HOUSTON, Texas — A new trial shows no benefit of hemostatic therapy with recombinant factor VII in patients with intracerebral hemorrhage (ICH) but supports the utility of a neuroimaging strategy for patient selection.
Researchers selected patients for the trial by using computed tomographic angiography (CTA) to look for a biomarker called the "spot sign," a bright area of contrast enhancement on the scan within the margin of the hematoma that indicates active bleeding and predicts further hematoma expansion and clinical deterioration.
The results, from two collaborative trials (called the SPOTLIGHT trial in Canada and STOP-IT in the United States), were presented here at the International Stroke Conference (ISC) 2017.
"In summary, this is our first attempt to use the CTA spot sign for patient selection in a randomized treatment trial of hemostatic therapy for ICH, but we did not see any benefit of therapy among the spot-positive patients who were enrolled into this study," lead author on the Canadian trial, David J. Gladstone, MD, PhD, University of Toronto, Ontario, concluded during a press briefing.
This was the first presentation of results of a pooled analysis between the two studies that ran in parallel using a harmonized study protocol. "These studies are innovative because they're the first to test a new image-guided patient selection protocol for hemostatic therapy in patients with intracerebral hemorrhage," Dr Gladstone said.
Currently, no effective treatments for ICH are available, so there is a "desperate" need to develop new strategies to reduce ICH expansion and improve patient outcomes, he noted.
"The ideal treatment is one that could be administered quickly at an early enough stage, while hemorrhages are still relatively small, to prevent expansion to a critical, life-threatening size," Dr Gladstone noted. One of the most promising treatments studied to date, he said, is recombinant activated factor VII; in previous trials, it reduced expansion, but that improvement didn't translate into clinical efficacy in the large phase 3 FAST trial.
That study, though, looked at a "broad, unselected patient population," he said. "So we attempted to build on the previous studies and to incorporate an imaging biomarker called the spot sign." Using CTA, they were "readily" able to distinguish spot-positive patients, those most at risk for expansion and deterioration, and most likely the best target for therapy, from spot-negative patients, who are likely to have already stopped bleeding.
They enrolled spot-positive patients from 26 sites in Canada and the United States between 2010 and 2016. Spot-positive patients were randomly assigned 1:1 within 6.5 hours after onset to receive 80 mg/kg recombinant factor VII or placebo, while spot-negative patients were enrolled into a prospective, observational cohort with similar inclusion criteria.
The primary outcome was the 24-hour ICH volume measured by CT scan and assessed in a pooled analysis combining the two studies, Dr Gladstone said.
"Recruitment into these trials proved very challenging," he said. Both trials were stopped early because of completion of funding and poor recruitment. A total of 69 spot-positive patients and 73 spot-negative patients were enrolled.
"In adjusted analysis, we did not see any significant benefit of factor VII, either on the primary outcome, or the secondary outcome, which was the total hematoma volume, combining intracerebral hemorrhage and intraventricular hemorrhage," Dr Gladstone said.
Table 1. SPOTLIGHT/STOP-IT: Hematoma Expansion in Spot-Positive ICH
|Endpoint||Spot-Positive Factor VII Group at Baseline||Spot-Positive Factor VII Group at 24 Hours||Spot-Positive Placebo Group at Baseline||Spot-Positive Placebo Group at 24 Hours||P Value|
|ICH volume, mL (median, interquartile range)||16 (10 - 39)||22 (10 - 53)||20 (9 - 33)||29 (14 - 52)||.9|
Looking at the absolute increase in ICH volume in spot-positive patients, they found that most patients had very little growth in their hematoma, less than 5 mL, with only a "handful" of patients with a larger degree of growth between baseline and 24 hours. "And those tended to cluster toward the earlier time window, although the numbers are very small," Dr Gladstone said. "Overall, the median absolute increase in ICH volume was about 2.5 mL only, surprisingly small for this group of spot-positive patients."
The timing was felt to be a critical issue, he noted. "The baseline CT scan was performed at about an hour and a half post-onset in the factor VII group, and the door-to-needle times were long: on average over an hour the factor VII group," he said. The median onset to needle time for treatment with factor VII was about 3 hours and 15 minutes, "with only about a third of patients in the factor VII group receiving treatment within the first 3 hours post-onset."
Patients who were negative for the spot sign presented with significantly smaller hemorrhage volumes at baseline, "and there was minimal increase at 24 hours, as expected," Dr Gladstone said.
