1. Applying Evidence – Blood Conservation in Clinical Practice Victor A. Ferraris, M.D., Ph.D. University of Kentucky Linda & Jack Gill Heart Institute Lexington, KY

2. Real-world guideline application Presenter Disclosure Information Victor A. Ferraris, M.D., Ph.D. Research grant support from American Heart Association, Aventis, Bayer, BioMarin Pharma, Guilford, Medtronic, NHLBI, and The Medicines Company. Lecture or consulting fees from AstraZeneca, Aventis, Bayer, Network for Advancement of Transfusion Alternatives (NATA), and The Medicines Company.

3. Real-world guideline application Blood Conservation Guidelines 61 recommendations regarding blood conservation. 6 Class I recommendations 39 Class II recommendations 20 Class IIa 19 Class IIb 16 Class III recommendations Ferraris, et al. Ann Thorac Surg, 2007. (in press)

4. Real-world guideline application Blood Conservation Interventions – Class I Recommendations Identify high risk preoperatively. Blood transfusion algorithm w/ point-of-care testing. Multimodality approach. Anti-fibrinolytic drugs (esp. for high risk) Cell saver & cell salvage Preop platelet count and HCT for risk prediction. Ferraris VA, et al. STS Guidelines on blood conservation. Ann Thorac Surg, 2007. In press.

5. Real-world guideline application Class IIa or IIb Blood Conservation Interventions Class IIa OPCAB DDAVP for high risk only. Stop clopidogrel 5 days before OR. Continue ASA unless totally elective. Class IIb BT/PFA-100 for screening in high risk. r-FVIIa for recalcitrant bleeding. Autologous hemodilution. Retrograde priming. Ferraris VA, et al. STS Guidelines on blood conservation. Ann Thorac Surg, 2007. In press.

6. Real-world guideline application Things That Are Not Indicated for Blood Conservation (Preliminary) Class III indications Unwashed shed mediastinal blood re- infusion. PEEP for control of bleeding. Dipyridamole for ‘platelet anesthesia’. Plasma or platelet-pheresis. Routine DDAVP. Leukocyte depletion filters during CPB. Ferraris VA, et al. STS Guidelines on blood conservation. Ann Thorac Surg, 2007. In press.

7. Real-world guideline application Purpose Apply evidence-based blood conservation interventions to real world situations. Describe the process of guideline development.

8. Real-world guideline application Case #1 – Clopidogrel – “the Devil’s Drug” Patient History 80 y/o woman w/ unstable angina & continued chest pain. Cath shows 3-v CAD w/ 60% left main. 600 mg clopidogrel loading dose before cath. (Class I recommendation by AHA/ACC). AODM, HTN, CRF (creat = 2.0), HCT = 34%. BSA = 1.5.

9. Real-world guideline application Case # 1 - Questions 1.Is this patient at high risk for bleeding? 2.Can you stop anti- platelet drugs? 3.What are the options to limit bleeding in this patient?

10. Real-world guideline application Transfusion Profile More than 50% do not get transfusion. Patients who receive > 10 units of blood are in 90 th percentile 10-20% of patients consume 80% of blood products. 4445 patients having cardiac procedures w/ CPB over 4 years. Ferraris, Int. J. Angiology, 2006.

11. Real-world guideline application Transfusion & Serious Morbidity Serious morbidity and mortality increase with the amount transfused.

12. Real-world guideline application Predictors of Postoperative Bleeding – The Big 6 1)Advanced age 2)Small body size or preoperative anemia (low RBC volume) 3)Anti-platelet & anti-thrombotic drugs. 4)Prolonged operation (CPB time) – high correlation with OR type. 5)Emergency operation 6)Other co-morbidities (CHF, COPD, HTN, PVD, renal failure, etc.) Ferraris VA, et al. STS Guidelines. Ann Thorac Surg. 2005;79:1454-61.; Ferraris VA, et al. Ann Surg. 2002;235:820- 7.

13. Real-world guideline application Two Causes of Postoperative Bleeding & Blood Transfusion Patient-related Age Red blood cell volume Co-morbidities CHF Renal failure COPD Procedure-related Prolonged operation Emergency operation Surgical site bleeding (‘hole in the artery’)

14. Real-world guideline application Age & RBC Volume 75 y/o, 55kg, women, with preop HCT = 35% Ferraris, Int. J. Angiology, 2006.

