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Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy
Bus, S. R., de Haan, R. J., Vermeulen, M., van Schaik, I. N., Eftimov, F.
The Cochrane database of systematic reviews. 2024;2(2):Cd001797
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Editor's Choice
Abstract
BACKGROUND Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) causes progressive or relapsing weakness and numbness of the limbs, which lasts for at least two months. Uncontrolled studies have suggested that intravenous immunoglobulin (IVIg) could help to reduce symptoms. This is an update of a review first published in 2002 and last updated in 2013. OBJECTIVES To assess the efficacy and safety of intravenous immunoglobulin in people with chronic inflammatory demyelinating polyradiculoneuropathy. SEARCH METHODS We searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and two trials registers on 8 March 2023. SELECTION CRITERIA We selected randomised controlled trials (RCTs) and quasi-RCTs that tested any dose of IVIg versus placebo, plasma exchange, or corticosteroids in people with definite or probable CIDP. DATA COLLECTION AND ANALYSIS We used standard Cochrane methods. Our primary outcome was significant improvement in disability within six weeks after the start of treatment, as determined and defined by the study authors. Our secondary outcomes were change in mean disability score within six weeks, change in muscle strength (Medical Research Council (MRC) sum score) within six weeks, change in mean disability score at 24 weeks or later, frequency of serious adverse events, and frequency of any adverse events. We used GRADE to assess the certainty of evidence for our main outcomes. MAIN RESULTS We included nine RCTs with 372 participants (235 male) from Europe, North America, South America, and Israel. There was low statistical heterogeneity between the trial results, and the overall risk of bias was low for all trials that contributed data to the analysis. Five trials (235 participants) compared IVIg with placebo, one trial (20 participants) compared IVIg with plasma exchange, two trials (72 participants) compared IVIg with prednisolone, and one trial (45 participants) compared IVIg with intravenous methylprednisolone (IVMP). We included one new trial in this update, though it contributed no data to any meta-analyses. IVIg compared with placebo increases the probability of significant improvement in disability within six weeks of the start of treatment (risk ratio (RR) 2.40, 95% confidence interval (CI) 1.72 to 3.36; number needed to treat for an additional beneficial outcome (NNTB) 4, 95% CI 3 to 5; 5 trials, 269 participants; high-certainty evidence). Since each trial used a different disability scale and definition of significant improvement, we were unable to evaluate the clinical relevance of the pooled effect. IVIg compared with placebo improves disability measured on the Rankin scale (0 to 6, lower is better) two to six weeks after the start of treatment (mean difference (MD) -0.26 points, 95% CI -0.48 to -0.05; 3 trials, 90 participants; high-certainty evidence). IVIg compared with placebo probably improves disability measured on the Inflammatory Neuropathy Cause and Treatment (INCAT) scale (1 to 10, lower is better) after 24 weeks (MD 0.80 points, 95% CI 0.23 to 1.37; 1 trial, 117 participants; moderate-certainty evidence). There is probably little or no difference between IVIg and placebo in the frequency of serious adverse events (RR 0.82, 95% CI 0.36 to 1.87; 3 trials, 315 participants; moderate-certainty evidence). The trial comparing IVIg with plasma exchange reported none of our main outcomes. IVIg compared with prednisolone probably has little or no effect on the probability of significant improvement in disability four weeks after the start of treatment (RR 0.91, 95% CI 0.50 to 1.68; 1 trial, 29 participants; moderate-certainty evidence), and little or no effect on change in mean disability measured on the Rankin scale (MD 0.21 points, 95% CI -0.19 to 0.61; 1 trial, 24 participants; moderate-certainty evidence). There is probably little or no difference between IVIg and prednisolone in the frequency of serious adverse events (RR 0.45, 95% CI 0.04 to 4.69; 1 cross-over trial, 32 participants; moderate-certainty evidence). IVIg compared with IVMP probably increases the likelihood of significant improvement in disability two weeks after starting treatment (RR 1.46, 95% CI 0.40 to 5.38; 1 trial, 45 participants; moderate-certainty evidence). IVIg compared with IVMP probably has little or no effect on change in disability measured on the Rankin scale two weeks after the start of treatment (MD 0.24 points, 95% CI -0.15 