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Alteplase for Intraventricular Hemorrhage Is Found to Save Lives, But Not Improve Function

ARTICLE IN BRIEF

Figure

OUTCOME DICHOTOMIES of modified Rankin Scale (mRS; left panels) and extended Glasgow Outcome Scale (eGOS, right panels). The left panel blue lines indicate the differences in proportion of 180 day mRS≤3 (110, or 45%] in the saline group vs. 118 (48%) in the alteplase group, and deceased participants (73, or 30%) in the saline group vs. 46 (19%) in the alteplase group. GR=good recovery; MD=moderate disability; SD=severe disability; VS=vegetative state.

Researchers reported that irrigation with alteplase did not substantially improve functional outcomes compared with saline in patients with intraventricular hemorrhage and a routine extraventricular drain.

Administering the thrombolytic drug tissue plasminogen activator (tPA, alteplase) through a catheter placed at the site of intraventricular hemorrhage (IVH) can save lives, but the increased survivorship might come at the expense of severe disability, according to a major stroke study known as CLEAR III, which was published in the February 11 issue of The Lancet.

Researchers had hoped that the targeted use of tPA to resolve intraventricular clots would lead to better functional outcomes in stroke patients with intracerebral hemorrhage. The CLEAR III (Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage) study fell short by that measure, but researchers said there were enough promising trends in the randomized, controlled trial to warrant further investigation of the treatment.

“We see multiple strong signals in the data that the greater the removal of the clot, the better the mortality and the better the functional outcome,” said Daniel F. Hanley, MD, FAAN, professor of neurology at Johns Hopkins University and lead author of the multicenter study. The results were also the focus of a “pro-con” panel discussion at the International Stroke Conference in Houston in February.

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DR. DANIEL F. HANLEY: “We see multiple strong signals in the data that the greater the removal of the clot the better the mortality and the better the functional outcome.”

Dr. Hanley told Neurology Today that he is in the process of designing another trial, likely to be called CLEAR IV, that he hopes will provide more definitive answers on whether irrigating the ventricle with tPA improves functional outcomes in stroke patients with intraventricular hemorrhage.

There is a pressing need to find an effective treatment because intraventricular hemorrhage resulting from intracerebral hemorrhage has devastating consequences. Mortality has been reported to be greater than 50 percent, with fewer than 20 percent of those who survive experiencing good functional outcomes, according to background information in the study.

Animal and human studies have suggested that “removal of intraventricular haemorrhage improves survival and long-term functional outcome by relieving acute obstructive hydrocephalus and reducing neurotoxicity,” the report said.

STUDY DESIGN

CLEAR III, which was conducted at 73 sites in the United States and elsewhere and funded by the National Institutes of Health, enrolled 500 patients who were in the intensive-care unit with non-traumatic intraventricular hemorrhage that was less than 30 mL in volume and intraventricular hemorrhage obstructing the third or fourth ventricle. The patients ranged in age from 18 to 80 and were considered stable on computed tomography scans. They all had a routinely placed intraventricular drainage catheter.

About half (249) of the patients were administered boluses of alteplase via the drainage tube (1 mg every eight hours, up to 12 doses). The control group (251 patients) received injections of saline solution.

The primary efficacy outcome was good functional outcomes, defined as a modified Rankin Scale score of 3 or less at 180 days as determined by blinded evaluators.

The study found no significant advantage to using alteplase for irrigating the ventricle where the blood was pooled. Good functional outcomes were achieved in 48 percent of the group that received the drug, compared to 45 percent of the saline group — with a risk ratio of 1.06 [95% CI 0.88-1.28; p=0.554).

Dr. Hanley said that sub-analyses of the CLEAR III data (including scores on the extended Glasgow Outcome Scale and patient-based Stroke Impact Scale) pointed to some positive trends with alteplase treatment, however. The subgroup with larger IVH (>20mL; n=285) demonstrated a 10 percent improved mRS 0-3 proportion (p=0.04). When the percentage removed is considered, the subjects with > 90 percent removed had an odds ratio for improved mRS outcome of 2.25 (p=0.05). These hypothesis-generating findings suggest that greater removal of toxic blood products may lead to the combination of improved survival and improved outcome.