15. Real-world guideline application Case #1 – Question #1 Is this patient high risk? Risk factors Age Anemia (red blood cell volume) Anti-platelet drugs Urgent operation Multiple co-morbidities (CRF, HTN, AODM, Answer Yes!

16. Real-world guideline application

18. Managing Risk Factors Anti-platelet drugs as an example Common problem – almost all patients have anti-platelet drug on-board at OR. Evidence is available to guide decisions. Likely to show tangible benefit.

19. Real-world guideline application Does Aspirin Cause Increased Postoperative Bleeding? 21 studies reviewed the effect of aspirin on postoperative bleeding. 5 of 6 RCT’s showed increased bleeding due to aspirin (Level A evidence). Evidence less convincing in 15 observational studies (Level B or C evidence). Ferraris VA, et al. STS Guidelines. Ann Thorac Surg. 2005;79:1454-61.

20. Real-world guideline application Long-term Efficacy of ASA in Reducing Death or MI in Patients with Unstable Angina Wallentin LC et al JACC 1991;18:1587–1593 0.00 0.05 0.10 0.15 0.20 0.25 036912 Months Probability of death or MI Placebo ASA 75 mg Risk ratio after 1 year 0.52 95% Cl 0.37–0.72 (p=0.0001)

21. Real-world guideline application Guidelines & Aspirin – the Dilemma Aspirin causes increased bleeding. Amount of bleeding is small (0.5 units/patient) Aspirin important for better outcome in acute coronary syndromes Nothing more important than aspirin including heparin, thrombolytics, 2b/3a, & PCI. STS recommendation – stop aspirin for a few days in very low risk patients, continue in all others. Ferraris VA, et al. STS Guidelines. Ann Thorac Surg. 2005;79:1454-61.

22. Real-world guideline application Adapted from Angiolillo DJ et al. Am J Cardiol. 2006;97:38-43. Variable Response to Dual Antiplatelet Therapy in the Steady State Phase of Treatment % Platelet Aggregation (LTA-ADP 20  mol/L) 97.5 92.5 87.5 82.5 77.5 72.5 67.5 62.5 57.5 52.5 47.5 42.5 37.5 32.5 27.5 22.5 17.5 12.5 7.5 2.52015 10 5 0 Number of Patients Bleeding risk Ischemic risk

23. Real-world guideline application There Is a Problem – Aspirin & Bleeding Time Some patients have hyper- response to aspirin. Bleeding time back to normal in 2-3 days even in hyper-responders. Ferraris VA, et al. Ann Surg. 2002;235:820-7.

24. Real-world guideline application Another Problem – Aspirin Resistance Topol, 2003 5–10% of patients taking usual doses of aspirin are ‘aspirin resistant’. Normal platelet aggregation to ADP & Arachidonic acid. Aspirin resistant patients have 2 to 3 times increased incidence of death, MI, or stroke. Gum PA, JACC. 2003;41:961-5.

25. Real-world guideline application

26. What to Expect From Guidelines Aspirin & postoperative bleeding. Guidelines recommend stopping aspirin in only very elective patients before operation. Class IIa recommendation. Variability in response to aspirin is common and should be expected. Practice variation should be reduced if guidelines are followed. Ferraris VA et al. Ann Thorac Surg. 1998;45:71- 4.;Gum PA, JACC. 2003;41:961-5.

27. Real-world guideline application Do Thienopyridines Cause Postoperative Bleeding? Evidence is more compelling than for aspirin 11 studies with clopidogrel & CABG. All studies show increased bleeding when clopidogrel given within 5 days of CABG – some with increased mortality. AHA/ACC & STS guidelines recommend stop clopidogrel for 5 days before operation, if possible. Ferraris VA, et al. STS Guidelines. Ann Thorac Surg. 2005;79:1454- 61.; www.acc.org, Accessed Jan. 2006.

