Surgery and ‘Care-Bundle’ Trials Raise Hopes for ICH Care

MUNICH, Germany—Two randomized trials testing different types of interventions for patients with acute intracerebral hemorrhage (ICH), presented here at the European Stroke Organisation Conference (ESOC), are raising cautious hopes for treating this often lethal and debilitating condition.

Improvements in functional outcomes and reductions in mortality were seen in both the ENRICH trial of ICH evacuation using minimally invasive parafascicular surgery (MIPS) and the INTERACT3 trial of a care-bundle protocol geared toward speedy correction of high blood pressure, hyperglycemia, and fever, along with reversal of warfarin anticoagulation, researchers reported in back-to-back presentations.

The feeling of excitement among attendees was palpable: the results signaled a shift in the right direction for ICH management, an area that has not seen the dramatic progress that has been made in the treatment of ischemic stroke.

“Anything that shows us any effect in ICH is promising,” Else Charlotte Sandset, MD, PhD (Oslo University Hospital, Norway), co-moderator of the session at which the results were presented, told TCTMD.

“We’ve had major improvements in the care for patients with ischemic stroke. We’ve gone from not being able to do anything for them to being able to have a patient with hemiplegia, aphasia, and you treat them with endovascular therapy and they walk out of the ward. We see that in our practice every day,” she said. “But with ICH patients, we are not able to provide that same treatment, so I think the excitement is that now there are positive things happening for the ICH patients, which I think will create a momentum and there will be more people wanting to participate in trials in patients with intracerebral hemorrhage. So I think this is really positive for patients with ICH for the future.”

Indeed, said Craig Anderson, MD, PhD (The George Institute for Global Health, University of New South Wales, Sydney, Australia), who presented the INTERACT3 results, “maybe the time is right that we should elevate intracerebral hemorrhage to the same urgency as we do to acute ischemic stroke.”

Minimally Invasive Surgical ICH Evacuation in ENRICH

There are some obvious reasons to consider surgery for ICH, according to Alex Hall, DHSc, MS, RN, who presented the results of ENRICH with Jonathan Ratcliff, MD (both from Emory University, Atlanta, GA). Those include early control of intracranial pressure and prevention of clot expansion and any secondary inflammation.

Two prior trials of early surgery versus initial conservative management in patients with acute ICH—STICH and STICH II—did not demonstrate significant benefits, although there were signals that aided in the design of ENRICH, Hall said. He noted that after their trial had started, a third trial, MISTIE III, failed to show that minimally invasive surgery with thrombolysis for ICH evacuation improved functional outcomes.

In ENRICH, conducted across 37 US centers, the investigators examined the impact of very early (within 24 hours of when the patient was last seen normal), minimally invasive evacuation of the hemorrhage compared with standard medical management in patients with acute spontaneous supratentorial ICH. They randomized 300 patients, using an adaptive design to enrich the study population with lobar ICH, accounting for 69%; the rest had hemorrhages in the anterior basal ganglia (ABG).

This is the first clinical trial to demonstrate a functional benefit of surgical clot evacuation. Jonathan Ratcliff

The primary outcome was functional outcome according to the mean utility-weighted modified Rankin Scale (mRS) score at 180 days, with a positive result defined by a Bayesian posterior probability for success exceeding 97.5%. This was met in the overall cohort, with a 98.1% probability for success with MIPS, and among patients with lobar ICH (99.7%), but it was not met in those with ABG hemorrhages (43.0%).

There was an overall lower risk of having a poor functional outcome in patients treated with MIPS (OR 0.636; 95% CI 0.421-0.959), a benefit seen as early as at 7 days or discharge (whichever came first).

The researchers hypothesized that the benefits of MIPS were related to hematoma evacuation, Ratcliff said, reporting that the median ICH volume after surgery was 14.9 mL, down from 50.5 mL before the operation. The median ICH reduction was 87.7%. Outcomes worsened with higher ICH volumes and improved with greater volume reductions.

Along with the gains in functional outcomes with MIPS, the procedure also lowered 30-day mortality compared with standard medical management (9.3% vs 18.1%; P = 0.027) and shortened mean length of stay in the ICU (7.0 vs 9.6 days; P < 0.001) and the hospital (14.7 vs 17.1 days; P = 0.021). The number needed to treat to prevent one death was 21, Ratcliff reported.

“This is the first clinical trial to demonstrate a functional benefit of surgical clot evacuation,” Ratcliff said, noting that “the overall benefit of MIPS importantly appears to be from the strong positive effect observed for participants in the lobar ICH cohort.”

The Care-Bundle Protocol in INTERACT3

Anderson followed the ENRICH presentation to report the results of INTERACT3, which were published simultaneously online in the Lancet. The stepped-wedge, cluster-randomized trial was conducted across 122 hospitals in nine low-to-middle-income countries (Brazil, China, India, Mexico, Nigeria, Pakistan, Peru, Sri Lanka, and Vietnam) and one high-income country (Chile). Hospitals were selected for participation if they didn’t have an ICH protocol, or an inconsistent one, but had a local champion who could lead the effort to introduce the care bundle.

