Mannitol is frequently used in the management of patients

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1 Mannitol and Outcome in Intracerebral Hemorrhage Propensity Score and Multivariable Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2 Results Xia Wang, MMed; Hisatomi Arima, MD, PhD; Jie Yang, MD, PhD; Shihong Zhang, MD; Guojun Wu, MD; Mark Woodward, PhD; Paula Muñoz-Venturelli, MD; Pablo M. Lavados, MD; Christian Stapf, MD; Thompson Robinson, MD; Emma Heeley, PhD; Candice Delcourt, MD; Richard I. Lindley, MD; Mark Parsons, MD, PhD; John Chalmers, MD, PhD; Craig S. Anderson, MD, PhD; for the INTERACT2 Investigators* Downloaded from by guest on June 17, 2018 Background and Purpose Mannitol is often used to reduce cerebral edema in acute intracerebral hemorrhage but without strong supporting evidence of benefit. We aimed to determine the impact of mannitol on outcome among participants of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2). Methods INTERACT2 was an international, open, blinded end point, randomized controlled trial of 2839 patients with spontaneous intracerebral hemorrhage (<6 hours) and elevated systolic blood pressure allocated to intensive (target systolic blood pressure, <140 mm Hg within 1 hour) or guideline-recommended (target systolic blood pressure, <180 mm Hg) blood pressure lowering treatment. Propensity score and multivariable analyses were performed to investigate the relationship between mannitol treatment (within 7 days) and poor outcome, defined by death or major disability on the modified Rankin Scale score (3 6) at 90 days. Results There was no significant difference in poor outcome between mannitol (n=1533) and nonmannitol (n=993) groups: propensity score matched odds ratio of 0.90 (95% confidence interval, ; P=0.30) and multivariable odds ratio of 0.87 (95% confidence interval, ; P=0.18). Although a better outcome was suggested in patients with larger ( 15 ml) than those with smaller (<15 ml) baseline hematomas who received mannitol (odds ratio, 0.52 [95% confidence interval, ] versus odds ratio, 0.91 [95% confidence interval, ]; P homogeneity <0.03 in propensity score analyses), the association was not consistent in analyses across other cutoff points ( 10 and 20 ml) and for differing grades of neurological severity. Mannitol was not associated with excess serious adverse events. Conclusions Mannitol seems safe but might not improve outcome in patients with acute intracerebral hemorrhage. Clinical Trial Registration URL: Unique identifier: NCT (Stroke. 2015;46: DOI: /STROKEAHA ) Key Words: blood pressure cerebral hemorrhage clinical trial mannitol propensity score Mannitol is frequently used in the management of patients with spontaneous intracerebral hemorrhage (ICH), 1 particularly in China 2 and India. 3 It is an intravascular osmostic agent that establishes an osmotic gradient between plasma and neurons, thereby drawing water from the cerebral extracellular space into the vasculature to reduce cerebral edema. 4 Mannitol also increases cardiac preload and cerebral perfusion pressure, which contributes to a decrease in intracranial pressure through cerebral vasoreactivity. Although guidelines recommend using mannitol where there is increased intracranial pressure in ICH, 5 uncertainty exists over the magnitude of potential benefit, with various observational studies, 6,7 clinical Received March 7, 2015; final revision received June 17, 2015; accepted July 10, From The George Institute for Global Health, School of Public Health, the University of Sydney, Sydney, Australia (X.W., H.A., M.W., P.M.-V., E.H., C.D., R.I.L., J.C., C.S.A.); Neurology Department, Royal Prince Alfred Hospital, Sydney, Australia (C.D., C.S.A.); Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China (J.Y.); Department of Neurology, West China Hospital, Sichuan University, Chengdu, China (S.Z.); Department of Neurology, Hebei Yutian Hospital, Tangshan, China (G.W.); Servicio de Neurología, Departamento de Medicina Clínica Alemana, Universidad del Desarrollo, Santiago, Chile (P.M.-V., P.M.L.); Departamento de Ciencias Neurológicas, Universidad de Chile, Santiago, Chile (P.M.L.); Department of Neurology, APHP-Hôpital Lariboisière and DHU NeuroVasc Paris-Sorbonne, Université Paris Diderot-Sorbonne Paris Cité, Paris, France (C.S.); Department of Cardiovascular Sciences and NIHR Biomedical Research Unit in Cardiovascular Disease, University of Leicester, Leicester, United Kingdom (T.R.); Department of Medicine, Westmead Hospital Clinical School, Westmead, New South Wales, Australia (R.I.L.); and Department of Neurology, John Hunter Hospital, and Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia (M.P.). *For a full list of INTERACT2 Investigators, see reference 11. The online-only Data Supplement is available with this article at /-/DC1. Correspondence to Craig S. Anderson, MD, PhD, The George Institute for Global Health, PO Box M201, Missenden Rd, NSW 2050, Australia. canderson@georgeinstitute.org.au 2015 American Heart Association, Inc. Stroke is available at DOI: /STROKEAHA

