1. Welcome Ask The Experts March 24-27, 2007 New Orleans, LA

2. Steven V. Manoukian, MD, FACC Director of Interventional Cardiology Assistant Professor of Medicine Emory University School of Medicine Prognostic Implications of Bleeding and Transfusions in Acute Coronary Syndromes and Percutaneous Coronary Intervention

3. Prognostic Implications of Bleeding and Transfusions in Acute Coronary Syndromes and Percutaneous Coronary Intervention Steven V. Manoukian, M.D., F.A.C.C., F.S.C.A.I. Director, Interventional Cardiology, Emory Crawford Long Hospital Emory University School of Medicine Atlanta, Georgia

4. Prognostic Implications of Bleeding and Transfusions Incidence Impact Risks Predictors of bleeding Predictors of mortality

5. Washington Hospital Center (N=10,974): Rates of Bleeding in PCI Kinnaird TD et al. Am J Cardiol 2003;92:930-935.

6. The REPLACE-2 Trial (N=6,010): Rates of Major Bleeding in PCI (Overall 3.2%) p=0.0251 p=0.0021 4.0% 2.5% 2.2% 4.1% Voeltz MD, Lincoff AM, Feit F, Manoukian SV. Circulation 2005;112(17):II-737. Major Bleeding REPLACE-2 Intracranial, retroperitoneal Observed bleed with fall in Hgb  3g/dL No observed bleed with fall in Hgb  4g/dL Transfusion  2 units PRBC or whole blood

7. The REPLACE-2 Trial (N=6,010): Major Bleeding and Mortality in PCI Feit F, Voeltz MD, Attubato MA, et al. Unpublished.

8. Moscucci M et al. Eur Heart J 2003;24:1815-23. The GRACE Registry (N=24,045): Rates of Major Bleeding in ACS Major Bleeding GRACE Life-threatening with transfusion  2 units Life-threatening with decrease in HCT >10% Resulting in death Hemorrhagic, subdural hematoma

9. Moscucci M et al. Eur Heart J 2003;24:1815-23. P<0.001 Overall Unstable NSTEMI STEMI ACS Angina ACS Angina Mortality (%) The GRACE Registry (N=24,045): Major Bleeding and Mortality in ACS Major Bleeding GRACE Life-threatening with transfusion  2 units Life-threatening with decrease in HCT >10% Resulting in death Hemorrhagic, subdural hematoma

10. OASIS Registry, OASIS-2, and CURE (N=34,146): Major Bleeding and Mortality in ACS Eikelboom JW et al. Circulation 2006;114:774-782.

11. The ACUITY Trial (N=13,819) Rates of Major Bleeding in ACS P Sup =0.38P Sup <0.0001P Sup =0.31P Sup <.001 Stone GW et al. N Engl J Med 2006;355:2203-16.

12. The ACUITY Trial (N=13,819) Major Bleeding and Events in ACS P<0.0001 for all Manoukian SV, Feit F, Mehran R, et al. J Am Coll Cardiol 2007;49:1362-8.

13. Severity of Bleeding and Mortality in ACS Rao SV, et al. Am J Cardiol. 2005. Kaplan Meier Curves for 30-Day Death, Stratified by Bleed Severity

14. Bleeding Definition and Events in ACS Rao SV, et al. JACC 2006. Increased Risk Decreased Risk 30-Day Death/MI, N=15,858

15. The ACUITY Trial (N=13,819) Major Bleeding and Baseline Characteristics Major Bleeding (N=644, 4.7%) No Major Bleeding (N=13,175, 95.3%) P-value Age (median [range], yrs) 69 [37-95]62 [20-93]<0.0001 Female49.4%29.1%<0.0001 Weight (median [IQR], kg) 79.5 [68-92]84 [73-95]<0.0001 Diabetes34.5%27.8%0.0002 Hypertension73.3%66.7%0.0005 CrCl ≥ 60 ml/min62.7%81.8%<0.0001 Current smoker24.7%29.3%0.0126 Prior PCI29.0%37.8%<0.0001 High risk (ST / biomarkers)82.0%71.8%<0.0001 CK-MB / Troponin +68.1%59%<0.0001 Manoukian SV, Feit F, Mehran R, et al. J Am Coll Cardiol 2007;49:1362-8.