The trial included 7,036 patients (mean age 62 years; 36% women) presenting with acute ICH within 6 hours who were randomized to management with the care-bundle protocol (n = 3,221) or usual care (n = 3,815); all of the hospitals started out delivering usual care and, in phases, gradually switched over to the care bundle as part of a quality-assurance program. Most of the participants (about 90%) were Chinese. The median NIHSS score at baseline was 12, and the median hematoma volume was 15 mL.

The aim of the intervention was to rapidly treat (within an hour) high blood pressure, hyperglycemia, and pyrexia, and to reverse warfarin anticoagulation. At baseline, most patients had elevated BP (about 90%), with a smaller proportion having hyperglycemia (about 36%). Fewer than 2% of patients had fever or altered warfarin-related anticoagulation.

Maybe the time is right that we should elevate intracerebral hemorrhage to the same urgency as we do to acute ischemic stroke. Craig Anderson

Once the care bundle was implemented, the primary intervention delivered was early lowering of BP, with IV medications administered in 79% of the intervention group and 71% of the control group. Glycemic control and antipyretic treatment were given in roughly 10%, and correction of abnormal coagulation was used in less than 2%.

Importantly, Anderson said, there was similar use of other management strategies, including decompressive surgery, mechanical ventilation, ICU admission, assisted feeding, and withdrawal of active care, in both groups.

Compared with usual care, the intervention led to significantly greater reductions in systolic BP at both 1 hour (by 7 mm Hg) and 24 hours (by 4 mm Hg), with lesser or no changes in other parameters, like diastolic BP, blood glucose, and body temperature.

And that was associated with a significant advantage for the care bundle on the primary outcome, which was the shift in mRS scores at 6 months. After adjustment, the intervention reduced the likelihood of a poor functional outcome (OR 0.84; 95% CI 0.73-0.97).

The effect varied across mRS categories, tending to be stronger at the more-severe end of the scale, a finding that was met with applause from the audience when Anderson showed the numbers.

Other efficacy and safety outcomes had point estimates pointing toward a benefit of the care bundle, with significant reductions in death (14.1%  vs 17.0%; P = 0.02) and serious adverse events (16% vs 20%; P = 0.01) at 6 months, and an improvement in quality of life according to the EQ-5D assessment (P = 0.001).

The number needed to treat was 35 for both improved functional outcomes and reduced mortality, Anderson said.

“We’re not the first RCT to provide level 1 evidence, ENRICH has done that, but we can claim to be the first published,” he joked.

“Active management improves outcome for intracerebral hemorrhage and care-bundle protocols and active management should be applied to all ICH patients,” he concluded.

Anderson pointed out that there are ongoing initiatives—the ABC-ICH in the United Kingdom and CODE ICH in the United States, for instance—to improve the ICH care. “Maybe it’s time for us to have a campaign to work together across all of our disciplines to have a more-active approach to the management of ICH,” he said.

‘We’re Pretty Excited’

Commenting on the trials for TCTMD, Pooja Khatri, MD (University of Cincinnati, OH), said demonstration that strategies for acute ICH can improve outcomes is “a really big deal.”

“We get a patient with a bleed and we can lower blood pressure and we think there’s some evidence that might help reduce expansion of the bleeding, but it actually hasn’t made a huge impact on outcomes,” Khatri said, noting that the effects seen in ENRICH and INTERACT3 are similar in magnitude to those accompanying some treatments for ischemic stroke.

“So we finally have something to do for patients,” she said.

In terms of MIPS for ICH evacuation, Khatri said she’d have to see a full manuscript before determining what impact it will ultimately have. “I really need to be able to dig into the details before I know for sure that it will change practice, but I think I like what I’m hearing right now and we’re pretty excited.”

We finally have something to do for patients. Pooja Khatri

And as for the care bundle evaluated in INTERACT3, “I’m not surprised that worked,” she said. “Right now, my overall impression is that it certainly makes sense that educating and training around the current standards of care is going to help and so it sort of confirms that.”

And the trial results could have an impact even in centers that have established ICH protocols, Khatri suggested. “It varies probably more than we’d like so it might raise our bar in that sense.”

Sandset indicated that a change in the care team’s mindset and a combined effect of all interventions, rather than any one in particular, explains the benefits seen in INTERACT3.

“Perhaps it’s the synergy of these interventions that provides a better outcome for the patient,” she said. “I also think while we are actively caring for patients in a very structured approach like the protocol they used in INTERACT3, we provide better overall care for the patients as well and it takes us a bit away from the nihilistic approach that many people have had [towards] the care for ICH patients.”