2 Wang et al Mannitol and Cerebral Hemorrhage 2763 Downloaded from by guest on June 17, 2018 trials, 8,9 and a systematic review, 10 unable to provide evidence of a clear treatment effect of mannitol in acute ICH. The present analysis aimed to determine the impact of use of mannitol on clinical outcome in patients with acute ICH who participated in the main phase Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2). Our hypothesis was that mannitol would improve outcome in patients with more severe ICH. Methods Study Design Details of the INTERACT2 study have been described elsewhere. 11,12 In summary, this was an international, multicenter, open, blinded end point assessed, randomized controlled trial, that involved 2839 adult patients with computed tomography-confirmed spontaneous ICH within 6 hours of onset and elevated systolic blood pressure (SBP, mm Hg) randomly assigned to receive intensive (SBP <140 mm Hg within 1 hour) or guideline-recommended (SBP <180 mm Hg) BP-lowering therapy. Exclusion criteria included a clear indication for, or contraindication to intensive BP lowering; low likelihood of benefit because of severe illness, comorbid condition, or high likelihood of death; and early planned surgical intervention. The study protocol was approved by the appropriate ethics committee at each participating site, and written informed consent was obtained from the patient or an appropriate surrogate. Procedures and Outcomes Patients allocated to the intensive BP-lowering group commenced a standardized treatment regime involving intravenous and later oral agents, with the goal of achieving a SBP target of <140 mm Hg within 1 hour and to maintain this level for 7 days in hospital. Specific treatment protocols were developed for each participating region/site, based on the availability of BP-lowering agents for routine use. For patients allocated to the guideline group, BP-lowering treatment was recommended to achieve a target SBP of 180 mm Hg. Data on any use of mannitol within 7 days of ICH were collected. The primary outcome was death or major disability (defined as a score of 3 6 on the modified Rankin Scale) 13 at 90 days. Secondary outcomes were major disability and death (modified Rankin Scale scores of 3 5, and 6, respectively) at 90 days. The outcome assessment was undertaken by a site investigator, who was not involved in the clinical management of the patient and blind to the randomized treatment allocation. 12 Statistical Analysis Because of significant variability in baseline covariates between patients treated with and without mannitol, we used propensity scores (PS) analyses and multivariable models to reduce imbalance. Predictors of mannitol treatment and the primary outcome among the baseline characteristics of participants were determined by a χ 2 test for binary measures, t test for approximately normally distributed variables, and Wilcoxon signed-rank test for skewed continuous variables. A multivariable logistic regression model, including all univariate significant predictors of mannitol treatment and the primary outcome, and other clinically important factors (sex and randomized BP-lowering treatment), was constructed to produce estimates of the treatment effect of mannitol (Tables I and II in the online-only Data Supplement). 14,15 On the basis of coefficients from this model, we generated a PS 14,16 for each patient. Only patients with complete data were included in the analyses to maximize balancing of the PS analysis with the largest number of variables and to avoid the need to impute data. As the variable, China region (for patient recruitment) was both associated with mannitol treatment and the primary outcome; it was not included in the PS building model because it was so closely matched with mannitol use as to be insensitive as a discriminator of mannitol-related outcomes. Various methods were used to account for the nonrandom allocation of mannitol to show consistency of the results. We used optimal matching 1:1 without replacement, with an initial caliper width matching algorithm that equates to 0.19 (20% of the SD of the logit of the PS). 14 A smaller caliper of 0.1 was also used to potentially provide better balancing of covariate imbalances. Generalized estimating equations were used to test the effect of mannitol on primary and secondary outcomes, accounting for matching in the PS-matched subpopulation. 15 We next estimated the impact of mannitol using inverse probability of treatment weighting (IPTW). Stabilized weights were used to reduce variance of the estimated effect of mannitol and were incorporated into a logistic regression model that only included the mannitol variable. 17 We also conducted an analysis that was stratified across fifths of the PS. A summary estimate was calculated using unadjusted logistic regression stratified by PS strata. 17 Finally, PS was used as a covariate in the logistic model to assess the impact of mannitol treatment. Effects of mannitol on outcomes were also estimated in multivariable logistic regression models with the same covariates as PS. The model was further adjusted by significant medical and surgical treatment factors at 7 days (admission to an intensive care unit, prophylactic treatment for deep venous thrombosis, hemostatic therapy, and any surgical intervention) to reduce management bias. Subgroup analyses were also undertaken by key demographic variables (age <65 versus 65 years; sex) and clinical severity (defined by baseline hematoma volume <15 versus 15 ml; and National Institutes of Health Stroke Scale [NIHSS] scores <15 versus 15 points). Consistency of any association of mannitol and outcome according to severity of ICH was assessed in sensitivity analyses using lower (<10 versus 10 ml) and higher (<20 versus 20 ml) cutoff points for ICH volume and at lower (<10 versus 10) and higher (<20 versus 20) NIHSS score thresholds for stroke severity. We assessed the heterogeneity of association in subgroups by adding an interaction term in the models. As it was not possible to adjust for China region in analyses because of manniol use in these participants, the data were stratified by China and non-china region to assess the consistency of any association in these broadly different populations using the same PS and multivariable modeling approaches. However, we were not able to adjust for unaccounted bias, including differences in background care. Thus, we used the modified ICH score, 18 which has been shown to provide high discrimination for 90-day poor outcome when compared with other popular prognostic scales, 19 to help interpreting this comparison. Data were presented with odds ratios (ORs) and 95% confidence intervals (CI). A 2-sided P<0.05 was set as the level for statistical significance. All statistical analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC). Results After excluding patients with missing data on the outcome or any covariates, 2526 (89%) patients were included in these analyses. A total of 1678 patients (839 mannitol users and 839 nonmannitol users) were PS matched. Table 1 shows the baseline characteristics of patients according to mannitol use; with all baseline variables included in the multivariable model to generate PS. Table 1 also shows improved balance in the distribution of covariates by mannitol use in the PS-matched and IPTW subpopulations. However, the 2 groups of patients were treated differently over the first 7 days post randomization, and the medical and surgical treatment variables were not evenly distributed in PS analyses. The distribution of PS is shown in Figure I in the online-only Data Supplement. Table 2 shows significantly fewer serious adverse events over 90 days in mannitol-treated patients. There were 775 (50.6%) patients in the mannitol treatment group than 566 (57%) of those in the nonmannitol treatment group, who were dead or had major disability at 90 days (crude OR, 0.77; 95%

