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International Stroke Conference: Mixed Results in Trial of Minimally Invasive Surgery for Intracerebral Hemorrhage

Article In Brief

A minimally-invasive surgical approach to removing clots from intracerebral hemorrhage appeared to reduce mortality, but overall did not improve functional outcomes compared with medical therapy at one year, according to findings of a large trial.


Modified Rankin Scale (mRS) and Glasgow Outcome Scale (eGOS) scores 365 days after stroke in the modified intention-to-treat analysis set: mRS scores range from 0 (no disability) to 6 (death). eGOS scores range from 8 (upper good recovery) to 1 (death).

HONOLULU—Intracerebral hemorrhage (ICH) is a decidedly difficult clinical diagnosis with limited treatment options. Promising results from recent meta-analyses have shown non-craniotomy techniques could potentially decrease mortality and poor functional outcomes, but the evidence has been limited and not of high quality. In this setting, findings from a large trial of a minimally invasive treatment for evacuating blood clots caused by ICH was widely anticipated—and the results were mixed.

The trial found that a minimally-invasive approach appeared to reduce mortality, but overall did not improve function among patients at one year, researchers reported here at the 2019 International Stroke Conference in February, sponsored by the American Stroke Association.

In the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation (MISTIE III) trial, about 45 percent of patients who underwent the combination of surgery and catheter-based clot evacuation in the modified intention-to-treat population, and about 41 percent of patients treated medically, achieved a modified Rankin Scale (mRS) score of 0-3, an indication of good functioning, but that difference failed to reach statistical significance (p=0.33), Daniel F. Hanley, MD, FAAN, professor of acute neurology at Johns Hopkins University in Baltimore, told Neurology Today.


“The trial confirmed that removal of the blood clot using the MISTIE procedure can be done safely as compared with supportive therapy. But there was no difference in functional recovery between those in the surgery group and the medical group.”—DR. DANIEL F. HANLEY

Still, at 365 days after stroke, the all-cause mortality was significantly lower in the MISTIE III group compared with patients who were treated medically, (p=0.037), Dr. Hanley reported in his oral, late-breaker presentation. The results were simultaneously published in the February 6 online edition of The Lancet.

Outcomes were enhanced if surgeons made a concerted effort to get more than an average amount of the clot out of the brain, a study co-author, Issam Awad, MD, director of neurovascular surgery at the University of Chicago Medicine and Biological Sciences told Neurology Today. Dr. Awad said that if 50 percent or more of the clot was removed, there was a benefit in mortality, but if more than 70 percent was removed to a point where less than 15 mL of the clot remained, there was also a benefit in function.

Dr. Hanley said that there was a 10.5 percent difference in achieving a mRS of 0-3 in favor of the surgery technique if the clot volume was below 15 mL when compared with the medically-treated controls (p=0.03).

The researchers noted that the minimally invasive treatment can be taught to those who have not attempted the procedure before the trial. In MISTIE III, 88 percent of the doctors were performing their first procedure. The MISTIE procedure avoids the damage of traditional craniotomy by using imaging to guide placement of a soft tube into the blood clot through a small hole in the skull to remove large amounts of blood and toxic blood components, Dr. Awad explained. The procedure involves a low mechanical impact procedure with suction and up to three days of gentle irrigation with the clot-busting drug alteplase, he said.

Alteplase was delivered every eight hours and up to nine doses were permitted, but the average number of doses was three, Dr. Awad said in his presentation. He suggested that many of the doctors, after removing a substantial amount of clot, decided to stop before reaching the 15 mL threshold.

“The more clot removed, the better the patient's outcome was,” Dr. Awad said. “For every 1mL removed beyond 15 mL, there was a subsequent 10 percent chance of further improvement in functional outcomes.”

“Despite the absence of benefit for our primary outcome in MISTIE III, the data demonstrate that approximately 43 percent of all patients achieved a good functional outcome, even those with large intracerebral hemorrhage,” Dr. Hanley and his coauthors noted in The Lancet. “These changes in functional outcome are consistent with a low frequency of withdrawal of care, guideline-driven intensive care unit care, and achievement of stability of hematoma growth,” they wrote.

“However, the fact that the proportion of all patients who achieved a good outcome was higher than expected is not solely because the patients were healthy,” they continued. “Accounting for all differences in functional outcome between randomized trials remains difficult,” they suggested.


By the Numbers: The MISTIE III Participants

The study authors noted that the estimated mortality difference between the intervention and standard care treatment groups was modest, with a number needed to treat of 17 to preserve one life, but mortality was not the primary outcome and, as a result of multiple testing, this estimate is exploratory.

“The trial confirmed that removal of the blood clot using the MISTIE procedure can be done safely as compared with supportive therapy,” Dr. Hanley told Neurology Today. “But there was no difference in functional recovery between those in the surgery group and the medical group. The trial results do suggest that patients have improved functional recovery when the blood clot size is reduced to about three tablespoonsful or less of blood. This will require further study, but, at a minimum, the trial data provide a sound basis to avoid limiting care in patients with large brain blood clots.”

