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Dott. Antonio Butera Lamezia Terme Roma, 20 marzo 2010 Lamezia Terme U. O. CARDIOLOGIA con UTIC Preparazione farmacologica alla PTCA: STEMI Negli ospedali.

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Presentazione sul tema: "Dott. Antonio Butera Lamezia Terme Roma, 20 marzo 2010 Lamezia Terme U. O. CARDIOLOGIA con UTIC Preparazione farmacologica alla PTCA: STEMI Negli ospedali."— Transcript della presentazione:

1 Dott. Antonio Butera Lamezia Terme Roma, 20 marzo 2010 Lamezia Terme U. O. CARDIOLOGIA con UTIC Preparazione farmacologica alla PTCA: STEMI Negli ospedali senza emodinamica

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4 2009 Facilitaded and Rescue PCI…non longer used…potentially misleading labels

5 Limitazione di eventi e riduzione del danno ischemico pre-PCI Facilitazione dellangioplastica Riduzione delle complicanze peri e post-procedurali (trombosi dello stent, ischemia) (Il tutto con minori effetti pro- emorragici) - I sanguinamenti maggiori moltiplicano MACE: GRACE EHJ 2003; Eikelboom JW et al: Circulation 2006; Nikolski E et al: EHJ 2007; CRUSADE Circulation 2009-

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7 La maggiore pervietà dellIRA prima dellangioplastica migliora loutcome Survival (%) Months 6 months mortality log-rank p for trend = % 98% 96% 94% 92% 90% % 2.8% 4.4% Stone GW Circulation 2001;104:636 TIMI 3 (n=375) TIMI 2 (n=295) TIMI 0/1 (n=1,657)

8 ASSENT- 4 PCI: study design ASA + UFH (bolus 40U/kg) + TNK-tPA Primary endpoints: death, heart failure or cardiogenic shock at 90 days n = 2000 Immediate PTCA Stent or clopidogrel at researchers discretion No anti-GP IIb/IIIa ASA + UFH (bolus 70u/Kg) Immediate PTCA Stent, clopidogrel or anti-GP IIb/IIIa at researchers discretion IMA ST (< 6h) Lancet 2006

9 ASSENT- 4 PCI Trial: TIMI Flow Grade TIMI grade 3 flow prior to PCI and TIMI grade 2/3 flow post-PCI (%) p<0.001 TIMI grade 3 flow prior to PCI was present more frequently in the TNK + PCI arm (43.6% vs 15.0%)TIMI grade 3 flow prior to PCI was present more frequently in the TNK + PCI arm (43.6% vs 15.0%) TIMI grade 2/3 post-PCI was slightly higher in the PCI alone group (95.3% vs 97.6%)TIMI grade 2/3 post-PCI was slightly higher in the PCI alone group (95.3% vs 97.6%) p=0.03 Lancet 2006

10 ASSENT-4: Primary Endpoint mortality, CHF, Shock at 90 days p=0.04 Lancet 2006

11 ASSENT-4 PCI : in-hospital cardiac events EventTNK+PCI (%)PCI alone (%)p Re-MI Abrupt vessel closure1.90.1<0.001 Repeat TVR4.41.0<0.001 Pericarditis Tamponade Cardiac rupture EM dissociation Pulmonary edema Ventricular fibrillation Lancet 2006

12 ASSENT-4 PCI: in-hospital stroke rates van de Werf F. European Society of Cardiology Congress 2005; September 4-7, 2005; Stockholm, Sweden. OutcomeTNK+PCI (%)PCI alone (%)p Total stroke1.810<0.001 Intracranial hemorrhage Ischemic stroke Hemorrhagic conversion Unclassified Lancet 2006

13 Conclusioni ASSENT - 4

14 Primary PCI with in lab Abciximab Major Objectives R Reteplase/Abciximab Facilitated Primary PCI ? Abciximab Facilitated Primary PCI To test if Reteplase/Abciximab is superior to facilitation with Abciximab alone To test if Abciximab facilitation is superior to Primary PCI with in lab Abciximab 2°: ? ? 1° - To test if Reteplase/Abciximab Facilitated PCI is superior to Primary PCI with in lab Abciximab Primary end-point:mortality, CHF, VF, Shock at 90 days NEJM 2008

