Association of Intraventricular Fibrinolysis With Clinical Outcomes in Intracerebral Hemorrhage: An Individual Participant Data Meta-Analysis
Authors: Kuramatsu Joji B. , Gerner Stefan T. , Ziai Wendy , Bardutzky Jürgen , Sembill Jochen A. , Sprügel Maximilian I. , Mrochen Anne , Kölbl Kathrin , Ram Malathi , Avadhani Radhika , Falcone Guido J. , Selim Magdy H. , Lioutas Vasileios-Arsenios , Endres Matthias , Zweynert Sarah , Vajkoczy Peter , Ringleb Peter A. , Purrucker Jan C. , Volkmann Jens , Neugebauer Hermann , Erbguth Frank , Schellinger Peter D. , Knappe Ulrich J. , Fink Gereon R. , Dohmen Christian , Minnerup Jens , Reichmann Heinz , Schneider Hauke , Röther Joachim , Reimann Gernot , Schwarz Michael , Bäzner Hansjörg , Claßen Joseph , Michalski Dominik , Witte Otto W. , Günther Albrecht , Hamann Gerhard F. , Lücking Hannes , Dörfler Arnd , Ishfaq Muhammad Fawad , Chang Jason J. , Testai Fernando D. , Woo Daniel , Alexandrov Andrei V. , Staykov Dimitre , Goyal Nitin , Tsivgoulis Georgios , Sheth Kevin N. , Awad Issam A. , Schwab Stefan , Hanley Daniel F. , Huttner Hagen B. , Sansing Lauren , Matouk Charles C. , Leasure Audrey , Sobesky Jan , Bauer Miriam , Schurig Johannes , Rizos Timolaos , Haeusler Karl Georg , Müllges Wolfgang , Kraft Peter , Schubert Anna-Lena , Stösser Sebastian , Ludolph Albert Christian , Nueckel Martin , Glahn Jörg , Stetefeld Henning , Rahmig Jan , Fisse Anna Lena , Michels Peter , Schwert Henning , Hagemann Georg , Rakers Florian , Wöhrle Johannes C. , Alshammari Fahid , Horn Markus , Bahner Dirk , Urbanek Christian , Palm Frederick , Grau Armin 
Published: May 2022

Background:
In patients with intracerebral hemorrhage (ICH), the presence of intraventricular hemorrhage constitutes a promising therapeutic target. Intraventricular fibrinolysis (IVF) reduces mortality, yet impact on functional disability remains unclear. Thus, we aimed to determine the influence of IVF on functional outcomes.

Methods:
This individual participant data meta-analysis pooled 1501 patients from 2 randomized trials and 7 observational studies enrolled during 2004 to 2015. We compared IVF versus standard of care (including placebo) in patients treated with external ventricular drainage due to acute hydrocephalus caused by ICH with intraventricular hemorrhage. The primary outcome was functional disability evaluated by the modified Rankin Scale (mRS; range: 0–6, lower scores indicating less disability) at 6 months, dichotomized into mRS score: 0 to 3 versus mRS: 4 to 6. Secondary outcomes included ordinal-shift analysis, all-cause mortality, and intracranial adverse events. Confounding and bias were adjusted by random effects and doubly robust models to calculate odds ratios and absolute treatment effects (ATE).

Results:
Comparing treatment of 596 with IVF to 905 with standard of care resulted in an ATE to achieve the primary outcome of 9.3% (95% CI, 4.4–14.1). IVF treatment showed a significant shift towards improved outcome across the entire range of mRS estimates, common odds ratio, 1.75 (95% CI, 1.39–2.17), reduced mortality, odds ratio, 0.47 (95% CI, 0.35–0.64), without increased adverse events, absolute difference, 1.0% (95% CI, −2.7 to 4.8). Exploratory analyses provided that early IVF treatment (≤48 hours) after symptom onset was associated with an ATE, 15.2% (95% CI, 8.6–21.8) to achieve the primary outcome.

Conclusions:
As compared to standard of care, the administration of IVF in patients with acute hydrocephalus caused by intracerebral and intraventricular hemorrhage was significantly associated with improved functional outcome at 6 months. The treatment effect was linked to an early time window <48 hours, specifying a target population for future trials.