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The efficacy of antifibrinolytic therapy in aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis
Fatima K, Ur Rehman MA, Asmar A, Farooq H, Ahmad NU, Danial A, Ur Rehman ME, Khan AA, Tahir S, Ahmed U, et al
Future science OA. 2023;9(6):Fso866
Abstract
AIM: The efficacy of antifibrinolytics in subarachnoid hemorrhage remains unclear due to conflicting evidence from studies. MATERIALS & METHODS Online databases were queried to include randomized controlled trials and propensity matched observational studies. We used Review Manager for the statistical analysis, presenting results as odds ratios with 95% CI. RESULTS The 12 shortlisted studies included 3359 patients, of which 1550 (46%) were in the intervention (tranexamic acid) group and 1809 (54%) in the control group. Antifibrinolytic therapy significantly reduced the risk of rebleeding (OR: 0.55; 95% CI: 0.40-0.75; p = 0.0002) with no significant decrease in poor clinical outcome (OR: 1.02; 95% CI: 0.86-1.20; p = 0.85) and all-cause mortality (OR: 0.92; CI: 0.72-1.17; p = 0.50). CONCLUSION In patients with subarachnoid hemorrhage, antifibrinolytics reduce the risk of rebleeding without significantly affecting mortality or clinical outcomes.
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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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Cerebral small vessel disease modifies outcomes after minimally invasive surgery for intracerebral haemorrhage
Li, Y., Cho, S. M., Avadhani, R., Ali, H., Hao, Y., Murthy, S. B., Goldstein, J. N., Xia, F., Hu, X., Ullman, N. L., et al
Stroke and vascular neurology. 2023
Abstract
BACKGROUND Minimally invasive surgery (MIS) for spontaneous supratentorial intracerebral haemorrhage (ICH) is controversial but may be beneficial if end-of-treatment (EOT) haematoma volume is reduced to ≤15 mL. We explored whether MRI findings of cerebral small vessel disease (CSVD) modify the effect of MIS on long-term outcomes. METHODS Prespecified blinded subgroup analysis of 288 subjects with qualified imaging sequences from the phase 3 Minimally Invasive Surgery Plus Alteplase for Intracerebral Haemorrhage Evacuation (MISTIE) trial. We tested for heterogeneity in the effects of MIS and MIS+EOT volume ≤15 mL on the trial's primary outcome of good versus poor function at 1 year by the presence of single CSVD features and CSVD scores using multivariable models. RESULTS Of 499 patients enrolled in MISTIE III, 288 patients had MRI, 149 (51.7%) randomised to MIS and 139 (48.3%) to standard medical care (SMC). Median (IQR) ICH volume was 42 (30-53) mL. In the full MRI cohort, there was no statistically significant heterogeneity in the effects of MIS versus SMC on 1-year outcomes by any specific CSVD feature or by CSVD scores (all P(interaction) >0.05). In 94 MIS patients with EOT ICH volume ≤15 mL, significant reduction in odds of poor outcome was found with cerebral amyloid angiopathy score <2 (OR, 0.14 (0.05-0.42); P(interaction)=0.006), absence of lacunes (OR, 0.37 (0.18-0.80); P(interaction)=0.02) and absence of severe white matter hyperintensities (WMHs) (OR, 0.22 (0.08-0.58); P(interaction)=0.03). CONCLUSIONS Following successful haematoma reduction by MIS, we found significantly lower odds of poor functional outcome with lower total burden of CSVD in addition to absence of lacunes and severe WMHs. CSVD features may have utility for prognostication and patient selection in clinical trials of MIS.
