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Time Course of Early Hematoma Expansion in Acute Spot-Sign Positive Intracerebral Hemorrhage: Prespecified Analysis of the SPOTLIGHT Randomized Clinical Trial
Al-Ajlan FS, Gladstone DJ, Song D, Thorpe KE, Swartz RH, Butcher KS, Del Campo M, Dowlatshahi D, Gensicke H, Lee GJ, et al
Stroke. 2023
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Editor's Choice
Abstract
BACKGROUND In the SPOTLIGHT trial (Spot Sign Selection of Intracerebral Hemorrhage to Guide Hemostatic Therapy), patients with a computed tomography (CT) angiography spot-sign positive acute intracerebral hemorrhage were randomized to rFVIIa (recombinant activated factor VIIa; 80 μg/kg) or placebo within 6 hours of onset, aiming to limit hematoma expansion. Administration of rFVIIa did not significantly reduce hematoma expansion. In this prespecified analysis, we aimed to investigate the impact of delays from baseline imaging to study drug administration on hematoma expansion. METHODS Hematoma volumes were measured on the baseline CT, early post-dose CT, and 24 hours CT scans. Total hematoma volume (intracerebral hemorrhage+intraventricular hemorrhage) change between the 3 scans was calculated as an estimate of how much hematoma expansion occurred before and after studying drug administration. RESULTS Of the 50 patients included in the trial, 44 had an early post-dose CT scan. Median time (interquartile range) from onset to baseline CT was 1.4 hours (1.2-2.6). Median time from baseline CT to study drug was 62.5 (55-80) minutes, and from study drug to early post-dose CT was 19 (14.5-30) minutes. Median (interquartile range) total hematoma volume increased from baseline CT to early post-dose CT by 10.0 mL (-0.7 to 18.5) in the rFVIIa arm and 5.4 mL (1.8-8.3) in the placebo arm (P=0.96). Median volume change between the early post-dose CT and follow-up scan was 0.6 mL (-2.6 to 8.3) in the rFVIIa arm and 0.7 mL (-1.6 to 2.1) in the placebo arm (P=0.98). Total hematoma volume decreased between the early post-dose CT and 24-hour scan in 44.2% of cases (rFVIIa 38.9% and placebo 48%). The adjusted hematoma growth in volume immediately post dose for FVIIa was 0.998 times that of placebo ([95% CI, 0.71-1.43]; P=0.99). The hourly growth in FFVIIa was 0.998 times that for placebo ([95% CI, 0.994-1.003]; P=0.50; Table 3). CONCLUSIONS In the SPOTLIGHT trial, the adjusted hematoma volume growth was not associated with Factor VIIa treatment. Most hematoma expansion occurred between the baseline CT and the early post-dose CT, limiting any potential treatment effect of hemostatic therapy. Future hemostatic trials must treat intracerebral hemorrhage patients earlier from onset, with minimal delay between baseline CT and drug administration. REGISTRATION URL: https://www. CLINICALTRIALS gov; Unique identifier: NCT01359202.
PICO Summary
Population
Patients with a computed tomography (CT) angiography spot-sign positive acute intracerebral haemorrhage (ICH) enrolled in the SPOTLIGHT trial (n= 50).
Intervention
Recombinant activated factor VIIa (n= 19).
Comparison
Placebo (n= 25).
Outcome
This prespecified analysis aimed to investigate the impact of delays from baseline imaging to study drug administration on haematoma expansion. Haematoma volumes were measured on the baseline CT, early post-dose CT, and 24 hours CT scans. Total haematoma volume (intracerebral haemorrhage + intraventricular haemorrhage) change between the 3 scans was calculated as an estimate of how much haematoma expansion occurred before and after studying drug administration. Of the 50 patients included in the trial, 44 had an early post-dose CT scan. Median time (interquartile range) from onset to baseline CT was 1.4 hours (1.2 - 2.6). Median time from baseline CT to study drug was 62.5 (55 - 80) minutes, and from study drug to early post-dose CT was 19 (14.5 - 30) minutes. Median (interquartile range) total haematoma volume increased from baseline CT to early post-dose CT by 10.0 mL (-0.7 to 18.5) in the rFVIIa arm and 5.4 mL (1.8 - 8.3) in the placebo arm. Median volume change between the early post-dose CT and follow-up scan was 0.6 mL (-2.6 to 8.3) in the rFVIIa arm and 0.7 mL (-1.6 to 2.1) in the placebo arm. Total haematoma volume decreased between the early post-dose CT and 24-hour scan in 44.2% of cases (rFVIIa 38.9% and placebo 48%). The adjusted haematoma growth in volume immediately post dose for FVIIa was 0.998 times that of placebo ([95% CI: 0.71 - 1.43]). The hourly growth in FFVIIa was 0.998 times that for placebo ([95% CI: 0.994 - 1.003]).
