1. Albumin Safety and Efficacy as a Resuscitative Therapy in the ICU: Are all ICU patients the same? Gary R. Haynes, M.D., Ph.D. Professor, Department of Anesthesiology Medical University of South Carolina Presented to: Blood Products Advisory Committee U.S. Food and Drug Administration March 17, 2005

2. “SAFE” Study One-Liners on Comparative Clinical Effectiveness of Albumin and Saline “In addition to providing evidence that colloids and crystalloids are equally effective...” Medscape Medical News, February 24, 2004 (report on SCCM 33rd Annual Congress, presentation by S. Finfer, 2/22/04) “Our study provides evidence that albumin and saline should be considered clinically equivalent treatments for intravascular volume resuscitation in a heterogeneous population of patients in the ICU.” Reuters Health (Medscape – Critical Care Medpulse), May 26, 2004 “In patients in the ICU, use of either 4 percent albumin or normal saline for fluid resuscitation results in similar outcomes at 28 days.” Finfer S, Bellomo R, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. New Engl J Med 2004:350:2247-56. QUESTION: Can we assume all ICU patients are the same?

3. 2004 Meta-analysis of Morbidity in 71 Trials in Acutely Ill Patients Vincent J-L, Navickis RJ and Wilkes MM. Crit Care Med 2004; 32:2029-38. All 71 trials0.92 (CI 0.86-0.98) favoring albumin Study subsetRisk ratio 32 trials with no albumin given to control group 0.77 (CI 0.67-0.88) favoring albumin 20 trials with low dose albumin given to control group 0.89 (CI 0.80-1.00) favoring albumin A highly significant inverse relationship was found between control group albumin dose and incidence of complications (p=0.002) Question: Does albumin reduce morbidity in critically ill patients? Method: Meta-analysis of 71 trials comparing morbidity in albumin vs. crystalloid, or low or moderate albumin dosing Results:

4. Volume Resuscitation in Non-Hemorrhagic Shock (primarily septic shock) Rackow EC, Falk JL, et al. Crit Care Med 1983; 11:839-50 Question:Does the safety of albumin versus crystalloid treatment differ in non-hemorrhagic shock resuscitation? Method:Compare volume replacement with 6% hetastarch or 5% albumin to saline (n = 26 in hypovolemic shock;18 confirmed sepsis) 6% hetastarch5% albumin 0.9% saline 22% developed pulmonary edema 22% developed pulmonary edema 87.5% developed pulmonary edema (p<.05) Results:

5. Albumin vs. Crystalloid: Oxygen Delivery in Critically Ill Shock Patients Question:Does albumin improve perfusion in patients with shock? Method:Compare changes in oxygen transport and hemodynamic parameters after infusion of albumin, blood, RBCs and LR Shoemaker WC. Vox Sang 1998; 74 (Suppl 2):69-74 Variable Whole blood, 1 unit (n=86) RBCs, 1 unit (n=32) Albumin, 500 mL (n=82) LR 1000 mL (n=35) CI, L/min/m 2 0.44 ±.090.02 ±.40.67 ± 0.90.23 ±.14 DO 2, mL/min/m 2 87 ± 1464 ± 2265 ± 14-3 ± 25 VO 2, mL/min/m 2 24 ± 677 ± 710 ± 40 ± 7 Results: CI=cardiac index; DO 2 =oxygen delivery; VO 2 =oxygen consumption; LR=lactated Ringer’s

6. Albumin Supplementation in Cirrhosis and Bacterial Peritonitis Outcome variableCefotaxime Cefotaxime + albuminp value Renal impairment 21 (33%)6 (10%)0.002 Deaths in hospital 18 (29%)6 (10%)0.01 Deaths at 3 months 26 (41%)14 (22%)0.03 Sort P, Navasa M, et al. New Engl J Med 1999; 341:403-9 Question:Does albumin help preserve renal function in patients with cirrhosis and spontaneous bacterial peritonitis? Method:Patients randomized to cefotaxime or cefotaxime + albumin (1.5 g/kg day 1; 1 g/kg day 3); baseline serum albumin=2.5-2.7 g/dL Result:

7. Calls for Confirmation of Trend in Mortality Reduction with Albumin in Sepsis “Resuscitation with iso-oncotic albumin in septic shock may confer survival benefits (RR for death with albumin, 0.87; 95% CI 0.74-1.02), but results from this subgroup require prospective confirmation.” Evidence-based colloid use in the critically ill: American Thoracic Society Consensus Statement. Am J Respir Crit Care Med 2004; 170; 1247-59. “Our study provides evidence that albumin and saline should be considered clinically equivalent treatments for intravascular volume resuscitation in a heterogeneous population of patients in the ICU. Whether either albumin or saline confers benefit in more highly selected populations of critically ill patients requires further study.” The SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. New Engl J Med 2004; 350:2247-56.

8. Potential Cost-Effectiveness Profile for Albumin vs. Xigris ® in Severe Sepsis 1 1 February 24, 2005 correspondence from K. Berman (Health Research Associates) to Blood Products Advisory Committee. 2 Approximately 2 liters of 5% albumin at a hospital-level cost of $75/liter (source: FFF Enterprises, Temecula, California; a major distributor of albumin to U.S. hospitals) If albumin yields a survival benefit similar to the mortality reduction documented in the SAFE study: the potential cost-effectiveness for albumin vs. Xigris® in severe sepsis StudyRandomization – nMortality (%) Risk reduction per 100 cases treated Treatment cost Nominal cost per life saved PROWESS Xigris – 850 Placebo – 840 Xigris (24.7%) Placebo (30.8%) 6.1 lives$9,800$160,000 SAFE* 4% albumin – 603 0.9% saline – 615 Albumin (30.7%) Saline (35.3%) 4.6 lives$150 2 $3,300 *Study findings in sepsis, RR=0.87, 95% CI, 0.74-1.02, P=0.09.

9.  The 1998 Cochrane meta-analysis had multiple design flaws A critical flaw was inclusion of several trials whose protocols specified excessive albumin dosing, well outside the standard of practice  The 2004 “SAFE” study established that albumin is not associated with an increased risk of mortality in a heterogeneous ICU population  The “SAFE” study findings do not demonstrate that albumin and saline are therapeutically equivalent in individual ICU patients requiring resuscitative therapy  The choice of resuscitative therapy should be individualized based on patient diagnosis, clinical presentation, relevant laboratory findings and a careful consideration of available evidence in the medical literature Albumin Safety and Efficacy: Recommend that FDA disseminate these points to physicians

10.  The “SAFE” trial documented a strong trend which suggests that albumin administration may increase survival in ICU patients with severe sepsis; definitive proof of clinical benefit awaits completion of an adequately powered trial  A trend toward increased mortality was identified with albumin administration in brain-injured (but not other) trauma patients; while definitive proof awaits completion of an adequately powered trial, albumin should be used with caution or avoided entirely in brain- injured trauma patients

11. In the Interest of the Severe Sepsis Population Requiring Fluid Volume Resuscitation: Strongly encourage the FDA to advocate for – or directly facilitate – an extension of the SAFE study protocol to enroll additional severe sepsis patients, to prove or disprove whether albumin use importantly reduces mortality in that population