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Tranexamic Acid for Intracerebral Hemorrhage in Patients on Non-Vitamin K Antagonist Oral Anticoagulants (TICH-NOAC): A Multicenter, Randomized, Placebo-Controlled, Phase 2 Trial
Polymeris, A. A., Karwacki, G. M., Siepen, B. M., Schaedelin, S., Tsakiris, D. A., Stippich, C., Guzman, R., Nickel, C. H., Sprigg, N., Kägi, G., et al
Stroke. 2023
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Abstract
BACKGROUND Evidence-based hemostatic treatment for intracerebral hemorrhage (ICH) associated with non-vitamin K antagonist oral anticoagulants (NOACs) is lacking. Tranexamic acid (TXA) is an antifibrinolytic drug potentially limiting hematoma expansion. We aimed to assess the efficacy and safety of TXA in NOAC-ICH. METHODS We performed a double-blind, randomized, placebo-controlled trial at 6 Swiss stroke centers. Patients with NOAC-ICH within 12 hours of symptom onset and 48 hours of last NOAC intake were randomized (1:1) to receive either intravenous TXA (1 g over 10 minutes followed by 1 g over 8 hours) or matching placebo in addition to standard medical care via a centralized Web-based procedure with minimization on key prognostic factors. All participants and investigators were masked to treatment allocation. Primary outcome was hematoma expansion, defined as ≥33% relative or ≥6 mL absolute volume increase at 24 hours and analyzed using logistic regression adjusted for baseline hematoma volume on an intention-to-treat basis. RESULTS Between December 12, 2016, and September 30, 2021, we randomized 63 patients (median age, 82 years [interquartile range, 76-86]; 40% women; median hematoma volume, 11.5 [4.8-27.4] mL) of the 109 intended sample size before premature trial discontinuation due to exhausted funding. The primary outcome did not differ between TXA (n=32) and placebo (n=31) arms (12 [38%] versus 14 [45%]; adjusted odds ratio, 0.63 [95% CI, 0.22-1.82]; P=0.40). There was a signal for interaction with onset-to-treatment time (P(interaction)=0.024), favoring TXA when administered within 6 hours of symptom onset. Between the TXA and placebo arms, the proportion of participants who died (15 [47%] versus 13 [42%]; adjusted odds ratio, 1.07 [0.37-3.04]; P=0.91) or had major thromboembolic complications within 90 days (4 [13%] versus 2 [6%]; odds ratio, 1.86 [0.37-9.50]; P=0.45) did not differ. All thromboembolic events occurred at least 2 weeks after study treatment, exclusively in participants not restarted on oral anticoagulation. CONCLUSIONS In a smaller-than-intended NOAC-ICH patient sample, we found no evidence that TXA prevents hematoma expansion, but there were no major safety concerns. Larger trials on hemostatic treatments targeting an early treatment window are needed for NOAC-ICH. REGISTRATION URL: https://clinicaltrials.gov; Unique identifier: NCT02866838.
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Neuroendoscopic evacuation improves outcomes compared to external ventricular drainage in patients with spontaneous intraventricular hemorrhage: a systematic review with meta-analyses
Mezzacappa FM, Weisbrod LJ, Schmidt CM, Surdell D
World neurosurgery. 2023
Abstract
BACKGROUND Spontaneous intraventricular hemorrhage (IVH) is a cause of significant morbidity and mortality. Treatment for the resulting obstructive hydrocephalus has traditionally been via an external ventricular drain (EVD). We aimed to compare patient outcomes after neuroendoscopic surgery (NES) evacuation of IVH versus EVD management. METHODS MEDLINE, EMBASE, and the Cochrane Library were searched on October 8, 2022, with adherence to PRISMA guidelines. Of the 252 records remaining after removal of duplicates, 12 met the study's inclusion criteria. After extraction of outcomes data, fixed-effects and random-effects models were used to establish odds-ratios with 95% confidence intervals (CIs) for intensive care-unit (ICU) length-of-stay (LOS), rate of permanent cerebrospinal fluid (CSF) diversion, Glasgow Outcomes Scale (GOS) score, and mortality rate. RESULTS The results of the pooled analysis showed that ICU LOS was shorter (OR -2.61 [95% CI -5.02, -0.19]; I(2)=97.76%; p=0.034), permanent CSF diversion was less likely (OR -0.79 [95% CI -1.17, -0.41]; I(2)=46.96%; p<0.001), higher GOS was more likely (OR 0.48 [95% CI 0.04, 0.93]; I(2)=60.12%; p=0.032), and all-cause mortality was less likely (OR -1.11 [95% CI -1.79, -0.44]; I(2)=0%; p=0.001) in the NES evacuation group compared to the EVD group. CONCLUSIONS NES for evacuation of spontaneous IVH results in reduced ICU LOS, reduced permanent CSF diversion rates, improved GOS, and reduced mortality when compared with EVD. More robust prospective, randomized studies are necessary to help inform the safety and utility of NES for IVH.
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Pre-treatment re-bleeding following aneurysmal subarachnoid hemorrhage: A systematic review of published prediction models with risk of bias and clinical applicability assessment
Dissanayake, A. S., Ho, K. M., Phillips, T. J., Honeybul, S., Hankey, G. J.
Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2023;119:102-111
Abstract
BACKGROUND Pre-treatment rebleeding following aneurysmal subarachnoid hemorrhage (aSAH) increases the risk of death and a poor neurological outcome. Current guidelines recommend aneurysm treatment "as early as feasible after presentation, preferably within 24 h of onset" to mitigate this risk, a practice termed ultra-early treatment. However, ongoing debate regarding whether ultra-early treatment is independently associated with reduced re-bleeding risk, together with the recognition that re-bleeding occurs even in centres practicing ultra-early treatment due to the presence of other risk-factors has resulted in a renewed need for patient-specific re-bleed risk prediction. Here, we systematically review models which seek to provide patient specific predictions of pre-treatment rebleeding risk. METHODS Following registration on the International prospective register of systematic reviews (PROSPERO) CRD 42023421235; Ovid Medline (Pubmed), Embase and Googlescholar were searched for English language studies between 1st May 2002 and 1st June 2023 describing pre-treatment rebleed prediction models following aSAH in adults ≥18 years. Of 763 unique records, 17 full texts were scrutinised with 5 publications describing 4 models reviewed. We used the semi-automated template of Fernandez-Felix et al. incorporating the Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (CHARMS) checklist and the Prediction model Risk Of Bias ASsessment Tool (PROBAST) for data extraction, risk of bias and clinical applicability assessment. To further standardize risk of bias and clinical applicability assessment, we also used the published explanatory notes for the PROBAST tool and compared the aneurysm treatment practices each prediction model's formulation cohort experienced to a prespecified benchmark representative of contemporary aneurysm treatment practices as outlined in recent evidence-based guidelines and published practice pattern reports from four developed countries. RESULTS Reported model discriminative performance varied between 0.77 and 0.939, however, no single model demonstrated a consistently low risk of bias and low concern for clinical applicability in all domains. Only the score of Darkwah Oppong et al. was formulated using a patient cohort in which the majority of patients were managed in accordance with contemporary, evidence-based aneurysm treatment practices defined by ultra-early and predominantly endovascular treatment. However, this model did not undergo calibration or clinical utility analysis and when applied to an external cohort, its discriminative performance was substantially lower that reported at formulation. CONCLUSIONS No existing prediction model can be recommended for clinical use in centers practicing contemporary, evidence-based aneurysm treatment. There is a pressing need for improved prediction models to estimate and minimize pre-treatment re-bleeding risk.
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Catheter Tract Hemorrhages and Intracerebral Hemorrhage Outcomes in the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage Trial
Garton, A. L. A., Oh, S. E., Müller, A., Avadhani, R., Zhang, C., Merkler, A. E., Awad, I., Hanley, D., Kamel, H., Ziai, W. C., et al
Neurosurgery. 2023
Abstract
BACKGROUND AND OBJECTIVES Factors associated with external ventricular catheter tract hemorrhage (CTH) are well studied; whether CTH adversely influence outcomes after intracerebral hemorrhage (sICH), however, is poorly understood. We therefore sought to evaluate the association between CTH and sICH outcomes. METHODS We performed a post hoc analysis of the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage trial. The exposure was CTH and evaluated on serial computed tomography scans between admission and randomization (approximately 72 hours). The primary outcomes were a composite of death or major disability (modified Rankin Score >3) and mortality alone, both assessed at 6 months. Secondary outcomes were functional outcomes at 30 days, permanent cerebrospinal fluid (CSF) shunt placement, any infection, and ventriculitis. We performed logistic regression adjusted for demographics, comorbidities, sICH characteristics, and treatment assignment, for all analyses. RESULTS Of the 500 patients included, the mean age was 59 (SD, ±11) years and 222 (44%) were female. CTH occurred in 112 (22.4%) patients and was more common in minority patients, those on prior antiplatelet therapy, and patients who had more than 1 external ventricular drain placed. The end of treatment intraventricular hemorrhage volume was higher among patients with CTH (11.7 vs 7.9 mL, P = .01), but there were no differences in other sICH characteristics or the total duration of external ventricular drain. In multivariable regression models, CTH was not associated with death or major disability (odds ratio, 0.7; 95% CI: 0.4-1.2) or death alone (odds ratio, 0.8; 95% CI, 0.5-1.4). There were no relationships between CTH and secondary outcomes including 30-day functional outcomes, permanent CSF shunt placement, any infection, or ventriculitis. CONCLUSION Among patients with sICH and large intraventricular hemorrhage, CTH was not associated with poor sICH outcomes, permanent CSF shunt placement, or infections. A more detailed cognitive evaluation is needed to inform about the role of CTH in sICH prognosis.