to 0.63; 1 trial, 45 participants; moderate-certainty evidence) or on change in mean disability measured with the Overall Neuropathy Limitation Scale (ONLS, 1 to 12, lower is better) 24 weeks after the start of treatment (MD 0.03 points, 95% CI -0.91 to 0.97; 1 trial, 45 participants; moderate-certainty evidence). The frequency of serious adverse events may be higher with IVIg compared with IVMP (RR 4.40, 95% CI 0.22 to 86.78; 1 trial, 45 participants, moderate-certainty evidence). AUTHORS' CONCLUSIONS Evidence from RCTs shows that IVIg improves disability for at least two to six weeks compared with placebo, with an NNTB of 4. During this period, IVIg probably has similar efficacy to oral prednisolone and IVMP. Further placebo-controlled trials are unlikely to change these conclusions. In one large trial, the benefit of IVIg compared with placebo in terms of improved disability score persisted for 24 weeks. Further research is needed to assess the long-term benefits and harms of IVIg relative to other treatments.
PICO Summary
Population
People with chronic inflammatory demyelinating polyradiculoneuropathy (9 randomised controlled trials, n= 372).
Intervention
Intravenous immunoglobulin (IVIg).
Comparison
Placebo; plasma exchange; corticosteroids (prednisolone and intravenous methylprednisolone (IVMP)).
Outcome
The primary outcome was significant improvement in disability within six weeks after the start of treatment. There was low statistical heterogeneity between the trial results, and the overall risk of bias was low for all trials that contributed data to the analysis. IVIg compared with placebo increases the probability of significant improvement in disability within six weeks of the start of treatment (risk ratio (RR) 2.40; 95% confidence interval (CI) [1.72, 3.36]; number needed to treat for an additional beneficial outcome (NNTB) 4; 95% CI [3, 5]; 5 trials, 269 participants, high-certainty evidence). The trial comparing IVIg with plasma exchange reported none of our main outcomes. IVIg compared with prednisolone probably has little or no effect on the probability of significant improvement in disability four weeks after the start of treatment (RR 0.91; 95% CI [0.50, 1.68]; 1 trial, 29 participants, moderate-certainty evidence). IVIg compared with IVMP probably increases the likelihood of significant improvement in disability two weeks after starting treatment (RR 1.46; 95% CI [0.40, 5.38]; 1 trial, 45 participants, moderate-certainty evidence).
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Long-term outcomes of plasma exchange versus intravenous immunoglobulin for the treatment of Guillain-Barré Syndrome: A double-blind, randomized clinical trial
Haridy, N. A., Shehab, M. M., Khedr, E. M.
Restorative neurology and neuroscience. 2024
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Editor's Choice
Abstract
BACKGROUND Most previous studies comparing the effectiveness of Plasma Exchange (PE) or intravenous immunoglobulin (IVIG) in treating Guillain-Barre syndrome (GBS) have focused on the short-term outcome at around 1 month. OBJECTIVE To compare the long-term efficacy of PE and IVIG at one year in adult patients with GBS. METHODS Eighty-one adult patients with acute GBS were randomized into two groups with a ratio of 2 : 1: PE (N = 54) and IVIG (N = 27). Patients were assessed with the Medical Research Council sum score (MRC sum score), GBS Disability Scale (GDS), and Functional assessment of acute inflammatory neuropathy (FAAIN) at baseline, ten days, one month, three months, and one year. Neurophysiological examinations were performed at baseline and three months following treatment. RESULTS There were no significant differences between groups in demographic, clinical, and laboratory data. Both treatments produced a significant improvement in all clinical rating scales in both groups that continued up to one year. There were significant differences in the time course of recovery in the MRC and FAAIN scales, with significantly more improvement in the IVIG group at 1 and 3 months, although there was no significant difference in outcome at one year. However the effect size showed measurable differences between the PE and IVIG groups across the different measures at one-year. Electrophysiological studies showed equal improvement in most measures in both groups at three months, with a slightly greater effect in the IVIG group. CONCLUSION long term outcomes of IVIG and PE were equivalent. However the effect size showed measurable differences between the PE and IVIG groups across the different measures at one-year follow-up that indicate the superiorty of IVIG. There was also a tendency for improvement to be slightly faster in the IVIG group.
