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Meta-Analysis
. 2019 Oct 8;322(14):1392-1403.
doi: 10.1001/jama.2019.13014.

Association of Surgical Hematoma Evacuation vs Conservative Treatment With Functional Outcome in Patients With Cerebellar Intracerebral Hemorrhage

Joji B Kuramatsu  1 , Alessandro Biffi  2   3 , Stefan T Gerner  1 , Jochen A Sembill  1 , Maximilian I Sprügel  1 , Audrey Leasure  4 , Lauren Sansing  4 , Charles Matouk  4 , Guido J Falcone  4 , Matthias Endres  5   6   7   8 , Karl Georg Haeusler  5   6   9 , Jan Sobesky  5   6 , Johannes Schurig  6 , Sarah Zweynert  5 , Miriam Bauer  6 , Peter Vajkoczy  10 , Peter A Ringleb  11 , Jan Purrucker  11 , Timolaos Rizos  11   12 , Jens Volkmann  9 , Wolfgang Müllges  9 , Peter Kraft  9 , Anna-Lena Schubert  9 , Frank Erbguth  13 , Martin Nueckel  13 , Peter D Schellinger  14 , Jörg Glahn  14 , Ulrich J Knappe  15 , Gereon R Fink  16 , Christian Dohmen  16 , Henning Stetefeld  16 , Anna Lena Fisse  17 , Jens Minnerup  17 , Georg Hagemann  18 , Florian Rakers  18 , Heinz Reichmann  19 , Hauke Schneider  19   20 , Jan Rahmig  19 , Albert Christian Ludolph  21 , Sebastian Stösser  21 , Hermann Neugebauer  9   21 , Joachim Röther  22 , Peter Michels  22 , Michael Schwarz  23 , Gernot Reimann  23 , Hansjörg Bäzner  24 , Henning Schwert  24 , Joseph Claßen  25 , Dominik Michalski  25 , Armin Grau  26 , Frederick Palm  26 , Christian Urbanek  26 , Johannes C Wöhrle  27 , Fahid Alshammari  27 , Markus Horn  28 , Dirk Bahner  28 , Otto W Witte  29 , Albrecht Günther  29 , Gerhard F Hamann  30 , Manuel Hagen  1 , Sebastian S Roeder  1 , Hannes Lücking  31 , Arnd Dörfler  31 , Fernando D Testai  32 , Daniel Woo  33 , Stefan Schwab  1 , Kevin N Sheth  4 , Hagen B Huttner  1
Affiliations
Meta-Analysis

Association of Surgical Hematoma Evacuation vs Conservative Treatment With Functional Outcome in Patients With Cerebellar Intracerebral Hemorrhage

Joji B Kuramatsu et al. JAMA. .

Abstract

Importance: The association of surgical hematoma evacuation with clinical outcomes in patients with cerebellar intracerebral hemorrhage (ICH) has not been established.

Objective: To determine the association of surgical hematoma evacuation with clinical outcomes in cerebellar ICH.

Design, setting, and participants: Individual participant data (IPD) meta-analysis of 4 observational ICH studies incorporating 6580 patients treated at 64 hospitals across the United States and Germany (2006-2015).

Exposure: Surgical hematoma evacuation vs conservative treatment.

Main outcomes and measures: The primary outcome was functional disability evaluated by the modified Rankin Scale ([mRS] score range: 0, no functional deficit to 6, death) at 3 months; favorable (mRS, 0-3) vs unfavorable (mRS, 4-6). Secondary outcomes included survival at 3 months and at 12 months. Analyses included propensity score matching and covariate adjustment, and predicted probabilities were used to identify treatment-related cutoff values for cerebellar ICH.

Results: Among 578 patients with cerebellar ICH, propensity score-matched groups included 152 patients with surgical hematoma evacuation vs 152 patients with conservative treatment (age, 68.9 vs 69.2 years; men, 55.9% vs 51.3%; prior anticoagulation, 60.5% vs 63.8%; and median ICH volume, 20.5 cm3 vs 18.8 cm3). After adjustment, surgical hematoma evacuation vs conservative treatment was not significantly associated with likelihood of better functional disability at 3 months (30.9% vs 35.5%; adjusted odds ratio [AOR], 0.94 [95% CI, 0.81 to 1.09], P = .43; adjusted risk difference [ARD], -3.7% [95% CI, -8.7% to 1.2%]) but was significantly associated with greater probability of survival at 3 months (78.3% vs 61.2%; AOR, 1.25 [95% CI, 1.07 to 1.45], P = .005; ARD, 18.5% [95% CI, 13.8% to 23.2%]) and at 12 months (71.7% vs 57.2%; AOR, 1.21 [95% CI, 1.03 to 1.42], P = .02; ARD, 17.0% [95% CI, 11.5% to 22.6%]). A volume range of 12 to 15 cm3 was identified; below this level, surgical hematoma evacuation was associated with lower likelihood of favorable functional outcome (volume ≤12 cm3, 30.6% vs 62.3% [P = .003]; ARD, -34.7% [-38.8% to -30.6%]; P value for interaction, .01), and above, it was associated with greater likelihood of survival (volume ≥15 cm3, 74.5% vs 45.1% [P < .001]; ARD, 28.2% [95% CI, 24.6% to 31.8%]; P value for interaction, .02).