Study Design

To be eligible for MISTIE III, patients had to have been adults who were diagnosed with a spontaneous, non-traumatic, supratentorial ICH of 30 mL or more due to cerebral small-vessel disease, with a Glasgow Coma Scale score of 14 or less or National Institutes of Health Stroke Scale (NIHSS) score of 6 or higher, a modified Rankin Scale score of 0 or 1 before the bleed, and an ICH that remained the same size or had growth of less than 5 mL for at least six hours after diagnostic CT scans.


Overall survival at 365 days for the MISTIE (red) and standard medical therapy groups (blue). Shaded areas show 95% CIs; hazard ratio (HR).

Between December 30, 2013, and August 15, 2017, 250 patients were randomly assigned to the intervention and 249 to standard medical care. At seven days, two patients (1 percent) in the intervention group had died compared with 10 (4 percent) in the standard medical care group (p=0.02); at 30 days, 24 (9 percent) in the intervention group died compared with 37 (15 percent) in the standard care group (p=0.07). And at 30 days, 76 (30 percent) in the MISTIE group and 84 (33 percent) in the standard care group had one or more serious adverse event, a statistically significant event (p=0.012).

“We did not enroll patients with expressed care limitations or those deemed to have life-threatening mass effect requiring surgery,” Dr. Hanley explained. “Local principal investigators determined eligibility and stability of hematoma growth and written, informed consent was then obtained from all patients.”

The mean NIHSS score at admission was 19 and 75 percent of the patients had Glasgow Coma Score of 9 or higher at admission. (For more on the study population, see “By the Numbers: The MISTIE III Participants.”)

Expert Commentary

In an editorial in The Lancet that accompanied the MISTIE III results, Rustam Al-Shahi Salman, BMBS, PhD, chair of clinical neurology at the University of Edinburgh in Scotland, and colleagues, wrote: “MISTIE III highlights the importance of good trial design, large sample size, high adherence to the intervention, and focused hypothesis-testing, which are factors that should be considered in ongoing randomized trials of minimally invasive surgery and decompressive hemicraniectomy.”

However, he and his colleagues noted, “These results suggest that minimally invasive surgery via a catheter with repeated instillation of alteplase cannot be recommended for intracerebral hemorrhage in standard practice.”

Another independent commentator noted, however, that the trial did provide useful clinical information. “Before MISTIE III we weren't really sure how much blood we could leave in the head after an intracerebral hemorrhage,” said Louise D. McCullough, MD, PhD, chair of neurology at the McGovern Medical School at the University of Texas at Houston Health Science Center, and vice-chair of the International Stroke Conference. “You could potentially make things worse if you were extracting normal brain tissue if you are trying to get every last bit of blood out. I think this study showed that if you can get to 15 mL, you are going to do really well. Less is more.”

“So I think this is really useful if we are going to design trials going forward because we did see an efficacy signal in the group of patients with less than 15 cc of blood left in the brain,” she said.

“I think we still need a trial that would show functional benefit. That is what matters to patients.

However, ICH is a terrible disease, there is no treatment for it, and there may be a signal that this can work for patients, especially those with no other options. I think that because it was easy to train doctors to do this procedure and there was very little downside in terms of increased mortality, this might be performed in selected patients,” Dr. McCullough said.


“The more clot removed, the better the patients outcome was. For every 1mL removed beyond 15 mL, there was a subsequent 10 percent chance of further improvement in functional outcomes.”—DR. ISSAM AWAD

“We would prefer to see a clinical trial done with the refinements suggested by MISTIE III, but at the very least they should be done in conjunction with a registry. I think my own institution will continue to do this because it is all we have to offer these patients, and I think all these cases should be done in a registry,” she said.

Bruce Ovbiagele, MD, MSc, FAAN, associate dean of the San Francisco VA Healthcare System, agreed that MISTIE III offered important messages. “It showed that the minimally invasive approach to removing the clot is safe when compared with standard treatment. We also saw that there was an effect on mortality, although this was a secondary outcome measure.”

“Mortality is a hard outcome,” he noted, “and it is encouraging to see this kind of effect, but it was puzzling to see an effect on mortality but no effect on functional outcome, which was the primary outcome of the trial,” Dr. Ovbiagele told Neurology Today.

The National Institute of Neurological Disorders and Stroke (NINDS) funded the study and Genentech Inc. donated alteplase.


Dr. Hanley has served as a consultant and on the advisory boards of BrainScope, Neurotrope, Portola Pharmaceuticals, Op2Lysis, and HeadSense. Dr. Awad had no disclosures.

Link Up for More Information

•. Hanley DF, Thompson RD, Rosenblum M, et al; for the MISTIE III Investigators. Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): A randomized, controlled, open-label, blinded endpoint phase 3 trial Lancet 2019; Epub Feb 6.
    •. Salman RAS, Klijn CCJM, Selim S. Comment: Minimally invasive surgery plus alteplase for intracerebral haemorrhage Lancet 2019; Epub Feb 6.