Stroke

CLEAR III trial: thrombolytic removal of intraventricular haemorrhage

In the setting of haemorrhagic stroke, presence of intraventricular haemorrhage is a hallmark of poor prognosis with case-fatality up to 60%.1,2 Data suggested that removal of intraventricular haemorrhage, by administration of recombinant tissue-type plasminogen activator (rtPA), improves survival and long-term functional outcome.3,4 Data from the The Clot Lysis: Evaluating Accelerated Resolution of IVH (CLEAR IVH) showed that rtPA accelerates resolution of intraventricular haemorrhage with a dose-dependent effect.5 The Evaluating Accelerated Resolution of Intraventricular Haemorrhage (CLEAR III) trial, a randomised, double-blinded study, tested possible benefits of the combination of extraventricular drainage and low dose alteplase as a method to remove intraventricular haemorrhage and improve functional outcomes.6

Comment:

In the setting of haemorrhagic stroke, presence of intraventricular haemorrhage is a hallmark of poor prognosis with case-fatality up to 60%.1,2 Data suggested that removal of intraventricular haemorrhage, by administration of recombinant tissue-type plasminogen activator (rtPA), improves survival and long-term functional outcome.3,4 Data from the The Clot Lysis: Evaluating Accelerated Resolution of IVH (CLEAR IVH) showed that rtPA accelerates resolution of intraventricular haemorrhage with a dose-dependent effect.5 The Evaluating Accelerated Resolution of Intraventricular Haemorrhage (CLEAR III) trial, a randomised, double-blinded study, tested possible benefits of the combination of extraventricular drainage and low dose alteplase as a method to remove intraventricular haemorrhage and improve functional outcomes.6

The CLEAR III trial6 included patients with stable non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology. All patients had a clinical diagnosis of obstructive hydrocephalus, and placement of an extraventricular drain pre-trial was a routine clinical care decision. Included patients were adaptively randomly assigned (1:1) via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of rtPA or 0.9% saline via the extraventricular drain. Investigators were asked to remove as much clot as possible, until a stopping point was obtained: 3rd and 4th ventricles open; intraventricular haemorrhage mass effect relieved; 80% of clot removed; or 12 doses given. The treating physician, clinical research staff, and participants were masked to treatment assignment. Computed tomography scans were obtained every 24 h throughout dosing.

The trial involved 73 sites; 500 patients were randomised: 249 to the rtPA group and 251 to the saline group. Participants received the first extraventricular drain at 7.5 h (IQR 5.0–12.0). Randomisation occurred at 52.1 h (IQR 39.1–66.5), with first treatment given 3.0 h (1.7–5.5) later.

In the alteplase group, the 3rd and 4th ventricles opened more rapidly than in the saline group (p<0·0001), however, active treatment did not improve functional outcome. The primary intention-to-treat analysis indicated that a modified Rankin Scale (mRS) score ≤ 3 was achieved by 117 patients (48%) in the rtPA group and 110 (45%) in the saline group (RR 1.06; 95% CI 0.88–1.28; p=0.554).

There was a 50% decrease in the odds of being dead for rtPA versus saline (adjusted OR 0.50; 95% CI 0.31–0·80; p=0.004). However, most of these survivors ended up with severe disability.

rtPA seemed safe when compared with saline. Safety parameters favoured rtPA: bacterial ventriculitis (7% vs 12%; RR 0.55; 95% CI 0.31–0.97; p=0.048) and serious adverse events (46% vs 60%; RR 0.76; 95% CI 0.64–0.90; p=0.002). The frequency of symptomatic bleeding was similar between groups (RR 1.21; 95% CI 0.37–3.91; p=0.771).

Clot removal analyses showed an association between amount of removal and improved odds of mRS ≤3. These findings raise the possibility that benefit of rtPA might be possible if greater clot removal could be achieved and, if it is achieved, more rapidly.

As the trial was neutral on primary outcome of functional improvement, authors suggested that current practice should not change. However, it cannot be excluded that clot removal may save lives and provide also functional benefits. Future investigations will need improved surgical placement of catheters to achieve effective clot reduction more frequently and more rapidly.

 

References:

1.      Sacco S, Ornello R, Degan D, Tiseo C, Pistoia F, Carolei A. Declining incidence of intracerebral hemorrhage over two decades in a population-based study. Eur J Neurol 2016;23:1627–34.

2.      Tuhrim S, Horowitz DR, Sacher M, Godbold JH. Volume of ventricular blood is an important determinant of outcome in supratentorial intracerebral hemorrhage. Critical Care Med 1999; 27: 617–21.

3.      Gaberel T, Magheru C, Parienti J-J, Huttner HB, Vivien D, Emery E. Intraventricular fi brinolysis versus external ventricular drainage alone in intraventricular hemorrhage a meta-analysis. Stroke 2011;42:2776–81.

4.      Moradiya Y, Murthy SB, Newman-Toker DE, Hanley DF, Ziai WC. Intraventricular thrombolysis in intracerebral hemorrhage requiring ventriculostomy a decade-long real-world experience. Stroke 2014; 45: 2629–35.

5.      Webb AJ, Ullman NL, Mann S, Muschelli J, Awad IA, Hanley DF. Resolution of intraventricular hemorrhage varies by ventricular region and dose of intraventricular thrombolytic: the Clot Lysis: Evaluating Accelerated Resolution of IVH (CLEAR IVH) program. Stroke 2012;43:1666–8.

6.      Hanley DF, Lane K, McBee N, Ziai W, Tuhrim S, Lees KR, Dawson J, Gandhi D, Ullman N, Mould WA, Mayo SW, Mendelow AD, Gregson B, Butcher K, Vespa P, Wright DW, Kase CS, Carhuapoma JR, Keyl PM, Diener-West M, Muschelli J, Betz JF, Thompson CB, Sugar EA, Yenokyan G, Janis S, John S, Harnof S, Lopez GA, Aldrich EF, Harrigan MR, Ansari S, Jallo J, Caron JL, LeDoux D, Adeoye O, Zuccarello M, Adams HP, Rosenblum M, Thompson RE, Awad IA, for the CLEAR III Investigators. Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial. Lancet 2017;389:603–11.

 

 

 

Key points:

1.      CLEAR III was performed on a small and selective sample of patients with intracerebral bleeding and obstructive hydrocephalus from intraventricular haemorrhage at the end of our current treatment spectrum: participants in the trial were those in whom physicians decided to use extraventricular drains and the control intervention represented an aggressive level of care not offered to every patient with intraventricular haemorrhage.

2.      CLEAR III trial shows that clot removal in intraventricular haemorrhage is neutral on functional outcome. Secondary analyses suggest that clot removal may improve mortality at the cost of increased disability.

3.      CLEAR III trial provides detailed evidence that the investigational protocol to remove intraventricular haemorrhage with alteplase is safe and that the 3rd and 4th ventricles open sooner if alteplase is used.

4.      The secondary results of the CLEAR III trial open a possible role of intraventricular haemorrhage volume reduction as a biomarker for treatment effects of intraventricular clot lysis: better outcomes were more likely achieved with enhanced intraventricular haemorrhage clearance, particularly in patients with larger initial intraventricular haemorrhage volume.