Hanley DF, Lane K, McBee N, et al. Lancet. 2017;389:603-11.
Study Question: Does intraventricular thrombolytic administration improve functional outcomes in patients with intraventricular hemorrhage (IVH)?
Study Description: This multicenter, prospective, double-blind trial included adults with IVH diagnosed within 24 hours of symptom onset and had an extraventricular drain (EVD) placed to manage obstructive hydrocephalus from September 2009 to January 2015. Patients were randomized to receive either alteplase 1 mg or normal saline placebo via EVD every 8 hours for up to 12 doses. CT scans were obtained daily during study drug administration. Patients received study drug until one of four pre-determined stopping points was reached: the 3rd and 4th ventricles were open, intraventricular mass effect was relieved, 80% of clot was removed, or all 12 doses were given. The primary outcome was defined as a mRS of ≤3 at 180 days.
Results: A total of 500 patients were included in the study (alteplase: n=249, placebo: n=251). Median National Institutes of Health Stroke Scale scores at randomization were similar (alteplase: 19, IQR 11-32 vs. placebo: 20, IQR 11-35), as were IVH (21.2, IQR 12.7-34.2 vs. 22.4 mL, IQR 12.7-39.1) and intracerebral volumes (8.3, IQR 2.9-15.2 vs. 7.2 mL, IQR 2.3-14.7) between groups. Patients in the alteplase group received a median of 5 doses (IQR 3-8) of study drug compared to 12 doses (IQR 9-12) in the placebo group (p<0.0001). There was no difference in the primary outcome between the two groups (48% vs. 45%; RR 1.06, 95% CI 0.88-1.28; p=0.554). Odds of mortality at 180 days were smaller in the alteplase group (OR 0.5, 95% CI 0.31-0.80; p=0.004), but more patients in this group had a mRS score of 5 (bedbound) at 180 days (17% vs. 9%; RR 1.99, 95% CI 1.22-3.26; p=0.007).
Conclusion: In patients with IVH and consequent hydrocephalus, intraventricular administration of alteplase was not associated with any difference in favorable functional outcomes at 180 days.
Perspective: This study does not lend support to the routine use of alteplase to assist with management of obstructive hydrocephalus associated with IVH. However, it was associated with increased clearance of clot, improved cerebral perfusion pressures, and shorter time to resolution of hydrocephalus. Additionally, there was a decrease in mortality at 180 days with treatment of alteplase. Further studies should evaluate the use of alteplase, quantity and location of EVDs, and rapidity of clot reduction.