Association of intraventricular fibrinolysis with clinical outcomes in ICH: an individual participant data meta-analysis

Background: In patients with intracerebral hemorrhage (ICH) the presence of intraventricular hemorrhage (IVH) constitutes an important 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 (IPD) meta-analysis pooled 1,501 patients from two randomized trials and seven observational studies enrolled during 2004 to 2015. We compared IVF vs standard of care (SoC, including placebo) in patients treated with external ventricular drainage due to acute hydrocephalus caused by ICH and/or IVH. 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:0-3 vs mRS:4-6. 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 (OR) and absolute treatment-effects (ATE). Results: Comparing treatment of 596 with IVF to 905 with SoC resulted in an ATE to achieve the primary outcome of 9.3%[95%CI4.4-14.1]. IVF treatment showed a significant shift towards improved outcome across the entire range of mRS estimates, common-OR:1.75[95%CI1.39-2.17], reduced mortality, OR:0.47[95%CI 0.35-0.64], without increased adverse events, absolute difference:1.0%[95%CI-2.7-4.8]. Exploratory analyses provided that early IVF-treatment (≤48 hours) after symptom onset was associated with an ATE:15.2%[95%CI8.6-21.8] to achieve the primary outcome. Conclusions: As compared to SoC, the administration of IVF in patients with acute hydrocephalus caused by intracerebral and intraventricular hemorrhage significantly improved functional outcome at 6 months. The treatment effect was linked to an early time-window<48h, specifying a target population for future trials.