1. Safety of Albumin Revisited Blood Products Advisory Committee Meeting March 17, 2005 Laurence Landow MD, FRCPC

2. 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

3. “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)

4. 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

5. “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

6. “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

7. “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

8. 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

9. 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?