2. Medical Rx (cath) Time AdmissionCathDischarge No Cath Cath PCI Surgery Medical Rx (no cath) Medical Rx No disease (82 % of total) (18 % of total) (52% of total, 63% of those undergoing cath) 40 % < 48 hrs 12 % > 48 hrs (12% of total, 15% of those undergoing cath) 63 % < 48 hrs 19 % > 48 hrs CRUSADE Registry 10/04-9/05 n=35,897 Patient X ACS Management Pathways Cath Medical Rx

3. SYNERGYLMWHESSENCE 1994199519961997199819992000200220032004200520062001 CUREClopidogrel Bleeding risk Ischemic risk GP IIb/IIIa blockers PRISM-PLUS PURSUIT ACUITY TACTICS TIMI-18 Early invasive PCI ~ 5% stents ~85% stents Drug-eluting stents ISAR-REACT 2 Milestones in ACS Management OASIS-5 [ Fondaparinux ] Anti-Thrombin Rx Anti-Platelet Rx Treatment Strategy Heparin Aspirin Conservative ICTUSBivalirudin REPLACE 2

4. Ischemic Complications Death MI Urgent TVR Death MI Urgent TVR Evolving Paradigm for Evaluating ACS Management Strategies Composite Adverse Event Endpoints

5. Ischemic Complications Hemorrhage HIT Death MI Urgent TVR Death MI Urgent TVR Major Bleeding Minor Bleeding Thrombocytopenia Major Bleeding Minor Bleeding Thrombocytopenia Composite Adverse Event Endpoints Evolving Paradigm for Evaluating ACS Management Strategies

6. Risk of events Risk of bleeding Thrombosis Hemostasis Two sides of the same coin Degree of Anticoagulation Risk Balancing Events and Bleeding

7. Death4.3% (Re)-Infarction2.5% CHF8.0% Cardiogenic Shock2.6% Stroke0.8% Non-CABG Transfusion9.9% Bhatt DL, et al. JAMA. 2004 Nov 3;292(17):2096-104. CRUSADE In-Hospital Outcomes

9. Quali sono i pazienti a rischio di sanguinamento? Bleeding in ACS Domanda:

10. Independent Predictors of Major Bleeding in Acute Coronary Syndromes Moscucci, GRACE Registry, Eur Heart J. 2003 Oct;24(20):1815-23. Predictors of Major Bleeding in ACS Older Age Older Age Female Gender Female Gender Renal Failure Renal Failure History of Bleeding History of Bleeding Right Heart Catheterization Right Heart Catheterization GPIIb-IIIa antagonists GPIIb-IIIa antagonists

11. P-value RR (95% CI) Risk ratio ± 95% CI Predictors of Major Bleeding Age >75 (vs. 55-75) Anemia CrCl <60mL/min Diabetes Female gender High-risk (ST / biomarkers) Hypertension Heparin(s) + GPI (vs. Bivalirudin) 1.56 (1.19-2.04) 0.0009 1.89 (1.48-2.41) <0.0001 1.68 (1.29-2.18) <0.0001 1.30 (1.03-1.63) 0.0248 2.08 (1.68-2.57) <0.0001 1.42 (1.06-1.90) 0.0178 1.33 (1.03-1.70) 0.0287 2.08 (1.56-2.76) <0.0001 Manoukian SV, Voeltz MD, Feit F et al. TCT 2006. Results: The ACUITY Trial PCI Population MA…

13. REPLACE-2 Multivariate Predictors of Major Bleeding RISK FACTORS Odds Ratio 95% CI p-value Baseline risk factors Age > 75 1.482 1.009 to 2.176 0.045 Gender (M vs. F) 0.652 0.477 to 0.890 0.0072 Prior Angina 1.589 1.077 to 2.345 0.0197 Creatinine clearance* 0.993 0.987 to 0.998 0.0061 Anemia1.403 1.015 to 1.939 0.0401 Peri-procedural risk factors Treatment Group (BIV vs. H+GPI) 0.508 0.352 to 0.733 0.0003 Provisional GPI received 2.679 1.591 to 4.512 0.0002 Procedure Duration >1h 2.049 1.217 to 3.449 0.0069 Time to Sheath Removal >6h 1.614 1.064 to 2.448 0.0244 ICU stay (days) 1.25 1.183 to 1.321 <0.0001 IABP8.705 3.433 to 22.072 <0.0001 Feit F et al.