3 2764 Stroke October 2015 Table 1. Distribution of Patient Characteristics by Mannitol Treatment in Overall, PS-Matched, and IPTW Populations Downloaded from by guest on June 17, 2018 Nonmannitol (n=993) Overall PS Matched IPTW* Mannitol (n=1533) Nonmannitol (n=839) Mannitol (n=839) Nonmannitol (n=993) Mannitol (n=1533) Demographic Age, y 67 (13) 61 (12)* 66 (13) 64 (13) 63.0 (15) 64.0 (12) Male 612 (62) 952 (62) 520 (62) 504 (60) (63) (62) Clinical features NIHSS (30) 421 (28) 244 (29) 237 (28) (29) (29) Time to randomization, h 3.6 ( ) 3.8 ( ) 3.6 ( ) 3.8 ( ) 3.8 ( ) 3.7 ( ) Systolic BP, mm Hg 179 (17) 179 (17) 179 (17) 179 (17) (19.1) (15.2) Prior intracerebral hemorrhage 65 (7) 134 (9) 61 (7) 71 (9) 99.3 (8) 96.0 (8) Prior ischemic/undifferentiated stroke 89 (9) 197 (13) 76 (9) 77 (9) (12) (11) Heart disease 160 (16) 114 (7) 86 (10) 79 (9) (11) (12) Diabetes mellitus 153 (15) 121 (8) 105 (13) 80 (10) (11) (13) Antihypertensive therapy 533 (54) 605 (40) 399 (48) 359 (43) (46) (47) Use of warfarin anticoagulation/aspirin 224 (23) 85 (6) 97 (12) 76 (9) (12) (14) Use of statin/other lipid-lowering agent 147 (15) 39 (3) 52 (6) 38 (5) 93.0 (7) (9) Deep location of hematoma 820 (83) 1295 (85) 690 (82) 697 (83) (83) (83) Left hemisphere site of hematoma 493 (50) 779 (51) 424 (51) 414 (49) (50) (51) Hematoma volume at baseline, ml 8.9 ( ) 12.1 ( ) 9.3 ( ) 10.3 ( ) 10.3 ( ) 10.8 ( ) Intraventricular extension 274 (28) 422 (28) 234 (28) 244 (29) (28) (28) Randomized intensive BP lowering 504 (51) 765 (50) 434 (52) 428 (51) (50) (50) Medical and surgical treatment Intubation 67 (7) 108 (7) 58 (7) 57 (7) (8) 94.9 (8) Admission to an intensive care unit 297 (30) 660 (43) 266 (32) 373 (45) (33) (45) Thromboembolism prophylaxis 503 (51) 72 (5) 398 (47) 45 (5) (48) 99.4 (8) Hemostatic therapy 56 (6) 32 (2) 31 (4) 18 (2) 48.5 (4) 28.5 (2) Any surgical intervention 37 (4) 105 (7) 31 (4) 55 (7) 51.6 (4) 84.3 (7) Withdraw active care 58 (6) 53 (4) 45 (5) 31 (4) 60.6 (5) 47.4 (4) Data are n (%), mean (SD), or median (interquartile range). BP indicates blood pressure; IPTW, inverse probability of treatment weighting; NIHSS, National Institutes of Health stroke scale; and PS, propensity score. *Synthetic n values derived from weights. P<0.05. Deep location refers to location in the basal ganglia or thalamus. The use of fresh frozen plasma, vitamin K, and recombinant tissue factor VIIa. CI, ; P<0.01; Figure 1). However, the association was no longer significant after adjustment for baseline imbalances (OR, 0.87; 95% CI, ; P=0.18), and further with the addition of treatment imbalances (OR, 1.02; 95% CI, ; P=0.86). These neutral results were confirmed by PS analyses: matching (OR, 0.90; 95% CI, ; P=0.30), IPTW (OR, 0.97; 95% CI, ; P=0.72), summary stratified (OR, 0.91; 95% CI, ; P=0.30), and covariate adjustment using PS (OR, 0.92; 95% CI, ; P=0.35). The PS-matched analysis with the smaller caliper of 0.10 showed a similar result (OR, 0.89; 95% CI, ; P=0.26). There was no association with the separate outcomes of death and major disability (data on request) and no heterogeneity according to sex and age (Figures II and III in the online-only Data Supplement, respectively). Our primary subgroup analysis by severity of ICH showed an association of mannitol and reduced poor outcome in patients with larger ( 15 ml) when compared with smaller (<15 ml) hematomas (OR, 0.52; 95% CI, versus OR, 0.91; 95% CI, ; P homogeneity 0.02 in PS-matched analysis; Figure 2). The association was also significant in IPTW, summary stratified, and covariate adjustment using PS analyses, but not either in multivariable-adjusted analyses or in other sensitivity analyses of different cutoff points (10 and 20 ml; Tables III and IV in the online-only Data Supplement, respectively), despite favorable trends in the point estimates. Associations for mannitol use by degree of neurological impairment were not consistent across analyses: whereas a better outcome was seen for mannitol use in those with greater clinical severity (NIHSS 15) in PS-matched analysis, summary stratified, and covariate adjustment using PS analyses (all P heterogeneity P<0.05), no significant heterogeneity was evident in the adjusted models, IPTW, and also in other sensitivity analyses of different cutoff points (10 and 20; Figure 3, Tables V and VI in the onlineonly Data Supplement, respectively). Moreover, subgroup

4 Wang et al Mannitol and Cerebral Hemorrhage 2765 Downloaded from by guest on June 17, 2018 Table 2. Safety Outcomes by Mannitol Treatment Nonmannitol (n=993) Mannitol (n=1533) P Value Neurological deterioration in first 24 h 161 (16) 216 (14) 0.12 Non-fatal serious adverse events* 312 (31) 295 (19) <0.01 Direct effects of the primary ICH event 31 (3) 60 (4) Cardiovascular disease 44 (4) 26 (2) Recurrent ICH 2 (0.2) 5 (0.5) Ischemic or undifferentiated stroke 10 (1) 4 (0.4) Acute coronary event 4 (0.4) 3 (0.3) Other cardiovascular disease 30 (3) 15 (1) Noncardiovascular disease 136 (14) 150 (10) Renal failure 7 (1) 5 (0.5) Respiratory infections 53 (5) 48 (3) Sepsis (includes other infections) 28 (3) 10 (1) Nonvascular medical 44 (4) 17 (1) Data are numbers (%). ICH indicates intracerebral hemorrhage. *One patient could have >1 event. analyses of patients with both large hematomas ( 15 ml) and greater clinical severity (NIHSS 15) and of younger patients (age <65 years) with either large hematoma (volume 15 ml) or more severe (NIHSS 15) showed no clear association of mannitol and outcome (Tables VII IX in the online-only Data Supplement, respectively). Analysis of patients recruited from China (Table X in the online-only Data Supplement) showed a similar neutral association of mannitol and outcome as seen for the whole population. However, use of mannitol was associated with an increased risk of death or major disability in non-chinese patients (Table XI in the online-only Data Supplement). There was no association in Chinese patients with larger ICH (Table XII in the online-only Data Supplement). The disparities in associations between Chinese and non-chinese patients might be explained by differences in characteristics, management, and prognosis that were not fully accounted for in analyses (Tables XIII XV in the online-only Data Supplement), which was supported by a lower proportion of poor outcome in Chinese patients with the same baseline modified ICH score as in non-chinese patients (Table XVI in the online-only Data Supplement). Discussion This is the largest study to investigate the impact of mannitol in patients with acute ICH. Overall, there was no significant difference in frequency of the conventional poor outcome of death or major disability at 90 days between mannitol and non mannitol-treated patients independent of other prognostic factors assessed across a variety of analyses that took account of significant imbalances in baseline and management covariates. Although there was an apparent benefit of mannitol in patients with larger hematomas ( 15 ml), this was not consistent in analyses across other cutoff points ( 10 and 20 ml) and for differing grades of neurological impairment (NIHSS score cut points of 10, 15, and 20). Moreover, the impact of mannitol was not consistent between Chinese and non-chinese patients, but this could be because of other diseases and management factors because patients with similar predicted prognosis had different outcomes between the 2 groups. Finally, there was no evidence that mannitol use was associated with any clear harms such as an increase in renal or cardiac complications, or of neurological deterioration, that may have occurred from rebound intracranial hypertension Few studies have investigated the effects of mannitol in acute ICH. An observational study 6 of 111 consecutive patients within 72 hours of ICH found no association of mannitol on survival. Similarly, 2 small randomized controlled trials of 21 ICH patients with medium- or small-sized hematomas, 8 and Figure 1. Association of mannitol treatment on death or major disability at 90 days. Solid boxes represent estimates of treatment effect on the risk of outcomes. Centers of boxes are placed at the estimates of the effect; areas of the boxes are proportional to the reciprocal of the variance of the estimates. Horizontal lines represent 95% confidence intervals (CIs). Adjusted model 1: adjusted by age, sex, National Institutes of Health Stroke Scale 15, time to randomization, systolic blood pressure (BP), prior intracerebral hemorrhage, prior ischemic or undifferentiated stroke, heart disease, diabetes mellitus, current use of antihypertensive therapy, use of warfarin anticoagulation or aspirin, use of statin or other lipid-lowering agent, deep location of hematoma, left hemisphere site of hematoma, log-transformed baseline hematoma volume, intraventricular extension, and randomized BP-lowering treatment. Adjusted model 2: model 1+admission to an intensive care unit, prophylactic treatment for deep venous thrombosis, hemostatic therapy, and any surgical intervention. IPTW indicates inverse probability of treatment weighting; and PS, propensity score.