PICO Summary
Population
Adult patients with acute Guillain-Barre syndrome (n= 81).
Intervention
Plasma exchange (PE), (n= 54).
Comparison
Intravenous immunoglobulin (IVIG), (n= 27).
Outcome
Patients were assessed with the Medical Research Council sum score (MRC sum score), GBS Disability Scale, and Functional assessment of acute inflammatory neuropathy (FAAIN) at baseline, ten days, one month, three months, and one year. Neurophysiological examinations were performed at baseline and three months following treatment. Both treatments produced a significant improvement in all clinical rating scales in both groups that continued up to one year. There were significant differences in the time course of recovery in the MRC and FAAIN scales, with significantly more improvement in the IVIG group at 1 and 3 months, although there was no significant difference in outcome at one year. However the effect size showed measurable differences between the PE and IVIG groups across the different measures at one-year. Electrophysiological studies showed equal improvement in most measures in both groups at three months, with a slightly greater effect in the IVIG group.
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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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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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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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Haemostatic therapies for stroke due to acute, spontaneous intracerebral haemorrhage
Eilertsen, H., Menon, C. S., Law, Z. K., Chen, C., Bath, P. M., Steiner, T., Desborough, M. J., Sandset, E. C., Sprigg, N., Al-Shahi Salman, R.
The Cochrane database of systematic reviews. 2023;10(10):Cd005951
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Abstract
BACKGROUND Outcome after acute spontaneous (non-traumatic) intracerebral haemorrhage (ICH) is influenced by haematoma volume. ICH expansion occurs in about 20% of people with acute ICH. Early haemostatic therapy might improve outcome by limiting ICH expansion. This is an update of a Cochrane Review first published in 2006, and last updated in 2018. OBJECTIVES To examine 1. the effects of individual classes of haemostatic therapies, compared with placebo or open control, in adults with acute spontaneous ICH, and 2. the effects of each class of haemostatic therapy according to the use and type of antithrombotic drug before ICH onset. SEARCH METHODS We searched the Cochrane Stroke Trials Register, CENTRAL (2022, Issue 8), MEDLINE Ovid, and Embase Ovid on 12 September 2022. To identify further published, ongoing, and unpublished randomised controlled trials (RCTs), we scanned bibliographies of relevant articles and searched international registers of RCTs in September 2022. SELECTION CRITERIA We included RCTs of any haemostatic intervention (i.e. procoagulant treatments such as clotting factor concentrates, antifibrinolytic drugs, platelet transfusion, or agents to reverse the action of antithrombotic drugs) for acute spontaneous ICH, compared with placebo, open control, or an active comparator. DATA COLLECTION AND ANALYSIS We used standard Cochrane methods. Our primary outcome was death/dependence (modified Rankin Scale (mRS) 4 to 6) by day 90. Secondary outcomes were ICH expansion on brain imaging after 24 hours, all serious adverse events, thromboembolic adverse events, death from any cause, quality of life, mood, cognitive function, Barthel Index score, and death or dependence measured on the Extended Glasgow Outcome Scale by day 90. MAIN RESULTS We included 20 RCTs involving 4652 participants: nine RCTs of recombinant activated factor VII (rFVIIa) versus placebo/open control (1549 participants), eight RCTs of antifibrinolytic drugs versus placebo/open control (2866 participants), one RCT of platelet transfusion versus open control (190 participants), and two RCTs of prothrombin complex concentrates (PCC) versus fresh frozen plasma (FFP) (47 participants). Four (20%) RCTs were at low risk of bias in all criteria. For rFVIIa versus placebo/open control for spontaneous ICH with or without surgery there was little to no difference in death/dependence by day 90 (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.74 to 1.05; 7 RCTs, 1454 participants; low-certainty evidence). We found little to no difference in ICH expansion between groups (RR 0.81, 95% CI 0.56 to 1.16; 4 RCTs, 220 participants; low-certainty evidence). There was little to no difference in all serious adverse events and death from any cause between groups (all serious adverse events: RR 0.81, 95% CI 0.30 to 2.22; 2 RCTs, 87 participants; very low-certainty evidence; death from any cause: RR 0.78, 95% CI 0.56 to 1.08; 8 RCTs, 1544 participants; moderate-certainty evidence). For antifibrinolytic drugs versus placebo/open control for spontaneous ICH, there was no difference in death/dependence by day 90 (RR 1.00, 95% CI 0.93 to 1.07; 5 RCTs, 2683 participants; high-certainty evidence). We found a slight reduction in ICH expansion with antifibrinolytic drugs for spontaneous ICH compared to placebo/open control (RR 0.86, 95% CI 0.76 to 0.96; 8 RCTs, 2866 participants; high-certainty evidence). There was little to no difference in all serious adverse events and death from any cause between groups (all serious adverse events: RR 1.02, 95% CI 0.75 to 1.39; 4 RCTs, 2599 participants; high-certainty evidence; death from any cause: RR 1.02, 95% CI 0.89 to 1.18; 8 RCTs, 2866 participants; high-certainty evidence). There was little to no difference in quality of life, mood, or cognitive function (quality of life: mean difference (MD) 0, 95% CI -0.03 to 0.03; 2 RCTs, 2349 participants; mood: MD 0.30, 95% CI -1.98 to 2.57; 2 RCTs, 2349 participants; cognitive function: MD -0.37, 95% CI -1.40 to 0.66; 1 RCTs, 2325 participants; all high-certainty evidence). Platelet transfusion likely increases death/dependence by day 90 compared to open control for antiplatelet-associated ICH (RR 1.29, 95% CI 1.04 to 1.61; 1 RCT, 190 participants; moderate-certainty evidence). We found little to no difference in ICH expansion between groups (RR 1.32, 95% CI 0.91 to 1.92; 1 RCT, 153 participants; moderate-certainty evidence). There was little to no difference in all serious adverse events and death from any cause between groups (all serious adverse events: RR 1.46, 95% CI 0.98 to 2.16; 1 RCT, 190 participants; death from any cause: RR 1.42, 95% CI 0.88 to 2.28; 1 RCT, 190 participants; both moderate-certainty evidence). For PCC versus FFP for anticoagulant-associated ICH, the evidence was very uncertain about the effect on death/dependence by day 90, ICH expansion, all serious adverse events, and death from any cause between groups (death/dependence by day 90: RR 1.21, 95% CI 0.76 to 1.90; 1 RCT, 37 participants; ICH expansion: RR 0.54, 95% CI 0.23 to 1.22; 1 RCT, 36 participants; all serious adverse events: RR 0.27, 95% CI 0.02 to 3.74; 1 RCT, 5 participants; death from any cause: RR 0.49, 95% CI 0.16 to 1.56; 2 RCTs, 42 participants; all very low-certainty evidence). AUTHORS' CONCLUSIONS In this updated Cochrane Review including 20 RCTs involving 4652 participants, rFVIIa likely results in little to no difference in reducing death or dependence after spontaneous ICH with or without surgery; antifibrinolytic drugs result in little to no difference in reducing death or dependence after spontaneous ICH, but result in a slight reduction in ICH expansion within 24 hours; platelet transfusion likely increases death or dependence after antiplatelet-associated ICH; and the evidence is very uncertain about the effect of PCC compared to FFP on death or dependence after anticoagulant-associated ICH. Thirteen RCTs are ongoing and are likely to increase the certainty of the estimates of treatment effect.
