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Minimally Invasive Surgery Plus tPA — The Benefits for Intracerebral Hemorrhage


Investigators reported that patients who underwent minimally invasive surgery to remove clots as well as tissue plasminogen activator (tPA) fared better in functional outcomes than those who received tPA alone.

A technique for treating intracerebral hemorrhage (ICH) stroke patients, involving minimally invasive surgery and applying recombinant tissue plasminogen activator (rtPA) with a catheter to reduce the clot size, has continued to show good results on patient function and cost compared with regular medical therapy.

The latest results from the phase 2 trial — Minimally Invasive Surgery plus tPA for Intracerebral Hemorrhage Evacuation, or MISTIE — were presented in February at the International Stroke Conference in Honolulu. The National Institute of Neurological Disorders and Stroke funded the MISTIE trial.

If the results are borne out in a larger trial, which is expected to begin in the fall of 2013, it could be a major breakthrough in the treatment of ICH patients, for whom standard surgery has not proven to be more effective than medical therapy, experts say.


The study involved 96 patients — randomized across 26 medical centers to either the minimally invasive surgery (MIS + tPA) or medical therapy — with clots averaging 46 ml of volume, about half the size of a golf ball. The procedure removed 57 percent of the clot volume, while there was natural dissolving in only about 5 percent of medical therapy group after a few days.

One year after stroke, patients fared 14 percent better in functional outcomes measured by the Modified Rankin Scale (mRS). That's better than the 180-day results, in which the MIS + tPA patients had an 11 percent advantage (p=.06), an indication that patients continue to improve over time. [The mRS measures the degree of disability or dependence in the daily living activities on a scale of 0-6; where 0 indicates no symptoms and 6 equals death.]

The results also showed that patients with better mRS scores continued to improve, as well as patients with mRS scores that were not as good — at one year, 21 percent of patients in the medical-treated group needed long-term facility care compared with 8 percent in the surgery group.

“The shifts in the Rankin are across all levels from 5 to 0 and they're about equal, and they're larger than they were at 180 days,” said lead author Daniel Hanley, MD, professor of neurology at Johns Hopkins Hospital and director of the Brain Injury Outcomes Division there. “So the benefit of surgery appears to be expanding with time.”

“It appears to improve both function and cost and it's probably doing this by saving tissue at risk,” Dr. Hanley said.

Researchers calculated that the MIS + tPA approach saved about $44,329 per patient in medical care costs. That was mainly because that group's median hospital stay was 38 days shorter than the standard medical care group (p=.015).

When doing the procedure, surgeons drill a hole the size of a dime in the patient's skull. Then they pass a catheter through the hole into the brain tissue, through the longest part of the clot that has formed from the pooled blood. They then apply rtPA to the clot with the catheter every eight hours for three days. The clot is removed through the catheter as it liquefies.

Dr. Hanley said the approach is based on the idea, “both novel and quite simple,” that reducing clot size might lower mortality and increase good outcomes. “How well or how poorly you reduce the clot size is related to the outcome,” Dr. Hanley said. He added that the findings suggest that getting to a clot down to a volume of 15 ml or smaller, a pre-specified surgical goal, trended toward more significance therapeutically.

“We've been dedicated to that goal for really the last eight to 10 years,” he said. “We probably have established some surgical goals for how much reduction should occur,” he said.

Patients who underwent the surgical procedure 36 to 72 hours after their stroke did just as well as those who were treated earlier.

“It looks like the time window for this procedure is much more permissive than the time window for ischemic stroke,” Dr. Hanley said.

Patients were 75 percent male and were an average age of 60. There was equal benefit across gender, race and age, although that needs to be further tested in a larger trial.

Researchers are hoping to do a 500-patient trial across 75 sites, Dr. Hanley said.


Osama Zaidat, MD, director of the neurointerventional program at the Medical College of Wisconsin, who was not involved with the study, said a larger trial is needed to confirm the results, but that clinicians will watch the trial's advancements closely, especially for evidence on which patients will benefit most.

“Knowing the limitations of the study, it is the best evidence available for new treatment for patients with this type of stroke that currently has no active therapy that's proven to be beneficial,” he said.

Dr. Zaidat said the ability to do the procedure more quickly, and the likelihood that the minimally invasive technique is less prone to complications and less tissue damage, make it an attractive prospect for clinicians.

But he questioned whether, in a larger trial, patients treated 36 to 72 hours after stroke would continue to show as much benefit as patients treated earlier, as this smaller study found.

“That will have to be confirmed with a larger study,” he said. “I'm not sure what will be panning out.”

He also noted that the average age of the patients was “pretty young” in MISTIE. “You have to watch as more people enroll, if it's more skewed toward elderly patients, whether that would change the results of the study,” he said.

DR. DANIEL HANLEY said combining minimally invasive surgery to remove the clot along with administration of tissue plasminogen activator is based on the idea, “both novel and quite simple,” that reducing clot size might lower mortality and increase good outcomes.

An even distribution of clot volume size is also important for the larger trial, he said, so as not to skew the results.

Dileep Yavagal, MD, director of interventional neurology at the University of Miami, said the approach has a “very sound biologic basis” and merits a larger study to confirm the benefits.

“Such an approach avoids the trauma to the surrounding normal brain that occurs with the traditional open surgical methods of brain hematoma removal,” he said. Something to watch for in the next trial, he said, is subsequent accumulation of blood in the surgical area, although there is no indication so far that this is a problem.

“The main concerns are whether the hematoma could actually re-accumulate bleeding due to the use of the thrombolytic tPA in the hematoma bed after the blood has been drained initially,” he said. “Another concern would be to see if the treated patients develop an adjacent area of bleeding, for example along the tract of the catheter device that was put in to drain the blood. The present study did not show these concerns and therefore is reassuring.”


• Mould WA, Carhuapoma JR, Hanley DF, et al, for the MISTIE Investigators. Minimally invasive surgery plus recombinant tissue-type plasminogen activator for intracerebral hemorrhage evacuation decreases perihematomal edema. Stroke 2013; E-pub 2013 Feb. 7.
    • More about the MISTIE trial: