST (QUality Evaluation of Stroke care and Treatment) study

Background and Purpose— Limited information exists on the long-term consequences of stroke in China. We aimed to describe the profile and determinants of health-related quality of life among 12-month survivors of stroke. Methods— The ChinaQUEST (QUality Evaluation of Stroke care and Treatment) study was a prospective 62-hospital registry study of patients with acute stroke (ischemic stroke and intracerebral hemorrhage). Health-related quality of life was determined in 12-month survivors using a 35-item quality-of-life questionnaire (QOL-35) designed specifically for use in Chinese people. Proxy responses were used in those who were unable to personally complete the QOL-35. Results— A total of 4283 12-month stroke survivors completed assessments directly (1730 [40.4%]) or by a proxy (2553 [59.6%]). Mean (SD) health-related quality of life scores were higher in self-responders (70 [0.3] out of a best possible 100 score) than in proxy responders (60 [0.3]; P<0.001). The strongest baseline variables that predicted “low” (below median) health-related quality of life scores in self-responders were having a lower income (income <10 000 Chinese Yuan Renminbi [CNY, approximately US