16. Il sanguinamento influenza la prognosi del paziente? Bleeding in ACS Domanda:

17. Moscucci M et al. Eur Heart J 2003;24:1815-23. P<0.001 Overall Unstable NSTEMI STEMI ACS Angina ACS Angina Patients (%) Major Bleeding Predicts Mortality in ACS 24,045 ACS patients in the GRACE registry, in-hospital death

18. 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 Rao SV, et al. Am J Cardiol. 2005 Nov 1;96(9):1200-6. Epub 2005 Sep 12 Kaplan Meier Curves for 30-Day Death, Stratified by Bleed Severity N=26,452 ACS patients from GUSTO IIb, PARAGON A, PARAGON B, & PURSUIT

19. Major Bleeding, Ischemic Endpoints, and Mortality P<0.0001 for all Manoukian SV, Voeltz MD, Feit F et al. TCT 2006. Results: The ACUITY Trial PCI Population (N=7,789)

20. Major Bleeding and Myocardial Infarction P<0.0001 for all Manoukian SV, Voeltz MD, Feit F et al. TCT 2006. Results: The ACUITY Trial PCI Population (N=7,789)

21. Major and Minor Bleeding in PCI Bleeding Increases Mortality and Events Kinnaird TD et al. AM J Cardiol 2003;92:930-5. 10,974 patients undergoing PCI, Washington Hospital Center, 1991-2000. In-Hospital Clinical Events Major(n=588)Minor(n=1,394)None(n=8,992) Death 7.5%* 7.5%* 1.8%*0.6% Q-wave myocardial infarction 1.2%* 0.7% 0.7% 0.2% Non-Q-wave myocardial infarction 30.7%* 30.7%* 16.8%*11.8% Repeat lesion angioplasty 1.9%* § 0.8% 0.8% 0.3% Major adverse cardiac event 6.6%* 6.6%* 2.2%*0.6% Bleeding Complication * p<0.001 versus none p<0.001 versus minor p<0.01 versus none § p<0.05 versus minor

22. Come valutare lentità del sanguinamento? Bleeding in ACS Domanda:

23. Bleeding Incidence in ACS Clinical Trials Rao SV, et al. J Am Coll Cardiol. 2006 Feb 21;47(4):809-16. Epub 2006 Jan 26

24. Bleeding Definitions TIMI Definition TIMI Definition l Major ICH ICH Associated with Hgb decrease 5 g/dl or HCT decrease 15% Associated with Hgb decrease 5 g/dl or HCT decrease 15% l Minor Observed blood loss associated with Hgb decrease 3 g/dl or HCT decrease 10% Observed blood loss associated with Hgb decrease 3 g/dl or HCT decrease 10% No identifiable source but Hgb decrease 4 g/dl or HCT decrease 12% No identifiable source but Hgb decrease 4 g/dl or HCT decrease 12% l Minimal Overt hemorrhage with Hgb drop < 3 g/dl or HCT drop < 9% Overt hemorrhage with Hgb drop < 3 g/dl or HCT drop < 9% Chesebro JH. Circulation 1987. Jul;76(1):142-54.

25. N Engl J Med. 1993 Nov 25;329(22):1615-22. Erratum in: N Engl J Med 1994 Feb 17;330(7):516 Bleeding Definitions GUSTO Definition GUSTO Definition l Severe or life threatening ICH or hemodynamic compromise requiring treatment ICH or hemodynamic compromise requiring treatment l Moderate Requiring transfusion Requiring transfusion l Mild Not meeting criteria for Severe or Moderate Not meeting criteria for Severe or Moderate

26. Bleeding Scales Among NSTE ACS Patients Bleeding Scales Among NSTE ACS Patients Rao SV, et al. J Am Coll Cardiol. 2006 Feb 21;47(4):809-16. Epub 2006 Jan 26 TIMI and GUSTO – Adjusted Hazard of 30 d Death/MI N=15,858

27. La trasfusione ha un impatto sulla prognosi? La trasfusione è in grado di correggere leffetto negativo del sanguinamento? La trasfusione ha un impatto sulla prognosi? La trasfusione è in grado di correggere leffetto negativo del sanguinamento? Bleeding in ACS Domanda:

28. 30-Day Survival By Transfusion Group Rao SV, et. al., JAMA 2004;292:1555–1562 Transfusion in ACS N=24,111N=24,111 METANALYSIS OF the GUSTOIIb,PURSUIT,and PARAGON b trials

29. *Transfusion as a time-dependent covariate PRBC Transfusion Among NSTE ACS Patients: Cox Model for 30-day Death PRBC Transfusion Among NSTE ACS Patients: Cox Model for 30-day Death Rao SV, et. al., JAMA 2004;292:1555–1562 N=24,111N=24,111 METANALYSIS OF the GUSTOIIb,PURSUIT,and PARAGON b trials

30. Adjusted Risk of In-Hospital Outcomes By Transfusion Status* Adjusted Risk of In-Hospital Outcomes By Transfusion Status* *Non-CABG patients only Yang X, J Am Coll Cardiol 2005;46:1490–5. N=74,271 ACS patients from CRUSADE

31. Transfusion, Ischemic Endpoints, and Mortality P<0.0001 for all Manoukian SV, Voeltz MD, Feit F et al. TCT 2006. Results: The ACUITY Trial (N=13,819)

32. Increased 1-year mortality in transfused patients Adjusted Odds Ratio 4.26 (2.25–8.08) Transfusion Post PCI: REPLACE 2 One Year Mortality P<0.0001 Manoukian SV, Voeltz MD, Attubato MJ, Bittl JA, Feit F, Lincoff AM. CRT 2005. Abstract.

