Joji B Kuramatsu1, Stefan T Gerner1, Wendy Ziai2, Stefan Schwab1, Daniel F Hanley2, Hagen B Huttner1, Jürgen Bardutzky3, Jochen A Sembill1, Maximilian I Sprügel1, Anne Mrochen1, Kathrin Kölbl1, Malathi Ram2, Radhika Avadhani2, Guido J Falcone4,5, Magdy H Selim6, Vasileios-Arsenios Lioutas6, Matthias Endres7,8,9,10, Sarah Zweynert7, Peter Vajkoczy11, Peter A Ringleb12, Jan C Purrucker12, Jens Volkmann13, Hermann Neugebauer13,14, Frank Erbguth15, Peter D Schellinger16, Ulrich J Knappe17, Gereon R Fink18, Christian Dohmen18,19, Jens Minnerup20, Heinz Reichmann21, Hauke Schneider21,22, Joachim Röther23, Gernot Reimann24, Michael Schwarz24, Hansjörg Bäzner25, Joseph Claßen26, Dominik Michalski26, Otto W Witte27, Albrecht Günther27, Gerhard F Hamann28, Hannes Lücking29, Arnd Dörfler29, Muhammad Fawad Ishfaq30, Jason J Chang31, Fernando D Testai32, Daniel Woo33, Andrei V Alexandrov30, Dimitre Staykov1, Nitin Goyal30, Georgios Tsivgoulis30,34, Kevin N Sheth5, Issam A Awad35. 1. Department of Neurology (J.B.K., S.T.G., J.A.S., M.I.S., A.M., K.K., D.S., S.S., H.B.H.), University of Erlangen-Nuremberg, Germany. 2. Division of Brain Injury Outcomes, Johns Hopkins University, Baltimore, MD (W.Z., M.R., R.A., D.F.H.). 3. Department of Neurology, University of Freiburg, Germany (J.B.). 4. Department of Neurology (G.J.F.), Yale University School of Medicine, New Haven, CT. 5. Department of Neurosurgery (G.J.F., K.N.S.), Yale University School of Medicine, New Haven, CT. 6. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (M.H.S., V.A.L.). 7. Department of Neurology (M.E., S.Z.), Charité-Universitätsmedizin Berlin, Germany. 8. Center for Stroke Research Berlin, Germany (M.E.). 9. German Centre for Cardiovascular Research (DZHK) (M.E.). 10. German Center for Neurodegenerative Diseases (DZNE) (M.E.). 11. Department of Neurosurgery (P.V.), Charité-Universitätsmedizin Berlin, Germany. 12. Department of Neurology, Heidelberg University Hospital, Germany (P.A.R., J.C.P.). 13. Department of Neurology, University of Würzburg, Germany (J.V., H.N.). 14. Department of Neurology, University of Ulm, Germany (H.N.). 15. Department of Neurology, Nuremberg General Hospital, Germany (F.E.). 16. Department of Neurology and Neurogeriatry (P.D.S.), Johannes Wesling Medical Center Minden, Germany. 17. Department of Neurosurgery (U.J.K.), Johannes Wesling Medical Center Minden, Germany. 18. Department of Neurology, University of Cologne, Germany (G.R.F., C.D.). 19. Department of Neurology, LVR-Hospital Bonn, Germany (C.D.). 20. Department of Neurology, University of Münster, Germany (J.M.). 21. Department of Neurology, University of Dresden, Germany (H.R., H.S.). 22. Department of Neurology, Klinikum Augsburg, Germany (H.S.). 23. Department of Neurology, Asklepios Klinikum Hamburg Altona, Germany (J.R.). 24. Department of Neurology, Klinikum Dortmund, Germany (G.R., M.S.). 25. Department of Neurology, Klinikum Stuttgart, Germany (H.B.). 26. Department of Neurology, University of Leipzig, Germany (J.C., D.M.). 27. Department of Neurology, University of Jena, Germany (O.W.W., A.G.). 28. Department of Neurology and Neurological Rehabilitation, Bezirkskrankenhaus Günzburg, Germany (G.F.H.). 29. Department of Neuroradiology (H.L., A.D.), University of Erlangen-Nuremberg, Germany. 30. Department of Neurology, University of Tennessee Health Science Center, Memphis (M.F.I., A.V.A., N.G., G.T.). 31. Department of Critical Care Medicine, MedStar Washington Hospital Center, Washington, DC (J.J.C.). 32. Department of Neurology and Rehabilitation, University of Illinois College of Medicine, Chicago (F.D.T.). 33. Department of Neurology and Rehabilitation Medicine, University of Cincinnati, OH (D.W.). 34. Second Department of Neurology, Attikon University Hospital, School of Medicine, Greece (G.T.). 35. Department of Neurosurgery, University of Chicago, IL (I.A.).
Abstract
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.
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.
Entities:
Keywords:
fibrinolysis; hydrocephalus; intracerebral hemorrhage; mortality; standard of care
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