28. Real-world guideline application Thienopyridines (Plavix ® ) & Postoperative Bleeding StudyPts.Outcome in clopidogrel-treated patients. CURE Investigators. NEJM, 2005; 345:492. 910 Increased major bleeding if plavix-treated within 5 days of CABG in UA/NSTEMI patients. van der Linden, Circulation.2005;112:I276. 37Increased bleeding & re-exploration – aprotinin used in one group Akowuah, ATS. 2005;80:149.24 Increased mortality, transfusion, and re-exploration in placebo - aprotinin & EACA used in one group. Von Heymann, CCM;2005:33:2241. 36Increased chest tube drainage & non-heme. Lindvall, ATS. 2005;80:922.18Increased transfusion (heme & non-heme), & re-exploration Ascione, ATS. 2005;79:1210.91Increased mortality, transfusion and re-exploration. Chu, ATS. 2004;78:1536.41Increased transfusion (heme & non-heme) Chen, JTCVS. 2004;128:425.45Increased transfusion (heme & non-heme) Gansera, Thorac Cardiovasc Surg.2003;51:185. 64Increased transfusion (heme and non-heme), & re-exploration Ray, BMC Cardiovasc Disord, 2003;3:3. 57Increased re-exploration & transfusion Yende, CCM. 2002;29:2271.51Increased transfusion (heme & non-heme) & re-exploration. Hongo, JACC. 2002:40:231.59Increased morbidity, transfusion, & re-exploration.

29. Real-world guideline application Variable Response to Plavix Large inter-individual variability in response to clopidogrel has been observed when a 300 mg loading dose (LD) is used. A 600 mg LD decrease the mean platelet reactivity (PR) but does not overcome the large inter- individual variability observed. Bonello, et al., In press EHJ 2008

30. Real-world guideline application VASP Index + ADP AC cAMP PKA VASP VASP-P GP 2b/3a complex Fibrinogen binding Inactivated Platelets PGE1 PGI2 - Activated platelets P2Y 12 ADP-receptor VASP index : standardized and reproducible. Highly specific for response to clopidogrel. Horstrup et al. Eur J Biochem 1994;225:21-7 Geiger et al. Arterioscler Thromb Vasc Biol. 1999;19:2007-11.

31. Real-world guideline application Definition of Low Response to Plavix Using VASP Index The negative predictive value of the VASP index to predict MACE after PCI was 100% using the cut-off value of 50% of PR. Bonello L, et al. J Thromb Haemost. 2007;5:1630-6 Therefore we defined low response as a post- treatment platelet reactivity ≥ 50% using the VASP index in the present study.

32. Real-world guideline application Bonnello – Study Design Non-emergent PCI : ACS and Stable angina (n=406) Loading dose (LD) ASA 250mg Clopidogrel 600mg VASP ≥ 50% Randomization (n=162) CONTROL (n=84)VASP-guided LD (n=78) Up-to 3 additional LD of 600 mg every 24 hours until VASP < 50% before PCI Maintenance dose ASA 160 mg Clopidogrel 75 mg 1° endpoint: MACE (CV death, MI, revascularization) at 30 days 2° endpoints: TIMI major and minor bleeding at 30 days

33. Real-world guideline application Efficacy of VASP Index in Guiding Plavix Therapy MACE; n (%) Control (n=84) VASP-guided (n=78) Cardiovascular death2 (2)0 Acute and Sub-acute stent thrombosis 4 (5) † 0 Revascularization2 (2)0 Overall MACE 8 (10)*0 † p =0.059 * p =0.007 MACE: CV death, MI, revascularization Log rank p =0.007 Bonello, et al., In press EHJ 2008

34. Real-world guideline application Bleeding Complications Using the VASP Index to Guide Plavix Therapy Bleeding, n (%) Control (n=84) VASP-guided (n=78) TIMI Major11 TIMI Minor 3 (4) 2 (3) All, n (%) 4 (5) 3 (4) Using additionnal clopidogrel LD in patients with low-response and according to platelet monitoring was safe. Bonello, et al., In press EHJ 2008

35. Real-world guideline application

37. Case #1 – Question #2 Can you stop clopidogrel? No good information. Common side-effect of evidence-based review. Identify knowledge deficits. Answer Unknown! Not enough evidence.

38. Real-world guideline application Evidence-Based Blood Conservation Strategies Top 4 Preoperative interventions Select high risk – “pull out all the stops” Limit anti-thrombotic & anti-platelet drug effect. Limit blood loss during operation Anti-fibrinolytics Off-pump procedures Perfusion strategies (centrifugal pump w/ membrane) Salvage & sequester blood (not as helpful in high-risk) Cell saver, pump salvage, etc. Hemodilution (predonation) Manage blood resources (process of care variables) Multimodality approach Transfusion algorithm & point-of-care testing.

