MISTIE III Misses Primary Outcome but Moves the Bar in Intracerebral Bleeds

Patrice Wendling

February 08, 2019

HONOLULU — Minimally invasive catheter evacuation followed by thrombolysis failed to improve functional outcomes after a large intracranial hemorrhage (ICH), although functional recovery appeared to rebound with more complete clot removal in the phase 3 MISTIE III trial.

At 1 year, 45% of patients who underwent the MISTIE procedure and 41% of patients treated with standard medical care had good functional outcome, defined as a modified Rankin Scale (mRS) score of 0 to 3. The adjusted 4% risk difference in the primary outcome fell well short of the hypothesized 13% (P = .33).

Exploratory analyses, however, showed that the likelihood of good functional recovery was 10.5% greater in the 58% of patients whose surgeon achieved the protocol goal of less than 15 mL of residual clot volume (P = .03).

Estimated all-cause mortality at 1 year was slightly higher with the MISTIE procedure than with standard care (9% vs 15%; log-rank P = .084; severity adjusted Cox proportional hazard ratio, 0.67; P = .037), Daniel F. Hanley, MD, director, brain injury outcomes division, Johns Hopkins University, Baltimore, reported here at the International Stroke Conference (ISC) 2019 to coincide with online publication in the Lancet.

The frequency of survival was only modestly improved with the MISTIE procedure, but it came without a price in surgical risk or vegetative state, he noted.

The results "will make the world realize that we've been nihilistic about the treatment of hemorrhagic stroke," Hanley told reporters. "It's going to help standardize care."

During the same late-breaking trial session, study cochair and surgical center director Issam Awad, MD, University of Chicago, showed that clot reduction beyond the 15 mL threshold increased the chance of good functional recovery by 10% for each additional 1 mL of hematoma removed (P = .002).

ICH removal of more than 70% was also independently associated with twice the likelihood of good functional outcome in multivariable analyses (odds ratio, 2.05; P = .025).

"Everybody knew that, on average, they needed to reach 15 mL, but when they got to 20 mL, they got skittish. They started to ask, 'If I go further, is it worth the risk?'" Awad told reporters. "But now we can tell them, you can do that. This makes a difference in the outcome."

Galvanizing the Community

"Until now, we only had theories that minimally invasive approaches would result in better outcomes. This trial shows that with their minimally invasive approach, when they were able to reach their target of greater than 70%, less than 15 mL, the patients had a real benefit," J. Mocco, MD, cerebrovascular center director, professor and system vice chair, Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York City, told the heart.org | Medscape Cardiology.

"This is exciting. This is going to galvanize a community that really cares about this disease to continue to work to improve," he said. "That's a big deal."

The MISTIE procedure and technique is generalizable, Mocco said, but he also likened the findings to the experience with thrombectomy in large-vessel occlusion stroke, where great strides made with early lytic-based therapies led to better patient selection and "one of the most efficacious therapies in all of medicine with thrombectomy for large-vessel occlusion."

"This trial is critically important for demonstrating a robust signal for potential benefit, but that benefit is dependent on the efficacy and adequacy of evacuation and, right now, with this approach, we did not quite get there," he said. "As physician experience and insight grows, and as technologic improvements occur, I see this becoming a very real possibility and efficacious treatment for ICH patients."

Current evidence and guidelines do not support the routine use of surgery with craniotomy to improve outcomes after ICH. However, meta-analysis of previous multisite MISTIE trials have suggested benefit, noted Hanley. Removing the blood might eliminate toxic materials that would normally take months to clean up and can trigger an inflammatory state.

"Obviously, it's always disappointing when you don't meet the primary end point, but I think there was an important message from the trial, particularly the issue of trying to remove as much of the clot as possible. I think that, more than anything else, is the biggest message of the trial," Bruce Ovbiagele, MD, MSc, MAS, MBA, University of California, San Francisco, and associate dean of the San Francisco VA Healthcare System, told theheart.org | Medscape Cardiology.

The issue moving forward, if there is to be a MISTIE IV, is the need for better training to improve the modest number of cases that adhered to the protocol, he said. While we await more definitive data, the question is whether surgeons will be more aggressive in removing clots in ICH cases.