16. Age ≥75 years 1.64 (1.32-2.02) <0.0001 Female gender 1.92 (1.61-2.29) <0.0001 Diabetes1.20 (1.00-1.44)0.06 Hypertension1.24 (1.01-1.52)<0.05 No prior PCI 1.32 (1.08-1.62) <0.01 Anemia*1.87 (1.54-2.28)<0.0001 Renal insufficiency † 1.53 (1.24-1.90) <0.0001 Baseline ST-segment deviation ≥1mm1.35 (1.13-1.61)<0.001 Baseline cardiac biomarker elevation 1.43 (1.19-1.74) <0.001 Heparin ‡ + GPI vs. Bivalirudin 1.95 (1.56-2.44) <0.0001 *Anemia was defined as baseline hemoglobin <13 g/dL in men and <12 g/dL in women. † Renal insufficiency was defined as a creatinine clearance <60 ml/minute as calculated by the Cockcroft-Gault equation. ‡ Unfractionated heparin or enoxaparin. Odds ratio ±95% CI The ACUITY Trial (N=13,819) Predictors of Major Bleeding in ACS P-valueOR (95% CI) Manoukian SV, Feit F, Mehran R, et al. J Am Coll Cardiol 2007;49:1362-8.

17. The REPLACE-2 Trial (N=6,010): Predictors of Major Bleeding in PCI Feit F, Voeltz MD, Attubato MA, et al. Unpublished. VariableOR95% CIp-value Baseline risk factors Age ≥ 751.4821.01, 2.180.045 Gender (Female)1.5351.12, 1.100.007 Creatinine Clearance1.0081.00, 1.010.006 Anemia1.4031.02, 1.940.040 Prior Angina1.5891.08, 2.350.02 Prior PCI0.6290.45, 0.880.007 Prior Thienopyridine0.6010.39, 0.930.023 Peri-procedural risk factors Treatment Group (Heparin + GPI vs. bivalirudin)1.9691.37, 2.840.0003 Provisional GPI received2.6791.59, 4.510.0002 Procedure Duration >1h2.0491.22, 3.450.007 Time to Sheath Removal >6h1.6141.06, 2.450.024 Intensive Care Unit stay (days)1.251.18, 1.32<0.0001 Intra-aortic Balloon Pump8.7053.43, 22.07<0.0001

18. The REPLACE-2 Trial (N=6,010): Bleeding and Chronic Kidney Disease in PCI ≥ 60 ml/min N=4824 < 60 ml/min N=886 p value 30-d Death5 (0.1%)14 (1.6%) < 0.001 30-d Myocardial infarction305 (6.3%)75 (8.5%) 0.018 30-D urgent revascularization61 (1.3%)10 (1.1%) 0.738 Triple ischemic endpoint338 (7.0%)84 (9.5%) 0.010 In-hospital protocol major bleeding 123 (2.5%)54 (6.1%) < 0.001 TIMI major + minor bleeding114 (2.4%)46 (5.2%) < 0.001 Creatinine Clearance Chew DP, Lincoff AM, Gurm H, et al. Am J Cardiol 2005;95:581–585.

19. The REPLACE-2 Trial (N=6,010): Major Bleeding and Anemia in PCI Overall REPLACE-2 Major bleeding = 3.2% Major Bleeding 2.8% 4.9% P=0.0001 Protocol definition: >3g/dL drop in HgB, intracranial, retroperitoneal, 2U transfusion Voeltz MD, Attubato MJ, Feit F, et al. J Am Coll Cardiol 2005;45(3)[Suppl A]:1037-12-31A.