Table 2. SPOTLIGHT/STOP-IT: Hematoma Expansion in Spot-Negative ICH
|Endpoint||Spot-Positive Placebo Group at Baseline||Spot-Positive Placebo Group at 24 Hours||Spot-Negative Group at Baseline||Spot-Negative Group at 24 Hours||P Value|
|ICH volume, mL (median, interquartile range)||20 (9 - 33)||29 (14 - 52)||12 (6 - 21)||13 (6 - 23)||.013|
At 90 days, mortality was similar between spot-positive treatment and placebo groups (P = .96), as was the proportion of patients scoring 5 to 6 on the modified Rankin Scale, indicating death or significant disability (20% vs 21%; P = .6).
"By comparison, spot-negative patients had a much more favorable prognosis," Dr Gladstone said. "By 90 days, only 6% had died, and about two thirds of the spot-negative patients achieved functional independence based on a Rankin 0 to 2."
There were no safety concerns with the treatment, he added, with no myocardial infarction or pulmonary embolism seen within 4 days of treatment; one ischemic stroke occurred in the placebo group.
"There is much to learn here," he said of their findings, and he reviewed several possible explanations for their neutral results. "The big issue, we believe, really, is that treatment was administered too late, after the majority of ICH expansion had already taken place. Recall that about two thirds of our factor VII–treated patients received the treatment more than 3 hours post-onset, and by that time, it's likely too little, too late."
Matt Flaherty, MD, a neurologist at the University of Cincinnati Neuroscience Institute, associate professor of neurology at the UC College of Medicine, Ohio, and lead author of the STOP-IT trial, said that part of the problem with the timing was logistics.
"Because we're testing a new treatment paradigm, people had to get the CT angiogram, recognize the spot sign, consent the patient in the trial, so there are a lot of steps you have to do," Dr Flaherty said. "So we think it's feasible, but it's not going to be easy, and it will require really good organization moving forward. It's also more challenging because there are fewer intracerebral hemorrhage patients than ischemic stroke patients, so you have fewer coming through the door to begin with, so it's harder to recruit a sizable number of people into the trial."
That delay might also explain why the spot-sign biomarker didn't perform as well as they had hoped, Dr Gladstone added. "Although it was statistically a significant predictor of final ICH volumes, the spot sign was not associated with a large magnitude of hematoma expansion," he said. "The magnitude of hematoma expansion that we observed was quite small indeed, and much less than expected based on the previous observational studies of spot-positive patients, and this may have to do with our other inclusion and exclusion criteria."
There was a higher proportion of deep bleeds rather than lobar, for example, but it may also relate to variability among spot signs, Dr Gladstone said. "As we're understanding more about the concept of the spot sign, we're realizing there can be many different types of spot signs associated with different rates of bleeding, and that ranges from the rapid gushers to the slow oozers, to other spot signs that behave more like spot-negative patients."
Further research will look more closely at the characteristics of the "big bleeders," he said, and future studies should perhaps use more refined tools, such as spot-sign scores, or other imaging features that might be more powerful predictors.
"Finally, the very small sample size limits our ability to make definitive conclusions here, so this remains an open, ongoing, unanswered research question, and we believe very strongly that hemostatic therapy research for ICH must be pursued further, but first we have to rethink how we use the spot sign for patient selection," Dr Gladstone concluded.
"Our data does support the value of the spot sign as a clinical tool for patient prognostication in the emergency department, but for clinical trial patient selection, it may not be an adequate substitute for a narrow time window," he added. They think the time window for effective intervention may be as short as within 90 minutes of stroke onset, like for ischemic stroke.
To facilitate this earlier treatment, they would like to see ICH trials move into the prehospital setting. "The advent of the mobile stroke unit is extremely exciting, and we would like to see ICH patients diagnosed and treated in the ambulance, and of course, this would be great facilitated by the use of waiver of informed consent procedures, and safer hemostatic agents where there is less worry about the potential for thrombotic complications."
Bruce Ovbiagele, MD, chairman of neurology at the Medical University of South Carolina in Charleston, and chair of the ISC 2017 Program Committee, also noted the issue of time to treatment.
"I think the attraction of the SPOTLIGHT/STOP-IT trial is that here you have a devastating condition with no treatment whatsoever, and you potentially have an imaging marker that is widely available," he noted during the press conference.
"The only issue was one of timing it looks like, for the most part," Dr Ovbiagele said. "So I endorse their trying to incorporate this into the prehospital model, so I would love to see this potentially investigated in that sense."
The findings also build on previous knowledge, he added. "It confirms the issue of the marker being valid, but it definitely tells us that we really need to be fast."
SPOTLIGHT was funded by the Canadian Institutes of Health Research, Ontario Stroke Network, and Ontario Ministry of Research & Innovation. STOP-IT was funded by the National Institute of Neurological Disorders and Stroke. Dr Gladstone has disclosed no relevant financial relationships.
International Stroke Conference (ISC) 2017. Abstract LB16. Presented February 24, 2017.
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