5 2766 Stroke October 2015 Downloaded from by guest on June 17, 2018 Figure 2. Association of mannitol treatment on death or major disability at 90 days by baseline hematoma volume. Solid boxes represent estimates of treatment effect on the risk of outcomes. Centers of boxes are placed at the estimates of the effect; areas of the boxes are proportional to the reciprocal of the variance of the estimates. Horizontal lines represent 95% confidence intervals (CIs). Adjusted model 1: adjusted by age, sex, National Institutes of Health Stroke Scale 15, time to randomization, systolic blood pressure (BP), prior intracerebral hemorrhage, prior ischemic or undifferentiated stroke, heart disease, diabetes mellitus, current use of antihypertensive therapy, use of warfarin anticoagulation or aspirin, use of statin or other lipid-lowering agent, deep location of hematoma, left hemisphere site of hematoma, intraventricular extension, and randomized BP-lowering treatment. Adjusted model 2: model 1+admission to an intensive care unit, prophylactic treatment for deep venous thrombosis, hemostatic therapy, and any surgical intervention. ICH indicates intracerebral hemorrhage; IPTW, inverse probability of treatment weighting; and PS, propensity score. 128 ICH patients within 6 days after onset, 9 found no effect of mannitol on early mortality. A Cochrane review of the topic concluded with uncertainty over whether mannitol is beneficial in this clinical setting. 10 The much larger data set of >2500 patients provided by the INTERACT2 study also indicates that mannitol has no effect in this population of predominantly mild to moderate severity of ICH. Strengths of this study include the large heterogeneous sample of patients recruited from a diverse range of hospitals and healthcare settings, who were assessed according to a Figure 3. Association between mannitol treatment and death or major disability at 90 days by National Institutes of Health Stroke Scale (NIHSS). Solid boxes represent estimates of treatment effect on the risk of outcomes. Centers of the boxes are placed at the estimates of the effect; areas of the boxers are proportional to the reciprocal of the variance of the estimates. Horizontal lines represent 95% confidence intervals (CIs). Adjusted model 1: adjusted by sex, age, time to randomization, systolic blood pressure (BP), prior intracerebral hemorrhage, prior ischemic or undifferentiated stroke, heart disease, diabetes mellitus, current use of antihypertensive therapy, use of warfarin anticoagulation or aspirin, use of statin or other lipid-lowering agent, deep location of hematoma, left hemisphere site of hematoma, log-transformed baseline hematoma volume, intraventricular extension, and randomized BP-lowering treatment. Adjusted model 2: model 1+admission to an intensive care unit, prophylactic treatment for deep venous thrombosis, hemostatic therapy, and any surgical intervention. IPTW indicates inverse probability of treatment weighting; and PS, propensity score.

6 Wang et al Mannitol and Cerebral Hemorrhage 2767 Downloaded from by guest on June 17, 2018 standardized protocol and objective measures. We also undertook PS-matched analysis, which allowed us to mimic some of the characteristics of a randomized controlled trial, and the numerous subgroup and sensitivity analyses strengthen the consistency of the findings. Although a benefit of mannitol was suggested in larger hematomas (>15 ml), the absence of a clear dose response relationship in smaller and larger hematomas indicates that the former was likely to have been a spurious finding. Furthermore, the worse outcome for mannitol use in non-chinese participants seems to relate more to background differences in prognosis between Chinese and non-chinese patients rather than from mannitol. However, there are limitations to our analytic approaches, where mannitol was administered according to the discretion of investigators, with variable doses and duration of treatment that were not captured in this study. Furthermore, mannitol was much more frequently used in China than for the other countries, which could have introduced bias despite our efforts to balance the baseline characteristics of patients. Because these analyses were not prespecified, they are prone to random error and incomplete adjustment for potential confounding, especially because we were unable to address all potential management confounders in analyses. Finally, the data are prone to selection bias by using a clinical trial population, where patients with a poor prognosis because of massive hematoma or deep coma, and those with early surgery, being excluded. Thus, the study sample may have been too small to adequately assess the effects of mannitol in patients with large hematomas. We conclude that the use of mannitol is safe but might not improve outcome in patients with acute ICH. In the absence of definitive evidence from future randomized controlled trials, these data may serve as a guide in the management of patients. Sources of Funding The second Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial study was supported by Program (571281) and Project ( and ) grants from the National Health and Medical Research Council of Australia. The study was designed, conducted, analyzed, and interpreted by the investigators independent of sponsors. Disclosures Dr Anderson reports membership of Advisory Boards for Pfizer and The Medicines Company, and receiving travel reimbursement and honorarium from Takeda China and Covidien. Dr Lavados reports grants from the George Institute for Global Health as a national leader of Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT) 2. References 1. Woster PS, LeBlanc KL. 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7 Downloaded from by guest on June 17, 2018 Mannitol and Outcome in Intracerebral Hemorrhage: Propensity Score and Multivariable Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2 Results Xia Wang, Hisatomi Arima, Jie Yang, Shihong Zhang, Guojun Wu, Mark Woodward, Paula Muñoz-Venturelli, Pablo M. Lavados, Christian Stapf, Thompson Robinson, Emma Heeley, Candice Delcourt, Richard I. Lindley, Mark Parsons, John Chalmers and Craig S. Anderson for the INTERACT2 Investigators Stroke. 2015;46: ; originally published online August 11, 2015; doi: /STROKEAHA Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX Copyright 2015 American Heart Association, Inc. All rights reserved. Print ISSN: Online ISSN: The online version of this article, along with updated information and services, is located on the World Wide Web at: Data Supplement (unedited) at: Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Stroke can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: Subscriptions: Information about subscribing to Stroke is online at:

