Thrombolytic Removal of Intraventricular Hemorrhage in Treatment of Severe Stroke
Does intraventricular alteplase improve functional outcome in patients with intraventricular hemorrhage (IVH)?
The CLEAR III trial was a phase 3, multicenter, randomized trial at 73 international sites that randomized patients with small intracerebral hemorrhage (ICH) (≤30 ml) with an intraventricular component, and obstructive hydrocephalus to intraventricular saline or alteplase, administered via an extraventricular drain (EVD). Patients received 1 mg of alteplase or saline placebo every 8 hours until the third and fourth ventricles were open, IVH mass effect was relieved, 80% of the intraventricular clot was removed, or 12 doses were administered. Head computed tomographies were performed every 24 hours throughout dosing. The primary outcome was disability at 6 months, as measured by a dichotomized modified Rankin Scale (mRS) score: ≤3 versus >3. A mRS score of 3 indicates moderate disability and lower values represent more functional independence. Investigators, patients, and endpoint evaluators were blinded to treatment assignment and the outcome mRS score was adjudicated centrally.
There were 500 patients randomized between September 2009 and January 2015. The analysis includes 246 patients in the alteplase group and 245 patients in the placebo group. The groups were well matched on clinical and demographic factors. The mean IVH volume was 21.8 ml and the mean ICH volume was 7.9 ml. There was no difference in the primary outcome between the two groups: 48% of patients in the alteplase group and 45% in the placebo group had a mRS score ≤3 (relative risk, 1.06; 95% confidence interval [CI], 0.88-1.28). Patients in the alteplase group were less likely to be dead at 6 months than those in the placebo group (adjusted odds ratio, 0.50; 95% CI, 0.31-0.80), although severe disability (mRS 5) was more common in the alteplase group. There were fewer infectious complications and serious adverse events in the alteplase group and no increased risk of bleeding. Only about one-fifth of patients had 80% of their intraventricular clot removed; 33% in the alteplase group versus 10% in the placebo group. After adjustment for prognostic factors, there were associations between clot removal and functional outcome and mortality.
The authors concluded that intraventricular alteplase does not improve functional outcome in patients with IVH.
ICH is a devastating disease and ICH patients with IVH are at high risk of mortality and disability. Prior studies have suggested that removal of IVH improves outcomes and this is the first phase 3 trial to test this hypothesis. While intraventricular alteplase did not reduce disability in this patient population in this trial, there are several limitations. Only about 20% of patients cleared 80% of their intraventricular blood. Since analyses suggest that patients who have more clearance of IVH do better, the lack of clearance of intraventricular blood may have limited the CLEAR III trial’s ability to show a treatment effect. While every patient had an EVD, there are no guidelines to direct providers about location and number of EVDs. Differences in the aggressiveness of EVD use could have impacted the results and will likely be the focus of future trials. Outcomes (disability and mortality) were better for participants in the trial than historical controls. This is likely due to participating centers aggressively treating ICH patients as well as advances in neurocritical care.
Keywords: Diagnostic Imaging, Secondary Prevention, Heart Valve Diseases, Cerebral Hemorrhage, Fibrinolytic Agents, Hydrocephalus, Primary Prevention, Risk, Stroke, Tissue Plasminogen Activator, Tomography, Vascular Diseases
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