33. 1.With time and storage, red blood cells undergo a reduction in their adenosine triphosphate and 2,3 diphosphoglycerate stores, which may decrease oxygen unloading at the tissue level 2.Storage may also affect the ability of red blood cells to deform and maneuver in capillaries, leading to diminished oxygen delivery to the myocardium via the large coronary arteries.

34. storage lesions: aumento fragilità di membrana (ridotta deformabilità) alterata capacità di trasporto dellossigeno pH ridotto riduzione del n° cellule vitali/unità aumento delle citochine pro-infiammatorie (leucociti contaminanti) alterata biologia dellNO nel sangue conservato bassi livelli di 2,3 difosfoglicerati -> aumentata affinità dellO 2 per lHb

35. EMOTRASFUSIONI NEGLI ANZIANI CON IMA Wu W-C NEJM 2001;345:1230 78.974 pz Medicare con IMA > 65 aa ematocrito (%) OR (95% CI) di morte < 30 gg con aggiustamento per i fattori clinici, i farmaci e i predittori di trasfusioni 5.0 – 24.0 0.22 (0.11 - 0.45) 24.1 – 27.0 0.48 (0.34 – 0.69) 27.1 – 30.0 0.60 (0.47 – 0.76) 30.1 – 33.0 0.69 (0.53 – 0.89) 33.1 – 36.0 1.13 (0.89 – 1.44) 36.1 – 39.0 1.38 (1.05 – 1.80) 39.1 – 38.0 1.46 (1.18 – 1.81)

36. High Risk Patient Subgroups

37. Bleeding RisksTransfusions by Age Alexander KA, JAMA 2005;294:3108–16.

38. 6,002 patients in REPLACE-2 806 patients (13.4%) classified as elderly, >75 years of age p<0.0001p=0.0001 REPLACE-2: Elderly Patients Have Increased Major Bleeding and Transfusions = Not Elderly, <75 = Elderly, >75 Voeltz MD, Lincoff AM, Feit F, Manoukian SV. Circulation 2005;112(17):II-613. Abstract.

39. p<0.0001 p=0.0001 6,002 patients in REPLACE-2. 806 patients (13.4%) classified as elderly, >75 years of age. 806 patients (13.4%) classified as elderly, >75 years of age. Elderly Patients in REPLACE-2: Increased 30-Day Mortality With Major Bleeding and Transfusions Voeltz MD, Lincoff AM, Feit F, Manoukian SV. Circulation 2005;112(17):II-613. Abstract.

40. Excessive Dosing of Anticoagulants by Age Alexander KA, JAMA 2005;294:3108–16. 12.5 28.7 8.5 33.1 37 12.5 64.5 38.5 16.5 0 10 20 30 40 50 60 70 LMW HeparinUF HeparinGP Iib/IIIa % Excsessive dose <65 yrs65-75 yrs>75 yrs

41. Excess Dosing of Gp IIb/IIIa and Bleeding in Women 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 N=32,601 patients from CRUSADE

42. Bleeding is Increased in Patients With Impaired Renal Function Undergoing PCI 60 ml/min N=4824 60 ml/min N=4824 < 60 ml/min N=886 p value 30-d Death 5 (0.1%) 14 (1.6%) < 0.001 < 0.001 30-d Myocardial infarction 305 (6.3%) 75 (8.5%) 0.018 0.018 30-d urgent revascularization 61 (1.3%) 10 (1.1%) 0.738 0.738 Triple ischemic endpoint 338 (7.0%) 84 (9.5%) 0.010 0.010 In-hospital protocol major bleeding 123 (2.5%) 54 (6.1%) < 0.001 < 0.001 TIMI major + minor bleeding 114 (2.4%) 46 (5.2%) < 0.001 < 0.001 Creatinine Clearance Chew DP et al. Am J Cardiol 2005;95:581–585.