He said the next trial to further test the approach is being designed so that greater clot resolution is achieved. Better placement of catheters should help get the drug to where it needs to be to work most effectively, he said.

“We think that in too many people the catheter was in the wrong place,” he said. “The drug didn't get to the right place.”

In the next trial, the drug treatment will also start sooner, he said.

“We want to get the catheters in earlier so the brain is exposed to the toxicity of blood for a shorter period of time.”

A SAFE APPROACH

An editorial accompanying the study noted that “patients in both treatment groups did much better than expected” when compared to previous reports of mortality and outcomes in patents with intraventricular hemorrhage. The targeted tPA treatment also seemed very safe, with no significant increase in bleeding or brain infections in those who received the drug compared to the saline group, the editorial noted.

“Unfortunately, only 30 percent of patients given alteplase reached the goal of 80 percent clot reduction, which might be one of the reasons that treatment was not effective in improving functional outcome,” wrote Alejandro A. Rabinstein, MD, FAAN, professor of neurology at the Mayo Clinic in Rochester, MN.

Dr. Rabinstein told Neurology Today that “the discouraging news was that the results do not warrant a change in practice. At this point, intrathecal alteplase cannot be recommended for routine practice. The encouraging news is that aggressive clearance of IVH, when achieved (which proved even more challenging than suspected), can improve outcomes. Therefore, the mechanistic rationale of the study was validated.”

Dr. Rabinstein pointed out in the editorial that while the jury is still out on alteplase and other various approaches being evaluated for intraventricular hemorrhage (including intensive blood-pressure lowering and treatment with recombinant activated factor VII), the CLEAR III results underscore that “doing what we can is still very useful.”

EXPERTS COMMENT

Steven M. Greenberg, MD, PhD, FAAN, professor of neurology at Harvard Medical School, said it was encouraging that irrigating the ventricle with alteplase appeared to be safe and that the overall mortality rates for the study participants were significantly lower than what has been previously reported for intraventricular hemorrhage. But he said the fact that there turned out to be more severe disability at 180 days in the group given alteplase was concerning.

“Most people would not be enthusiastic about adding treatment that doesn't improve good outcome,” said Dr. Greenberg, vice chairman of neurology and director of the Hemorrhagic Stroke Research Program at Massachusetts General Hospital. Still, he agreed that that further investigation of the use of alteplase is justified given that CLEAR III indicates “there is some possibility for improved outcome with greater extents of clot removal.”

Dr. Greenberg said that more effort also needs to go into preventing intracerebral hemorrhage, which is usually due to high blood pressure when extending to the ventricles. Particularly when there is intraventricular hemorrhage involved, “these hemorrhages are deadly and have the worst outcomes of essentially any form of stroke,” he said.

Sheryl Martin-Schild, MD, PhD, state medical director of stroke for the Louisiana Emergency Response Network, said that while bleeding into the ventricles of the brain is harmful because it can lead to hydrocephalus, “there is growing evidence that supports the idea that blood where it doesn't belong is toxic to the brain. The toxicity of the blood itself may reduce the chances of having a functional outcome.”

But she said it remains to be proved that “making the blood go away faster makes any difference in terms of functional outcome.” Does administering alteplase into the ventricles do “anything other than make the CT scan look better?” she asked.

Dr. Martin-Schild said a follow-up study to build on the insight gained from CLEAR III would be welcome because “this is such a hopeful intervention for a disease with limited therapeutic options.” •

LINK UP FOR MORE INFORMATION:

• Hanley DF, Lane K, McBee N, et al; 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 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32410-2/abstract. Lancet 2017; 389(10069):603–611.
• Rabinstein AA. Intracerebral hemorrhage: No good treatment but treatment helps http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)30002-8/references. Lancet 2017; 389 (10069); 575–576.