8 SUPPLEMENTAL MATERIAL Mannitol and outcome in intracerebral hemorrhage: propensity score and multivariable INTERACT2 results Xia Wang MMed, 1 Hisatomi Arima MD PhD, 1 Jie Yang PhD, 3 Shihong Zhang MD, 4 Guojun Wu MD, 5 Mark Woodward PhD, 1 Paula Muñoz-Venturelli MD, 1,6 Pablo M Lavados MD, 6,7 Christian Stapf MD, 8 Thompson Robinson MD, 9 Emma Heeley PhD, 1 Candice Delcourt MD, 1,2 Richard I Lindley MD, 1,10 Mark Parsons MD PhD, 11 John Chalmers MD, 1 Craig S Anderson MD PhD, 1,2 for the INTERACT2 Investigators 1 The George Institute for Global Health, School of public health, the University of Sydney 2 Royal Prince Alfred Hospital, Sydney, Australia 3 Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China 4 Department of Neurology, West China Hospital, Sichuan University, Chengdu, China 5 Department of Neurology, Hebei Yutian Hospital, Tangshan, China 6 Servicio de Neurología, Departamento de Medicina Clínica Alemana, Universidad del Desarrollo, Santiago, Chile 7 Universidad de Chile, Santiago, Chile 8 Department of Neurology, APHP - Hôpital Lariboisière and DHU NeuroVasc Paris - Sorbonne, Univ Paris Diderot - Sorbonne Paris Cité, Paris, France 9 Department of Cardiovascular Sciences and NIHR Biomedical Research Unit in Cardiovascular Disease, University of Leicester, Leicester, UK 10 Westmead Hospital Clinical School, Westmead, NSW, Australia 11 Department of Neurology, John Hunter Hospital, University of Newcastle, Newcastle, New South Wales, Australia Author for correspondence: Professor Craig Anderson The George Institute for Global Health PO Box M201, Missenden Road, NSW 2050, AUSTRALIA T: , F: canderson@georgeinstitute.org.au 1

9 Supplemental Table I. Baseline characteristics by mannitol use Variable Non-mannitol (N=1037) Mannitol (N=1707) P value Age, yr 67 (13) 61 (12) <0.01 Male 648 (63) 165 (62) 0.96 Recruited from China 292 (28) 1583 (93) <0.01 NIHSS 10 (6-16) 11 (6-15) 0.50 NIHSS (29) 468 (27) 0.39 Time to randomization, hr 3.7 ( ) 3.8 ( ) 0.03 Systolic BP, mmhg, 179 (17) 179 (17) 0.41 Diastolic BP, mmhg, 97 (16) 104 (13) <0.01 History of hypertension 757 (73) 1229 (72) 0.60 Prior intracerebral hemorrhage 67 (7) 152 (9) 0.02 Prior ischemic/undifferentiated stroke 92 (9) 221 (13) <0.01 Heart disease 166 (16) 124 (7) <0.01 Diabetes mellitus 159 (15) 136 (8) <0.01 Current use of antihypertensive therapy 555 (54) 684 (40) <0.01 Use of warfarin anticoagulation/aspirin 231 (22) 93 (6) <0.01 Use of insulin/oral hypoglycemic agents 114 (11) 65 (4) <0.01 Use of statin/other lipid lowering 151 (15) 42 (3) <0.01 Deep location of hematoma* 820 (83) 1308 (85) 0.18 Left hemisphere site of hematoma 493 (50) 785 (51) 0.58 Hematoma volume at baseline, ml 8.9 ( ) 12.1 ( ) <0.01 Intraventricular extension 274 (28) 434 (28) 0.79 Randomized BP lowering treatment 512 (49) 850 (50) 0.83 Data are numbers (%), mean (SD) or median (IQR) NIHSS, denotes National Institutes of Health (NIH) stroke scale; BP, blood pressure *Deep location refers to location in the basal ganglia or thalamus 2

10 Supplemental Table II. Baseline characteristics and death or major disability at 90 days Death or major disability Variable No (n=1290) Yes (n=1504) P value Age, yr 60 (12) 67 (13) <0.01 Male 822 (64) 931 (62) 0.32 Recruited from China 999 (77) 911 (61) <0.01 NIHSS 7 (4-11) 18 (14-22) <0.01 NIHSS (11) 665 (44) <0.01 Time to randomization, hr 3.8 ( ) 3.6 ( ) <0.01 Systolic BP, mmhg, 178 (17) 180 (17) <0.01 Dystolic BP, mmhg, 102 (14) 100 (15) <0.01 History of hypertension 942 (73) 1079 (72) 0.50 Prior intracerebral hemorrhage 88 (7) 138 (9) 0.02 Prior ischemic/undifferentiated stroke 133 (10) 186 (12) 0.09 Heart disease 93 (7) 200 (13) <0.01 Diabetes mellitus 106 (8) 194 (13) <0.01 Current use of antihypertensive therapy 562 (44) 693 (46) 0.17 Use of warfarin anticoagulation or aspirin 99 (8) 231 (15) <0.01 Use of insulin/oral hypoglycemic agents 67 (5) 115 (8) 0.01 Use of statin/other lipid lowering 63 (5) 134 (9) <0.01 Deep location of hematoma* 971 (82) 1189 (85) 0.01 Left hemisphere site of hematoma 569 (48) 728 (52) 0.03 Hematoma volume at baseline, ml 8.3 ( ) 14.1 ( ) <0.01 Intraventricular extension 249 (21) 481 (35) <0.01 Randomized BP lowering treatment 663 (51) 719 (48) 0.06 Data are numbers (%), mean (SD) or median (IQR) NIHSS, denotes NIH stroke scale; BP, blood pressure *Deep location refers to location in the basal ganglia or thalamus 3