Conclusions and relevance: Among patients with cerebellar ICH, surgical hematoma evacuation, compared with conservative treatment, was not associated with improved functional outcome. Given the null primary outcome, investigation is necessary to establish whether there are differing associations based on hematoma volume.

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Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Huttner reports receipt of personal fees (advisory board services) from Boehringer Ingelheim, Bayer AG, and CSL Behring; and research grants from Medtronic, Novartis, and UCB outside the submitted work. Dr Bäzner reports receipt of personal fees (honoraria for lectures) from Bayer Vital, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo outside the submitted work. Dr Endres reports receipt of grants to his institution (Mondafis trial and Berlin AFib registry) from Bayer; other from Bayer (lectures, consulting, and advisory board participation), Boehringer Ingelheim and Amgen (lectures and advisory board participation), Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Sanofi, and Novartis (lectures), and Daiichi Sankyo and Coviden (advisory board participation) (all fees paid to the institution) outside the submitted work. Dr Fink reports receipt of personal fees (lectures) from Bayer, Pfizer, Desitin, Novartis, GlaxoSmithKline, DKV, FomF (Forum for Medical Education), and Medica Academy during the conduct of the study. Dr Günther reports grants from Daichii Sankyo, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Bayer, and Ipsen Pharma outside the submitted work. Dr Haeusler reports receipt of grants and personal fees from Bayer; personal fees from Boehringer Ingelheim, Daiichi Sankyo, Bristol-Myers Squibb, Pfizer, Medtronic, Biotronik, W.L. Gore and Associates, and Edwards Lifesciences, and nonfinancial support from Getemed AG outside the submitted work. Dr Kraft reports receipt of grants and personal fees from Daiichi Sankyo and personal fees from Pfizer, Boehringer Ingelheim, and Bayer outside the submitted work. Dr Kuramatsu reports grants from Johannes and Frieda Marohn Foundation during the conduct of the study; personal fees from Boehringer Ingelheim, Bayer AG, CSL Behring, and Sanofi, and grants from Medtronic outside the submitted work. Dr Muellges reports receipt of speakers honoraria from Bayer and by Boehringer Ingelheim outside the submitted work. Dr Palm reports receipt of personal fees (speakers honoraria) from Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo outside the submitted work. Dr Purrucker reports receipt of personal fees and nonfinancial support from Pfizer and personal fees from Boehringer Ingelheim, Daiichi Sankyo, and Akcea outside the submitted work. Dr Ringleb reports receipt of personal fees from Bayer, Boehringer Ingelheim, and Pfizer outside the submitted work. Dr Rizos reports receipt of consulting honoraria, speakers honoraria, and travel support from BMS Pfizer, Boehringer Ingelheim, Bayer Healthcare, and Daiichi Sankyo outside the submitted work. Dr Sansing reports receipt of grants from the National Institute of Neurological Disorders and Stroke (NINDS) and personal fees from Genentech outside the submitted work. Dr Schellinger reports receipt of personal fees from Boehringer Ingelheim and Daiichi Sankyo during the conduct of the study; personal fees from Medtronic and German Courts (expert witness) outside the submitted work. Dr Schwert reports receipt of grants from Bayer Healthcare during the conduct of the study. Dr Sheth reports receipt of grants from the National Institutes of Health (NIH)/NINDS and from Novartis during the conduct of the study; grants from Bard, Hyperfine, and the American Heart Association outside the submitted work. Dr Sobesky reports receipt of speakers honoraria from Pfizer, Boehringer Ingelheim, and Daiichi Sankyo. Dr Testai reports receipt of grants from NIH/NINDS during the conduct of the study. Dr Wöhrle reports receipt of personal fees (speakers honoraria) from Boehringer Ingelheim GmbH and Daiichi Sankyo GmbH outside the submitted work. Dr Woo reports receipt of grants from NIH during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flow Diagram of Study Population and Data Analysis
