LONDON, United Kingdom — Albumin was no more effective than saline control and was associated with more adverse effects in the treatment of patients with acute stroke in a phase 3 study.
The results, from the ALbumin In Acute Stroke (ALIAS) trial, were presented here at the XXII European Stroke Conference (ESC) 2013 by Myron D. Ginsberg, MD, University of Miami Miller School of Medicine, Florida.
Despite this neutral trial and an issue with adverse effects, Dr. Ginsberg was reluctant to give up on albumin, given its encouraging results in rat models of stroke. "I wouldn't write it off, but the present study is not encouraging," he said. "Albumin was thought to be a promising treatment but like so many other neuroprotectants it seems to work in animals but not in humans."
But commenting on the study for Medscape Medical News, Michael Hennerici, MD, University of Heidelberg, Germany, who was chair of the conference program committee said: "Rats are very different from humans. You can't really translate findings from one to the other."
ALIAS: 2 Attempts
Dr. Ginsberg noted that in those previous preclinical studies, albumin has shown a protective effect in stroke. "It appears to retard processes that cause brain tissue to be derived of blood flow, showing consistently reduced infarct size and improved behavior by increasing perfusion, reducing brain swelling and reversing microvascular changes."
He added that rats treated with albumin functioned better and the volume of damaged brain tissue was reduced, but they had to be treated within 4 hours of the stroke. It also reversed the accumulation of thrombotic material and increased flow distal to the thrombus.
On the basis of these findings, a phase 2 pilot study was started in 82 stroke patients with doses of up to 2 g/kg. Ginsberg noted that the upper 3 doses were in the range shown to be therapeutic in animals. This study, which was primarily a safety study, showed that albumin was associated with the adverse effect of pulmonary edema, which occurred in 13% of patients.
"This was treated with diuretics and had predictable consequences but was not life threatening," Dr. Ginsberg reported. Exploratory efficacy analysis showed the modified Rankin score was better in patients receiving the higher 3 doses than in those receiving the lower 3 doses.
So the phase 3 ALIAS trial was started. But the first part of this trial was stopped by the data and safety monitoring board (DSMB) after 434 patients had been enrolled because of safety concerns. There appeared to be an increased early death rate in the albumin group (13% vs 5.5% control).
"This mainly occurred in the very elderly who were given too much fluid," Dr. Ginsberg said. "So we excluded patients over 83 years of age, excluded patients with heart failure or a recent MI [myocardial infarction], and improved the fluid guidelines, and started the trial again."
The ALIAS Part 2 trial tested human albumin, 2 g/kg, given by intravenous infusion over 2 hours. There was mandatory restriction of intravenous fluids to a maximum of 4200 mL over the first 48 hours. Patients enrolled had an average age of 64 years, 54% were male, 20% were African American, and 71% had a history of hypertension. Tissue plasminogen activator was given to 85% of patients in the trial, and average time to albumin/control administration was 206 minutes from symptom onset.
The trial was stopped by the DSMB after 841 patients because of futility. There was no difference in the primary outcome, a score of 0 to 1 on the National Institutes of Health Stroke Scale and/or modified Rankin scale at 90 days. This occurred in 44.1% of patients in the albumin group vs 44.2% in the control group. All other measures of efficacy were also almost identical.
Dr. Ginsberg noted that in patients enrolled during the first year of the trial there did appear to be an improvement with albumin, with a favorable outcome attained by 44% to 45% of the active treatment group vs about 31% in the control group. Very frustratingly, 2 prespecified interim analyses both showed benefit of albumin over control, but at the third interim analysis the DSMB suspected futility and at the final analysis the curves were identical in both groups.
"There was a 10-12% absolute difference between the arms early on which as very encouraging," he said. "But as time passed the curves went together and by the end of the trial at 3.5 years the control arm had improved to the same level as the albumin group."
Dr. Ginsberg described the improvement in the control group over time as "strange phenomenon which remains unexplained."
Pulmonary Edema Again a Problem
In terms of adverse effects, pulmonary edema was again a problem, occurring at almost exactly the same rate as in the pilot trial. In addition, rates of shortness of breath, atrial fibrillation within 48 hours, and symptomatic intracerebral hemorrhage within 24 hours were higher in the albumin group.
Table. ALIAS: Adverse Effects
|Endpoint||Albumin (%)||Control (%)||Relative Risk|
|Shortness of breath||4.3||1.7||2.58|
|Atrial fibrillation within 48 h||7.8||4.6||1.69|
|Symptomatic intracerebral hemorrhage at 24 h||4.1||1.69||2.4|
He said the investigators plan to analyze the 2 parts of the ALIAS study together and look at subgroups to see whether they can tease out any benefits.
The ALIAS trial was funded by the National Institutes of Health.
XXII European Stroke Conference (ESC) 2013. Large Clinical Trials B: 3, 4. Presented May 30, 2013.
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Cite this: ALIAS: No Benefit of Albumin in Acute Stroke - Medscape - Jun 07, 2013.