1. Blood Management in the Cath Lab Sunil V. Rao MD Associate Professor of Medicine Duke University Medical Center Durham VA Medical Center Duke Clinical Research Institute

2. Disclosures n Consultant l Sanofi-Aventis, Bristol Myers Squibb l The Medicines Company l Astra Zeneca l Terumo Corporation n Research funding l Cordis Corporation l Ikaria n Off-label uses of drugs/devices may be discussed

4. Improving PCI outcomes n Why talk about blood transfusion in the cath lab? l Drivers of transfusion in cath patients n Data on transfusion and outcomes in patients with CAD n Reducing bleeding risk – risk assessment, drug therapy, vascular access

5. Thrombus formation Thrombin plays a central role among tissue injury, coagulation, and platelet response. Collagen Tissue Factor Thrombin Platelet activation Prothrombin ADP TXA 2 Plasma Clotting cascade THROMBUS FibrinogenFibrin Platelet aggregation

7. Twenty-five year trends in PCI outcomes N=24,410 procedures at the Mayo Clinic Singh M., et. al. Circulation 2007

8. In Hospital PCI Mortality & Bleeding Peterson ED ACC 2007 Mehta SR ACC 2007

9. log rank p-value for all four categories <0.0001 log-rank p-value for no bleeding vs. mild bleeding = 0.02 log-rank p-value for mild vs. moderate bleeding <0.0001 log-rank p-value for moderate vs. severe <0.001 Bleeding & Outcomes N=26,452 pts from PURSUIT, GUSTO IIb, PARAGON A & B Rao SV, et al. Am J Cardiol. 2005 Kaplan Meier Curves for 30-Day Death, Stratified by Bleed Severity

10. Bleeding and Outcomes 26,452 patients from PURSUIT, PARAGON A, PARAGON B, GUSTO IIb NST Bleeding severity and adjusted hazard of death Bleeding severity 30d Death 30d Death/MI 6 mo Death Mild* 1.61.31.4 Moderate* 2.73.32.1 Severe* 10.65.67.5 *p<0.0001 Rao SV, et. al. AJC 2005

11. Bleeding and Outcomes 26,452 patients from PURSUIT, PARAGON A, PARAGON B, GUSTO IIb NST Adjusted hazard ratios for 30d Death Stratified by Procedure and Non-procedure related bleeds Bleeding severity Procedure Related Non-procedure Related Mild1.2 2.1* Moderate 3.7* 2.5* Severe 16.5* 10.9* *p<0.0001 Rao SV, et. al. AJC 2005

12. Bleeding and resource use Predictors of total costs N=1235 pts from GUSTO IIb Mod/sev bleed Per patient cost - $530 Transfusion - $2080, P < 0.01 Per patient cost - $287 Mod/sev bleed Per patient cost - $530 Transfusion - $2080, P < 0.01 Per patient cost - $287 Model C-index=0.87 Adjusted for patient characteristics Model C-index=0.87 Adjusted for patient characteristics Rao SV, et. al. AHJ 2008

13. Risk versus benefit Thrombosis Bleeding Transfusion

14. Bleeding – Mechanisms of harm n Severe bleeding l Hypotension l Reversal of antithrombotic therapy n Mild or Moderate bleeding l Cessation of antithrombotic therapy l Blood transfusion

15. Bleeding and Evidence-based Therapies N=2498 ACS patients from the PREMIER Registry Discharge ASA and thienopyridine Pts. with bleeding vs. pts. without bleeding Wang TY, et. al. Circulation 2008 Discharge 1 Month 6 Months 1 Year Aspirin OR (95% CI) Thienopyridine 0.5 1.0 2.0 0.45 (0.31, 0.64) 0.68 (0.50, 0.92) 0.63 (0.46, 0.87) 0.62 (0.42, 0.91) 0.94 (0.66, 1.34) 0.83 (0.59, 1.17) 1.06 (0.78, 1.45) 1.12 (0.81, 1.55)