PICO Summary
Population
Adults with acute spontaneous intracerebral haemorrhage (ICH), (20 randomised controlled trials (RCTs), n= 4,652).
Intervention
Recombinant activated factor VII (rFVIIa), antifibrinolytic drugs, platelet transfusion, prothrombin complex concentrates (PCC).
Comparison
Placebo, standard care, or an active comparator.
Outcome
This systematic review was an update of a Cochrane Review first published in 2006, and last updated in 2018. Of the 20 included studies, 9 nine RCTs compared rFVIIa vs. placebo/standard care (n= 1,549), 8 RCTs compared antifibrinolytic drugs vs. placebo/standard care (n= 2,866), 1 RCT compared platelet transfusion vs. standard care (n= 190), and 2 RCTs compared PCC vs. fresh frozen plasma (FFP), (n= 47). Four (20%) RCTs were at low risk of bias in all criteria. The authors concluded that rFVIIa likely results in little to no difference in reducing death or dependence after spontaneous ICH with or without surgery; antifibrinolytic drugs result in little to no difference in reducing death or dependence after spontaneous ICH, but result in a slight reduction in ICH expansion within 24 hours; platelet transfusion likely increases death or dependence after antiplatelet-associated ICH; and the evidence is very uncertain about the effect of PCC compared to FFP on death or dependence after anticoagulant-associated ICH.
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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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7.
Evaluation of Direct Oral Anticoagulant Reversal Agents in Intracranial Hemorrhage: A Systematic Review and Meta-analysis
Chaudhary R, Singh A, Chaudhary R, Bashline M, Houghton DE, Rabinstein A, Adamski J, Arndt R, Ou NN, Rudis MI, et al
JAMA network open. 2022;5(11):e2240145
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Editor's Choice
Abstract
IMPORTANCE Direct oral anticoagulant (DOAC)-associated intracranial hemorrhage (ICH) has high morbidity and mortality. The safety and outcome data of DOAC reversal agents in ICH are limited. OBJECTIVE To evaluate the safety and outcomes of DOAC reversal agents among patients with ICH. DATA SOURCES PubMed, MEDLINE, The Cochrane Library, Embase, EBSCO, Web of Science, and CINAHL databases were searched from inception through April 29, 2022. STUDY SELECTION The eligibility criteria were (1) adult patients (age ≥18 years) with ICH receiving treatment with a DOAC, (2) reversal of DOAC, and (3) reported safety and anticoagulation reversal outcomes. All nonhuman studies and case reports, studies evaluating patients with ischemic stroke requiring anticoagulation reversal or different dosing regimens of DOAC reversal agents, and mixed study groups with DOAC and warfarin were excluded. DATA EXTRACTION AND SYNTHESIS Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used for abstracting data and assessing data quality and validity. Two reviewers independently selected the studies and abstracted data. Data were pooled using the random-effects model. MAIN OUTCOMES AND MEASURES The primary outcome was proportion with anticoagulation reversed. The primary safety end points were all-cause mortality and thromboembolic events after the reversal agent. RESULTS A total of 36 studies met criteria for inclusion, with a total of 1832 patients (967 receiving 4-factor prothrombin complex concentrate [4F-PCC]; 525, andexanet alfa [AA]; 340, idarucizumab). The mean age was 76 (range, 68-83) years, and 57% were men. For 4F-PCC, anticoagulation reversal was 77% (95% CI, 72%-82%; I2 = 55%); all-cause mortality, 26% (95% CI, 20%-32%; I2 = 68%), and thromboembolic events, 8% (95% CI, 5%-12%; I2 = 41%). For AA, anticoagulation reversal was 75% (95% CI, 67%-81%; I2 = 48%); all-cause mortality, 24% (95% CI, 16%-34%; I2 = 73%), and thromboembolic events, 14% (95% CI, 10%-19%; I2 = 16%). Idarucizumab for reversal of dabigatran had an anticoagulation reversal rate of 82% (95% CI, 55%-95%; I2 = 41%), all-cause mortality, 11% (95% CI, 8%-15%, I2 = 0%), and thromboembolic events, 5% (95% CI, 3%-8%; I2 = 0%). A direct retrospective comparison of 4F-PCC and AA showed no differences in anticoagulation reversal, proportional mortality, or thromboembolic events. CONCLUSIONS AND RELEVANCE In the absence of randomized clinical comparison trials, the overall anticoagulation reversal, mortality, and thromboembolic event rates in this systematic review and meta-analysis appeared similar among available DOAC reversal agents for managing ICH. Cost, institutional formulary status, and availability may restrict reversal agent choice, particularly in small community hospitals.
