Abstract

Human serum albumin has shown remarkable efficacy in rodent models of ischemic stroke, while results from relevant clinical research on albumin therapy remain controversial. We conducted a meta-analysis of published studies to quantitatively analyze the neurofunctional outcomes of patients with ischemic stroke treated with albumin. PubMed, Embase, and Cochrane Library were searched in July 2020. A total of four studies and 1611 patients were included. The aggregated results indicated that there were 635 patients with good neurological outcomes, among which 321 patients were in the albumin group (39.8%) and 314 patients in the control group (39.1%), showing no statistically significant difference between the albumin and control groups (OR = 1.04, 95% CI 0.85-1.27). The results suggest that albumin therapy at the acute stage of ischemic stroke has no beneficial effect on the long-term neurological function of patients with ischemic stroke. Considering pulmonary edema and other complications are more likely to occur in such patients after albumin infusion, the administration of albumin therapy for acute ischemic stroke should be done with utmost caution.

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.

Abstract

OBJECTIVE To determine whether there is any differential benefit of albumin administration within 2 h of onset of ischemia and in settings (severe ischemia with reperfusion in cardioembolic strokes with National Institutes of Health Stroke Scale [NIHSS] ≥15), most representative of experimental models of cerebral ischemia in which albumin was effective in reducing neurological injury. BACKGROUND High-dose intravenous (IV) albumin treatment for acute ischemic stroke (ALIAS) trial did not show overall clinical benefit in ischemic stroke patients in contrast to preclinical studies; however, models of preclinical studies were not completely followed. METHODS A total of 1275 patients combined from ALIAS trials I and II were included in our analysis. We analyzed preclinical studies and selected patients with large ischemic stroke (NIHSS ≥15) related to cardioembolic etiology (n = 189). Outcomes were then studied including time from onset to IV albumin administration. RESULTS The odds of excellent outcome (mRS 0-1) at 3 months was not different with high-dose IV albumin infusion (n = 100) compared with placebo (n = 89) ((odds ratio [OR]) 1.632 [0.719-3.708], p value 0.2419). When we further classified these subjects according to time of IV albumin administration, we observed significantly higher odds of excellent outcome at 3 months when patients received IV albumin within 2 h, OR 9.369 (CI 1.040-84.405), p value 0.0461, after adjusting for age, gender, baseline NIHSS score, and any therapeutic procedure. CONCLUSION A trend for benefit is noted in ischemic stroke patients with large cardioembolic stroke (NIHSS ≥15) when high-dose albumin was initiated within 2 h, suggesting that certain ischemic stroke subgroups of patients most representative of preclinical settings may benefit from such a treatment. Additional clinical trials maybe needed to stratify subjects and treatment assignments according to NIHSS severity and timely randomization to evaluate this concept further.

Abstract

BACKGROUND AND PURPOSE The ALIAS (Albumin in Acute Ischemic Stroke) part 1 and 2 trials evaluated whether 25% human serum albumin improves clinical outcomes after acute ischemic stroke above and beyond standard of care using similar protocols. The part 1 trial ended prematurely because of safety concerns, and the part 2 trial terminated early because of futility of finding a statistically significant effect of albumin over saline (control) administration. We combine the subject-level data of the part 1 and 2 trials to reevaluate the efficacy and safety outcomes with the larger sample size. METHODS The combined data analyses closely follow those conducted in the part 2 trial. The primary outcome is the composite of the modified Rankin Scale and the National Institutes of Health Stroke Scale defined as a composite of modified Rankin Scale score 0 to 1 and National Institutes of Health Stroke Scale score 0 to 1 at 90 days from randomization. The unadjusted analyses use a simple Chi-square test, and those adjusting for baseline covariates use a generalized linear model with log link (to obtain relative risks). RESULTS The participant characteristics at baseline were generally similar between the treatment groups and between the trials; however, thrombolysis use was greater in part 2 (84% versus 75%), and the upper age limit imposed in part 2 resulted in a younger sample (mean age in part 1 was 69 versus 64 in part 2). In the combined sample, the proportions of good outcome in the 2 treatment groups were identical (41%). Similar results were observed in all secondary efficacy outcomes. Pulmonary edema was a consistent safety concern, with a 6-fold increase in the albumin arm (13%) compared with saline (2%; relative risk =7.76, 95% confidence interval 3.87-15.57). CONCLUSIONS Treatment with intravenous albumin 25% at 2 g/kg was not associated with improved outcome at 90 days and was associated with increased rates of intracerebral hemorrhage and pulmonary edema. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov. Unique identifier: NCT00235495.

