Albumin Administration in Acute Ischemic Stroke: Safety Analysis of the ALIAS Part 2 Multicenter Trial

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

Second asymptomatic carotid surgery trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy

Background: Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods: ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings: Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21). Interpretation: Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. Funding: UK Medical Research Council and Health Technology Assessment Programme

The Albumin in Acute Stroke (ALIAS) Multicenter Clinical Trial: Safety Analysis of Part 1 and Rationale and Design of Part 2

BACKGROUND AND PURPOSE: Enrollment in the ALIAS Trial was suspended in late 2007 due to a safety concern. Here 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) begun within 5h of stroke onset would confer neuroprotection in subjects with acute ischemic stroke and baseline NIH Stroke Scale of 6 or above. 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 NIHSS and modified Rankin scales at 90 days. The intended sample size was 1,800. RESULTS: 434 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 older than 83 years, 90-day death rates were 2.3-fold higher with ALB than with saline (95% CI, 1.04-5.12). Similarly, 90-day deaths in subjects receiving excessive fluids were 2.10-fold greater with ALB than with saline (CI, 1.10-3.98). CONCLUSIONS: The ALIAS Part 2 Trial, which commenced 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 IV fluids in the first 48 hours to 4200 ml or less; mandatory diuretic at 12-24h; and detailed site re-training. Because of insufficient non-thrombolysed subjects (22%) in Part 1, the two-cohort design was eliminated. The DSMB has reviewed the safety data of Part 2 three times and has approved continuation of the trial

High-dose albumin treatment for acute ischaemic stroke (ALIAS) part 2: a randomised, double-blind, phase 3, placebo-controlled trial

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. 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. 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 0·96, 95% CI 0·84–1·10, 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%. 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. National Institute of Neurological Disorders and Stroke, US National Institutes of Health; and Baxter Healthcare Corporation

The Albumin in Acute Stroke Part 1 Trial An Exploratory Efficacy Analysis

BACKGROUND: The ALIAS Part 2 Trial is directly testing whether 2g/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 non-thrombolysis cohorts combined and separately in a “target population” by excluding subjects who would not have been eligible for the ALIAS Part 2 Trial; the latter comprised patients greater than 83 years of age, those with elevated baseline troponin, and those with in-hospital stroke. We examined the differences in the primary composite outcome, defined as a modified Rankin Scale (mRS) score of 0-1 and/or a National Institutes of Health Stroke Scale score (NIHSS) of 0-1 at 90 days post-randomization. RESULTS: In the combined thrombolysis plus non-thrombolysis cohorts of the target population, 44.7% of subjects in the ALB group had a favorable outcome compared to 36.0% in the saline group [absolute effect size: 8.7% (CI(95) -2.2% to 19.5%)]. Among thrombolysed subjects of the target population, 46.7% had a favorable outcome in the ALB group compared to 36.6% in the saline group [absolute effect size: 10.1% (CI(95) -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

The Albumin in Acute Stroke Part 1 Trial

BACKGROUND: The ALIAS Part 2 Trial is directly testing whether 2g/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 non-thrombolysis cohorts combined and separately in a “target population” by excluding subjects who would not have been eligible for the ALIAS Part 2 Trial; the latter comprised patients greater than 83 years of age, those with elevated baseline troponin, and those with in-hospital stroke. We examined the differences in the primary composite outcome, defined as a modified Rankin Scale (mRS) score of 0-1 and/or a National Institutes of Health Stroke Scale score (NIHSS) of 0-1 at 90 days post-randomization. RESULTS: In the combined thrombolysis plus non-thrombolysis cohorts of the target population, 44.7% of subjects in the ALB group had a favorable outcome compared to 36.0% in the saline group [absolute effect size: 8.7% (CI(95) -2.2% to 19.5%)]. Among thrombolysed subjects of the target population, 46.7% had a favorable outcome in the ALB group compared to 36.6% in the saline group [absolute effect size: 10.1% (CI(95) -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

Baseline and Treatment Characteristics of the Subjects in Safety Sample.

<p>* tPA = tissue plasminogen activator</p><p>** OCSP = Oxfordshire Community Stroke Project stroke classification (TACS = total anterior circulation syndrome; PACS = partial anterior circulation syndrome; LACS = lacunar syndrome; POCS = posterior circulation syndrome)</p><p><b>¶</b>BP = blood pressure; IV = intravenous; ECG = electrocardiogram</p><p>† Race and ethnic group were self-reported.</p><p>‡ The National Institutes of Health Stroke Scale (NIHSS) is a 42-point scale that quantifies neurological deficits in 11 categories, with 0 indicating normal function without deficits, and higher scores indicating greater severities of deficit.</p><p>§ The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) uses computed tomography to assess 10 regions of the brain; a score of 1 indicates a normal region and 0 indicates a region showing signs of ischemia. Total scores range from 10 (no evidence of early ischemia) to 0 (all 10 regions of the affected hemisphere show early ischemic changes).</p><p>Baseline and Treatment Characteristics of the Subjects in Safety Sample.</p

Clinical Outcomes by Adverse Event.

<p>¹CHF = congestive heart failure</p><p>²ICH = intracranial hemorrhage</p><p>³HI1 = hemorrhagic infarction type 1; HI2 = hemorrhagic infarction type 2; PH1 = parenchymal hematoma type 1; PH2 = parenchymal hematoma type2; rPH = remote parenchymal hematoma–according to the ECASS-3 classification of hemorrhage[<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0131390#pone.0131390.ref028" target="_blank">28</a>]</p><p>*Adjusted for age, sex, baseline NIHSS score</p><p>Clinical Outcomes by Adverse Event.</p

Neurological adverse events.

<p>¹ICH = intracranial hemorrhage</p><p>²HI1 = hemorrhagic infarction type 1; HI2 = hemorrhagic infarction type 2; PH1 = parenchymal hematoma type 1; PH2 = parenchymal hematoma type2; rPH = remote parenchymal hematoma</p><p>Note: There are 18 subjects without a 24 hour centrally read CT such that the denominator for the Albumin group is 407 and for the Saline group is 405.</p><p>Neurological adverse events.</p