Mannitol and Outcome in Intracerebral Hemorrhagestroke.ahajournals.org/content/strokeaha/46/10/2762.full.pdfWang et al Mannitol and Cerebral Hemorrhage 2763 trials,8,9 and a systematic

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Mannitol is frequently used in the management of patients with spontaneous intracerebral hemorrhage (ICH),1 par-

ticularly in China2 and India.3 It is an intravascular osmostic agent that establishes an osmotic gradient between plasma and neurons, thereby drawing water from the cerebral extra-cellular space into the vasculature to reduce cerebral edema.4

Mannitol also increases cardiac preload and cerebral perfu-sion pressure, which contributes to a decrease in intracranial pressure through cerebral vasoreactivity. Although guidelines recommend using mannitol where there is increased intracra-nial pressure in ICH,5 uncertainty exists over the magnitude of potential benefit, with various observational studies,6,7 clinical

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, 0.75–1.09; P=0.30) and multivariable odds ratio of 0.87 (95% confidence interval, 0.71–1.07; 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, 0.35–0.78] versus odds ratio, 0.91 [95% confidence interval, 0.72–1.15]; 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: http://www.clinicaltrials.gov. Unique identifier: NCT00716079.

(Stroke. 2015;46:2762-2767. DOI: 10.1161/STROKEAHA.115.009357.)

Key Words: blood pressure ◼ cerebral hemorrhage ◼ clinical trial ◼ mannitol ◼ propensity score

Mannitol and Outcome in Intracerebral HemorrhagePropensity 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*

Received March 7, 2015; final revision received June 17, 2015; accepted July 10, 2015.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 http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.

115.009357/-/DC1.Correspondence to Craig S. Anderson, MD, PhD, The George Institute for Global Health, PO Box M201, Missenden Rd, NSW 2050, Australia. E-mail

[email protected]© 2015 American Heart Association, Inc.

Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.115.009357

by guest on July 10, 2018http://stroke.ahajournals.org/

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http://www.clinicaltrials.gov

http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA. 115.009357/-/DC1

http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA. 115.009357/-/DC1

mailto:[email protected]

http://stroke.ahajournals.org/



























Wang et al Mannitol and Cerebral Hemorrhage 2763

trials,8,9 and a systematic review,10 unable to provide evidence of a clear treatment effect of mannitol in acute ICH. The pres-ent analysis aimed to determine the impact of use of mannitol on clinical outcome in patients with acute ICH who partici-pated 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.

MethodsStudy DesignDetails 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, 150–220 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 in-dication for, or contraindication to intensive BP lowering; low like-lihood 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 OutcomesPatients 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 assess-ment 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 AnalysisBecause 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 χ2 test for binary measures, t test for approximately normally distributed variables, and Wilcoxon signed-rank test for skewed continuous vari-ables. A multivariable logistic regression model, including all uni-variate 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 PS14,16 for each patient. Only patients with complete data were included in the analyses to maximize balancing of the PS analy-sis with the largest number of variables and to avoid the need to im-pute 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 alloca-tion of mannitol to show consistency of the results. We used opti-mal 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 esti-mating 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 in-verse 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 strati-fied 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 man-nitol 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 demograph-ic 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 us-ing lower (<10 versus ≥10 mL) and higher (<20 versus ≥20 mL) cut-off points for ICH volume and at lower (<10 versus ≥10) and higher (<20 versus ≥20) NIHSS score thresholds for stroke severity. We as-sessed 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 be-cause of manniol use in these participants, the data were stratified by China and non-China region to assess the consistency of any as-sociation 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 com-pared 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).

ResultsAfter 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 randomiza-tion, 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%


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CI, 0.66–0.91; P<0.01; Figure 1). However, the association was no longer significant after adjustment for baseline imbal-ances (OR, 0.87; 95% CI, 0.71–1.07; P=0.18), and further with the addition of treatment imbalances (OR, 1.02; 95% CI, 0.81–1.30; P=0.86). These neutral results were confirmed by PS analyses: matching (OR, 0.90; 95% CI, 0.75–1.09; P=0.30), IPTW (OR, 0.97; 95% CI, 0.83–1.14; P=0.72), sum-mary stratified (OR, 0.91; 95% CI, 0.77–1.08; P=0.30), and covariate adjustment using PS (OR, 0.92; 95% CI, 0.77–1.10; P=0.35). The PS-matched analysis with the smaller caliper of 0.10 showed a similar result (OR, 0.89; 95% CI, 0.73–1.09; P=0.26). There was no association with the separate outcomes of death and major disability (data on request) and no het-erogeneity 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 out-come in patients with larger (≥15 mL) when compared with

smaller (<15 mL) hematomas (OR, 0.52; 95% CI, 0.35–0.78 versus OR, 0.91; 95% CI, 0.72–1.15; 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 multivari-able-adjusted analyses or in other sensitivity analyses of dif-ferent 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 man-nitol 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 online-only Data Supplement, respectively). Moreover, subgroup