Abstract

BACKGROUND Albumin treatment of ischemic stroke was associated with cardiopulmonary adverse events in previous studies and a low incidence of intracranial hemorrhage. We sought to describe the neurological and cardiopulmonary adverse events in the ALIAS Part 2 Multicenter Trial. METHODS Ischemic stroke patients, aged 18-83 and a baseline NIHSS > 6, were randomized to treatment with ALB or saline control within 5 hours of stroke onset. Neurological adverse events included symptomatic intracranial hemorrhage, hemicraniectomy, neurological deterioration and neurological death. Cardiopulmonary adverse events included pulmonary edema/congestive heart failure, acute coronary syndromes, atrial fibrillation, pneumonia and pulmonary thromboembolism. RESULTS Among 830 patients, neurological and cardiopulmonary adverse events were not differentially associated with poor outcome between ALB and saline control subjects. The rate of symptomatic intracranial hemorrhage in the first 24h was low overall (2.9%, 24/830) but more common in the ALB treated subjects (RR = 2.4, CI95 1.01-5.8). The rate of pulmonary edema/CHF in the first 48h was 7.9% (59/830) and was more common among ALB treated subjects (RR = 10.7, CI95 4.3-26.6); this complication was expected and was satisfactorily managed with mandated diuretic administration and intravenous fluid guidelines. Troponin elevations in the first 48h were common, occurring without ECG change or cardiac symptoms in 52 subjects (12.5%). CONCLUSIONS ALB therapy was associated with an increase in symptomatic ICH and pulmonary edema/congestive heart failure but this did not affect final outcomes. Troponin elevation occurs routinely in the first 48 hours after acute ischemic stroke. TRIAL REGISTRATION ClincalTrials.gov NCT00235495.

Abstract

BACKGROUND In animal models of ischaemic stroke, 25% albumin reduced brain infarction and improved neurobehavioural outcome. In a pilot clinical trial, albumin doses as high as 2 g/kg were safely tolerated. We aimed to assess whether albumin given within 5 h of the onset of acute ischaemic stroke increased the proportion of patients with a favourable outcome. METHODS We did a randomised, double-blind, parallel-group, phase 3, placebo-controlled trial between Feb 27, 2009, and Sept 10, 2012, at 69 sites in the USA, 13 sites in Canada, two sites in Finland, and five sites in Israel. Patients aged 18-83 years with ischaemic (ie, non-haemorrhagic) stroke with a baseline National Institutes of Health stroke scale (NIHSS) score of 6 or more who could be treated within 5 h of onset were randomly assigned (1:1), via a central web-based randomisation process with a biased coin minimisation approach, to receive 25% albumin (2 g [8 mL] per kg; maximum dose 750 mL) or the equivalent volume of isotonic saline. All study personnel and participants were masked to the identity of the study drug. The primary endpoint was favourable outcome, defined as either a modified Rankin scale score of 0 or 1, or an NIHSS score of 0 or 1, or both, at 90 days. Analysis was by intention to treat. Thrombolytic therapies were permitted. This trial is registered with ClinicalTrials.gov, number NCT00235495. FINDINGS 422 participants were randomly assigned to receive albumin and 419 to receive saline. On Sept 12, 2012, the trial was stopped early for futility (n=841). The primary outcome did not differ between patients in the albumin group and those in the saline group (186 [44%] vs 185 [44%]; risk ratio 096, 95% CI 084-110, adjusted for baseline NIHSS score and thrombolysis stratum). Mild-to-moderate pulmonary oedema was more common in patients given albumin than in those given saline (54 [13%] of 412 vs 5 [1%] of 412 patients); symptomatic intracranial haemorrhage within 24 h was also more common in patients in the albumin group than in the placebo group (17 [4%] of 415 vs 7 [2%] of 414 patients). Although the rate of favourable outcome in patients given albumin remained consistent at 44-45% over the course of the trial, the cumulative rate of favourable outcome in patients given saline rose steadily from 31% to 44%. INTERPRETATION Our findings show no clinical benefit of 25% albumin in patients with ischaemic stroke; however, they should not discourage further efforts to identify effective strategies to protect the ischaemic brain, especially because of preclinical literature showing convincing proof-of-principle for the possibility of this outcome. FUNDING National Institute of Neurological Disorders and Stroke, US National Institutes of Health; and Baxter Healthcare Corporation. Copyright 2013 Elsevier Ltd. All rights reserved.