Flow diagram providing the systematic database search, screening, eligibility, exclusion, and generation of the study population available for individual participant data (IPD) contribution, based on PRISMA-IPD (Preferred Reporting Items for Systematic Review and Meta-analysis of IPD) guidelines. This study consisted of a systematic review and aggregate data meta-analysis of previously published studies and an IPD meta-analysis. aIndicates institutional data sharing regulations not allowing IPD contribution. bIndicates study design not fulfilling PRISMA-IPD criteria. cParticipation was refused due to conflicting ongoing investigations. dOverall, IPD of 6580 adult patients with primary spontaneous ICH were provided by four observational studies (NCT01829581, NCT03093233, NCT03183167, NCT01202864) and 578 patients with cerebellar ICH according to predefined eligibility criteria were identified. The German studies (NCT01829581, NCT03093233, NCT03183167) contributed 342 cerebellar ICH patients recruited at 22 hospitals, and the American study (NCT01202864) contributed 236 cerebellar ICH patients recruited at 42 hospitals. eEarly care limitations indicate the initiation of comfort care measures within 24 hours after hospital admission. fThe modified Rankin Scale (mRS) score ranges from 0 (indicating no deficit) to 6 (death). ICH indicates intracerebral hemorrhage.
Figure 2.
Figure 2.. Distribution of Modified Rankin Scale Scores at 3 and 12 Months for the Propensity Score–Matched Cohort
The modified Rankin Scale (mRS) scores range from 0 (indicating no deficit) to 6 (death). Each cell corresponds with a score on the mRS; the width of the cell indicates the proportion of patients with equivalent scores, and the number of patients is shown within the cell. The diagonal line between the 2 study groups indicates the comparison of outcome in each severity stratum. Statistical analyses compared scores (mRS 0-3 vs 4-6 and mRS 0-5 vs 6) according to treatment exposure with corresponding significance level (χ2 model). Favorable outcome was defined as a score of 0 to 3 (3 indicates being able to walk independently with a walker or a cane).
Figure 3.
Figure 3.. Exploratory Subgroup Analyses of Primary and Secondary Outcomes According to Treatment Exposure of the Propensity Score–Matched Cohort
Panel A shows the primary outcome (modified Rankin Scale [mRS] 0-3 vs 4-6); panel B shows the secondary outcome (mRS 0-5 vs 6) using logistic regressions by a generalized estimating equations model, as described in the Statistical Analysis section. Exploratory subgroup analyses of the propensity score matched–cohort were displayed as forest plots using as dependent variables primary and secondary outcomes without the subgroup-defining variable on categorized regression models. Heterogeneity was considered significant for P values of less than .5 and interactions of exploratory subgroup analyses were tested using the subgroup-defining variable (variable × intervention) and conservative treatment as reference. Adjusted results and unadjusted frequency distributions and multiplicity correction are available online (eTables 8-11 in the Supplement). mRS score range: 0 (no deficit) to 6 (death).
Figure 4.
Figure 4.. Independent Associations of the Intervention With ICH Volumes
Panels A and C: graphical linear regression applied on predicted probability values to achieve the primary outcome (panel A, modified Rankin Scale [mRS 0-3]) and the secondary outcome (survival) (panel C, mRS 0-5) derived from an adjusted logistic regression (generalized estimating equations) model. Values were calculated for each individual patient of the entire cohort using the same adjustments and interaction terms as described. Adjustments: age, Glasgow Coma Scale, intracerebral hemorrhage (ICH) volume, intraventricular hemorrhage, interaction terms (study × intervention, on-hour admission × intervention, reversal treatment × intervention), and the coefficient of variation for ICH volume measurements. Intersections of the 95% CIs of graphical linear regression analysis (surgical hematoma evacuation vs conservative treatment) were used to identify cutoff values. Panels B and D: validation of predicted associations based on observed data points graphically depicted as adjusted odds ratio (OR) estimates for surgical hematoma evacuation vs conservative treatment with the primary outcome (panel B, mRS 0-3) and the secondary outcome (survival) panel D, mRS 0-5). Adjusted OR estimates were calculated within specific volume frames (frames = sliding windows, using a variable volume range determined by the median of this window sliding upwards at 1-cm3 steps) corrected for measurement error by the coefficient of variation and for overestimation by the method of moving averages. Mean estimates are shown with 95% CIs for volume intervals of 3 cm3. Circle size indicates the proportional number of patients included within regression models. An identical procedure was used for the secondary outcome (survival at 3 months).
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