PICO Summary
Population
Adult patients with intracranial hemorrhage receiving treatment with a direct oral anticoagulant (36 studies, n= 1,832).
Intervention
4-factor prothrombin complex concentrate (4F-PCC), (n= 967).
Comparison
Andexanet alfa (AA), (n= 525). Idarucizumab(n= 340).
Outcome
For 4F-PCC, anticoagulation reversal was 77% (95% CI 72% to 82%; I2 = 55%); all-cause mortality, 26% (95% CI 20% to 32%; I2 = 68%), and thromboembolic events, 8% (95% CI 5% to 12%; I2 = 41%). For AA, anticoagulation reversal was 75% (95% CI 67% to 81%; I2 = 48%); all-cause mortality, 24% (95% CI 16% to 34%; I2 = 73%), and thromboembolic events, 14% (95% CI 10% to 19%; I2 = 16%). Idarucizumab for reversal of dabigatran had an anticoagulation reversal rate of 82% (95% CI 55% to 95%; I2 = 41%), all-cause mortality, 11% (95% CI 8% to 15%, I2 = 0%), and thromboembolic events, 5% (95% CI 3% to 8%; I2 = 0%). A direct retrospective comparison of 4F-PCC and AA showed no differences in anticoagulation reversal, proportional mortality, or thromboembolic events.
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Safety and Short-term Outcomes of High-Dose Erythropoietin in Preterm Infants With Intraventricular Hemorrhage: The EpoRepair Randomized Clinical Trial
Wellmann S, Hagmann CF, von Felten S, Held L, Klebermass-Schrehof K, Truttmann AC, Knöpfli C, Fauchère JC, Bührer C, Bucher HU, et al
JAMA network open. 2022;5(12):e2244744
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Abstract
IMPORTANCE Intraventricular hemorrhage (IVH) is a major cause of neonatal morbidity and mortality in preterm infants without a specific medical treatment to date. OBJECTIVE To assess the safety and short-term outcomes of high-dose erythropoietin in preterm infants with IVH. DESIGN, SETTING, AND PARTICIPANTS Between April 1, 2014, and August 3, 2018, a randomized double-blind clinical trial enrolled 121 preterm infants (gestational age <32 weeks or birth weight <1500 g) aged 8 or less days with moderate to severe IVH identified by cerebral ultrasonography from 8 Swiss and Austrian tertiary neonatal units. Statistical analyses were performed between October 1, 2019, and September 12, 2022. INTERVENTIONS Infants received intravenous high-dose erythropoietin (2000 units/kg body weight) or placebo at 4 time points between weeks 1 and 4 of life. MAIN OUTCOMES AND MEASURES Secondary outcomes included (1) mortality and morbidity rates and (2) brain magnetic resonance imaging findings at term-equivalent age (TEA). The primary outcome was the composite intelligence quotient at 5 years of age (not available before 2023). RESULTS Sixty infants (48% male [n = 29]) were randomly assigned to receive erythropoietin, and 61 infants (61% male [n = 37]) were randomly assigned to receive placebo. The median birth weight was 832 g (IQR, 687-990 g) in the erythropoietin group and 870 g (IQR, 680-1110 g) in the placebo group. Median gestation was 26.1 weeks (IQR, 24.8-27.3 weeks) in the erythropoietin group and 27.0 weeks (24.9-28.1 weeks) in the placebo group. The 2 groups had similar baseline characteristics and morbidities. Up to TEA, 10 newborns died (16.7%) in the erythropoietin group, and 5 newborns (8.2%) died in the placebo group (adjusted odds ratio, 2.24 [95% CI, 0.74-7.66]; P = .15). Infants receiving erythropoietin had higher mean hematocrit levels. Conventional magnetic resonance imaging at TEA for 100 infants showed no significant differences in global or regional brain injury scores. CONCLUSIONS AND RELEVANCE This preliminary report of a randomized clinical trial found no evidence that high-dose erythropoietin in preterm infants with IVH affects brain injury scores on conventional magnetic resonance imaging at TEA. Higher mortality in the erythropoietin group was not significant but should be reassessed based on future results from similar trials. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02076373.