11 Supplemental Table III. Mannitol and death or major disability at 90 days by baseline hematoma volume 10mL Model Baseline hematoma volume 10mL Mannitol N Events (%) OR (95%CI) P homogeneity Adjusted 1 No No (44.0) Yes (35.7) 0.92 ( ) Yes No (73.0) Yes (63.0) 0.87 ( ) Adjusted 2 No No (44.0) Yes (35.7) 1.18 ( ) Yes No (73.0) Yes (63.0) 0.91 ( ) PS matched No No (40.2) Yes (37.1) 0.88 ( ) Yes No (70.3) Yes (64.8) 0.78 ( ) IPTW No No (44.0) Yes (35.7) 1.05 ( ) Yes No (73.0) Yes (63.0) 0.85 ( ) Summary stratified No No (44.0) Yes (35.7) 0.91 ( ) Yes No (73.0) Yes (63.0) 0.77 ( ) Covariate adjustment Using the PS No No (44.0) Yes (35.7) 0.94 ( ) Yes No (73.0) Yes (63.0) 0.80 ( ) CI denotes confidence interval; OR, odds ratio; PS, propensity score; IPTW, inverse probability of treatment weighting. Adjusted model 1: Adjusted by age, sex, NIHSS 15, time to randomization, systolic BP, prior intracerebral hemorrhage, prior ischemic or undifferentiated stroke, heart disease, diabetes mellitus, current use of antihypertensive therapy, use of warfarin anticoagulation or aspirin, use of 4

12 statin or other lipid lowering agent, deep location of hematoma, left hemisphere site of hematoma, intraventricular extension, and randomized BP lowering treatment Adjusted model 2: model 1 + admission to an intensive care unit, prophylactic treatment for deep venous thrombosis, hemostatic therapy, and any surgical intervention 5

13 Supplemental Table IV. Mannitol and death or major disability at 90 days by greater ( 20mL) baseline hematoma volume Model Baseline hematoma volume 20mL Mannitol N Events (%) OR(95%CI) P homogeneity Adjusted 1 No No (50.2) Yes (42.8) 0.95 ( ) Yes No (82.4) Yes (73.9) 0.98 ( ) Adjusted 2 No No (50.2) Yes (42.8) 1.19 ( ) Yes No (82.4) Yes (73.9) 0.96 ( ) PS matched No No (47.3) Yes (44.3) 0.89 ( ) Yes No (79.3) Yes (75.4) 0.80 ( ) IPTW No No (50.2) Yes (42.8) 1.04 ( ) Yes No (82.4) Yes (73.9) 0.95 ( ) Summary stratified No No (50.2) Yes (42.8) 0.95 ( ) Yes No (82.4) Yes (73.9) 0.90 ( ) Covariate adjustment Using the PS No No (50.2) Yes (42.8) 0.97 ( ) Yes No (82.4) Yes (73.9) 0.96 ( ) CI denotes confidence interval; OR, odds ratio; PS, propensity score; IPTW, inverse probability of treatment weighting. Adjusted model 1: Adjusted by age, sex, NIHSS 15, time to randomization, systolic BP, prior intracerebral hemorrhage, prior ischemic or undifferentiated stroke, heart disease, diabetes mellitus, current use of antihypertensive therapy, use of warfarin anticoagulation or aspirin, use of statin or other lipid lowering agent, deep location of hematoma, left hemisphere site of hematoma, intraventricular extension, and randomized BP lowering treatment 6

14 Adjusted model 2: model 1 + admission to an intensive care unit, prophylactic treatment for deep venous thrombosis, hemostatic therapy, and any surgical intervention 7

15 Supplemental Table V. Mannitol and death or major disability at 90 days by NIHSS score 10 Model NIHSS 10 Mannitol N Events (%) OR (95%CI) P homogeneity PS matched No No (29.6) Yes (22.4) 0.69 ( ) Yes No (77.1) Yes (73.5) 0.82 ( ) IPTW No No (32.3) Yes (24.2) 0.86 ( ) Yes No (78.4) Yes (71.3) 0.96 ( ) Summary stratified Covariate adjustment Using the PS No No (29.6) Yes (22.4) 0.79 ( ) Yes No (77.1) Yes (73.5) 0.89 ( ) No No (29.6) Yes (22.4) 0.82 ( ) Yes No (77.1) Yes (73.5) 0.88( ) CI denotes confidence interval; OR, odds ratio; NIHSS, NIH stroke scale; PS, propensity score; IPTW, inverse probability of treatment weighting 8

16 Supplemental Table VI. Mannitol and death or major disability at 90 days by NIHSS score 20 Model NIHSS 20 Mannitol N Events (%) OR (95%CI) P homogeneity PS matched No No (49.9) Yes (47.3) 0.90 ( ) Yes No (91.6) Yes (83.2) 0.45 ( ) IPTW No No (52.8) Yes (46.5) 0.93 ( ) Yes No (91.8) Yes (84.2) 0.90 ( ) Summary stratified Covariate adjustment Using the PS No No (49.9) Yes (47.3) 0.88 ( ) Yes No (91.6) Yes (83.2) 0.62 ( ) No No (49.9) Yes (47.3) 0.89 ( ) Yes No (91.6) Yes (83.2) 0.62 ( ) CI denotes confidence interval; OR, odds ratio; NIHSS, NIH stroke scale; PS, propensity score; IPTW, inverse probability of treatment weighting 9

17 Supplemental Table VII. Mannitol and death or major disability at 90 days in patients with both large ( 15mL) hematomas and greater clinical severity (NIHSS 15) Model Mannitol N Events (%) OR (95%CI) P value Crude No (89.7) Yes (82.8) 0.55 ( ) Adjusted ( ) Adjusted ( ) PS matched No (87.8) Yes (80.4) 0.57 ( ) IPTW No (89.7) Yes (82.8) 1.03 ( ) Summary stratified No (89.7) Covariate adjustment using the PS Yes (82.8) 0.83 ( ) No (89.7) Yes (82.8) 0.79 ( ) CI denotes confidence interval; NIHSS, NIH stroke scale; OR, odds ratio; PS, propensity score; IPTW, inverse probability of treatment weighting. Adjusted model 1: Adjusted by age, sex, time to randomization, systolic BP, prior intracerebral hemorrhage, prior ischemic or undifferentiated stroke, heart disease, diabetes mellitus, current use of antihypertensive therapy, use of warfarin anticoagulation or aspirin, use of statin or other lipid lowering agent, deep location of hematoma, left hemisphere site of hematoma, intraventricular extension, and randomized BP lowering treatment Adjusted model 2: model 1 + admission to an intensive care unit, prophylactic treatment for deep venous thrombosis, hemostatic therapy, and any surgical intervention 10