Table 1. Distribution of Patient Characteristics by Mannitol Treatment in Overall, PS-Matched, and IPTW Populations

Overall PS Matched IPTW*

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) 791.4 (63) 786.1 (62)

Clinical features

NIHSS≥15 293 (30) 421 (28) 244 (29) 237 (28) 367.8 (29) 367.2 (29)

Time to randomization, h 3.6 (2.7–4.6) 3.8 (2.8–4.8) 3.6 (2.7–4.6) 3.8 (2.9–4.8) 3.8 (2.8–4.7) 3.7 (2.9–4.7)

Systolic BP, mm Hg 179 (17) 179 (17) 179 (17) 179 (17) 179.1 (19.1) 179.1 (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) 144.9 (12) 143.0 (11)

Heart disease 160 (16) 114 (7)† 86 (10) 79 (9) 137.1 (11) 145.3 (12)

Diabetes mellitus 153 (15) 121 (8)† 105 (13) 80 (10) 134.1 (11) 158.2 (13)

Antihypertensive therapy 533 (54) 605 (40)† 399 (48) 359 (43)† 577.4 (46) 589.1 (47)

Use of warfarin anticoagulation/aspirin 224 (23) 85 (6)† 97 (12) 76 (9) 152.5 (12) 178.9 (14)

Use of statin/other lipid-lowering agent 147 (15) 39 (3)† 52 (6) 38 (5) 93.0 (7) 118.6 (9)

Deep location of hematoma‡ 820 (83) 1295 (85) 690 (82) 697 (83) 1044.4 (83) 1045.7 (83)

Left hemisphere site of hematoma 493 (50) 779 (51) 424 (51) 414 (49) 629.7 (50) 651.2 (51)

Hematoma volume at baseline, mL 8.9 (4.3–17.1) 12.1 (6.7–19.9)† 9.3 (4.5–17.9) 10.3 (5.8–18.0) 10.3 (5.4–20.5) 10.8 (5.9–18.7)

Intraventricular extension 274 (28) 422 (28) 234 (28) 244 (29) 357.7 (28) 353.5 (28)

Randomized intensive BP lowering 504 (51) 765 (50) 434 (52) 428 (51) 634.2 (50) 627.9 (50)

Medical and surgical treatment

Intubation 67 (7) 108 (7) 58 (7) 57 (7) 100.4 (8) 94.9 (8)

Admission to an intensive care unit 297 (30) 660 (43)† 266 (32) 373 (45)† 417.1 (33) 576.0 (45)†

Thromboembolism prophylaxis 503 (51) 72 (5)† 398 (47) 45 (5)† 601.2 (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.


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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).

DiscussionThis 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 fac-tors 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.20–23

Few studies have investigated the effects of mannitol in acute ICH. An observational study6 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 recipro-cal 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 anticoagula-tion 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 indi-cates inverse probability of treatment weighting; and PS, propensity score.

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.


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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 benefi-cial 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 hospi-tals and healthcare settings, who were assessed according to a

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 intra-cerebral 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.

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% con-fidence 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 hema-toma, 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.


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standardized protocol and objective measures. We also under-took 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 man-nitol 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 discre-tion 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 con-founding, 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 popu-lation, where patients with a poor prognosis because of mas-sive 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 FundingThe second Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial study was supported by Program (571281) and Project (512402 and 1004170) grants from the National Health and Medical Research Council of Australia. The study was designed, con-ducted, analyzed, and interpreted by the investigators independent of sponsors.

DisclosuresDr 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.

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12. Delcourt C, Huang Y, Wang J, Heeley E, Lindley R, Stapf C, et al; INTERACT2 Investigators. The second (main) phase of an open, ran-domised, multicentre study to investigate the effectiveness of an intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT2). Int J Stroke. 2010;5:110–116. doi: 10.1111/j.1747-4949. 2010.00415.x.