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Deferoxamine in intracerebral hemorrhage: Systematic review and meta-analysis
Sun T, Zhao YY, Xiao QX, Wu M, Luo MY
Clinical neurology and neurosurgery. 2023;227:107634
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Editor's Choice
Abstract
BACKGROUND Intracerebral hemorrhage (ICH) is a stroke with a high morbidity and mortality rate. Deferoxamine (DFX) is thought to be effective in treating Intracerebral Hemorrhage. In our study, we performed a meta-analysis to evaluate the treatment effects of DFX. METHODS We systematically searched PubMed, Embase, Web of Science, the Cochrane Central Register of Controlled Trials, and Chinese Biomedical Literature Database in Jan 2022 for studies on DFX for ICH patients. Outcome measures included relative hematoma volume, relative edema volume, good neurological functional outcome and adverse events. Odds risk (OR) and weighted mean difference (WMD) were used to evaluate clinical outcomes. RESULTS After searching 636 articles, 4 RCTs, 2 NRCTs, and 1cohort study were included. We found that DFX was effective in hematoma absorption on day 7 after onset, but the difference was not significant on day 14. DFX could suppress edema expansion on days 3, 7, and 14 after onset. DFX did not contribute to better outcomes after 3 and 6 months when used the modified Rankin Scale and the Glasgow Outcome Scale to evaluate neurological prognosis. The pooled results showed no statistically significant difference in Serious adverse events between the experimental and control groups. CONCLUSIONS DFX could limit edema expansion on days 3, 7, and 14 after commencement and facilitate hematoma absorption at week 1 without significantly increasing the risk of adverse events, but it did not improve neurological prognosis.
PICO Summary
Population
Patients with intracerebral haemorrhage (n= 7 studies).
Intervention
Deferoxamine (DFX).
Comparison
Placebo.
Outcome
Outcome measures included relative haematoma volume, relative oedema volume, good neurological functional outcome and adverse events. DFX was effective in haematoma absorption on day 7 after onset, but the difference was not significant on day 14. DFX could suppress oedema expansion on days 3, 7, and 14 after onset. DFX did not contribute to better outcomes after 3 and 6 months when used the modified Rankin Scale and the Glasgow Outcome Scale to evaluate neurological prognosis. The pooled results showed no statistically significant difference in serious adverse events between the experimental and control groups.
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Desmopressin for patients with spontaneous intracerebral haemorrhage taking antiplatelet drugs (DASH): a UK-based, phase 2, randomised, placebo-controlled, multicentre feasibility trial
Desborough, M. J. R., Al-Shahi Salman, R., Stanworth, S. J., Havard, D., Woodhouse, L. J., Craig, J., Krishnan, K., Brennan, P. M., Dineen, R. A., Coats, T. J., et al
The Lancet. Neurology. 2023;22(7):557-567
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Editor's Choice
Abstract
BACKGROUND The risk of death from spontaneous intracerebral haemorrhage is increased for people taking antiplatelet drugs. We aimed to assess the feasibility of randomising patients on antiplatelet drug therapy with spontaneous intracerebral haemorrhage to desmopressin or placebo to reduce the antiplatelet drug effect. METHODS DASH was a phase 2, randomised, placebo-controlled, multicentre feasibility trial. Patients were recruited from ten acute stroke centres in the UK and were eligible if they had an intracerebral haemorrhage with stroke symptom onset within 24 h of randomisation, were aged 18 years or older, and were taking an antiplatelet drug. Participants were randomly assigned (1:1) to a single dose of intravenous desmopressin 20 μg or matching placebo. Treatment allocation was concealed from all staff and patients involved in the trial. The primary outcome was feasibility, which was measured as the number of eligible patients randomised and the proportion of eligible patients approached, and analysis was by intention to treat. The trial was prospectively registered with ISRCTN (reference ISRCTN67038373), and it is closed to recruitment. FINDINGS Between April 1, 2019, and March 31, 2022, 1380 potential participants were screened for eligibility. 176 (13%) participants were potentially eligible, of whom 57 (32%) were approached, and 54 (31%) consented and were subsequently recruited and randomly assigned to receive desmopressin (n=27) or placebo (n=27). The main reason for eligible patients not being recruited was the patient arriving out of hours (74 [61%] of 122 participants). The recruitment rate increased after the enrolment period was extended from 12 h to 24 h, but it was then impaired due to the COVID-19 pandemic. Of the 54 participants included in the analysis (mean age 76·4 years [SD 11·3]), most were male (36 [67%]) and White (50 [93%]). 53 (98%) of 54 participants received all of their allocated treatment (one participant assigned desmopressin only received part of the infusion). No participants were lost to follow-up or withdrew from the trial. Death or dependency on others for daily activities at day 90 (modified Rankin Scale score >4) occurred in six (22%) of 27 participants in the desmopressin group and ten (37%) of 27 participants in the placebo group. Serious adverse events occurred in 12 (44%) participants in the desmopressin group and 13 (48%) participants in the placebo group. The most common adverse events were expansion of the haemorrhagic stroke (four [15%] of 27 participants in the desmopressin group and six [22%] of 27 participants in the placebo group) and pneumonia (one [4%] of 27 participants in the desmopressin group and six [22%] of 27 participants in the placebo group). INTERPRETATION Our results show it is feasible to randomise patients with spontaneous intracerebral haemorrhage who are taking antiplatelet drugs to desmopressin or placebo. Our findings support the need for a definitive trial to determine if desmopressin improves outcomes in patients with intracerebral haemorrhage on antiplatelet drug therapy. FUNDING National Institute for Health Research.
