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

Abstract

Summary 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.

Minimally invasive endoscopic hematoma evacuation vs best medical management for spontaneous basal-ganglia intracerebral hemorrhage

“…The MISTIE technique requires several days to effect clearance of the hemorrhage and entails the additional risk of an indwelling parenchymal catheter that must be manipulated multiple times over several days for tissue plasminogen activator (tPA) injections. It also requires many follow-up CT scans to monitor catheter position and the hemorrhage evacuation, and is thus relatively time and resource-intensive 17. In contrast to the prolonged thrombolytic drainage required in MISTIE, the Apollo system achieves immediate hematoma evacuation during the procedure and does not require tPA administration.…”

Magnetic resonance–guided, high-intensity focused ultrasound sonolysis: potential applications for stroke

“…The results of recent randomized trials suggest that catheter-based hematoma evacuation may be advantageous in select patients. 24,48,52 However, an important consideration in this approach is catheter alignment along the long axis of the clot, which can be challenging without compromising critical structures. 51 Alternatively, MRg-HIFU sonolysis is not only noninvasive but also selectively targets clots of any shape, located in any deep brain region.…”

“…Thus, MRg-HIFU sonolysis may be a particularly effective therapy for patients with intraventricular hemorrhage for whom surgical clot evacuation is not beneficial. 24 One drawback of MRg-HIFU is its inability to lyse clots within 2 cm of the calvaria because of bony attenuation and heat generation; however, these superficial clots are more likely to be amenable to surgical evacuation. 39,61 In addition, technical complexity and time requirements represent limitations to the current application of MRg-HIFU sonolysis in both AIS and ICH.…”

Hyperacute management of intracerebral haemorrhage

“…However, evidence so far has shown that additional clot lysis with thrombolytic agents reduces mortality without improving functional outcome so this intervention requires further investigation before it might be considered beneficial. 21 An individual patient data meta-analysis of trials where early haematoma evacuation was tested for supratentorial ICH suggests certain patient characteristics may be associated with benefit from early haematoma evacuation, including age 50-70 years old, a Glasgow Coma Scale score of 9-12 or an ICH volume of 20-50 mL. 22 Minimally invasive surgery with or without clot lysis is in late stage investigation.…”