MISTIE III Misses Primary Endpoint, but Stroke Experts See Encouraging Results

HONOLULU, HI—An imaging-guided, minimally-invasive surgical technique fails to influence functional outcomes in patients with intracerebral hemorrhage (ICH), data from the MISTIE III trial show, but experts believe the results give members of the stroke community important information to consider as they think about ways to improve outcomes in this population.

At 1 year, the proportion of patients with a modified Rankin Scale (mRS) score of 3 or less was not significantly higher in patients treated with the MISTIE procedure—which involves clot evacuation with a catheter followed by intracerebral administration of alteplase (Activase; Genentech)—versus those who received standard medical care (45% vs 41%; P = 0.33).

As reported by Daniel Hanley, MD (Johns Hopkins University, Baltimore, MD), here at the International Stroke Conference, however, a number of exploratory secondary analyses suggested that surgeons might be on the right track toward improving outcomes in this setting.

Most notably, among the 58% of patients who had their hematoma reduced to a volume of 15 mL or less—the surgical goal—there was a 10.5% difference in the likelihood of achieving a good functional outcome favoring the MISTIE group (P = 0.03).

“The impact of procedural performance on MISTIE is really important,” Hanley said during his presentation. “Improved function and increased survival is produced with surgical reduction below 15 mL.”

Christopher Kellner, MD (Cerebrovascular Center at Mount Sinai, New York, NY), who was not involved in the trial, viewed that hypothesis-generating result, along with others hinting at some benefit of the approach, as compelling. While there’s no justification to use MISTIE in any patients at this point, he said, “the information that they have presented suggests that a procedure that was more effective in removing the blood clot might be more effective in improving the patient’s functional outcome.”

Kellner pointed to the more detailed results presented by the trial’s surgical co-chair Issam Awad, MD (University of Chicago, IL), showing that there is a significant relationship between a lesser amount of residual clot and a greater likelihood of achieving a good functional outcome.

We now know that to improve functional outcome we have to leave no more than 15 mL. Christopher Kellner

“That’s something that hasn’t been shown in any intracerebral hemorrhage surgical trial in the past, and it gives us a marker to look for as we’re doing surgical procedures. We now know that to improve functional outcome we have to leave no more than 15 mL,” Kellner said. Awad’s analysis also showed that surgeons don’t have to be as aggressive in removing blood to get a survival benefit, but Kellner said “the Holy Grail here is going for improved functional outcome.”

What can be gleaned from MISTIE III as trials of other minimally invasive surgical techniques in patients with ICH are ongoing “is you have to get the blood clot out to improve functional outcome,” Kellner said.

The main analysis was published simultaneously online in the Lancet.

‘Pragmatic Use of MISTIE Cannot Be Recommended’

Trials evaluating patients with supratentorial ICH have not shown a benefit of hematoma evacuation with open craniotomy, and guidelines have called for more evidence before making any recommendations about routine use of surgical interventions in this setting. There is some preliminary evidence, however, that the less-invasive MISTIE technique may provide better outcomes.

The MISTIE III trial, conducted at 78 sites in North America, Europe, Australia, and Asia, was designed to provide a more definitive evaluation of the approach. The trial enrolled 506 patients presenting with a supratentorial ICH with a volume of at least 30 mL who did not have any vascular malformations on CT and could be randomized 12 to 72 hours after onset. They were randomized to MISTIE or standard medical management.

The MISTIE procedure starts with CT-based navigation to develop a plan, after which a rigid cannula is placed in the middle of the clot. Then surgeons insert a soft drainage catheter, which facilitates up to nine injections of alteplase and passive clot removal. Evacuation was stopped when a hematoma size of 15 mL or less was achieved, as confirmed by daily CT scans.

MISTIE led to a mean reduction in hematoma size of 69% compared with standard therapy, but more than 40% of patients did not reach the goal of 15 mL or less.

In the modified intention-to-treat population that excluded seven patients who were randomized but were later determined to be ineligible, the likelihood of a good functional outcome was not increased with the MISTIE procedure.

For secondary outcomes, there was no benefit in terms of the extended Glasgow Outcome Scale at 1 year, but mortality was lower in the MISTIE group at 7 days and 1 year.

In addition, an as-treated analysis focused on the MISTIE patients who achieved a hematoma size of 15 mL or less showed a benefit of the procedure for functional outcomes.

“These secondary analyses are not adjusted for multiplicity and should be interpreted as exploratory,” the authors note in their paper.

Because MISTIE is a new procedure and the vast majority of participating surgeons (87%) had never performed it, safety was a key focus of the trial, Hanley said. The results show that the minimally invasive technique does not increase mortality (and, in fact, seems to reduce it), symptomatic bleeds, or brain infections, although asymptomatic bleeding was more frequent in the MISTIE arm (32% vs 8%; P < 0.0001). Total serious adverse events were slightly more common in the control group (33% vs 30%; P = 0.01).

“We produced new scientific understanding in each of the three areas we investigated—mortality and functional change, effect of surgical performance on outcome, and the safety of the MISTIE procedure,” said Hanley, who added that the procedure “was safely adopted by a large number of surgeons new to the technique.”

Awad added to the lessons learned during his presentation: “Generalization of best performance with this procedure, and other techniques of this kind, will require strict articulation of the goals of the surgical task and pursuit thereof, focused surgeon education emphasizing technical nuances, and better demonstrated experience.”

Ultimately, though, “pragmatic use of MISTIE cannot be recommended,” the investigators write.

Lessons ‘Supremely Important’

Commenting for TCTMD, American Heart Association/American Stroke Association spokesperson Bruce Ovbiagele, MD (University of California, San Francisco), said the lessons obtained from MISTIE III are “supremely important in helping us to better understand what’s going on” with these patients.

“Obviously when a trial does not meet its primary endpoint, sometimes it’s disappointing, but I think there are a lot of important lessons that will help to inform a future trial and it gives us a little bit of a better understanding of the potential biology of the whole process,” he said, referring specifically to the analyses showing that functional outcome improved along with increasing amounts of clot removed.

It’s important to do another trial, he said, to help define how aggressive surgeons should be in hematoma evacuation to balance the functional benefits with risks of mortality.

I think there are a lot of important lessons that will help to inform a future trial. Bruce Ovbiagele

In the meantime, it’s premature to make any changes to clinical practice on the basis of MISTIE III, Ovbiagele said.

“Other than within a clinical trial, I would not encourage surgeons . . . to be more aggressive with clot removal up until we have more information about it, because we’ve been in these situations before where a signal from one trial is tested in a subsequent trial and doesn’t pan out,” he said. “But I think it’s encouraging to see that we are beginning to learn more and more about this process and about what we might potentially need to do about it.”

Kellner noted that there are at least three ongoing studies evaluating minimally invasive surgical techniques in patients with ICH—ENRICH, MIND, and INVEST. Based on preliminary data, he added, these procedures seem to be more effective at removing the clot and therefore might be more successful at improving functional outcomes than MISTIE.

“I think the ultimate treatment that we need to figure out—and I think people will continue looking for other surgical options here—is a surgical treatment that treats all ICH patients [and] maybe especially patients who are at risk for expansion,” Kellner said.