CLEAR III: tPA Clot Removal Hope for Intraventricular Hemorrhage

February 19, 2016

LOS ANGELES — Using low-dose tissue plasminogen activator (tPA; alteplase) delivered by surgical catheter to remove clots of pooled blood from the brain's ventricles after intraventricular hemorrhage did not significantly improve the primary endpoint of a good functional outcome, defined as a modified Rankin Scale (mRS) score of 0 to 3, in the overall study population in the CLEAR III trial.

But the treatment was associated with a 10% reduction in mortality without increasing the number of patients left in a vegetative state or requiring nursing home care.

Subgroup analysis also showed that the intervention had the best results in patients who had the most blood removed. In those who had the larger clots with more than 20 mL of blood removed, there was a significant 10% increase in the number of patients achieving a good functional outcome, researchers report.

Presenting the CLEAR III results at the International Stroke Conference (ISC) 2016, Daniel Hanley, MD, Johns Hopkins University of Medicine, Baltimore, Maryland, said, "This treatment saves lives. Our results suggest that physicians should begin to think about using it for stable hemorrhagic stroke patients."

The CLEAR III researchers are now starting an educational campaign on how to manage intraventricular hemorrhage at comprehensive stroke centers around the United States.

They are also planning another trial — CLEAR IV — in patients with larger clots, which is awaiting a funding application.

"Great Hope for the Future"

Commenting for Medscape Medical News, American Heart Association/American Stroke Association spokesperson Daniel Lackland, MD, Medical University of South Carolina, Charleston, said the CLEAR III results showed great promise.

"While it is disappointing that they didn't meet the primary endpoint and they haven't answered all the questions yet, this study certainly sets up good directions for further trials and gives great hope for the future," he said.

Dr Hanley explained that there are no direct treatments currently approved for hemorrhagic stroke, with the standard of care being supportive therapy, including blood pressure control, ventilator-assisted breathing, and controlling brain swelling. He estimated that around half of the 120,000 patients admitted to the hospital with a brain hemorrhage each year in the United States die, and only around 20% return home to live independently.

However, in the CLEAR III study, which compared flushing the blood from the brain with saline or alteplase, both groups had much better outcomes, with almost 50% of patients living independently at home after 180 days. "So just inserting a drain itself seems to be having a positive effect," Dr Hanley said.

"Outside this study, catheter drainage is used in only around 8% of hemorrhagic stroke patients and we showed this technique can really make a difference," he added. "But those given alteplase showed some other very hopeful effects, including an additional reduction in mortality."

He explained that brain hemorrhage normally starts as an intracerebral bleed, and in half of these cases blood spreads into the ventricles. The CLEAR III study included patients with small volumes of intracerebral hemorrhage but larger intraventricular bleeds obstructing the internal ventricular system.

"In this trial we wanted to test the effect of removing blood from the ventricles, so we didn't include patients who would be badly affected by the intracerebral hemorrhage. We have another study underway — MISTIE — looking at the same treatment in patients with intracerebral hemorrhage. It may be that in future patients may receive this treatment directed to both locations."

Best Results If Catheter Inserted Into Clot

The trial also found that the benefit of the procedure was dependent on where exactly the catheters were inserted. Dr Hanley explained: "We recommended that surgeons inserted the catheter into the clot but many of them didn't do this. Our data showed better results if the catheter was inserted into the clot. Now we have some data. We hope this will inform the procedure for the next trials and future clinical practice."

For the CLEAR III trial, 500 patients within 12 to 72 hours of onset of an intraventricular hemorrhage (mean National Institutes of Health Stroke Scale score, 20) underwent insertion of a brain catheter and were randomly assigned to receive saline or tPA (1 mg) every 8 hours for up 12 doses or until the ventricles were cleared of blood.

The primary endpoint, functional independence (mRS score, 0 - 3) at 180 days, occurred in 48% of the alteplase group vs 45% of the saline group, a nonsignificant difference. "We had hoped for a 13% difference but we achieved a 3% difference," Dr Hanley said.

Use of alteplase was associated with a 10% reduction in mortality in the whole population (P < .007). There was an increase in mRS score of 5, but there was no difference in Glasgow Outcome Scale severe disability or vegetative state and there was a 10% increase in patients living at home or in rehabilitation at 180 days (P = .06) in the alteplase group.

In terms of safety, symptomatic bleeding occurred in 2% of both groups and alteplase was associated with a reduction in bacterial ventriculitis (P = .05).

Further analysis showed that the likelihood of a good outcome with alteplase improved with the volume of blood that was cleared, with best results seen in patients who had 90% of the clot removed.

Patients who received additional doses of alteplase and had multiple drainage catheters inserted had higher clot removal. In patients who started with less than 20 mL of blood in the ventricles, no benefits were seen.

Co-chair of the study, Issam Awad, MD, University of Chicago Medicine, Illinois, said, "When we started the trial we had little idea about how to best use this therapy. Now we have clear data on how best to implement the procedure and for at least a group of patients — those with larger amounts of clot removed — it appears to be able to double the likelihood of a favourable outcome."

The study was funded by the National Institute of Neurological Disorders and Stroke.

International Stroke Conference (ISC) 2016. Abstracts LB12 and LB13. Presented February 18, 2016.


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