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HONOLULU -- A minimally invasive, gentle surgical approach to removing stable clot material left after large intracranial bleeds didn't improve outcomes overall in the MISTIE III trial, although results were promising with more complete removal.

Good functional outcome at 1 year (modified Rankin Scale [mRS] score of 0-3) adjusted for factors like clot size and location was no more likely with the intervention than standard medical care in the primary efficacy analysis of all eligible, randomly assigned patients who were exposed to treatment (45% vs 41%, P=0.33).

However, functional recovery was significantly tied to how much clot was left behind, Daniel Hanley, MD, of Johns Hopkins University, reported here at the American Heart Association's International Stroke Conference. The results were also .

The 58% of patients left with less than 15 mL of clot -- the aim of the procedure -- did have a significant benefit from surgery in an exploratory analysis, with a 10.5% greater likelihood (P=0.03) of mRS scores of 0–3 at 1 year adjusted for initial severity factors and severity matching.

A second presentation by Issam Awad, MD, of the University of Chicago, at the same session showed that intracerebral hemorrhage (ICH) removal beyond the 15 mL threshold increased the chance of a good functional outcome by 10% per additional 1 mL (P=0.002) and that removal of more than 70% was similarly independently associated with functional outcome.

There was no increased risk of death, brain infection, or symptomatic bleeds. In fact, estimated all-cause mortality as a secondary outcome was significantly lower with intervention at 1 year, with a severity-adjusted Cox proportional HR of 0.67 in the overall population (P=0.037).

"The frequency of survival is modestly improved with MISTIE without a price in surgical risk or vegetative state," Hanley told the audience.

"We have to go back and do a similar trial showing that with knowing the goals and that we must reach the goal, there can be a general benefit," he told reporters.

‘Landmark’ Trial

"It's clear less is more," commented session moderator Louise McCullough, MD, PhD, of the University of Texas Health Science Center at Houston.

J Mocco, MD, of Icahn School of Medicine at Mount Sinai in New York City, drew parallels to mechanical thrombectomy for large vessel occlusion strokes.

“The groundbreaking therapy was done with lytic therapies that provided the first evidence that this is something we should pursue,” he told 名媛直播. “Based on those experiences, physicians developed and pioneered improved selection and improved tools to remove blood clots, and now we have one of the most efficacious treatments that exist in medicine. Likewise for ICH, I think this study is landmark in that it provides the critical data to encourage all of us to do better.”

So while “the technique was not as successful as they hoped, they correctly estimated what needed to be achieved to demonstrate benefit,” Mocco added. “This provides a threshold, a bar, for other future and ongoing studies to achieve.”

Brian Silver, MD, of UMass Memorial Medical Center in Worcester, Massachusetts, likewise pointed to thrombectomy. ”We would not have adopted that if we said ‘game over’ after the first three negative trials — they just had to redesign things a little bit, change the tool that they used, selection criteria.”

He predicted that a redesign with altered selection criteria and endpoints could be successful for minimally-invasive surgery in ICH.

“The fact that we see these very strong trends and evidence that the patients who had the good removal rates had good outcomes, we should push forward to try to new therapies,” agreed Gregory Albers, MD, of Stanford University Medical Center in Stanford, California.

Broader Implications

Even now, though, the trial can have a big impact because of the high survival rates found with good medical care, Awad argued.

At 1 year, 83% of patients were alive and at home or in acute rehabilitation, "which has not ever been recorded," he said. "It's the end of nihilism. ... The trial as a whole allowed us to show we can do better than previously thought."

"I think this is going to make the world realize that we've been nihilistic about the treatment of hemorrhagic stoke. I think it's going to help standardize treatment," he told reporters, pointing to the better outcomes across both groups than seen in the prior MISTIE II trial.

One reason why surgery for ICH has failed in the past and isn't recommended in the guidelines may be that it caused too much secondary damage, Awad suggested.

"There is almost definitely a role for minimally invasive surgery," he said. "We think that the least invasive and least mechanically disruptive, the better."

Removing the blood may eliminate toxins that cause edema and inhibit recovery, the researchers suggested.

The Procedure

The procedure was done under general anaesthesia and CT imaging guidance after the hematoma has stopped expanding but within 72 hours. It involved drilling a hole in the skull, placing a rigid cannula into the hematoma, clot aspiration with suction by hand, and then placement of a soft catheter with closed drainage system. Alteplase (Activase) was injected into the clot through that catheter at 6 hours after catheter placement, and then at 1.0 mg in 1 mL followed by 3 mL flush every 8 hours for up to nine doses until no more than 15 mL of hematoma remained or there was clinically symptomatic rebleeding. Treatment was open label.

All 506 patients got care as recommended by the American Heart Association and European Stroke Organisation recommendations, including monitoring airways, ventilation, intracranial pressure, sedation, and pharmacological treatment of intracranial mass effect.

"If you skimp on those and just do the procedures, you're not going to get the outcomes," Awad said. "All of the components of care matter."

As expected, the intervention cut hematoma size much more than standard care, by a mean 69% versus 3% for an average end-of-treatment volume of 16 versus 47 mL.

Inclusion criteria were ICH of at least 30 mL, with vascular defects excluded by CT angiography.

The techniques used in the trial are skills all neurosurgeons have, Hanley noted. "We think it's easily exportable worldwide."

Results didn't vary by size of ICH or by time since symptom onset to treatment. "The window appears to be quite wide," Hanley said, so "most Americans are going to be eligible."

Other approaches to hematoma removal are being developed, but "ours is the gentlest technique" with just hand suction and no negative pressure or use of cutting devices, Hanley noted. There may be more brain injury with the other approaches, but future studies will be required to sort out which approach is best for outcomes, he added.