# Presentation: 950577

## Safety of Albumin Revisited

- Blood Products Advisory Committee Meeting
- March 17, 2005
- Laurence Landow MD, FRCPC

## Agenda

- Introduction and background
- Laurence Landow MD
- Review of the Cochrane Report
- Paul Hebert MD, Vice-Chair of Research, Ottawa Health Research Institute, Ontario Canada
- Review of the SAFE study
- Simon Finfer MD, Senior Staff Specialist in Intensive Care, University of Sydney, Australia

## “Human albumin administration in critically ill patients: systematic review of randomized controlled trials”Cochrane Injuries Group. BMJ 1998;317:235-40

- _Design_: Systematic review of all randomized controlled trials published by March 1998 comparing administration of albumin with no administration or with crystalloid in ICU patients with hypovolemia, burns, or hypoalbuminemia
- _Primary Endpoint_: All-cause mortality
- _Conclusions_: There is no evidence that albumin reduces mortality and a strong suggestion that it may increase mortality
- Aggregate relative risk: 1.68 (1.26, 2.23)
- Hypovolemia: 1.46 (0.97,2.22)
- Burns: 2.40 (1.11, 5.19)
- Hypoproteinemia: 1.69 (1.07, 2.67)

## FDA “Letter to Healthcare Providers”

- It is FDA’s current view that the BMJ meta-analysis warrants serious consideration.
- FDA encourages additional controlled trials on the use of albumin
- Until the results of further...studies are available, the FDA urges treating physicians to exercise discretion in use of albumin ...based on their own assessment of these data.

- August 19, 1998

## “Patient survival after human albumin administration”

- _Design_: Systematic review of randomized controlled trials comparing administration of albumin with crystalloid, no albumin, or lower doses of albumin in ICU patients with trauma, hypovolemia, burns, hypoalbuminemia, ascites, and high-risk neonates
- _Primary Endpoint_: All-cause mortality
- _Conclusions_: No effect on mortality was detected...This finding supports the safety of albumin
- Aggregate relative risk: 1.11 (0.95, 1.28)
- Cochrane meta-analysis: 1.68 (1.26, 2.23)
- Hypovolemia: 1.59 (0.91, 2.78)
- Cochrane meta-analysis: 2.40 (1.07, 2.67)
- Burns: 1.76 (0.97, 3.17)
- Cochrane meta-analysis: 2.40 (1.11, 5.19)
- Hypoproteinemia: 1.59 (0.91, 2.78)
- Cochrane meta-analysis: 1.69 (1.07, 2.67)

- Wilkes & Navickis. *Ann Intern Med* 2001;135:149-164

## “Colloid use for fluid resuscitation: evidence and spin”

- “Wilkes and Navickis conclude that their findings should serve to allay concerns regarding the safety of albumin
- But these results are reassuring only insofar as they fail to show a statistically significant increase in mortality. In each case, the point estimate ─ the best estimate of the true effect of treatment ─ shows an increase in the relative risk for death of more than 10% overall...
- Confidence intervals estimate the range within which the true effect plausibly lies. These confidence intervals indicate ...a relative overall increase in mortality of 28% (aggregate relative risk 1.11 (0.95, 1.28)
- Point estimates that suggest harm and confidence intervals that include important increases in mortality cannot allay concerns about the potentially harmful effects of albumin”

- Cook & Guyatt. *Ann Intern Med* 2001;135:205-8

## “A comparison of albumin and saline for fluid resuscitation in the Intensive Care Unit”

- _Design_: Randomized, double-blind trial comparing resuscitation with albumin or saline in a heterogeneous population of hypovolemic ICU patients
- Subjects with burns, cardiac surgery, or liver transplantation were excluded
- Stratified randomization at baseline for trauma, severe sepsis, and ARDS
- _Primary Endpoint_: All-cause mortality
- _Conclusions_: Use of either albumin or normal saline results in similar outcomes at 28 days
- Aggregate relative risk: 0.99 (0.91, 1.09)
- Cochrane meta-analysis: 1.68 (1.26, 2.23)
- Wilkes and Navickis meta-analysis: 1.11 (0.95, 1.28)
- Trauma: 1.36 (0.99, 1.86)
- Trauma + TBI: 1.62 (1.12, 2.34)
- Trauma without TBI: 1.00 (0.56, 1.79)
- Severe sepsis: 0.87 (0.74-1.02)
- ARDS: 0.93 (0.61, 1.41)

- SAFE study investigators. *N Engl J Med* 2004;350:2247-56

## Letter to FDA from Plasma Protein Therapeutics Association

- These [SAFE study] data prove clinically that albumin is a safe therapy and clearly refute the findings of a meta-analysis from the Cochrane Collaboration which was the subject of a 1998 Dear Doctor letter from the Food and Drug Administration (FDA).
- ...A subsequent meta-analysis of Wilkes and Navickis could not replicate the finding of excess albumin-associated mortality reported by the Cochrane investigators. In fact, the results of the SAFE trial corroborate the conclusions of this second and more rigorous meta-analysis.

- 21-DEC-2004

## Question for the Committee

- 1. Have data from the SAFE study resolved the safety concerns that were raised in the meta-analysis by the Cochrane Group for
- a. critically ill patients in general?
- b. subgroups of critically ill patients with burns, hypovolemia, or hypoproteinemia?