20. PRBC Transfusion in ACS 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

21. The REPLACE-2 Trial (N=6,010): Bleeding and Transfusion in Elderly PCI = Elderly, >75 = Not Elderly, <75 p<0.0001p=0.0001 Voeltz MD, Lincoff AM, Feit F, Manoukian SV. Circulation 2005;112(17):II-613. More: female, Caucasian, prior CVD, risk factors. Lower: BMI, Hgb, CrCl, tobacco. Ischemic outcomes did not differ between elderly and younger patients.

22. The REPLACE-2 Trial (N=6,010): Mortality, Bleeding, Transfusion in Elderly PCI = Yes = No p<0.0001p=0.0001 30-Day Mortality Voeltz MD, Lincoff AM, Feit F, Manoukian SV. Circulation 2005;112(17):II-613. More: female, Caucasian, prior CVD, risk factors. Lower: BMI, Hgb, CrCl, tobacco. Ischemic outcomes did not differ between elderly and younger patients.

23. The REPLACE-2 Trial (N=6,010): Mortality with Transfusion in PCI Non-transfusedTransfused*p<0.0001 Manoukian SV, Voeltz MD, Attubato MJ, Bittl JA, Feit F, Lincoff AM. CRT 2005. CRT 2005

24. Results: The ACUITY Trial (N=13,819) Transfusion and Events in ACS P<0.0001 for all Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

25. The REPLACE-2 Trial (N=6,010): Predictors of One-Year Mortality in PCI Voeltz MD, Patel AD, Feit F, et al. Am J Cardiol, June 2007, in press. VariableOR (95%CI) p-value Age ≥ 752.28 (1.51, 3.46)0.0001 Pre-procedural Anemia2.12 (1.49, 3.13)0.0002 BMI > 25 (vs. 20-25)0.61 (0.40, 0.99)0.007 Pre-procedure LVEF ≤ 50%2.15 (1.44, 3.21)0.0002 CHF3.58 (2.27, 5.65)<.0001 Prior Angina2.16 (1.25, 3.75)0.006 Major Bleeding2.66 (1.44, 4.92)0.002 MI2.46 (1.44, 4.20)0.001 Revascularization3.30 (1.36, 8.00)0.008 Major Bleeding REPLACE-2 Intracranial, retroperitoneal Observed bleed with fall in Hgb  3g/dL No observed bleed with fall in Hgb  4g/dL Transfusion  2 units PRBC or whole blood

26. Age ≥75 years 2.55 (1.68-3.87) <0.0001 Left ventricular ejection fraction ≤50% 2.96 (1.99-4.39) <0.0001 Prior stroke 1.94 (1.09-3.44) <0.05 Baseline ST-segment deviation ≥1mm2.32 (1.54-3.50)<0.0001 Baseline cardiac biomarker elevation 1.97 (1.23-3.17) <0.01 Treatment strategy (CABG vs. PCI)3.40 (2.11-5.49)<0.0001 Myocardial infarction within 30 days 3.96 (2.45-6.42) <0.0001 Major bleeding 7.55 (4.68-12.18) <0.0001 Odds ratio ±95% CIP-valueOR (95% CI) The ACUITY Trial (N=13,819) Predictors of 30-Day Mortality in ACS Manoukian SV, Feit F, Mehran R, et al. J Am Coll Cardiol 2007;49:1362-8.

27. Conclusion: Prognostic Implications of Bleeding and Transfusions Frequent complication of PCI and ACS. Associated with increased mortality and ischemic event rates. Rivals risk attributed to the ischemic complication of MI. Factors often associated with increased risk: –baseline factors: age, female, renal disease, anemia; –presentation factors: high-risk ACS presentation; –treatment factors: heparin(s) + GPI, procedure/sheath time. Knowledge of these factors is important in assessment of the: –hemorrhagic risk of, –ischemic risk of, and –subsequent decision-making for an individual patient.

28. Question&Answer

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