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for the INTERACT2 InvestigatorsCandice Delcourt, Richard I. Lindley, Mark Parsons, John Chalmers and Craig S. AndersonMuñoz-Venturelli, Pablo M. Lavados, Christian Stapf, Thompson Robinson, Emma Heeley, Xia Wang, Hisatomi Arima, Jie Yang, Shihong Zhang, Guojun Wu, Mark Woodward, Paula

Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2 ResultsMannitol and Outcome in Intracerebral Hemorrhage: Propensity Score and Multivariable

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1

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

1The George Institute for Global Health, School of public health, the University of Sydney

2Royal Prince Alfred Hospital, Sydney, Australia

3Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing,

China

4Department of Neurology, West China Hospital, Sichuan University, Chengdu, China

5Department of Neurology, Hebei Yutian Hospital, Tangshan, China

6Servicio de Neurología, Departamento de Medicina Clínica Alemana, Universidad del

Desarrollo, Santiago, Chile

7Universidad de Chile, Santiago, Chile

8Department of Neurology, APHP - Hôpital Lariboisière and DHU NeuroVasc Paris -

Sorbonne, Univ Paris Diderot - Sorbonne Paris Cité, Paris, France

9Department of Cardiovascular Sciences and NIHR Biomedical Research Unit in

Cardiovascular Disease, University of Leicester, Leicester, UK

10Westmead Hospital Clinical School, Westmead, NSW, Australia

11Department 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: +61-2-9993-4500, F: +61-2-9993-4502

Email: [email protected]

mailto:[email protected]

2

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 ≥15 300 (29) 468 (27) 0.39

Time to randomization, hr 3.7 (2.8-4.6) 3.8 (2.9-4.8) 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 (4.3-17.1) 12.1 (6.6-19.9) <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

3

Supplemental Table II. Baseline characteristics and death or major disability at 90 days

Variable

Death or major disability

P value No

(n=1290)

Yes

(n=1504)

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 ≥15 135 (11) 665 (44) <0.01

Time to randomization, hr 3.8 (2.9-4.8) 3.6 (2.7-4.7) <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 (4.1-14.0) 14.1 (7.8-25.5) <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

4

Supplemental Table III. Mannitol and death or major disability at 90 days by baseline hematoma volume ≥10mL

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

Model Baseline hematoma volume ≥10mL Mannitol N Events (%) OR (95%CI) P homogeneity

Adjusted1 No No 548 241 (44.0) 0.966

Yes 620 221 (35.7) 0.92 (0.69-1.22)

Yes No 445 325 (73.0)

Yes 913 554 (63.0) 0.87 (0.65-1.16)

Adjusted2 No No 548 241 (44.0) 0.977

Yes 620 221 (35.7) 1.18 (0.85-1.64)

Yes No 445 325 (73.0)

Yes 913 554 (63.0) 0.91 (0.64-1.30)

PS matched No No 455 183 (40.2) 0.554

Yes 455 169 (37.1) 0.88 (0.67-1.16)

Yes No 381 268 (70.3)

Yes 381 247 (64.8) 0.78 (0.58-1.05)

IPTW No No 548 241 (44.0) 0.185

Yes 620 221 (35.7) 1.05 (0.83-1.33)

Yes No 445 325 (73.0)

Yes 913 554 (63.0) 0.85 (0.68-1.06)

Summary stratified No No 548 241 (44.0) 0.190

Yes 620 221 (35.7) 0.91 (0.71-1.17)

Yes No 445 325 (73.0)

Yes 913 554 (63.0) 0.77 (0.59-1.00)

Covariate adjustment

Using the PS

No No 548 241 (44.0) 0.174

Yes 620 221 (35.7) 0.94 (0.73-1.21)

Yes No 445 325 (73.0)

Yes 913 554 (63.0) 0.80 (0.61-1.04)

5

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

6

Supplemental Table IV. Mannitol and death or major disability at 90 days by greater (≥20mL) baseline hematoma volume





lowering treatment

Model Baseline hematoma volume ≥20mL Mannitol N Events (%) OR(95%CI) P homogeneity

Adjusted1

No No 783 393 (50.2) 0.638

Yes 1150 492 (42.8) 0.95 (0.77-1.18)

Yes No 210 173 (82.4)

Yes 383 283 (73.9) 0.98 (0.60-1.61)

Adjusted2 No No 783 393 (50.2) 0.888

Yes 1150 492 (42.8) 1.19 (0.92-1.55)

Yes No 210 173 (82.4)

Yes 383 283 (73.9) 0.96 (0.54-1.73)