15 TIMI Flow in IRA Pre-PCI % Subjects with TIMI 2/3 (Patency) Pre-PCI 12 % 13 % 11 % 15 % 25 % 36 % 25 % 26 % 61 % Primary PCI (in lab Abciximab) (n=790) Abciximab Facilitated PCI (n=809) Reteplase/Abciximab Facilitated PCI (n=815) Percentage TIMI 2 TIMI 3 p <

16 Primary Endpoint: mortality, CHF, VF, Shock at 90 days p=0.55

17 TIMI Major or Minor Bleeding (nonintracranial) through Discharge/Day7 p=0.025 p<0.001 p=0.127 p=0.008 p=0.141 p<0.001 p=0.006 p=0.547

18 …il rapporto rischio/beneficio della pPCI con Abciximab somministrato direttamente in emodinamica è migliore delle due strategie di facilitazione… CONCLUSIONI

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20 (19 studi)

21 Ma se la pPCI non si potesse proprio fare….specialmente nei pazienti ad alto rischio…

22 Primary outcome: Death, Reinfarction, Refractory Ischemia at 30 Days CARESS Study design STEMI patients <12 hrs from symptom onset Admitted to centres without PCI facilities and high risk feature at least one high risk feature: >15 mm ST Elevation new onset LBBB, previous MI, Killip Class >2, < 35% LVEF Urgent transfer after lysis to nearest PCI centre for PCI plus stenting Admit to CCU and only transfer for PCI if persistent ST elevation at 90 min (>50% basal ECG), chest pain or haemodynamic compromise ASA mg iv; ASA mg iv; Reteplase half dose; UFH (40 U/kg -max 3000-; 7 U/kg/h); Abciximab 0.25 mg/kg bolus g/kg/min x 12 h Lancet 2008

23 Primary outcome: Death, Reinfarction, Refractory Ischemia at 30 Days

24 Il beneficio del trasferimento immediato si è ottenuto malgrado 1/3 dei pazienti del braccio di controllo sia stato trattato con la Rescue. Il rischio di sanguinamento non è stato differente nei due Gruppi (e comunque basso: solo 5 ICH nei 598 pz )

25 PCI Centre Cath Lab CommunityHospitalEmergencyDepartment Cath / PCI within 6 hrs regardless of reperfusion status Cath and Rescue PCI GP IIb/IIIa Inhibitor TNK + ASA + Heparin / Enoxaparin + Clopidogrel Pharmacoinvasive PharmacoinvasiveStrategy Urgent Transfer to PCI Centre Assess chest pain, ST resolution at minutes after randomization at minutes after randomization High Risk ST Elevation MI within 12 hours of symptom onset Failed Reperfusion * Successful Reperfusion Elective Cath PCI PCI > 24 hrs later Standard Treatment * ST segment resolution < 50% & persistent chest pain, or hemodynamic instability Repatriation of stable patients within 24 hrs of PCI Randomization stratified by age (75 vs. > 75) and by enrolling site NEJM 2009

26 Primary end-point: 30-day composite Death, Reinfarction, recurrent ischemia, CHF, Shock

27 Conclusioni In paz con STEMI ad alto rischio sottoposti alla fibrinolisi in centri periferici, il trasferimento entro 6 ore al centro hub per eseguire la PCI si associa ad una riduzione significativa di eventi ischemici, (malgrado il ricorso in circa il 40% dei pazienti alla PCI rescue) senza incrementare gli eventi emorragici, La PCI precoce dopo trombolisi, si è dimostrata più safe che nei precedenti trials (progressi con gli stent ed altra terapia concomitante –Clopidogrel-?)

