1. Age of Transfused Blood: Short-Term Mortality and Long-Term Survival after Cardiac Surgery Mark Stafford-Smith, MD, CM, FRCPC, FASE Professor of Anesthesiology Division of Cardiothoracic Anesthesia & Critical Care Medicine Duke Heart Center, Durham, NC Thursday May 1, 2008 FDA Blood Products Advisory Committee 91 st Annual Meeting Rockville, MD

2. Disclosure: No financial relationships to disclose pertinent to the content of this CME presentation Consultant for Polymedix Inc. Age of Transfused Blood: Short-term Mortality and Long-term Survival after Cardiac Surgery

3. http://www.resource4thepeople.com/defectivedrugs/avandia.html

4. Problems for Established Therapeutic Interventions Efficacy vs. Safety 2002 - estrogen/medroxyprogesterone acetate vs. myocardial infarction http://www.fda.gov/cder/drug/safety/WHI_statement.htm http://washingtontimes.com/national/20040208-123823-1958r.htm 2004 - SSRI antidepressants, teen suicide link 2005 - cyclooxygenase 2 inhibitor (Vioxx) vs. myocardial infarction http://www.fda.gov/cder/drug/infopage/cox2/NSAIDdecisionMemo.pdf McEvoy et al. Anesth Analg 2007; 105:949-962 2007 - rosiglitazone (Avandia) vs. myocardial infarction 2008 - aprotinin (Trasylol) vs. postop kidney dysfunction and mortality

5. Ho et al. Crit Care Med 2003;31:S687-97 2003 - UK – SHOT analysis, TRALI and plasma donor gender

6. Liberal versus Restrictive Transfusion Hébert et al. New Engl J Med 1999;340:409-17 N=838 critically ill patients Hb<9.0g/dL Randomized to one of two groups within 72h of ICU admission Transfusion Strategy Restrictive – trigger <7.0g/dL, target 7-9 Liberal – trigger <10g/dL, target 10-12

7. n=78,974 elderly (>65y) with MI crude 30-day mortality correlated with decreasing admission Hct 3,680 (4%) received a transfusion Wu W-C et al N Engl J Med 2001;345;1230-6 Myocardial Infarction and Transfusion Odds ratio for 30 day mortality for patients who received a blood transfusion as compared to those who did not.

8. Ho et al. Crit Care Med 2003;31:S687-97 Mortality in-hosp, 30d.- meta-analysis (15 trials) 60d, 90d no association leukored vs. non Vox Sang 2002;82:141-149 Multiorgan failure- trauma patients, prospective cohort transfusion Arch Surg 1997;132:620-5 Mortality 24h/in-hosp- trauma patients, prospective and LOS ICU/Hosp transfusion J Trauma 2003;54:898-907 ICU mortality and - postop cardiac surgery patients, prospective cohort mechanical ventilation transfusion Anesthesiology 2003;98:815-22 Harm Associated with Transfusion 30 day mortality- critically ill patients, prospective RCT restrictive vs. liberal N Engl J Med 1999;340:409-17 28 day / ICU mortality- critically ill patients, prospective cohort and LOS transfusion JAMA 2002;288:1499-1507 (cardiac surgery subgroup (3RCTs) – leukoreduced reduced 22-66 months mortality)

9. Age Distribution of Transfused Blood DeSimone et al. Anesth Analg 2005;100:SCA7 VanMatre et al. Anesth Analg 2007;104:SCA23 20% of packed red cells are transfused > 28 days old 10-38% packed red cells transfused within 2 days of expiry Vamvakas et al. Transfusion 2000;40:101-9 Ho et al. Crit Care Med 2003;31:S687-97

10. Adverse Changes (“Storage Lesion”) in Stored Red Blood Cells Bennett-Guerrero et al PNAS 2007;43:17063-8

11. Ho et al. Crit Care Med 2003;31:S687-97 Prolonged Storage and Outcomes after Red Cell Transfusion Length of ICU stay- 698 septic patients, retrospective blood >14days Clin Invest Med 1994;17:B21 Mortality- 31 septic patients, retrospective blood >16days Can J Anaesth 1997;44:1256-61 Multiorgan failure- trauma patients, prospective cohort #units >14days, >21days Am J Surg 1999;178:570-2 Postop pneumonia- 416 CABG surgery patients, retrospective age of blood Transfusion 1999;39:701-10 Gastric pH- septic patients, prospective blood >16days JAMA 1993;269:3024-3029 Major infections- cardiac surgery patients, retrospective age of oldest unit Anesthesiology 2003;98:815-22