PICO Summary
Population
Preterm infants with intraventricular haemorrhage enrolled in the EpoRepair trial, in 8 Swiss and Austrian tertiary neonatal units (n= 121).
Intervention
Intravenous high-dose erythropoietin (n= 60).
Comparison
Placebo (n= 61).
Outcome
The median birth weight was 832 g (IQR, 687-990 g) in the erythropoietin group and 870 g (IQR, 680-1110 g) in the placebo group. Median gestation was 26.1 weeks (IQR, 24.8-27.3 weeks) in the erythropoietin group and 27.0 weeks (24.9-28.1 weeks) in the placebo group. Both groups had similar baseline characteristics and morbidities. Up to term-equivalent age (TEA), 10 newborns died (16.7%) in the erythropoietin group, and 5 newborns (8.2%) died in the placebo group (adjusted odds ratio, 2.24 (95% CI 0.74 to 7.66)). Infants receiving erythropoietin had higher mean haematocrit levels. Conventional magnetic resonance imaging at TEA for 100 infants showed no significant differences in global or regional brain injury scores.
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Safety and Efficacy of Tranexamic Acid in Aneurysmal Subarachnoid Hemorrhage: A Meta-Analysis of Randomized Controlled Trials
Ren J, Qian D, Wu J, Ni L, Qian W, Zhao G, Huang C, Liu X, Zou Y, Xing W
Frontiers in neurology. 2021;12:710495
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Abstract
BACKGROUND In recent decades, tranexamic acid (TXA) antifibrinolytic therapy before aneurysm clipping or embolization has been widely reported, but its safety and efficacy remain controversial. This meta-analysis evaluated the efficacy and safety of TXA therapy in aneurysmal subarachnoid hemorrhage (aSAH) patients, aiming to improve the evidence-based medical knowledge of treatment options for such patients. METHODS Pubmed, Web of Science, and Cochrane Library databases were searched up to 1 March 2021 for randomized controlled trials (RCTs). We extracted safety and efficacy outcomes and performed a meta-analysis using the Review Manager software. We performed two group analyses of TXA duration and daily dose. RESULTS Ten RCT studies, enrolling a total of 2,810 participants (1,410 with and 1,400 without TXA therapy), matched the selection criteria. In the TXA duration group: TXA did not reduce overall mortality during the follow-up period [RR 1.00 (95% CI 0.81-1.22)]. The overall rebleeding rate in the TXA group was 0.53 times that of the control group, which was statistically significant [RR 0.53 (95% CI 0.39-0.71)]. However, an RR of 0.43 was not statistically significant in the subgroup analysis of short-term therapy [RR 0.43 (95% CI 0.13-1.39)]. The overall incidence of hydrocephalus was significantly higher in the TXA group than in the control group [RR 1.13 (95% CI 1.02-1.24)]. However, the trend was not statistically significant in the subgroup analysis [short-term: RR 1.10 (95% CI 0.99-1.23); long-term: RR 1.22 (95% CI 0.99-1.50)]. Treatment with TXA did not cause significant delayed cerebral ischemia [RR 1.18 (95% CI 0.89-1.56)], and its subgroup analysis showed an opposite and insignificant effect [short-term: RR 0.99 (95% CI 