43. enoxaparinCrCl < 30controindicata o dose fondaparinuxCrCl < 30 controindicata – tuttavia emorragie vs enox bivalirudin CrCl < 30 emodialisi dose 1 mg/kg/h dose 0.25 mg/kg/h tirofibanCrCl < 30 dose 50 % eptifibatide CrCl < 50 < 30 dose 50 % controindicato abciximab valutazione attenta del rischio emorragico farmaci antitrombotici e antiaggreganti, insufficienza renale e rischio emorragico

44. Major Bleeding is Increased in Anemic Patients Undergoing PCI 6,010 patients in REPLACE-2. 1,362 patients (22.7%) classified as anemic based upon WHO definition. 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, Lincoff AM, Manoukian SV. J Am Coll Cardiol 2005;45(3)[Suppl A]:1037- 13-31A. Abstract.

45. NSTE-ACS Mortality Stratified by Hemoglobin Sabatine MS. Circulation 2005 Unadjusted Hb (g/dL)nOR(95% Cl)OR(95% Cl)P value >17 2161.47(1.03–2.10)1.45(0.94–2.23)0.093 16–17 8121.21(0.97–1.51)1.27(0.98–1.65)0.066 15–1621301.0 reference1.0 reference 14–1533901.06(0.89–1.22)1.11(0.93–1.33)0.251 13–1435201.02(0.88–1.19)1.04(0.86–1.24)0.709 12–1323311.09(0.92–1.28)1.07(0.88–1.30)0.514 11–12 9761.20(0.97–1.47)1.04(0.81–1.34)0.755 10–11 3431.41(1.05–1.89)1.29(0.92–1.82)0.145 9–10 3422.44(1.88–3.18)2.69(2.01–3.60)<0.001 9–10 3422.44(1.88–3.18)2.69(2.01–3.60)<0.001 8–9 3062.24(1.69–2.96)2.45(1.80–3.33)<0.001 <8 1373.97(2.76–5.70)3.49(2.35–5.20)<0.001 Abbreviations: CI, confidence interval; Hb, hemoglobin; OR, odds ration. Adapted with permission. Abbreviations: CI, confidence interval; Hb, hemoglobin; OR, odds ration. Adapted with permission. Unadjusted and adjusted odds ratios for cardiovascular mortality in patients with non-ST elevation acute coronary syndromes at 30 days stratefied by hemoglobin Adjusted for baseline characteristics

49. Thrombocytopenia Induced by Abciximab Abciximab is a widely used chimeric (human–mouse) Fab fragment that is specific for β3 integrin (glycoprotein IIIa); It blocks platelet–fibrinogen interaction; Abciximab itself does not cause thrombocytopenia because it lacks the Fc domain required for recognition of antibody-coated platelets by phagocytes; However, in about 1% of patients given abciximab for the first time, and in more than 10% of those treated a second time, acute thrombocytopenia develops within a few hours of starting an infusion; In some patients the onset of thrombocytopenia is delayed until 5 to 8 days after the initial 24- to 48-hour period of exposure to the drug; Abciximab- induced thrombocytopenia is often mild, but fatalities have been recorded.

50. indicazioni alla trasfusione di piastrine 4Shander A Pharmacotherapy 2007;27(9 Pt 2):57S piastrinopenia severa (< 50 x 10 3 /mmc) in caso di sanguinamento attivo prevenzione del sanguinamento in caso di piastrinopenia molto severa (< 5-10 x 10 3 /mmc) piastrinopenia severa (< 50 x 10 3 /mmc) prima di una procedura invasiva prevenzione del sanguinamento spontaneo in pazienti con piastrinopenia severa (<10-50 x 10 3 /mmc), in caso di sepsi, uso di antibiotici, altre anoma- lie della coagulazione nei disordini della funzione piastrinica (uremia, tromboastenia, farmaci antipiastrinici), in caso di sanguinamento attivo.

51. E causata da anticorpi diretti contro il complesso PF4 piastrinico ed eparina Compare dopo circa 5-10 giorni dall inizio della terapia in pazienti non precedentemente esposti (oltre 100 gg), in poche ore se vi è stato un recente trattamento Può essere molto severa anche valori inferiori a 10.000 per mmc, con lenta risalita (4-14 gg), dopo la sospensione del farmaco. E raramente associata a fenomeni emorragici, invece predominano le complicanze trombotiche (25-50% dei pz) con un rischio di trombosi 30 volte maggiore che nella popolazione di controllo E 10 volte più frequente nei pz trattati con UHF vs LMWH Se sospetto clinico ricerca di anticorpi per il complesso PF4-eparina, eventuale test funzionali di aggregazione piastrinica -> sospensione della terapia eparinica -> anticoagulazione

52. 1.Associazione temporale 2.Nova insorgenza di trombosi 3.Risalita dopo sospensione

55. dosaggio ASA (+ clopidogrel) ed emorragie - CURE - 4Peters RJG Circulation 2003;108:1682.

56. THANK YOU FOR YOUR ATTENTION