39. Real-world guideline application What Works for Blood Conservation? Multiple interventions are better than a few ‘favorite’ interventions. TQM approach – ‘Measurement & Management’. ‘Outcome greater than sum of parts’ Examples Normovolumic hemodilution Aprotinin

40. Real-world guideline application Normovolemic Hemodilution – Class IIb Recommendation 5 prospective studies 3 showed no benefit 2 showed benefit Not possible to do meta-analysis. Contraindications Urgent operation Anemia Sepsis May be beneficial when used as part of a multimodality approach.

41. Real-world guideline application Meta-analysis – Aprotinin & CABG 21 of 29 studies showed significant reduction in blood transfusion in aprotinin-treated.

42. Real-world guideline application Aprotinin Safety Issues Safety concerns 3 observational studies suggest increased renal toxicity, possibly increased mortality, and no benefit in blood usage. No mortality benefit despite reduced transfusion – problem of competing risks. Bayer no longer markets aprotinin Only available for compassionate use.

43. Real-world guideline application Anti-fibrinolytic Drugs & Guidelines Class I. Anti-fibrinolytic drugs indicated to reduce blood transfusion & re-exploration in high risk patient. Aprotinin is probably best but not readily available.

44. Real-world guideline application Case #1 – Question #3 Are there interventions that can help? Multimodality blood management program is best. 61 recommendations, not just ‘one magic bullet’. Aprotinin is not the only blood conservation intervention! Answer Yes!

45. Real-world guideline application Case #2 – Postoperative Bleeding Patient history 62 year-old man Unstable angina. Drug-eluting stent 2 years ago (now on ASA only) Started on eptifibatide (Integrelin®) in CCU Uneventful 3-v CABG 4-6 hours after stopping eptifibitide. Four hours after operation, he is bleeding 100 to 200 cc per hour. Stat Hg is 7 mg/dL He has had 1000cc of 5% albumin and 1000cc of crystalloid solution.

46. Real-world guideline application Postoperative Bleeding Should you be worried? You’d better start swimming Or you’ll sink like a stone. … It’ll soon shake your windows And rattle your walls. For the times they are a-changin. Bob Dylan

47. Real-world guideline application Case #2 - Questions 1.Will this patient benefit from transfusion? 2.Is there an evidence-based transfusion algorithm that guides therapy in this patient? 3.Should routine clotting & coagulation tests be ordered?

48. Real-world guideline application More Is Known About the Risks of Blood Transfusion Than the Benefits! RBC Shape Change During Storage Day 1 Day 21 Day 35 Horvav T et al Transfusion 1999 39(3):277-281

49. Real-world guideline application Bleeding After PCI Is a Risk for 1- year Mortality (5,384 patients) Independent predictors of 1-year mortality. Ndrepepa, 2008 VariableHazard Ratio (95% CI) Bleeding w/in 30 days2.96 (1.96 -4.48) MI w/in 30 days2.29 (1.52 – 3.46) Urgent revascularization w/in 30d2.49 (1.16 - 5.35) Age (years)2.27 (1.78 – 2.89) Diabetes1.47 (1.11 – 1.96) Multivessel CAD2.72 (1.58 -4.67) Elevated troponin1.77 (1.27 -2.47) LV ejection fraction0.71 (0.60 – 0.85) Creatinine1.10 (1.06 – 1.14)

50. Real-world guideline application Two Evil Things About Postoperative Bleeding Blood loss Hypovolemia Shock Worse outcome from organ failure Re-operation for tamponade or bleeding. Blood transfusion Diseases transmission Immune modulation (TRALI) Transfusion errors

51. Real-world guideline application Competing Risks Risk of intervention (e.g. PCI, CABG) Bleeding Transfusion Reintervention MI, stroke, etc. Risks of disease state (e.g. UA/NSTEMI) Death MI Stroke Equation favors interventions in highest risk patients

52. Real-world guideline application Case #2 – Question #1 Will this patient benefit from transfusion? Jehovah’s witness would say no. There are two bad things about blood management Blood loss Blood transfusion Answer Highly uncertain ‘Maybe’ (consensus) Biggest benefit may be to increase cardiac output.

53. Real-world guideline application Two Reasons For Variability in Transfusion Practices Physician & institution practices are hard to manage (control is a bad word!). Accurate & timely information is not available (‘lab’ takes too long). Stover, Anesthesiology. 1998;88:327.