"I think we have to be a little bit careful because the big issue is when we saw that relationship between the more clot you take out and the better function, we don't know how that affects mortality," Ovbiagele said. "It could either mitigate what seemed to be the beneficial effect on mortality or make mortality worse. I think that was the apprehension many surgeons had in not wanting to be aggressive."

Protocol, Surgical Details

For MISTIE III, investigators at 78 hospitals in the United States, Canada, Europe, Australia, and Asia enrolled 506 patients with an ICH of at least 30 mL, a Glasgow Coma Scale score of 14 or less, or a National Institutes of Health Stroke Scale Score of at least 6, and an mRS score of 1 or less before the bleed. Patients were randomly assigned to receive standard treatment — typically intense blood pressure control, artificial ventilation, swelling management, and watchful waiting — or the MISTIE procedure after the hematoma had stabilized but within 72 hours.

The surgery involved drilling a dime-sized hole in the skull, performing image-guided aspiration with a rigid cannula, and then placing a soft drainage catheter in the epicentre of the hematoma. Alteplase (1.0 mg in 1 mL every 8 hours) was then delivered to the clot with the soft catheter until less than 15 mL ICH was reached or 9 doses of alteplase were given.

Most procedures (43.8%) were performed by surgeons who had shown training and proficiency in stereotactic image guidance but had not performed previous cases in the trial, 31.8% of surgeons had performed 103 trial cases, and 24.4% had performed three or more trial cases. Regardless, there was no significant difference in catheter placement accuracy or the extent of ICH evacuation among surgeons in the three qualification tiers, Awad said.

Surgery reduced hematoma size by an average of 69%, compared with 3% for standard care. The average end-of-treatment ICH volumes were 16 mL and 47 mL, respectively (< .0001), with 58% of the MISTIE group and less than 1% of control subject reaching the surgical threshold.

Catheter placement was done through one of three trajectories: A, frontal burr hole, anterior approach for caudate putamen bleeds; B, parieo-occipital burr hole, posterior approach for thalamic bleeds; or C, burr hole over the cortical area of closest extension for lobar bleeds.

The frontal trajectory A was most commonly used (47.5%); the parioccipital trajectory B was most likely to require catheter repositioning; and trajectory C was least likely to result in the target of less than 15 mL (P = .027).

Notably, overall results did not vary by ICH size, patient age, or time from symptom onset.

The time window for the MISTIE approach "appears to be quite wide," Hanley told reporters. This "would allow most Americans — whether they are living rurally or in a big city, whether they have immediate or delayed access to a center that has a neurosurgeon and image guidance — to be eligible."

Although there are other techniques and devices being developed, "ours is the gentlest technique," he said. "Other devices use suction at 300 centimeters of water or use cutting devices, so there may be more brain injury with the others."

In MISTIE III, the frequency of serious adverse events was similar in the two groups. At 30 days, 13% of patients had returned home and by 1 year, 83% of patients were living at home or in acute rehabilitation.

Commenting to theheart.org | Medscape Cardiology, Joseph Broderick, MD, professor of neurology and rehabilitation medicine, University of Cincinnati, said, "This is a step forward but not necessarily a step where we're incorporating it into practice."

The lack of a significant benefit in terms of functional recovery is a key sticking point, particularly given the cost of surgery, compared with standard treatment, and the cost of long-term rehabilitation.

"The equivalent is that we know that hemicraniectomy improves mortality above the age of 60, but it has no effect on functional outcomes and so we don't recommend that generally because it's just survival," he said. "So this is kind of in that grey zone."

The MISTIE trial was funded by the National Institute of Neurological Disorders and Stroke (NINDS). Genentech donated alteplase at no cost to all North American study sites.

Hanley reported grants from National Institutes of Health (NIH)/NINDS and consulting for BrainScope, Neurotrope, Op2Lysis, Portola Pharmaceuticals, and Medtronic. Awad reports NIH support as the MISTIE III cochair and surgical center director.

Mocco is a principal investigator for the FDA IDE INVEST Trial evaluating minimally invasive endoscopic evacuation with the Apollo or Artemis systems, and is a consultant to Rebound Therapeutics, a start-up company developing minimally invasive technology to treat various pathologies, including ICH.

Lancet. Published online February 7, 2019. Abstract

International Stroke Conference (ISC) 2019: Abstracts LB4 and LB5. Presented February 7, 2019.

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