Abstract

INTRODUCTION Prothrombin complex concentrates are used for rapid reversal of vitamin K antagonists in patients with bleeding or those requiring surgery or invasive procedures. Current guidelines suggest 4-factor products are preferred over 3-factor prothrombin complex concentrates. MATERIALS AND METHODS We performed a systematic review comparing the effectiveness of 3-factor to 4-factor prothrombin complex concentrates in normalizing the international normalized ratio to <=1.5 in patients with acquired coagulopathy due to vitamin K antagonist use. Studies reporting administration of prothrombin complex concentrates for emergent reversal of vitamin K antagonists that included results of baseline prothrombin time/international normalized ratio and follow-up testing within 60minutes of prothrombin complex concentrates administration were included. RESULTS A total of 18 studies were included representing 654 patients. The most common indications for prothrombin complex concentrate were intracerebral hemorrhage, urgent surgery or invasive procedure, and gastrointestinal bleeding. Baseline international normalized ratio values ranged from 3.3-5.1 in the 3-factor group and from 2.3 to greater than 20 in the 4-factor group. The international normalized ratio repeated within one hour of prothrombin complex concentrates administration ranged from 1.2-1.9 in the 3-factor group and 1.0-1.9 in the 4-factor group. International normalized ratio decreased to <=1.5 within one hour after prothrombin complex concentrates administration in 6 of 9 studies in the 3-factor group, and 12 of 13 studies in the 4-factor group. CONCLUSION More reliable correction of the international normalized ratio was seen with 4-factor compared to 3-factor prothrombin complex concentrates which may have clinical implications since 4-factor products are unavailable in some countries. Copyright Copyright 2012 Elsevier Ltd. All rights reserved.

Abstract

BACKGROUND Intracerebral haemorrhage is the most feared complication in patients who are on treatment with vitamin K antagonists. Vitamin K antagonist related intracerebral haemorrhage occurs in about 10% of patients. Intracerebral haemorrhage has the worst prognosis of all subtypes of stroke including spontaneous intracerebral haemorrhage, and a mortality rate of up to about 65%. The higher rate of haematoma expansion due to rebleeding is thought to be responsible for the higher mortality. Current international treatment recommendations include fresh frozen plasma and prothrombin complex concentrate. It is known that these substances lower the international normalised ratio, and thus it is assumed that normalisation of coagulopathy may lead to haemostasis and reduction of rebleeding. However, the issue of whether to use fresh frozen plasma or prothrombin complex concentrate for urgent reversal of vitamin K antagonists is unresolved: safety and efficacy of these treatments have never been studied in a randomised controlled trial. Our questions are: how effective are the two substances in normalisation of the international normalized ratio? How feasible is it to apply either of these treatments in an acute situation? What is the safety profile of each of these substances? Is there a difference in haematoma growth and clinical outcome? METHOD We designed a prospective, randomised, controlled multicentre trial to compare biological efficacy and safety of fresh frozen plasma and prothrombin complex concentrate in vitamin K antagonist related intracerebral haemorrhage. The study is observer-blinded for laboratory, neuroradiological, and clinical outcomes. Patients will be included if a computed tomography scan shows an intraparenchymal or subdural haematoma within 12 h after onset of symptoms, if the patient is on treatment with vitamin K antagonists, and the international normalized ratio is ‰¥2. Primary endpoint is the normalisation of the international normalized ratio (<=1·2) within three-hours after the start of antagonising therapy. Main exclusion criteria are secondary intracerebral haemorrhage, other known coagulopathies, and known acute ischaemic events. DISCUSSION We discuss the rationale of our trial on the basis of the current recommendations and specific aspects of trial design as, time window, choice of endpoints, dosing of fresh frozen plasma and prothrombin complex concentrate, monitoring and analysis of safety parameters, and rescue treatment. CONCLUSION This will be the first prospective trial comparing fresh frozen plasma and prothrombin complex concentrate in the indication of vitamin K antagonist related intracerebral hemorrhage. Recruitment of subjects started in August 2009. Until now, 19 patients have been included.