16. 1945 --  C.O. 1970 --  mortality Hgb < 10 1998 --  ischemia HCT < 28 2001 –  mortality HCT < 33 1945 --  C.O. 1970 --  mortality Hgb < 10 1998 --  ischemia HCT < 28 2001 –  mortality HCT < 33 1996 -- No  ischemia Hgb < 10 1996 -- No  mortality until Hgb < 6 1998 -- No  ischemia Hgb < 10 1999 -- No ∆ Hgb 9 vs 7 2004 -  mortality for Tx at HCT >25% 2009 – No  MACE for Sx-driven Tx 1996 -- No  ischemia Hgb < 10 1996 -- No  mortality until Hgb < 6 1998 -- No  ischemia Hgb < 10 1999 -- No ∆ Hgb 9 vs 7 2004 -  mortality for Tx at HCT >25% 2009 – No  MACE for Sx-driven Tx 12 million units of blood transfused annually Evidence for and against the “10/30” Rule

17. 1.0 Less than USMore than US Unadjusted Adjusted for baseline characteristics Adjusted for baseline characteristics and procedures Adjusted for baseline characteristics, procedures, and bleeding 0.24 (0.19 – 0.30) 0.19 (0.15 – 0.25) 0.69 (0.54 – 0.88) 0.76 (0.59 – 1.00) Geographic variation in transfusion relative to U.S. N=24,112 Rao SV, et. al. AJC 2008

18. Variations in Transfusion Rates for NSTE ACS Across Hospitals Yang X, et. al. JACC 2005 Percentage of Patients Receiving Blood Transfusions (%) Percentage of Hospitals (%) Non-CABG Overall

19. Cooperative Cardiovascular Project 30 day death by transfusion and Hct n 78,974 pts > 65 years with confirmed MI n Grouped into categories of admission hematocrit n Excluded pts with bleeding and those with CABG n Primary endpoint: 30-day mortality Wu W, NEJM 2001 Odds ratio for 30 day mortality Odds ratio for 30 day mortality HigherHigher LowerLower HCT< 33 %

20. Transfusion in ACS N=24,111 pts from PURSUIT, PARAGON B, GUSTO IIb Rao SV, et. al., JAMA 2004

21. PRBC Transfusion Among NSTE ACS Patients: Cox model for 30-day Death (N=24,111) *Transfusion as a time-dependent covariate 1.010-4.0 Adjusted for transfusion propensity Adjusted for baseline characteristics Characteristics, bleeding propensity, transfusion Propensity, & nadir HCT 3.77 (3.14, 4.52) 3.54 (2.96, 4.23) 3.94 (3.26, 4.75) Rao SV, et. al., JAMA 2004

22. Cochrane Collaboration Systematic Review 30-day mortality by strategy Carless P, et. al. Cochrane Database of Systematic Reviews 2010

23. FOCUS Trial Post-op Hip Fx CV disease Hgb < 10 g/dl Post-op Hip Fx CV disease Hgb < 10 g/dl Transfusion for Hgb < 10 g/dl Transfusion for Hgb < 10 g/dl Transfusion for Sx or Hgb < 8 g/dl Transfusion for Sx or Hgb < 8 g/dl FunctionalRecovery At 60 days FunctionalRecovery N=2600 Secondary endpoints: Transfusion errors, cardiac ischemia N=2600 www.clinicaltrials.govwww.clinicaltrials.gov

24. FOCUS Trial N=2013 Carson JL, AHA 2009 Reported MI rate: Liberal 2.3% vs. Restrictive 3.8%, P=NS

25. CRIT Pilot Trial NSTEMI Hct ≤ 0.30 within 72 hrs of admission NSTEMI N=45 Maintain Hct 0.24 - 0.27 Transfuse if Hct < 0.24 Maintain Hct 0.24 - 0.27 Transfuse if Hct < 0.24 Maintain Hct 0.30 - 0.33 Transfuse if Hct < 0.30 Maintain Hct 0.30 - 0.33 Transfuse if Hct < 0.30 In-hospital Death, MI, or CHF Cooper HA, et. al. AJC 2011 13%38% P=0.046

26. Properties of PRBCs n Low 2,3 DPG* n High O 2 affinity* n Depleted of Nitric Oxide l NO plays a fundamental role in O 2 exchange † n Low 2,3 DPG* n High O 2 affinity* n Depleted of Nitric Oxide l NO plays a fundamental role in O 2 exchange † *Welch HG, et. al. Ann Int Med 1992 †Stamler JS, et. al. Science 1997

27. Nitric Oxide NO/SNO TFeNOSHVein Stamler JS, et. al. Science 1997 O2O2O2O2Lungs Artery R FeO 2 SNO O2O2O2O2 SNOCapillary T FeNOSH Vein