18 Supplemental Table VIII. Mannitol and death or major disability at 90 days in patients who were aged <65 years with large hematomas ( 15mL) Model Mannitol N Events (%) OR (95%CI) P value Crude No (70.0) Yes (60.3) 0.65 ( ) Adjusted ( ) Adjusted ( ) PS matched No (69.2) Yes (55.6) 0.56 ( ) IPTW No (70.0) Yes (60.3) 0.70 ( ) Summary stratified No (70.0) Yes (60.3) 0.84 ( ) Covariate adjustment Using the PS No (70.0) Yes (60.3) 0.86 ( ) CI denotes confidence interval; OR, odds ratio; PS, propensity score; IPTW, inverse probability of treatment weighting. Adjusted model 1: Adjusted by sex, NIHSS 15, time to randomization, systolic BP, prior intracerebral hemorrhage, prior ischemic or undifferentiated stroke, heart disease, diabetes mellitus, current use of antihypertensive therapy, use of warfarin anticoagulation or aspirin, use of statin or other lipid lowering agent, deep location of hematoma, left hemisphere site of hematoma, intraventricular extension, and randomized BP lowering treatment Adjusted model 2: model 1 + admission to an intensive care unit, prophylactic treatment for deep venous thrombosis, hemostatic therapy, and any surgical intervention 11

19 Supplemental Table IX. Mannitol and death or major disability at 90 days in patients who were aged <65 years with baseline NIHSS scores 15 Model Mannitol N Events (%) OR (95%CI) P value Crude No (76.5) Yes (70.3) 0.73 ( ) Adjusted ( ) Adjusted ( ) PS matched No (75.7) Yes (70.3) 0.76 ( ) IPTW No (76.5) Yes (70.3) 0.95 ( ) Summary stratified No (76.5) Yes (70.3) 0.88 ( ) Covariate adjustment Using the PS No (76.5) Yes (70.3) 0.88 ( ) CI denotes confidence interval; OR, odds ratio; PS, propensity score; IPTW, inverse probability of treatment weighting. Adjusted model 1: Adjusted by sex, time to randomization, systolic BP, prior intracerebral hemorrhage, prior ischemic or undifferentiated stroke, heart disease, diabetes mellitus, current use of antihypertensive therapy, use of warfarin anticoagulation or aspirin, use of statin or other lipid lowering agent, deep location of hematoma, left hemisphere site of hematoma, log transformed baseline hematoma volume, intraventricular extension, and randomized BP lowering treatment Adjusted model 2: model 1 + admission to an intensive care unit, prophylactic treatment for deep venous thrombosis, hemostatic therapy, and any surgical intervention 12

20 Supplemental Table X. Mannitol and death or major disability at 90 days in patients from China Model Mannitol N Events (%) OR (95%CI) P value Crude No (34.7) Yes (48.4) 1.76 ( ) < Adjusted ( ) Adjusted ( ) PS matched No (34.7) Yes (41.0) 1.31 ( ) IPTW No (34.7) Yes (48.4) 1.16 ( ) Summary stratified No (34.7) Yes (48.4) 1.14 ( ) Covariate adjustment Using the PS No (34.7) Yes (48.4) 1.11 ( ) CI denotes confidence interval; OR, odds ratio; PS, propensity score; IPTW, inverse probability of treatment weighting. Adjusted model 1: Adjusted by age, sex, NIHSS 15, time to randomization, systolic BP, prior intracerebral hemorrhage, prior ischemic or undifferentiated stroke, heart disease, diabetes mellitus, current use of antihypertensive therapy, use of warfarin anticoagulation or aspirin, use of statin or other lipid lowering agent, deep location of hematoma, left hemisphere site of hematoma, log transformed baseline hematoma volume, intraventricular extension, and randomized BP lowering treatment Adjusted model 2: model 1 + admission to an intensive care unit, prophylactic treatment for deep venous thrombosis, hemostatic therapy, and any surgical intervention 13

21 Supplemental Table XI. Mannitol and death or major disability at 90 days in non-china patients Model Mannitol N Events (%) OR (95%CI) P value Crude No (65.2) Yes (78.6) 1.95 ( ) Adjusted ( ) Adjusted ( ) PS matched No (65.8) Yes (79.3) 1.99 ( ) IPTW No (65.2) Yes (78.6) 1.67 ( ) Summary stratified No (65.2) Yes (78.6) 1.61 ( ) Covariate adjustment Using the PS No (65.2) Yes (78.6) 1.61 ( ) CI denotes confidence interval; OR, odds ratio; PS, propensity score; IPTW, inverse probability of treatment weighting. Adjusted model 1: Adjusted by age, sex, NIHSS 15, time to randomization, systolic BP, prior intracerebral hemorrhage, prior ischemic or undifferentiated stroke, heart disease, diabetes mellitus, current use of antihypertensive therapy, use of warfarin anticoagulation or aspirin, use of statin or other lipid lowering agent, deep location of hematoma, left hemisphere site of hematoma, log transformed baseline hematoma volume, intraventricular extension, and randomized BP lowering treatment Adjusted model 2: model 1 + admission to an intensive care unit, prophylactic treatment for deep venous thrombosis, hemostatic therapy, and any surgical intervention 14

