Ericka Samantha Teleg, MD

Kuramatsu JB, Gerner ST, Ziai WC, Bardutzky J, Sembill JA, Sprügel MI, Mrochen A, Kölbl K, Ram M, Avadhani R, et al. Association of Intraventricular Fibrinolysis With Clinical Outcomes in ICH: An Individual Participant Data Meta-Analysis. Stroke. 2022.

This meta-analysis examines the utilization of intraventricular fibrinolysis (IVF) and its impact on clinical outcomes in intracerebral hemorrhage. Despite several studies showing intraventricular clot resolution and safety among an intracerebral hemorrhage (ICH) population with a small hematoma volume but larger intraventricular hemorrhage volumes, the primary efficacy analyses for functional outcomes were neutral. Thus, tailoring clinical selection of patients that may benefit from IVF may determine functional benefit.

The statistical method that the authors have utilized to summarize data from several trials and observational data is crucial, as this kind of method used in meta-analysis preserves the clustering of the cohorts of patients from the different studies. This method also allows a large sample to be studied. This is the strength of the data and its results. The Individual Participant Data meta-analysis included 9 studies. The IPD set was compiled and analyzed in an academic center, University Hospital Erlangen in Germany. The eligibility for IPD inclusion included the following: (1) supratentorial primary ICH or IVH with IVH causing acute hydrocephalus treated with an external ventricular drainage (EVD); (2) patients aged >18 years; (3) pre-morbid modified Rankin Scale (mRS) < 3; (4) >10 patients treated with IVF within each study framework; (5) no evidence of early care limitations or death within 48 hours after admission; (6) no evidence of secondary ICH-etiologies; (7) no other competing treatment intervention; (8) use of validated imaging methods; (9) standardized scoring of neurological status; (10) availability of standardized functional outcome assessed by the mRS. 

IVF as the intervention consisted in alteplase (1m/ml) through an EVD until the stopping point was achieved. The stopping point was defined as the radiographic opening on the 3rd and 4th ventricles, relieved IVH mass effect, or reached a maximum dose according to individual study protocols. This was compared to standard of care, placebo treatment (CLEAR III), or EVD management.

The meta-analysis included 1,501 patients from 2 randomized trials and 7 observational studies from 2004 to 2015. Five hundred ninety-six patients received IVF compared to 905 patients who received standard of care. The primary outcome was pre-defined as the proportion of patients achieving favorable functional outcome at 6 months. Dichotomous mRS include mRS: 0-3 and mRS: 4-6. Secondary outcomes included ordinal shift of analysis of the mRS values at 6 months, all-cause mortality at 6 months and adverse events defined as any intracranial bleeding complication or bacterial infection occurring within 30 days after the index event.

Overall, results derived from the analyses of the primary outcome with the adjusted absolute treatment effect of IVF to achieve a favorable functional outcome at 6 months was 9.3% (p<0.001) according to the most conservative model identified by sensitivity analyses. Factors that were related to improve outcome included early time window (<48 hours) with an effect-size of 15%. The authors have tried to determine why the IPD analyses showed positive associations while individual trials showed neutral results. In their discussion, the differences in patient selection and treatment characteristics among the observational studies may account for these differences. Authors emphasized that such a priori selection bias was addressed by the statistical methods applied. The challenge of this IPD analysis incorporating such large data sets is that large differences in patient data exist and are needed to answer several clinical questions for applicability.

The study has utilized two important subgroups from the CLEAR III cohort. These are patients with intermediate sized IVH volumes. Also, time from symptom onset to randomization was considered. Hence, individualizing the treatment may surely determine better benefit and outcome. This, in effect, applies to the intervention trials in stroke that have been undergone.