Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial

Abstract

Background: Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome.

Methods: In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134.

Findings: Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88-1·28; p=0·554]). A difference of 3·5% (RR 1·08 [95% CI 0·90-1·29], p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41-0·86], p=0·006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1·99 [95% CI 1·22-3·26], p=0·007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0·55 [95% CI 0·31-0·97], p=0·048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0·76 [95% CI 0·64-0·90], p=0·002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1·21 [95% CI 0·37-3·91], p=0·771) was similar.

Interpretation: In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status.

Funding: National Institute of Neurological Disorders and Stroke.

Copyright © 2017 Elsevier Ltd. All rights reserved.

Figures

Figure 1:. Trial profile

In the alteplase group, one participant who was initially thought to be lost to follow-up at day 30 was located and assessed at day 180.

Figure 2:. Outcome dichotomies of mRS (left panel; scores range from 0 [no disability] to 6 [death]) and eGOS (right panel; scores range from 8 [upper good recovery] to 1 [death]) scores at 30 days and 180 days by treatment

The left panel blue lines indicate the differences in proportion of 180 day mRS ≤3 (112 [45%] in the saline group vs 118 [48%] in the alteplase group; p=0·477) and deceased participants (73 [30%] in the saline group vs 46 [19%] in the alteplase group; p=0O04). mRS=modified Rankin Scale. eGOS=extended Glasgow Outcome Scale. GR=good recovery. MD=moderate disability. SD=severe disability. VS=vegetative state.

Figure 3:. Kaplan-Meier survival estimates from day of randomisation to observed day of death with truncation at 193 days for late and missed 180-day visits (n=36), which corresponds to the longest in-window 180-day visit

Estimated survival probabilities were higher throughout 180 days of follow-up with alteplase compared with saline (p=0·006). Shading shows 95% CI.

Figure 4:. Subgroup analysis

Forest plot of interaction terms, adjusted for age, sex, thalamic intracerebral haemorrhage location, stability intracerebral haemorrhage, intraventricular haemorrhage volume, and GCS (mild, 13–15; moderate, 9–12; severe, 3–8) at admission. The size of points indicates the relative sizes of the subgroups. Scores on the Glasgow Coma Scale (GCS) range from 15 (fully conscious) to 3 (deep coma). sIVH=stability intraventricular haemorrhage volume. ICH=intracerebral haemorrhage. Rnd Sx=randomised after symptom onset.