PS matched No No 662 313 (47.3) 0.370

Yes 662 293 (44.3) 0.89 (0.71-1.10)

Yes No 179 142 (79.3)

Yes 179 135 (75.4) 0.80 (0.49-1.30)

IPTW No No 783 393 (50.2) 0.690

Yes 1150 492 (42.8) 1.04 (0.87-1.24)

Yes No 210 173 (82.4)

Yes 383 283 (73.9) 0.95 (0.65-1.39)


Yes 1150 492 (42.8) 0.95 (0.78-1.16)

Yes No 210 173 (82.4)

Yes 383 283(73.9) 0.90 (0.57-1.42)


Using the PS

No No 783 393 (50.2) 0.305

Yes 1150 492 (42.8) 0.97 (0.79-1.18)

Yes No 210 173 (82.4)

Yes 383 283 (73.9) 0.96 (0.61-1.51)

7



8

Supplemental Table V. Mannitol and death or major disability at 90 days by NIHSS

score ≥10

CI denotes confidence interval; OR, odds ratio; NIHSS, NIH stroke scale; PS, propensity

score; IPTW, inverse probability of treatment weighting

Model NIHSS ≥10 Mannitol N Events (%) OR (95%CI) P homogeneity

PS matched No No 389 115 (29.6) 0.406

Yes 389 87 (22.4) 0.69 (0.51-0.94)

Yes No 445 343 (77.1)

Yes 445 327 (73.5) 0.82 (0.61-1.11)

IPTW No No 458 148 (32.3) 0.567

Yes 670 162 (24.2) 0.86 (0.66-1.12)

Yes No 533 418 (78.4)

Yes 853 608 (71.3) 0.96 (0.75-1.22)

Summary

stratified

No No 389 115 (29.6) 0.984

Yes 389 87 (22.4) 0.79 (0.60-1.06)

Yes No 445 343 (77.1)

Yes 445 327 (73.5) 0.89 (0.68-1.17)

Covariate

adjustment

Using the

PS

No No 389 115 (29.6) 0.973

Yes 389 87 (22.4) 0.82 (0.61-1.09)

Yes No 445 343(77.1)

Yes 445 327(73.5) 0.88(0.67-1.16)

9

Supplemental Table VI. Mannitol and death or major disability at 90 days by NIHSS

score ≥20

CI denotes confidence interval; OR, odds ratio; NIHSS, NIH stroke scale; PS, propensity

score; IPTW, inverse probability of treatment weighting

Model NIHSS ≥20 Mannitol N Events (%) OR (95%CI) P homogeneity

PS matched No No 738 368 (49.9) 0.169

Yes 738 349 (47.3) 0.90 (0.74-1.10)

Yes No 95 87 (91.6)

Yes 95 79 (83.2) 0.45 (0.17-1.18)

IPTW No No 881 465 (52.8) 0.923

Yes 1358 631 (46.5) 0.93 (0.79-1.10)

Yes No 110 101 (91.8)

Yes 165 139 (84.2) 0.90 (0.45-1.78)

Summary

stratified

No No 738 368 (49.9) 0.220

Yes 738 349 (47.3) 0.88 (0.73-1.06)

Yes No 95 87 (91.6)

Yes 95 79 (83.2) 0.62 (0.27-1.43)

Covariate

adjustment

Using the

PS

No No 738 368 (49.9) 0.210

Yes 738 349 (47.3) 0.89 (0.74-1.08)

Yes No 95 87 (91.6)

Yes 95 79 (83.2) 0.62 (0.27-1.42)

10

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)

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

Model Mannitol N Events (%) OR (95%CI) P value

Crude No 175 157 (89.7)

Yes 262 217 (82.8) 0.55 (0.31-0.99) 0.047

Adjusted1 0.90 (0.47-1.71) 0.737

Adjusted2 0.60 (0.25-1.48) 0.271

PS matched No 148 130 (87.8)

Yes 148 119 (80.4) 0.57 (0.31-1.03) 0.063

IPTW No 175 157 (89.7)

Yes 262 217 (82.8) 1.03 (0.61-1.73) 0.927

Summary stratified No 175 157 (89.7)

Yes 262 217 (82.8) 0.83 (0.45-1.51) 0.533


using the PS

No 175 157 (89.7)

Yes 262 217 (82.8) 0.79 (0.43-1.46) 0.455

11

Supplemental Table VIII. Mannitol and death or major disability at 90 days in patients

who were aged <65 years with large hematomas (≥15mL)