Abstract

BACKGROUND AND PURPOSE The Albumin in Acute Stroke (ALIAS) Part 2 Trial is directly testing whether 2 g/kg of 25% human albumin (ALB) administered intravenously within 5 hours of ischemic stroke onset results in improved clinical outcome. Recruitment into Part 1 of the ALIAS Trial was halted for safety reasons. ALIAS Part 2 is a new, reformulated trial with more-stringent exclusion criteria. Our aim was to explore the efficacy of ALB in the ALIAS Part 1 data and to assess the statistical assumptions underlying the ALIAS Part 2 Trial.METHODS ALIAS is a multicenter, blinded, randomized controlled trial. Data on 434 subjects, comprising the ALIAS Part 1 subjects, were analyzed. We examined both the thrombolysis and nonthrombolysis cohorts combined and separately in a target populationby excluding subjects who would not have been eligible for the ALIAS Part 2 Trial; the latter comprised patients >83 years of age, those with elevated baseline troponin values, and those with in-hospital stroke. We examined the differences in the primary composite outcome, defined as a modified Rankin Scale score of 0 to 1 and/or a National Institutes of Health Stroke Scale score of 0 to 1 at 90 days after randomization.RESULTS In the combined thrombolysis plus nonthrombolysis cohorts of the target population, 44.7% of subjects in the ALB group had a favorable outcome compared with 36.0% in the saline group (absolute effect size=8.7%; 95% CI, -2.2% to 19.5%). Among thrombolyzed subjects of the target population, 46.7% had a favorable outcome in the ALB group compared with 36.6% in the saline group (absolute effect size=10.1%; 95% CI, -2.0% to 20.0%).CONCLUSIONS Preliminary results from the ALIAS Part 1 suggest a trend toward a favorable primary outcome in subjects treated with ALB and support the validity of the statistical assumptions that underlie the ALIAS Part 2 Trial. The ALIAS Part 2 Trial will confirm or refute these results.CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov/ALIAS. Unique identifier: NCT00235495.

Abstract

BACKGROUND AND PURPOSE enrollment in the Albumin in Acute Stroke (ALIAS) Trial was suspended in late 2007 due to a safety concern. We present the safety data of that Trial (Part 1) and the rationale for the design of Part 2.METHODS ALIAS Part 1 was designed to assess whether 25% albumin (ALB) started within 5 hours of stroke onset would confer neuroprotection in subjects with acute ischemic stroke and baseline National Institutes of Health Stroke Scale of >=6. Exclusion criteria included recent or current congestive heart failure, myocardial infarction, or cardiac surgery. The study comprised 2 cohorts: subjects who received thrombolysis and those who did not, each with 1:1 randomization to ALB or placebo. The primary outcome was the National Institutes of Health Stroke Scale and modified Rankin Scales at 90 days. The intended sample size was 1800.RESULTS four hundred thirty-four subjects were enrolled, and 424 were used in the safety analysis (ALB 207, saline 217). There were 36 deaths within the first 30 days in the ALB group and 21 in the saline group. In contrast, death rates after 30 days were similar by treatment. Large strokes were the predominant cause of early death in both groups. In subjects >83 years of age, 90-day death rates were 2.3-fold higher with ALB than with saline (95% CI, 1.04 to 5.12). Similarly, 90-day deaths in subjects receiving excessive fluids were 2.10-fold greater with ALB than with saline (CI, 1.10 to 3.98).CONCLUSIONS The ALIAS Part 2 Trial, which started in early 2009, was modified as follows to enhance safety: upper age limit of 83 years; requirement for normal baseline serum troponin level; restriction of total intravenous fluids in the first 48 hours to <= 4200 mL; mandatory diuretic at 12 to 24 hours; and detailed site retraining. Because of insufficient nonthrombolysed subjects (22%) in Part 1, the 2-cohort design was eliminated. The Data Safety Monitoring Board has reviewed the safety data of Part 2 3 times and has approved continuation of the trial.