HOUSTON—Acute hemostatic treatment with a clotting protein does not improve short- or long-term outcomes in patients with intracerebral hemorrhage (ICH), according to research presented at the International Stroke Conference 2017.
When patients who displayed a high-risk imaging marker suggestive of active bleeding were given recombinant activated blood coagulation factor VII (rFVII), it did not significantly reduce 24-hour hemorrhage volume or improve 90-day stroke outcomes, relative to placebo, said David Gladstone, MD, PhD, Director of the Sunnybrook Regional Stroke Prevention Clinic and Rapid Transient Ischemic Attack Clinic in Toronto.This is not the first time rFVII has been investigated as an acute treatment for ICH, said Dr. Gladstone. In the large phase III FAST trial, rFVII reduced the growth of hematoma, but did not improve survival or functional outcome in an unselected population.
No medical interventions are available for patients with ICH, and investigators hope to identify a narrower patient population with active bleeding that might be more responsive to rFVII. This goal prompted the initiation of the SPOTLIGHT and STOP-IT studies, said Dr. Gladstone. The former study was Canadian, and the latter American.
Spot Sign Imaging Biomarker
For both studies, researchers stratified patients using the spot sign, a relatively new imaging biomarker thought to reflect active bleeding in the ICH hematoma. The hyperintense signal can easily be seen on cerebral angiography.
“It shows up like a flashlight as a bright spot in the margin of the hematoma,” Dr. Gladstone said. “When we see this, we know this patient has a possible active bleed that is likely to expand and get worse. They are at highest risk for ICH expansion and should be the best candidates for hemostatic therapy.”
Spot-positive patients were randomized to placebo or to a single IV bolus of 80 µg/kg of rFVII given in the emergency department within 6.5 hours of stroke onset. Spot-negative patients were enrolled in a prospective observational cohort, which provided data to support the sign’s use as a predictor of outcome.
Exclusion criteria included brainstem ICH; ICH with secondary cause (eg, tumor or trauma); additional treatments such as plasma or prothrombin; acute coronary ischemia; history of other strokes, angioplasty, or stenting; past thrombotic events; a Glasgow Coma Scale score less than 8; or a modified Rankin Scale (mRS) score more than 2.
These criteria, plus the relative infrequency of ICH events, compared with other cerebrovascular events, made recruitment difficult. After six years, the trials together enrolled 69 spot-positive and 72 spot-negative patients. Both studies were stopped because of the low numbers and insufficient funds.
The studies’ primary efficacy end point was 24-hour ICH volume. Secondary outcomes were 24-hour total ICH plus intraventricular hemorrhage volumes, 90-day mRS of 5 to 6, and comparisons between the spot-negative and spot-positive groups. The primary safety outcome was acute myocardial infarction, ischemic stroke, or pulmonary embolism within four days of treatment.
Results by Spot Status
Patients’ mean age was 70, although spot-positive patients were older than spot-negative patients (71 vs 61). Spot-positive patients were also less likely to have a Glasgow Coma Scale score of 15 to 16 (56% vs 66%). The mean NIH Stroke Scale score was 16 in the spot-positive group and 10 in the spot-negative group. Intraventricular hemorrhage was also more common in the spot-positive group (44% vs 18%).
After researchers adjusted for baseline ICH volume and onset-to-needle time, rFVII exerted no significant effect on either 24-hour ICH volume or 24-hour total volume. In the treated group, median ICH volume increased from 16 mL at baseline to 22 mL by 24 hours. In the placebo group, it increased from 20 mL at baseline to 29 mL at 24 hours.
In the treated group, the median total volume (ICH plus intraventricular hemorrhage) increased from 24 mL at baseline to 26 mL at 24 hours. In the placebo group, it increased from 25 mL at baseline to 31 mL at 24 hours. Researchers did not observe a significant difference between groups in the number of patients who had a volume increase of more than 6 mL or more than 33% (41% vs 43%).
A Predictor of Continued Bleeding
Spot-negative patients had lower baseline and 24-hour total hematoma volumes. In the spot-negative group, total volumes increased from a median of 13 mL at baseline to 14 mL at 24 hours. Significantly fewer spot-negative patients than spot-positive patients had hematoma growth of more than 6 mL or 33% (11% vs 43%).
The spot sign was a good predictor of continued bleeding. In all spot-positive patients, median ICH volume expanded by a median of 9 mL over 24 hours (ie, from 20 mL to 29 mL), compared with a median ICH expansion of 1 mL over 24 hours (ie, from 12 mL to 13 mL) for spot-negative patients.
There were no significant differences in 90-day mRS scores between the treated and placebo groups. One-fifth of each group had a score of 1–2, and one-fifth died. The proportion of patients with mRS scores of 3 to 5 also was similar between the groups.
Despite similar scores, the spot-negative patients had significantly better outcomes. Approximately 38% had an mRS of 0–1 at 90 days. Six percent of this group died.
In addition, treatment time intervals were prolonged in these studies, compared with those that have been achieved with antithrombotic therapy in ischemic stroke. Time from stroke onset to the emergency department was similar in both spot-positive groups taking rFVII and spot-positive controls (64 min and 66 min). Onset-to-CT time was significantly longer in the rFVII patients than in controls (89 min vs 83 min). Door-to-needle time was also longer in the rFVII patients than in controls (104 min vs 87 min), as was onset-to-needle time (195 min vs 161 min).
Thirty-seven percent of spot-positive patients receiving rFVII were treated in less than three hours. This proportion was significantly lower than the 65% that were treated that quickly in the spot-positive placebo group. No significant adverse events were related to rFVII.
Future Directions
“The spot sign predicted final ICH volume, but the magnitude of ICH expansion was small: less than we expected,” Dr. Gladstone said. “The median absolute ICH volume increase overall was only 2.5 mm, which is surprisingly small for this group of patients. And I do believe that treatment was administered too late, after most of the ICH expansion had already happened.”
Nonetheless, “there is much to learn here,” he said. “The biggest issue is that treatment was just too little, too late. We need to be catching these patients at a much earlier phase to make a difference, and that is probably the largest reason we did not see a difference.
“The spot sign “was a statistically significant predictor of final ICH volumes,” Dr. Gladstone said. It is easy to recognize on an imaging study that is routinely acquired for stroke patients.
“We are also beginning to understand that there are many different types of spot signs associated with different kinds of bleeding at different times,” he said. “We need to understand this variation further, and this should allow us to characterize the patients who are likely to be big bleeders.”
—Michelle G. Sullivan