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




hematoma, intraventricular extension, and randomized BP lowering treatment




Crude No 120 84 (70.0)

Yes 368 222 (60.3) 0.65 (0.42-1.02) 0.058

Adjusted1 0.84 (0.51-1.37) 0.478

Adjusted2 0.67 (0.37-1.22) 0.187

PS matched No 117 81 (69.2)

Yes 117 65 (55.6) 0.56 (0.32-0.96) 0.035

IPTW No 120 84 (70.0)

Yes 368 222 (60.3) 0.70 (0.48-1.01) 0.059


Yes 368 222 (60.3) 0.84 (0.52-1.35) 0.474


Using the PS

No 120 84 (70.0)

Yes 368 222 (60.3) 0.86 (0.54-1.38) 0.534

12

Supplemental Table IX. Mannitol and death or major disability at 90 days in patients

who were aged <65 years with baseline NIHSS scores ≥15



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




Crude No 115 88 (76.5)

Yes 232 163 (70.3) 0.73 (0.43-1.21) 0.221

Adjusted1 0.83 (0.48-1.44) 0.514

Adjusted2 0.49 (0.22-1.07) 0.071


Yes 111 78 (70.3) 0.76 (0.42-1.38) 0.365

IPTW No 115 88 (76.5)

Yes 232 163 (70.3) 0.95 (0.59-1.51) 0.817


Yes 232 163 (70.3) 0.88 (0.52-1.50) 0.646


Using the PS

No 115 88 (76.5)

Yes 232 163 (70.3) 0.88 (0.52-1.51) 0.643

13

Supplemental Table X. Mannitol and death or major disability at 90 days in patients

from China



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




Crude No 268 93 (34.7)

Yes 1421 687 (48.4) 1.76 (1.34-2.31) <0.0001

Adjusted1 1.11 (0.81-1.52) 0.507

Adjusted2 1.10 (0.80-1.51) 0.557


Yes 268 110 (41.0) 1.31 (0.93-1.84) 0.119

IPTW No 268 93 (34.7)

Yes 1421 687 (48.4) 1.16 (0.96-1.40) 0.137


Yes 1421 687 (48.4) 1.14 (0.85-1.52) 0.394


Using the PS

No 268 93 (34.7)

Yes 1421 687 (48.4) 1.11 (0.82-1.49) 0.499

14

Supplemental Table XI. Mannitol and death or major disability at 90 days in non-China

patients



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




Crude No 725 473 (65.2)

Yes 112 88 (78.6) 1.95 (1.21-3.15) 0.006

Adjusted1 1.94 (1.10-3.43) 0.023

Adjusted2 1.91 (1.05-3.48) 0.034


Yes 111 88 (79.3) 1.99 (1.09-3.64) 0.025

IPTW No 725 473 (65.2)

Yes 112 88 (78.6) 1.67 (1.23-2.26) 0.001


Yes 112 88 (78.6) 1.61 (0.99-2.62) 0.057


Using the PS

No 725 473 (65.2)

Yes 112 88 (78.6) 1.61 (0.98-2.64) 0.058

15

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

Adjusted1

No No 227 66 (29.1) 0.116

Yes 894 345 (38.6) 1.50 (1.06-2.14)

Yes No 41 27 (65.9)

Yes 527 342 (64.9) 0.75 (0.36-1.57)

Adjusted2 No No 227 66 (29.1) 0.141

Yes 894 345 (38.6) 1.45 (1.01-2.07)

Yes No 41 27 (65.9)

Yes 527 342 (64.9) 0.77 (0.37-1.63)

PS matched No No 227 66 (29.1) 0.379

Yes 227 84 (37.0) 1.43 (0.96-2.14)

Yes No 41 27 (65.9)

Yes 41 26 (63.4) 0.90 (0.35-2.34)

IPTW No No 227 66 (29.1) 0.676

Yes 894 345 (38.6) 1.23 (0.96-1.57)

Yes No 41 27 (65.9)

Yes 527 342 (64.9) 1.13 (0.80-1.58)


Yes 894 345 (38.6) 1.22 (0.88-1.70)

Yes No 41 27 (65.9)

Yes 527 342 (64.9) 0.85 (0.43-1.68)


Using the PS

No No 227 66 (29.1) 0.505

Yes 894 345 (38.6) 1.19 (0.85-1.66)

Yes No 41 27 (65.9)

Yes 527 342 (64.9) 0.83 (0.42-1.65)

16


lowering treatment



17

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 (2.8-4.7) 3.8 (2.9-4.7) 0.02

Age, yr 68±13 61.3±12 0.02

Male 584 (64) 1196 (62) 0.31

Systolic BP, mmHg 180±17 179±17 0.04

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

18

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 (2.8-5.3) 4.1 (3.0-5.5) 0.01

Time from randomisation to BP lowering treatment, hr 0.2 (0.0-0.6) 0.1 (0.0-0.7) 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.

