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Clinical Trial
. 2019 Dec 1;76(12):1493-1501.
doi: 10.1001/jamaneurol.2019.2636.

Effect of Recombinant Activated Coagulation Factor VII on Hemorrhage Expansion Among Patients With Spot Sign-Positive Acute Intracerebral Hemorrhage: The SPOTLIGHT and STOP-IT Randomized Clinical Trials

Affiliations
Clinical Trial

Effect of Recombinant Activated Coagulation Factor VII on Hemorrhage Expansion Among Patients With Spot Sign-Positive Acute Intracerebral Hemorrhage: The SPOTLIGHT and STOP-IT Randomized Clinical Trials

David J Gladstone et al. JAMA Neurol. .

Abstract

Importance: Intracerebral hemorrhage (ICH) is a devastating stroke type that lacks effective treatments. An imaging biomarker of ICH expansion-the computed tomography (CT) angiography spot sign-may identify a subgroup that could benefit from hemostatic therapy.

Objective: To investigate whether recombinant activated coagulation factor VII (rFVIIa) reduces hemorrhage expansion among patients with spot sign-positive ICH.

Design, setting, and participants: In parallel investigator-initiated, multicenter, double-blind, placebo-controlled randomized clinical trials in Canada ("Spot Sign" Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy [SPOTLIGHT]) and the United States (The Spot Sign for Predicting and Treating ICH Growth Study [STOP-IT]) with harmonized protocols and a preplanned individual patient-level pooled analysis, patients presenting to the emergency department with an acute primary spontaneous ICH and a spot sign on CT angiography were recruited. Data were collected from November 2010 to May 2016. Data were analyzed from November 2016 to May 2017.

Interventions: Eligible patients were randomly assigned 80 μg/kg of intravenous rFVIIa or placebo as soon as possible within 6.5 hours of stroke onset.

Main outcomes and measures: Head CT at 24 hours assessed parenchymal ICH volume expansion from baseline (primary outcome) and total (ie, parenchymal plus intraventricular) hemorrhage volume expansion (secondary outcome). The pooled analysis compared hemorrhage expansion between groups by analyzing 24-hour volumes in a linear regression model adjusted for baseline volumes, time from stroke onset to treatment, and trial.

Results: Of the 69 included patients, 35 (51%) were male, and the median (interquartile range [IQR]) age was 70 (59-80) years. Baseline median (IQR) ICH volumes were 16.3 (9.6-39.2) mL in the rFVIIa group and 20.4 (8.6-32.6) mL in the placebo group. Median (IQR) time from CT to treatment was 71 (57-96) minutes, and the median (IQR) time from stroke onset to treatment was 178 (138-197) minutes. The median (IQR) increase in ICH volume from baseline to 24 hours was small in both the rFVIIa group (2.5 [0-10.2] mL) and placebo group (2.6 [0-6.6] mL). After adjustment, there was no difference between groups on measures of ICH or total hemorrhage expansion. At 90 days, 9 of 30 patients in the rFVIIa group and 13 of 34 in the placebo group had died or were severely disabled (P = .60).

Conclusions and relevance: Among patients with spot sign-positive ICH treated a median of about 3 hours from stroke onset, rFVIIa did not significantly improve radiographic or clinical outcomes.

Trial registration: ClinicalTrials.gov identifier: NCT01359202 and NCT00810888.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Gladstone has received grants from the Canadian Institutes of Health Research, Ontario Ministry of Research and Innovation, and Ontario Stroke Network. Dr Demchuk has received personal fees from Medtronic. Dr Khoury has received grants from the National Institute of Neurological Disorders and Stroke. Dr Sucharew has received grants from the National Institutes of Health. Dr Dowlatshahi has received grants from the Heart and Stroke Foundation of Canada and has a patent issued for automated dynamic spot sign detection software. Ms Hall has received grants from the Canadian Institutes of Health Research. Dr Mamdani has received personal fees from Allergan, Amgen, and Novo Nordisk. Dr Swartz has received personal fees from the Canadian Medical Protective Association. Dr Cucchiara has received grants from Bristol-Myers Squibb and Novo Nordisk, served on advisory boards for Novo Nordisk and Portola Pharmaceuticals, and served as a consultant for AstraZeneca. Dr Panagos has received grants from the National Institute of Neurological Disorders and Stroke. Ms Carrozzella has received grants from the National Institutes of Health via the University of Cincinnati. Dr Goldstein has received grants from Boehringer Ingelheim, Pfizer, and Portola Pharmaceuticals and consulting fees from CSL Behring, Octapharma Plasma, Philips Healthcare, and Prolong Pharmaceuticals. Dr Broderick has received nonfinancial support for the STOP-IT trial from Novo Nordisk and monies to the Department of Neurology educational fund from Pfizer for consulting work. Dr Flaherty has received nonfinancial support for the STOP-IT trial from Novo Nordisk and personal fees from CSL Behring, Janssen Pharmaceuticals, and Portola Pharmaceuticals and has a patent issued and licensed to Sense Diagnostics for a noninvasive cerebral nervous system sensor that can monitor intracranial bleeding. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flow Diagram
CT indicates computed tomography; ICH, intracerebral hemorrhage; rFVIIa, recombinant activated coagulation factor VII. aOne enrolled patient did not meet eligibility criteria, was not treated, and was not included in the analysis.
Figure 2.
Figure 2.. Distribution of Intracerebral Hemorrhage (ICH) Expansion Volumes for Individual Patients by Time From Stroke Onset to Baseline Computed Tomography (CT) Scan
rFVIIa indicates recombinant activated coagulation factor VII.
Figure 3.
Figure 3.. 24-Hour Intracerebral Hemorrhage (ICH) Volumes as a Function of Baseline ICH Volumes and Treatment
The shaded regions indicate 95% CIs. rFVIIa indicates recombinant activated coagulation factor VII.

Comment in

References

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