54. Real-world guideline application Problems with Interventions - Consensus Guidelines for RBC Transfusion Transfusion indicatedTransfusion not indicatedUncertain benefit of transfusion Hgb ≤ 6.0 on CPBHgb ≥ 10 after CPB without critical end- organ ischemia. Hgb between 8 -10g/dl in a stable patient benefit is unclear. Hgb ≤ 8.0 in high risk (age > 65, and/or co- morbidity). Acute blood loss (30% of blood volume). Rapid blood loss without immediate control. Hgb ≤ 10 g/dl in certain patients with critical end-organ ischemia. Ferraris VA, et al. STS Guidelines on blood conservation. Ann Thorac Surg, 2006. In press.

55. Real-world guideline application Guidelines for Transfusion of Non-red Cell Hemostatic Factors No evidence base! Transfuse for clinical bleeding only. Can be guided by accurate & timely point-of-care tests (e.g. Platelet count, PFA-100, TEG, POC PT/PTT, etc.). Ferraris VA, et al. STS Guidelines on blood conservation. Ann Thorac Surg, 2006. In press.

56. Real-world guideline application Transfusion Algorithms 7 RCT’s tested transfusion algorithms w/ point-of-care testing to reduce transfusion. 6 of 7 RCT’s showed reduced transfusion or re-exploration rates. Didn’t matter what type of POC testing. Various algorithms used. Ferraris VA, et al. STS Guidelines on blood conservation. Ann Thorac Surg, 2006. In press.

57. Real-world guideline application Point-of-Care Testing Fibrinolysis & fibrinogen TEG, MCA 210, TAS system Coagulation factors Whole blood aPTT & PT Platelets Bleeding time, PFA-100, TEG, RPFA Despotis, Semin Thorac Cardiovasc Surg, 11:84-104. 1999

58. Real-world guideline application Transfusion Algorithms & POC Testing – An Example StudyPtsAlgorithmPOC testsOutcome Avidan, 2004 210Transfuse PRBC for Hb ≤ 8.0. DDAVP for abnormal PFA- 100 followed by platelets if no response to DDAVP. Aprotinin for abnormal TEG amplitude. Explore for failure to respond & continued bleeding. TEG PFA-100 Hepcon Decreased transfusion of heme & non-heme blood products. Avidan MS, Br J Anaesth. 2004; 92:178.

59. Real-world guideline application Case #2 – Question #2 Is there an evidence-based transfusion algorithm that guides therapy in this patient? Defining an algorithm is more important than the content of the algorithm. Answer Yes! (if everybody agrees on algorithm)

60. Real-world guideline application Case #2 – Question #3 Should routine clotting & coagulation tests be ordered? Routine tests don’t help – too little too late Answer No! (point-of-care tests are best, combined with algorithm).

61. Real-world guideline application Conclusions – Take Home Messages High risk patients benefit most. Multimodality approach is best – especially with algorithm-driven transfusion. Benefits of blood transfusion not as great as expected. Inconsistent response to interventions is common (e.g. aspirin and plavix). Guideline preparation identifies deficit in data.

62. Real-world guideline application STS Evidence-Based Workforce Blood conservation writing group WriterOrganization Victor A. Ferraris, M.D., Ph.D. (Chair)University of Kentucky Suellen P. Ferraris, Ph.D.University of Kentucky Sibu P. Saha, M.D., M.B.A.University of Kentucky Constance K. Haan, M.D.University of Florida B. David Royston, M.D.Harefield Hospital, UK Charles R. Bridges, M.D. (Chair, Evidence-Based Workforce) University of Pennsylvania Robert S.D. Higgins, M.D.Rush Presbyterian, St. Luke’s Medical Center George J. Despotis, M.D.Washington University Jeremiah R. Brown, Ph.D.Dartmouth Univ.

63. Real-world guideline application Society of Cardiovascular Anesthesia Guideline Reviewers Blood conservation reviewing group ReviewerOrganization Bruce Spiess, M.D. (Chair)Virginia Commonwealth University Linda Shore-Lesserson, M.D.Mount Sinai School of Medicine Mark Stafford-Smith, M.D.Duke University C. David Mazer, M.D.St. Michael’s Hospital, Toronto Elliott Bennett-Guerrero, M.D.Duke University Steven E. Hill, M.D.Duke University Simon Body, M.B., Ch.B., M.P.H.Harvard University

64. Real-world guideline application Thanks Questions?