19

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 (0.38-0.53) <0.01 0.66 (0.54-0.82) <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.

20

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)

21

Supplemental Figure I. Propensity score distribution stratified by mannitol treatment

0

.2

.4

.6

.8

1

Pro

pe

nsity S

core

No Yes

Mannitol treatment

22

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




hematoma, log transformed baseline hematoma volume, intraventricular extension, and

randomized BP lowering treatment


deep venous thrombosis, hemostatic therapy, and any surgical intervention.

23

Supplemental Figure III. Association between mannitol treatment and death or major

disability at 90 days by age (yr)

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. Centres 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 sex, NIHSS ≥15, time to randomization, systolic BP, prior




hematoma, log transformed baseline hematoma volume, intraventricular extension, and

randomized BP lowering treatment


deep venous thrombosis, hemostatic therapy, and any surgical intervention.

25

뇌내출혈에서 만니톨과 결과성향점수와 다변수 INTERACT2

(Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 2) 결과

Mannitol and Outcome in Intracerebral HemorrhagePropensity 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 Munoz-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

(Stroke. 2015;46:2762-2767.)

Key Words: blood pressure ■ cerebral hemorrhage ■ clinical trial ■ mannitol ■ propensity score

Abstract 1

배경과 목적

만니톨은 급성뇌내출혈에서 뇌부종을 줄이기 위해 종종 사용되

지만 그 효과의 강력한 근거는 없다. 이 연구는 급성뇌출혈에서

Intensive Blood Pressure Reduction in Acute Cerebral

Hemorrhage Trial 2 (INTERACT2) 참가자들에서 만니톨의 효

과를 확인하고자 하였다.

방법

INTERACT2는 수축기 혈압상승을 동반한 자발성뇌내출혈(6시

간 이내) 환자 2839명을 집중적(1시간 이내 목표 수축기혈압

＜140 mmHg) 또는 가이드라인-권장(목표 수축기혈압 ＜180

mmHg) 혈압강하 치료를 비교한 국제, 공개, 눈가림 종결점, 무

작위 배정 대조군 연구였다. 만니톨 치료(7일 이내)와 90일째

mRS 3-6점의 사망 또는 주요 장애로 정의된 나쁜 결과 사이의

관계를 조사하기 위해 성향점수 및 다변수분석이 시행되었다.

결과

만니톨군(n=1533)과 비만니톨군(n=993) 사이에 나쁜 결과의 유

의한 차이는 없었다: 성향점수-짝지음 교차비 0.90 (95% CI,

0.75–1.09; P=0.30) 및 다변수 교차비 0.87 (95% CI, 0.71–

1.07; P=0.18). 비록 더 큰(≥15 mL) 초기 혈종을 가진 환자에서

더 작은(＜15 mL) 혈종을 가진 환자보다 만니톨 투여의 더 나은

결과가 예상되었지만(OR, 0.52 [95% CI, 0.35–0.78] vs. OR

0.91 [95% CI, 0.72–1.15]; 성향점수분석에서의 P homogeneity

(균질성)＜0.03), 이러한 관련성은 다른 기준점(cutoff point, ≥

10 및 ≥20 mL)을 통한 분석 및 신경학적 중증도의 정도에 따라

구분하면 동일하게 나타나지 않았다. 만니톨은 중대한 이상반응

의 증가와 관련이 없었다.

결론

만니톨은 급성뇌내출혈 환자에서 안전해 보이나 결과를 개선시

키지는 않는 것 같다.


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).

DiscussionThis 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 fac-tors 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.20–23

Few studies have investigated the effects of mannitol in acute ICH. An observational study6 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 recipro-cal 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 anticoagula-tion 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 indi-cates inverse probability of treatment weighting; and PS, propensity score.

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.

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.

Documents

Mannitol and Outcome in Intracerebral Hemorrhagestroke.ahajournals.org/content/strokeaha/46/10/2762.full.pdfWang et al Mannitol and Cerebral Hemorrhage 2763 trials,8,9 and a systematic