PICO Summary
Population
Patients with spontaneous intracerebral haemorrhage taking antiplatelet drugs, enrolled in the DASH feasibility randomised phase 2 trial, in the UK (n= 54)
Intervention
Single dose of intravenous desmopressin (n= 27).
Comparison
Matching placebo (n= 27).
Outcome
The primary outcome was feasibility, which was measured as the number of eligible patients randomised and the proportion of eligible patients approached, and analysis was by intention to treat. 1380 potential participants were screened for eligibility. 176 (13%) participants were potentially eligible, of whom 57 (32%) were approached, and 54 (31%) consented and were subsequently recruited and randomly assigned. The main reason for eligible patients not being recruited was the patient arriving out of hours (74 [61%] of 122 participants). No participants were lost to follow-up or withdrew from the trial. Death or dependency on others for daily activities at day 90 occurred in six (22%) of 27 participants in the desmopressin group and 10 (37%) of 27 participants in the placebo group. Serious adverse events occurred in 12 (44%) participants in the desmopressin group and 13 (48%) participants in the placebo group.
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Exploring Hematoma Expansion Shift with Recombinant Factor VIIa: A Pooled Analysis of Four Randomized Controlled Trials
Yogendrakumar, V., Mayer, S. A., Steiner, T., Broderick, J. P., Dowlatshahi, D.
Stroke. 2023
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Abstract
Background: Hematoma expansion shift (HES) analysis can be used to assess the biological effect of a hemostatic therapy for intracerebral hemorrhage. In this study we applied HES analysis to individual patient data from four randomized controlled trials evaluating recombinant Factor VIIa (rFVIIa) 80 μg/kg to placebo. Methods: We generated polychotomous strata of HES using absolute growth thresholds (≤0mL/<6mL/≥6mL) and quintiles of percent volume change. The relationship between treatment and HES was assessed using proportional odds models. Differences in subgroups based on baseline volume (≥ or <20 mL) and time from symptom onset to treatment (≤ or >2 hours) were explored with testing for interactions. Results: The primary analysis included 721 patients. At 24 hours, 36% (134/369) of rFVIIa treated patients exhibited no hematoma expansion as compared to 25% of placebo (88/352) treated patients. Significant expansion (≥6 mL) was reduced by 10% in those treated with rFVIIa (acOR:0.57, 95% CI:0.43-0.75). An examination of percent change similarly showed a shift across the spectrum of expansion (acOR: 0.61, 95% CI: 0.47-0.80). In both groups, mild to moderate expansion was observed in 38 to 47% of patients, depending on the threshold used. Differences in absolute HES between the rFVIIa and placebo groups were more pronounced in patients with baseline hemorrhage volumes ≥20 mL (acOR 0.48, 95% CI: 0.30-0.76 versus <20 mL: acOR:0.67, 95% CI:0.47-0.95, p(interaction)= 0.02). No treatment interaction in patients treated within 2 or after 2 hours from onset was observed (acOR:0.42, 95% CI:0.19-0.91 versus >2 hours: acOR:0.59, 95% CI:0.44-0.79, p(interaction)=0.30). Conclusions: The association between rFVIIa and hematoma growth arrest is most pronounced in patients with larger baseline volumes but is evident across the full spectrum of treated patients.