HOUSTON – Acute hemostatic treatment with a clotting protein didn’t improve either short- or long-term outcomes in patients with intracerebral hemorrhage (ICH), according to findings from twin studies.

When given to patients who displayed a high-risk imaging marker suggestive of active bleeding, recombinant activated blood coagulation factor VII (rFVII) didn’t significantly reduce 24-hour hemorrhage volume or improve 90-day stroke outcomes, relative to placebo, David Gladstone, MD, said at the International Stroke Conference sponsored by the American Heart Association.

This isn’t the first time rFVII has been investigated as an acute treatment for ICH, said Dr. Gladstone, director of the Sunnybrook Regional Stroke Prevention Clinic and the Rapid Transient Ischemic Attack Clinic, Toronto. In the large phase III FAST trial, rFVII reduced growth of the hematoma but did not improve survival or functional outcome in an unselected population.

But based on this promise of efficacy – and because there are no existing medical interventions for ICH patients – investigators weren’t willing to give up. They were determined to identify a narrower patient population with active bleeding that might be more responsive to the treatment.

Their determination was the genesis of the two studies, SPOTLIGHT (Canada) and STOP-IT (United States), that Dr. Gladstone reported at the meeting.

Both studies stratified patients using the “spot sign,” a relatively new imaging biomarker thought to reflect active bleeding in the ICH hematoma. The hyperintense signal can be easily 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-negative patients, on the other hand, are at low risk for ICH expansion and would not benefit from hemostatic therapy, he said.

Both SPOTLIGHT and STOP-IT stratified their subjects by the presence of this sign. Spot-positive patients were randomized to placebo or to a single intravenous bolus of 80 mcg/kg rFVII given in the emergency department and 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.

In order to obtain the most focused patient population, the investigators imposed a number of exclusion criteria – a choice that may have contributed to the lackluster results, Dr. Gladstone noted. Exclusion criteria were brain stem ICH; ICH with secondary cause, such as a 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 of less than 8; or a modified Rankin Scale (mRS) score more than 2.

These stringent criteria, plus the uncommon nature of ICH events, compared with other cerebrovascular events, made recruitment a struggle, Dr. Gladstone said. After 6 years, the trials together managed to enroll only 69 spot-positive and 72 spot-negative patients. At that point, both studies were stopped because of the low numbers and because they had run out of money.

The studies’ primary efficacy endpoint was 24-hour ICH volume. Secondary outcomes were 24-hour total ICH plus intraventricular hemorrhage volumes, 90-day mRS of 5-6, and comparisons between the spot-negative and spot-positive groups. The primary safety outcome was acute myocardial infarction, ischemic stroke, or pulmonary embolism within 4 days of treatment.

Patients were a mean of about 70 years, although spot-positive patients were older than were spot-negative patients (71 years vs. 61 years). Spot-positive patients were also less likely to have a Glasgow coma score of 15-16 (56% vs. 66%). The National Institutes of Health Stroke Scale score was a mean of 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 (between-group difference, P = 0.9).

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 later (between-group difference, P = .9).

There was no significant difference in the number of patients who had a volume increase of more than 6 mL or more than 33% (41% vs. 43%, respectively).

In contrast, 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 experienced hematoma growth of more than 6 mL or 33% (11% vs. 43%, respectively.)

However, the spot sign was a very good predictor of continued bleeding. In all spot-positive patients, median ICH volume expanded 9 mL over 24 hours (from 20 mL at baseline to 29 mL at 24 hours), compared with a median ICH expansion of only 1 mL over 24 hours (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 (20%) had a score of 1-2, and one-fifth died. mRS scores of 3-5 were also similar between the groups.

Despite similar scores, other factors showed that the spot-negative patients did significantly better. Only 6% of this group died. More than a third (38%) had an mRS of 0-1 at 90 days.

Dr. Gladstone was not pleased about the treatment time intervals, which were prolonged, 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 rFVIIa and spot-positive placebo patients (64 and 66 minutes, respectively). Onset-to-CT time was significantly longer in the rFVIIa patients than in placebo patients (89 vs. 83 minutes, respectively). Door-to-needle time also was longer in the rFVIIa patients than in the placebo patients (104 vs. 87 minutes, respectively), as was onset-to-needle time (195 vs. 161 minutes, respectively).

Only 37% of spot-positive patients receiving rFVIIa were treated in less than 3 hours – significantly less than the 65% that were treated that quickly in the spot-positive placebo group.

rFVII had a positive safety profile, with no significant events related to the study medication. No patient had a heart attack or pulmonary embolism within 4 days. An ischemic stroke developed in one patient in the placebo group. One patient had a possible thrombosis in the middle cerebral artery, but this was asymptomatic.

“What we are left with is that 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 I think 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 didn’t see a difference.”

On the upside, the spot sign “was a statistically significant predictor of final ICH volumes,” Dr. Gladstone said. It’s an easy sign to catch, and it’s obvious on an imaging study that’s 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 noted. “We need to understand this variation further, and this should allow us to characterize the patients who are likely to be big bleeders.”

SPOTLIGHT was funded by the Canadian Institutes of Health Research, the Ontario Stroke Network, and the Ontario Ministry of Research, Innovation, and Science. STOP-IT was funded by the National Institute of Neurological Disorders and Stroke.

Dr. Gladstone had no financial disclosures.

msullivan@frontlinemedcom.com

On Twitter @alz_gal

rFVII didn’t improve hemorrhagic stroke outcomes in twin trials