28. Effects of Transfusion n Packed red cells l Depleted of NO Function as NO “sinks” Lead to vasoconstriction Platelet aggregation Ineffective O 2 delivery l Associated with increases in CRP and IL6* n Packed red cells l Depleted of NO Function as NO “sinks” Lead to vasoconstriction Platelet aggregation Ineffective O 2 delivery l Associated with increases in CRP and IL6* *Fransen E, et. al. Chest 1999

29. MINT Trial Planned N=200 patients with ACS or CAD + Hgb < 10 g/dl STEMI, NSTEMI, or Sig. CAD/PCI Hgb < 10 g/dl Tx for symptoms Or Hgb < 8 g/dl Tx to keep Hgb ≥ 10 g/dl Restrictive Liberal 30-day Death, MI, Urgent Revasc 6-month Mortality

30. Strategies to deal with bleeding and transfusion risks n Prevention is KEY n Pharmacological strategies n Dosing n Newer agents n Vascular access

31. Excessive Dosing of Anticoagulants by Age Alexander KP, et. al. JAMA 2005

32. Excess dosing of Gp IIb/IIIa and bleeding in women N=32,601 patients from CRUSADE OverallOverall WomenWomen MenMen 1.46 (1.22, 1.73) 1.72 (1.30, 2.28) 1.27 (0.97, 1.66) 0.50.5 1.01.01.51.52.02.02.52.5 Excess Dosing More Likely to Bleed Alexander KP, et. al. Circulation 2006

33. STEEPLE IV enoxaparin STEEPLE OASIS 5 Fondaparinux Fondaparinux REPLACE-2ACUITYHORIZONSBivalirudinREPLACE-2ACUITYHORIZONSBivalirudin STEEPLE Investigators. NEJM 2006 OASIS Investigators. NEJM 2006 Lincoff AM, et. al. JAMA 2003 Stone GW. ACC 2006 STEEPLE Investigators. NEJM 2006 OASIS Investigators. NEJM 2006 Lincoff AM, et. al. JAMA 2003 Stone GW. ACC 2006 PLATOticagrelor

34. Bleeding in PCI Trials: Frequency and site* *All transfemoral access Among bleeders Rao SV, et. al., JACC 2010 (in press)

35. Unadjusted Relative RiskP-Value Access site2.33 (1.53 – 3.53)<0.0001 Non-access site5.40 (4.32 – 6.74)<0.0001 Adjusted Hazard ratio Access site1.82 (1.17–2.83)0.008 Non-access site3.94 (3.07–5.15)<0.0001 Risk for 1 year mortality No Bleed TIMI Major + Minor Bleed ●Combined REPLACE-2, ACUITY, HORIZONS-AMI (n=17,393) ●1-year mortality risk of non-access site bleeding vs access site = HR 2.27 (95%CI 1.42-3.64), p=0.0007 Verheugt JACC Cardio Interv 2011;4:191-7:

36. PCI-related complications and costs N=335,477 Medicare pts undergoing PCI in 2002 Kugelmass A, et. al. AJC 2006

37. Updated meta-analysis including RIVAL Jolly SS, et. al. Lancet 2011

38. Radial access and 1-year mortality N=38,872 procedures Chase AJ, et. al. BMJ 2008

39. Prevalence of radial approach in the US Rao SV, et. al. JACC: CI 2008 N = 593,094 PCI procedures 2004-2007 606 sites 606 sites 1.3% of all PCI procedures N = 593,094 PCI procedures 2004-2007 606 sites 606 sites 1.3% of all PCI procedures 8.5% of diagnostics, 7.8% of PCIs at end of 2010 (118% growth 2009-2010) Google stock 106% growth 2009-2010

40. Blood management in the cath lab Summary (1) n Patients with acute ischemic heart disease and those undergoing cath/intervention are at high risk for bleeding/transfusion n Antithrombotic therapy to reduce complications n Arteriotomy n Bleeding and transfusions have emerged as an important events that are associated with increased morbidity, mortality, and costs

41. Blood management in the cath lab Summary (2) n Reducing ischemic events while minimizing bleeding and transfusion risk is a clinical priority n Strategies that achieve this balance are associated with improved survival n The optimal transfusion strategy is not known…but prevention is the best approach n Appropriate choice/dosing of antithrombotics n Radial approach

42. Duke Univ. Medical Center Duke Clinical Research Institute