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SYNERGY

Anti-Thrombin Rx. Heparin. LMWH. Bivalirudin. [ Fondaparinux ]. Anti-Platelet Rx. GP IIb/IIIa blockers. Aspirin. Clopidogrel. Treatment Strategy. Conservative. Early invasive. PRISM-PLUS. REPLACE 2. OASIS-5. PURSUIT. CURE. ESSENCE. TACTICS TIMI-18. PCI. ~ 5% stents.

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SYNERGY

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  1. Anti-Thrombin Rx Heparin LMWH Bivalirudin [ Fondaparinux ] Anti-Platelet Rx GP IIb/IIIa blockers Aspirin Clopidogrel Treatment Strategy Conservative Early invasive PRISM-PLUS REPLACE 2 OASIS-5 PURSUIT CURE ESSENCE TACTICS TIMI-18 PCI ~ 5% stents ~85% stents Drug-eluting stents Milestones in ACS Management ICTUS ISAR-REACT 2 ACUITY SYNERGY 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Ischemic risk Bleeding risk

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

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

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

  5. Death 4.3% (Re)-Infarction 2.5% CHF 8.0% Cardiogenic Shock 2.6% Stroke 0.8% Non-CABG Transfusion 9.9% CRUSADE In-Hospital Outcomes Bhatt DL, et al. JAMA. 2004 Nov 3;292(17):2096-104.

  6. Bleeding in ACS • Qualisonoipazienti a rischiodisanguinamento? Domanda:

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

  8. Predictors of Major Bleeding Results: The ACUITY Trial PCI Population Risk ratio ± 95% CI RR (95% CI) P-value MA… Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

  9. REPLACE-2Multivariate Predictors of Major Bleeding Feit F et al.

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

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

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

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

  14. Major and Minor Bleeding in PCIBleeding Increases Mortality and Events 10,974 patients undergoing PCI, Washington Hospital Center, 1991-2000. Bleeding Complication * p<0.001 versus none † p<0.001 versus minor ‡ p<0.01 versus none § p<0.05 versus minor Kinnaird TD et al. AM J Cardiol 2003;92:930-5.

  15. Bleeding in ACS • Come valutarel’entità del sanguinamento? Domanda:

  16. 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

  17. Bleeding Definitions • TIMI Definition • Major • ICH • Associated with Hgb decrease ≥ 5 g/dl or HCT decrease ≥ 15% • Minor • 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% • Minimal • Overt hemorrhage with Hgb drop < 3 g/dl or HCT drop < 9% Chesebro JH. Circulation 1987. Jul;76(1):142-54.

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

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

  20. Bleeding in ACS • La trasfusione ha un impattosullaprognosi? • La trasfusione è in gradodicorreggerel’effettonegativo del sanguinamento? Domanda:

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

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

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

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

  25. “storage lesions”: aumento fragilità di membrana (ridotta deformabilità) alterata capacità di trasporto dell’ossigeno pH ridotto riduzione del n° cellule vitali/unità aumento delle citochine pro-infiammatorie (leucociti contaminanti) alterata biologia dell’NO nel sangue conservato bassi livelli di 2,3 difosfoglicerati -> aumentata affinità dell’O2 per l’Hb

  26. EMOTRASFUSIONI NEGLI ANZIANI CON IMA 78.974 pz Medicare con IMA > 65 aa Wu W-C NEJM 2001;345:1230

  27. High Risk Patient Subgroups

  28. Bleeding Risks—Transfusions by Age Alexander KA, JAMA 2005;294:3108–16.

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

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

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

  32. Overall 1.46 (1.22, 1.73) Women 1.72 (1.30, 2.28) Men 1.27 (0.97, 1.66) 1.0 1.5 2.0 2.5 0.5 Excess Dosing More Likely to Bleed Excess Dosing of Gp IIb/IIIa and Bleeding in Women N=32,601 patients from CRUSADE Alexander KP, et. al. Circulation 2006

  33. Bleeding is Increased in Patients With Impaired Renal Function Undergoing PCI Creatinine Clearance Chew DP et al. Am J Cardiol 2005;95:581–585.

  34. farmaci antitrombotici e antiaggreganti, insufficienza renale e rischio emorragico

  35. Major Bleeding is Increasedin 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% 4.9% P=0.0001 2.8% Protocol definition: >3g/dL drop in HgB, intracranial, retroperitoneal, 2U transfusion Major Bleeding Voeltz MD, Attubato MJ, Feit F, Lincoff AM, Manoukian SV. J Am Coll Cardiol 2005;45(3)[Suppl A]:1037-13-31A. Abstract.

  36. NSTE-ACS MortalityStratified by Hemoglobin Unadjusted and adjusted odds ratios for cardiovascular mortality in patientswith non-ST elevation acute coronary syndromes at 30 days stratefied by hemoglobin Unadjusted Adjusted for baseline characteristics Hb (g/dL) n OR (95% Cl) OR (95% Cl) P value >17 216 1.47 (1.03–2.10) 1.45 (0.94–2.23) 0.093 16–17 812 1.21 (0.97–1.51) 1.27 (0.98–1.65) 0.066 15–16 2130 1.0 reference 1.0 reference 14–15 3390 1.06 (0.89–1.22) 1.11 (0.93–1.33) 0.251 13–14 3520 1.02 (0.88–1.19) 1.04 (0.86–1.24) 0.709 12–13 2331 1.09 (0.92–1.28) 1.07 (0.88–1.30) 0.514 11–12 976 1.20 (0.97–1.47) 1.04 (0.81–1.34) 0.755 10–11 343 1.41 (1.05–1.89) 1.29 (0.92–1.82) 0.145 9–10 342 2.44 (1.88–3.18) 2.69 (2.01–3.60) <0.001 8–9 306 2.24 (1.69–2.96) 2.45 (1.80–3.33) <0.001 <8 137 3.97 (2.76–5.70) 3.49 (2.35–5.20) <0.001 Abbreviations: CI, confidence interval; Hb, hemoglobin; OR, odds ration. Adapted with permission. Sabatine MS. Circulation 2005

  37. indicazioni alla trasfusione di piastrine piastrinopenia severa (< 50 x 103/mmc) in caso di sanguinamento attivo prevenzione del sanguinamento in caso di piastrinopenia molto severa (< 5-10 x 103/mmc) piastrinopenia severa (< 50 x 103/mmc)prima di una procedura invasiva prevenzione del sanguinamento spontaneo in pazienti con piastrinopenia severa (<10-50 x 103/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. • Shander A Pharmacotherapy 2007;27(9 Pt 2):57S

  38. 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

  39. Associazione temporale • Nova insorgenza di trombosi • Risalita dopo sospensione

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

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