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Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial
Sholzberg M, Tang GH, Rahhal H, AlHamzah M, Kreuziger LB, Áinle FN, Alomran F, Alayed K, Alsheef M, AlSumait F, et al
BMJ (Clinical research ed.). 2021;375:n2400
Abstract
OBJECTIVE To evaluate the effects of therapeutic heparin compared with prophylactic heparin among moderately ill patients with covid-19 admitted to hospital wards. DESIGN Randomised controlled, adaptive, open label clinical trial. SETTING 28 hospitals in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and US. PARTICIPANTS 465 adults admitted to hospital wards with covid-19 and increased D-dimer levels were recruited between 29 May 2020 and 12 April 2021 and were randomly assigned to therapeutic dose heparin (n=228) or prophylactic dose heparin (n=237). INTERVENTIONS Therapeutic dose or prophylactic dose heparin (low molecular weight or unfractionated heparin), to be continued until hospital discharge, day 28, or death. MAIN OUTCOME MEASURES The primary outcome was a composite of death, invasive mechanical ventilation, non-invasive mechanical ventilation, or admission to an intensive care unit, assessed up to 28 days. The secondary outcomes included all cause death, the composite of all cause death or any mechanical ventilation, and venous thromboembolism. Safety outcomes included major bleeding. Outcomes were blindly adjudicated. RESULTS The mean age of participants was 60 years; 264 (56.8%) were men and the mean body mass index was 30.3 kg/m(2). At 28 days, the primary composite outcome had occurred in 37/228 patients (16.2%) assigned to therapeutic heparin and 52/237 (21.9%) assigned to prophylactic heparin (odds ratio 0.69, 95% confidence interval 0.43 to 1.10; P=0.12). Deaths occurred in four patients (1.8%) assigned to therapeutic heparin and 18 patients (7.6%) assigned to prophylactic heparin (0.22, 0.07 to 0.65; P=0.006). The composite of all cause death or any mechanical ventilation occurred in 23 patients (10.1%) assigned to therapeutic heparin and 38 (16.0%) assigned to prophylactic heparin (0.59, 0.34 to 1.02; P=0.06). Venous thromboembolism occurred in two patients (0.9%) assigned to therapeutic heparin and six (2.5%) assigned to prophylactic heparin (0.34, 0.07 to 1.71; P=0.19). Major bleeding occurred in two patients (0.9%) assigned to therapeutic heparin and four (1.7%) assigned to prophylactic heparin (0.52, 0.09 to 2.85; P=0.69). CONCLUSIONS In moderately ill patients with covid-19 and increased D-dimer levels admitted to hospital wards, therapeutic heparin was not significantly associated with a reduction in the primary outcome but the odds of death at 28 days was decreased. The risk of major bleeding appeared low in this trial. TRIAL REGISTRATION ClinicalTrials.gov NCT04362085.
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Randomized trials of therapeutic heparin for COVID-19: A meta-analysis
Sholzberg M, da Costa BR, Tang GH, Rahhal H, AlHamzah M, Baumann Kreuziger L, Ní Áinle F, Almarshoodi MO, James PD, Lillicrap D, et al
Research and practice in thrombosis and haemostasis. 2021;5(8):e12638
Abstract
BACKGROUND Pulmonary endothelial injury and microcirculatory thromboses likely contribute to hypoxemic respiratory failure, the most common cause of death, in patients with COVID-19. Randomized controlled trials (RCTs) suggest differences in the effect of therapeutic heparin between moderately and severely ill patients with COVID-19. We did a systematic review and meta-analysis of RCTs to determine the effects of therapeutic heparin in hospitalized patients with COVID-19. METHODS We searched PubMed, Embase, Web of Science, medRxiv, and medical conference proceedings for RCTs comparing therapeutic heparin with usual care, excluding trials that used oral anticoagulation or intermediate doses of heparin in the experimental arm. Mantel-Haenszel fixed-effect meta-analysis was used to combine odds ratios (ORs). RESULTS AND CONCLUSIONS There were 3 RCTs that compared therapeutic heparin to lower doses of heparin in 2854 moderately ill ward patients, and 3 RCTs in 1191 severely ill patients receiving critical care. In moderately ill patients, there was a nonsignificant reduction in all-cause death (OR, 0.76; 95% CI, 0.57-1.02), but significant reductions in the composite of death or invasive mechanical ventilation (OR, 0.77; 95% CI, 0.60 0.98), and death or any thrombotic event (OR, 0.58; 95% CI, 0.45-0.77). Organ support-free days alive (OR, 1.29; 95% CI, 1.07-1.57) were significantly increased with therapeutic heparin. There was a nonsignificant increase in major bleeding. In severely ill patients, there was no evidence for benefit of therapeutic heparin, with significant treatment-by-subgroup interactions with illness severity for all-cause death (P = .034). In conclusion, therapeutic heparin is beneficial in moderately ill patients but not in severely ill patients hospitalized with COVID-19.
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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
Gladstone DJ, Aviv RI, Demchuk AM, Hill MD, Thorpe KE, Khoury JC, Sucharew HJ, Al-Ajlan F, Butcher K, Dowlatshahi D, et al
JAMA neurology. 2019
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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 mug/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.