Intraventricular delivery of t-PA improves outcomes in intraventricular hemorrhage

Catheter delivery of tissue plasminogen activator (t-PA) improves survival and functional outcomes at 6 months in patients with intraventricular hemorrhage (IVH), according to the final results from a phase 2b study known as Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR IVH).

Catheter delivery of tissue plasminogen activator (t-PA) improves survival and functional outcomes at 6 months in patients with intraventricular hemorrhage (IVH), according to the final results from a phase 2b study known as Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage (CLEAR IVH).

The finding has paved the way for a phase 3 study in 500 patients with IVH, which will be funded by the National Institutes of Neurological Disorders and Stroke, said Daniel Hanley, MD, professor of neurology, Johns Hopkins University, Baltimore, who presented the 180-day results from CLEAR IVH at the International Stroke Conference 2009.

CLEAR IVH consisted of 2 open-label studies, a dose-response study of t-PA-mediated clearance of blood from the ventricular system in 16 patients with IVH (CLEAR A) and an efficacy study of 36 patients using more frequent dosing with shorter dose intervals (CLEAR B).In CLEAR A, intraventricular injections of t-PA 0.3 mg or 1.0 mg were given every 12 hours for up to 8 doses.

In CLEAR B, up to 3 doses of t-PA 1.0 mg were delivered into the ventricle through a catheter every 8 hours until the third ventricle opened and the lateral shift was reduced. In these trials, t-PA was delivered into the ventricle with 3 mL of saline, the catheter system was closed for 1 hour to allow t-PA to interact with the clot, and the system was then opened and drained for 7 hours.

Previously, it had been demonstrated from this trial that once bleeding has been stabilized, catheter delivery of t-PA safely dissolves clots in the ventricles and reduces the risk of death. Thirty-day mortality in the IVH population treated medically or with extraventricular drainage is typically 60% to 80% and is a function of IVH size. Further, with conservative management, functional outcomes are poor, with only 10% of patients showing good functional outcome.

A rapid drop in blood volume occurs with t-PA treatment of IVH, said Dr Hanley. In CLEAR A and CLEAR B, 30-day mortality was 17% with t-PA treatment; 4% of patients had symptomatic bleeding and 2% developed bacterial ventriculitis.

Functional outcomes at 180 days were presented for the final 36 patients from CLEAR B. “Appropriate criticism of the CLEAR idea is that you’re going to preserve life but not improve function and you’re going to leave people in an end-of-care state,” Dr Hanley said. “I would submit to you that we’re not seeing that. At 30 days, we had 5 individuals who were totally normal” based on their scores on the modified Rankin scale (mRs).

“The good outcomes expand over time-between 90 and 180 days,” he said. Seventeen of the 36 patients in CLEAR B had an mRs of 0 to 3 at 180 days, with the proportion of patients with mRs of 1, 2, and 3 expanding over time.

An assessment of patients with an mRs score of 0 demonstrated that “these patients are highly functional,” said Dr Hanley. “The average score on the Barthel Index is 100, the average NIHSS . . . is 0, and their Glasgow Outcomes Scale is 0.” Functional outcomes were also good for patients with an mRs score of 1 or 2.