22 Supplemental Table XII. Mannitol and death or major disability at 90 days by baseline hematoma volume in patients from China Model Baseline hematoma volume 15mL Mannitol N Events (%) OR (95%CI) P homogeneity Adjusted 1 No No (29.1) Yes (38.6) 1.50 ( ) Yes No (65.9) Yes (64.9) 0.75 ( ) Adjusted 2 No No (29.1) Yes (38.6) 1.45 ( ) Yes No (65.9) Yes (64.9) 0.77 ( ) PS matched No No (29.1) Yes (37.0) 1.43 ( ) Yes No (65.9) Yes (63.4) 0.90 ( ) IPTW No No (29.1) Yes (38.6) 1.23 ( ) Yes No (65.9) Yes (64.9) 1.13 ( ) Summary stratified No No (29.1) Yes (38.6) 1.22 ( ) Yes No (65.9) Yes (64.9) 0.85 ( ) Covariate adjustment Using the PS No No (29.1) Yes (38.6) 1.19 ( ) Yes No (65.9) Yes (64.9) 0.83 ( ) CI denotes confidence interval; OR, odds ratio; PS, propensity score; IPTW, inverse probability of treatment weighting. Adjusted model 1: Adjusted by age, sex, NIHSS 15, time to randomization, systolic BP, prior intracerebral hemorrhage, prior ischemic or undifferentiated stroke, heart disease, diabetes mellitus, current use of antihypertensive therapy, use of warfarin anticoagulation or aspirin, use of 15

23 statin or other lipid lowering agent, deep location of hematoma, left hemisphere site of hematoma, intraventricular extension, and randomized BP lowering treatment Adjusted model 2: model 1 + admission to an intensive care unit, prophylactic treatment for deep venous thrombosis, hemostatic therapy, and any surgical intervention 16

24 Supplemental Table XIII. Baseline characteristics of participants by region Parameter Non-China (N=909) China (N=1920) P value Time from onset of ICH to randomization, hr 3.6 ( ) 3.8 ( ) 0.02 Age, yr 68± ± Male 584 (64) 1196 (62) 0.31 Systolic BP, mmhg 180±17 179± Diastolic BP, mmhg 96±16 104±13 <0.01 NIHSS score* 12 (7-17) 10 (5-14) <0.01 GCS score 15 (13-15) 14 (12-15) <0.01 History of hypertension 641/909 (71) 1407/1917 (73) 0.11 Current use of antihypertensive drugs 507/909 (56) 767/1917 (40) <0.01 Prior intracerebral hemorrhage 58/909 (6) 171/1917 (9) 0.02 Prior ischemic or undifferentiated stroke 78/909 (9) 245/1920 (13) <0.01 Prior acute coronary event 52/909 (6) 29/1917 (2) <0.01 Diabetes mellitus 152/909 (17) 153/1764 (8) <0.01 Use of warfarin anticoagulation 73/909 (8) 8/1917 (0) <0.01 Use of aspirin or other antiplatelet agent 198/909 (22) 67/1920 (4) <0.01 Baseline hematoma volume, ml 11 (6-23) 11 (6-18) 0.40 Deep location of hematoma 707/876 (81) 1475/1737 (85) 0.01 Left hemisphere site of hematoma 436/876 (50) 877/1737 (51) 0.73 Intraventricular extension of hemorrhage 273/876 (31) 467/1737 (27) 0.02 Data are n (%), mean (SD), or median (IQR). BP indicates blood pressure; NIHSS, National Institutes of Health stroke scale. *Scores range from 0 (normal) to 42 (coma with quadriplegia). Scores range from 15 (normal) to 3 (deep coma) Location in the basal ganglia or thalamus 17

25 Supplemental Table XIV. Management of patients by region Parameter Non-China (N=909) China (N=1920) P value Time from ICH to BP lowering treatment, hr 3.9 ( ) 4.1 ( ) 0.01 Time from randomisation to BP lowering treatment, hr 0.2 ( ) 0.1 ( ) 0.04 Any BP lowering treatment in first 24 hours 743 (82) 1130 (59) <0.01 Intubation 112/894 (13) 77/1885 (4) <0.01 Admission to an intensive care unit 304/894 (34) 757/1885 (40) <0.01 Prophylactic treatment for deep venous thrombosis 596/894 (67) 14/1885 (1) Compression stockings used 283/894 (32) 10/1885 (1) Subcutaneous heparin administered 489/894 (55) 4/1885 (0) Use of intravenous mannitol 127/894 (14) 1592/1885 (85) <0.01 Hemostatic therapy* 70/894 (8) 27/1885 (1) <0.01 Any surgical intervention 49/894 (6) 105/1885 (6) 0.92 Evacuation or decompression of the hematoma 24/894 (3) 57/1885 (3) 0.62 Insertion of a ventricular drain 29/894 (3) 56/1885 (3) 0.70 Decision to withdraw active treatment and care 58/894 (7) 63/1885 (3) <0.01 ICH denotes intracerebral haemorrhage; BP, blood pressure *Includes the use of fresh frozen plasma, vitamin K, and recombinant tissue Factor VIIa. 18

26 Supplemental Table XV. Death or major disability at 90 days by region Outcome Non-China (N=909) China (N=1920) OR (95% CI) P value aor (95% CI)* P value Death or major disability 593/884 (67) 911/1910 (48) 0.45 ( ) < ( ) <0.01 OR denotes odds ratio; CI, confidence interval; aor, adjusted OR *adjusted by age, sex, prior ICH, antithrombotictherapy, national Institutes of Health stroke scale (NIHSS) score 15, baseline hematoma volume, deep location of hematoma, and randomized treatment. 19

27 Table XVI. Modified intracerebral haemorrhage score and death or major disability by region Death or major disability, n(%) MICH score China Non-China 0 231(29.2) 202(51.9) 1 340(54.4) 200(75.8) 2 174(75.7) 102(83.6) 3 57(85.1) 59(92.2) 4 15(93.8) 13(100.0) 20

28 No Mannitol treatment Yes Supplemental Figure I. Propensity score distribution stratified by mannitol treatment 21

29 Supplemental Figure II. Association between mannitol treatment and death or major disability at 90 days, by gender 95% CI, 95% confidence interval; PS, propensity score; IPTW, inverse probability of treatment weighting. Solid boxes represent estimates of treatment effect on the risk of outcomes. Centers of the boxes are placed at the estimates of the effect; areas of the boxers are proportional to the reciprocal of the variance of the estimates. Horizontal lines represent 95% CIs. Adjusted model 1: Adjusted by age, NIHSS 15, time to randomization, systolic BP, prior intracerebral hemorrhage, prior ischemic or undifferentiated stroke, heart disease, diabetes mellitus, current use of antihypertensive therapy, use of warfarin anticoagulation or aspirin, use of statin or other lipid lowering agent, deep location of hematoma, left hemisphere site of hematoma, log transformed baseline hematoma volume, intraventricular extension, and randomized BP lowering treatment Adjusted model 2: model 1 + admission to an intensive care unit, prophylactic treatment for deep venous thrombosis, hemostatic therapy, and any surgical intervention. 22