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The Albumin in Acute Stroke Part 1 Trial: an exploratory efficacy analysis.

ABSTRACT: 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.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 population" by 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.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%).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.URL: http://www.clinicaltrials.gov/ALIAS. Unique identifier: NCT00235495.

SUBMITTER: Hill MD

PROVIDER: S-EPMC3118599 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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The Albumin in Acute Stroke Part 1 Trial: an exploratory efficacy analysis.

Hill Michael D MD Martin Renee H RH Palesch Yuko Y YY Tamariz Diego D Waldman Bonnie D BD Ryckborst Karla J KJ Moy Claudia S CS Barsan William G WG Ginsberg Myron D MD

Stroke 20110505 6

<h4>Background and purpose</h4>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 ...[more]

PMID: 21546491

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Project description:Background and purposeenrollment 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.MethodsALIAS 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.Resultsfour 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).ConclusionsThe 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.

Project description:BackgroundIn 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.MethodsWe 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.Findings422 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%.InterpretationOur 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.FundingNational Institute of Neurological Disorders and Stroke, US National Institutes of Health; and Baxter Healthcare Corporation.

Project description:ImportancePrior trials of dual antiplatelet therapy excluded patients with moderate ischemic stroke. These patients were included in the Acute Stroke or Transient Ischaemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death (THALES) trial, but results have not been reported separately, raising concerns about safety and efficacy in this subgroup.ObjectiveTo evaluate the efficacy and safety of ticagrelor plus aspirin in patients with moderate ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score of 4 to 5).Design, setting, and participantsThe THALES trial was a randomized trial conducted at 414 hospitals in 28 countries in January 2018 and December 2019. This exploratory analysis compared patients with moderate stroke (baseline NIHSS score of 4 to 5) with patients with less severe stroke (NIHSS score of 0 to 3). A total of 9983 patients with stroke were included in the present analysis, after excluding 2 patients with NIHSS scores greater than 5 and 1031 patients with transient ischemic attack. Data were analyzed from March to April 2021.InterventionsTicagrelor (180-mg loading dose on day 1 followed by 90 mg twice daily on days 2 to 30) or placebo within 24 hours after symptom onset. All patients received aspirin, 300 to 325 mg, on day 1 followed by aspirin, 75 to 100 mg, daily on days 2 to 30. Patients were observed for 30 additional days.Main outcomes and measuresThe primary outcome was time to stroke or death within 30 days. The primary safety outcome was time to severe bleeding.ResultsIn total, 3312 patients presented with moderate stroke and 6671 presented with less severe stroke. Of those in the moderate stroke group, 1293 (39.0%) were female, and the mean (SD) age was 64.5 (10.8) years; of those in the less severe stroke group, 2518 (37.7%) were female, and the mean (SD) age was 64.8 (11.2) years. The observed primary outcome event rate in patients with moderate stroke was 7.6% (129 of 1671) for those in the ticagrelor group and 9.1% (150 of 1641) for those in the placebo group (hazard ratio, 0.84; 95% CI, 0.66-1.06); the primary outcome event rate in patients with less severe stroke was 4.7% (158 of 3359) for those in the ticagrelor group and 5.7% (190 of 3312) for those in the placebo group (hazard ratio, 0.82; 95% CI, 0.66-1.01) (P for interaction = .88). Severe bleeding occurred in 8 patients (0.5%) in the ticagrelor group and in 4 patients (0.2%) in the placebo group in those with moderate stroke compared with 16 patients (0.5%) and 3 patients (0.1%), respectively, with less severe stroke (P for interaction = .26).Conclusions and relevanceIn this study, patients with a moderate ischemic stroke had consistent benefit from ticagrelor plus aspirin vs aspirin alone compared with patients with less severe ischemic stroke, with no further increase in the risk of intracranial bleeding or other severe bleeding events.Trial registrationClinicalTrials.gov Identifier: NCT03354429.

Project description:ImportanceStudies of neurological deterioration in stroke have focused on the subacute period, but stroke treatment is increasingly migrating to the prehospital setting, where the neurological course has not been well delineated.ObjectiveTo describe the frequency, predictors, and outcomes of neurological deterioration among patients in the ultra-early period following ischemic stroke or intracranial hemorrhage.Design, settings, and participantsExploratory analysis of the prehospital, randomized Field Administration of Stroke Therapy-Magnesium (FAST-MAG) Trial conducted from 2005 to 2013 within 315 ambulances and 60 stroke patient receiving hospitals in Southern California. Participants were consecutively enrolled patients with suspected acute stroke who were transported by ambulance within 2 hours of stroke onset.Main outcomes and measuresThe main outcome was neurological deterioration, defined as a worsening of 2 or more points on the Glasgow Coma Scale (GCS), a level of consciousness scale ranging from 3 to 15, with higher scores indicating more alertness. Imaging outcomes were ischemic or hemorrhagic injury extent identified during the first brain imaging scan. Outcomes at 3 months included global disability level (assessed using the modified Rankin Scale [mRS]; range, 0-6, with higher numbers indicating greater disability) and mortality.ResultsAmong the 1690 patients (99.4%), the mean (SD) age was 69.4 (13.5) years, and 43% were female. Final diagnoses were acute cerebral ischemia in 1237 patients (73.2%), intracranial hemorrhage in 386 patients (22.8%), and neurovascular mimic in 67 patients (4.0%). The median (interquartile range [IQR]) minutes between the last well-known time and GCS assessments were 23 (14-42) minutes for prehospital, 58 (46-79) minutes for ED arrival, and 149 (120-180) minutes for early ED course assessments. From prehospital to early postarrival, ultra-early neurological deterioration (U-END) occurred in 200 of 1690 patients (11.8%), more often among patients with intracranial hemorrhage than among those with acute cerebral ischemia (119 of 386 [30.8%] vs 75 of 1237 [6.1%], P < .001). Patterns of U-END were prehospital U-END without early recovery in 30 of 965 patients (3.1%), stable prehospital course but early ED deterioration in 49 of 965 patients (5.1%), and continuous deterioration in both prehospital and early ED phases in 27 of 965 patients (2.8%). Ultra-early neurological deterioration was associated with worse 3-month outcomes, including increased global disability (mRS score, 4.6 vs 2.4; P < .001), reduced functional independence (mRS score 0-2, 32 of 200 [16.0%] vs 844 of 1490 [56.6%]; P < .001), and increased mortality (87 of 200 [43.5%] vs 176 of 1490 [11.8%]; P < .001).Conclusions and relevanceUltra-early neurological deterioration occurs in 1 in 8 ambulance-transported patients with acute cerebrovascular disease, including 1 in 3 patients with intracranial hemorrhage and 1 in 16 patients with acute cerebral ischemia, and is associated with markedly reduced functional independence and increased mortality. Averting U-END may be a target for future prehospital therapeutics.Trial registrationClinicalTrials.gov Identifier: NCT00059332.

Project description: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.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).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).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.URL: https://www.clinicaltrials.gov. Unique identifier: NCT00235495.

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The Albumin in Acute Stroke Part 1 Trial: an exploratory efficacy analysis.

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The Albumin in Acute Stroke Part 1 Trial: an exploratory efficacy analysis.

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