0.79-1.25); long-term: RR 1.38 (95% CI 0.86-2.21)]. Results in the daily dose group were consistent with those in the TXA duration group. CONCLUSIONS Tranexamic acid does not reduce overall mortality in patients with aSAH, nor does it increase the incidence of delayed cerebral ischemia. Tranexamic acid in treating aSAH can reduce the incidence of rebleeding. However, there is no statisticalsignificance in the ultra-early short-term and low daily dose TXA therapy, which may be due to the lack of relevant studies, and more RCT experiments are needed for further study. SYSTEMATIC REVIEW REGISTRATION https://www.crd.york.ac.uk/PROSPERO/display_record.asp? PROSPERO, identifier: 244079.
PICO Summary
Population
Aneurysmal subarachnoid haemorrhage patients (10 studies, n= 2,810).
Intervention
Tranexamic acid (TXA), (n= 1,410).
Comparison
Conventional treatment without TXA (n= 1,400).
Outcome
The overall re-bleeding rate in the TXA group was 0.53 times that of the control group. The overall incidence of hydrocephalus was significantly higher in the TXA group than in the control group. Treatment with TXA did not cause significant delayed cerebral ischemia.
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10.
Surgical vs. Conservative Management for Lobar Intracerebral Hemorrhage, a Meta-Analysis of Randomized Controlled Trials
Akram MJ, Zhao R, Shen X, Yang WS, Deng L, Li ZQ, Hu X, Zhao LB, Xie P, Li Q
Frontiers in neurology. 2021;12:742959
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Abstract
BACKGROUND Outcomes regarding the conventional surgical and conservative treatment for the lobar intracerebral hemorrhage (ICH) have not been previously compared. The current meta-analysis was designed to review and compile the evidence regarding the management of patients with lobar intracerebral hemorrhage. METHODS Online electronic databases, including PubMed, Embase, Medline, Cochrane Library, and Google Scholar, were searched for randomized controlled trials (RCTs). Studies were selected on the basis of the inclusion and exclusion criteria. Trials with CT-confirmed lobar intracerebral hemorrhage patients of which treatment regimen was started within 72 h following the stroke were included. Low quality trials were excluded. Death or dependence was defined as primary outcome and death at the end of the follow up was the secondary outcome. RESULTS One hundred five RCTs were screened and 96 articles were excluded on the basis of abstract. Nine articles were assessed for the eligibility and 7 trials were included that involved 1,102 patients. The Odds ratio (OR) for the primary outcome was 0.80 (95% CI, 0.62-1.04, p = 0.09) and for the secondary outcome was 0.79 (95%CI, 0.60-1.03, p = 0.09). CONCLUSION Our findings suggested that surgical treatments did not significantly improve the functional outcome as compared with the conservative medical management for patients with lobar ICH.
PICO Summary
Population
Patients with lobar intracerebral haemorrhage (7 studies, n= 1,102).
Intervention
Surgical treatment, including: endoscopic surgery, open craniotomy, stereotactic aspiration, and endoscopic surgery plus stereotactic aspiration, (n= 552).
Comparison
Conservative management, including non-surgical or pharmacological (n= 550).
Outcome
The overall results showed a non-significant trend toward better prognosis in the surgical group (OR 0.80). No significant difference was observed for death at the end of the follow up between surgical and conservative medical management groups.