12. Longer storage of blood + WBC’s → greater accumulation of WBC-derived cytokines Interaction between Leukoreduction and Blood Storage http://images.encarta.msn.com/xrefmedia/sharemed/targets/images/pho/35a5c/35A5C297.jpg Postop pneumonia- 416 CABG surgery patients, retrospective age of blood, non- vs. leukored Transfusion 1999;39:701-10

13. Hebert et al. Anesth Analg 2005;100:1433-8 - 57 transfused ICU/cardiac surgery patients - Canadian Medical Centers Standard group - Median age transfusion 19 days Experimental group - Median age transfusion 19 days

14. Age of Stored Blood and Post-Cardiac Surgery Mortality Risk Koch et al. New Engl J Med 2008;358:1229-39

15. - single institution - transfused CABG, Valve or CABG/Valve surgery patients - June 30, 1998 - January 30, 2006 - 2,872 patients - blood stored <14 days (8,802 units) - 3,130 patients - blood stored >14 days (10,782 units) Age of Stored Blood and Post-Cardiac Surgery Mortality Risk - Propensity-adjusted, multivariable logistic regression analysis to examine the association of storage age on postoperative mortality - Kaplan-Meier and Brownstone Decompensation method to assess association of storage age on long-term survival Koch et al. New Engl J Med 2008;358:1229-39

16. Age of Stored Blood and Post-Cardiac Surgery Mortality Risk Koch et al. New Engl J Med 2008;358:1229-39

17. Age of Stored Blood and Post-Cardiac Surgery Mortality Risk

18. Koch et al. New Engl J Med 2008;358:1229-39 Age of Stored Blood and Post-Cardiac Surgery Mortality Risk

19. Koch et al. New Engl J Med 2008;358:1229-39 Age of Stored Blood and Post-Cardiac Surgery Mortality Risk

20. Koch et al. New Engl J Med 2008;358:1229-39 Age of Stored Blood and Post-Cardiac Surgery Mortality Risk

21. Koch et al. New Engl J Med 2008;358:1229-39 Age of Stored Blood and Long-Term Survival

22. - single institution - 4643 transfused CABG surgery patients - September 1993 - June 2002 Age of Stored Blood and Post-Cardiac Surgery Mortality Risk DeSimone et al. Anesth Analg 2005;100:SCA7 VanMatre et al. Anesth Analg 2007;104:SCA23 30 Day MortalityN (deaths)P value All units ≤ 141.681605 (27)0.14 All units > 142.382187 (52) Oldest unit ≤ 141.681605 (27)0.003 Oldest unit > 143.152984 (94) Oldest unit ≤ 141.681605 (27)<0.0001 Oldest unit >14, ≤ 282.421774 (43) Oldest unit >284.211210 (51)

23. Age of Stored Blood and Post-Cardiac Surgery Mortality Risk - Propensity-adjusted, multivariable logistic regression analysis to examine the association of storage age of the oldest transfusion on postoperative mortality - Cubic-Splines analysis to assess for curvilinear relationships - Kaplan-Meier method to assess the association of storage age of the oldest transfusion on long-term survival DeSimone et al. Anesth Analg 2005;100:SCA7 VanMatre et al. Anesth Analg 2007;104:SCA23

24. DeSimone et al. Anesth Analg 2005;100:SCA7 Age of Stored Blood and Post-Cardiac Surgery Mortality Risk

25. VanMatre et al. Anesth Analg 2007;104:SCA23 Age of Stored Blood and Post-Cardiac Surgery Mortality Risk

26. “…the COX-2 saga has served to demonstrate that an approach (to drug development) based on studies powered to show effectiveness, no longer meets societal expectations for a comprehensive review of acceptable drug safety.” Stafford-Smith Can J Anaesth 2006;53:973-977