28 1.Se possibile pPCI 2.Se non possibile pPCI

29 2009

30 Molti studi eseguiti prima della doppia antiaggregazione non più attuali. BRAVE-3 (Abciximab): clinicamente neutro; ON-TIME 2 (Tirofiban): clinicamente neutro. MULTISTRATEGY: Abciximab vs Tirofiban e BMS vs DES (Sirolimus) – vantaggio del DES. FINESSE: Braccio abciximab clinicamente neutro (con + emorragie rispetto alla somministrazione in emodinamica)

31 2009

32 Am Heart J 2008 Come identificare, eventualmente, i pazienti della Classe 2B?

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36 Early abciximab administration before primary percutaneous coronary intervention improves clinical outcome in elderly patients transferred with ST-elevation myocardial infarction: Data from the EUROTRANSFER registry Dziewiers et al: Int J Cardiol day death 30-day death + Reinfarction % % P = Nessuna differenza per emorragie nel gruppo >/= 65 aa P = 0.001

37 2009

38 ISIS-2 ISIS-2 (Second International Study of Infarct Survival) Collaborative Group, Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarctions: ISIS-2. Lancet 1988 ii %

39 NNT = 26

40 ACC/AHA Guidelines 2004 (invariate per lASA) ESC Guidelines 2008

41 Schomig A. N Engl J Med 2009 Biotransformation and Mode of Action of Clopidogrel, Prasugrel, and Ticagrelor

42 Medical Rx Group Placebo Clopidogrel RR: 0.80 ( ) CVD/MI/Stroke Clopidogrel PCI Group Placebo RR: 0.72 ( ) CVD/MI/Stroke CURE Primary end-point: CVD+MI+Stroke) -19% -30% NEJM 2001

43 PCI - The CURE Investigators: Lancet 2001

44 NEJM 2005 Clarity TIMI 28 (Fibrinolisi) -36% JAMA 2005 PCI- Clarity TIMI %

45 Clopidogrel No Trial PretreatmentPretreatment PCI-CURE CREDOn/an/a PCI-CLARITY Overall ClopidogrelNo Trial PretreatmentPretreatment PCI-CURE CREDO PCI-CLARITY Overall Meta-Analysis of Clopidogrel Pretreatment OR (95% CI) OR 0.67 P=0.005 P=0.005 Favors Pretreatment Favors No Pretreatment OR 0.71 P=0.004 P=0.004 Sabatine MS et al. JAMA 2005 MI before PCI (%) CVD or MI after PCI (%)

46 CURRENT OASIS : Study Design, Flow and Compliance 25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%) Planned Early (<24 h) Invasive Management with intended PCI Ischemic ECG Δ (80.8%) or cardiac biomarker (42%) 25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%) Planned Early (<24 h) Invasive Management with intended PCI Ischemic ECG Δ (80.8%) or cardiac biomarker (42%) PCI 17,232 (70%) Angio 24,769 (99%) Angio 24,769 (99%) No PCI 7,855 (30%) No Sig. CAD 3,616CABG 1,809CAD 2,430 Randomized to receive (2 X 2 factorial): CLOPIDOGREL : Double-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg then 75 mg/d) ASA: High Dose ( mg/d) vs Low dose ( mg/d) Efficacy Outcomes: CV Death, MI or stroke at day 30 Stent Thrombosis at day 30 Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major) Key Subgroup: PCI v No PCI Complete Followup 99.8%

47 Cumulative Hazard Clopidogrel Standard Clopidogrel Double HR % CI P= % RRR CURRENT OASIS: Double vs Standard Dose Primary Outcome (CV Death, MI or Stroke): PCI Patients Days ESC 2009

48 Days Cumulative Hazard Clopidogrel Standard Dose Clopidogrel Double Dose 42% RRR HR % CI P=0.001 CURRENT OASIS 7: Double vs Standard Dose Definite Stent Thrombosis (Angio confirmed) ESC 2009

49 Overall NSTEMI/UA STEMI Male Female Age <= 65 yrs Age > 65 yrs Non-Diabetic Prev Diabetic No Inhosp GPIIb/IIIa GPIIb in hosp No Prot Pump Inhib Prot Pump Inhib Non-smoker Current Smoker ASA Low ASA High CV Death, MI or StrokeMI or Stent Thrombosis Clopidogrel: Double v Standard Dose PCI Cohort Subgroups Std %Double %Std %Double % Intxn P Double Dose Better 2N

50 Clopidogrel Double vs Standard Dose Bleeding Overall Population Clopidogrel Standard N=12579 Double N=12508 Hazard Ratio 95% CI P TIMI Major CURRENT Major CURRENT Severe Fatal ICH RBC transfusion 2U CABG-related Major

51 TRITON TIMI 38: Study Design Double-blind ACS: STEMI (35%) or UA/NSTEMI) & Planned PCI ASA PRASUGREL 60 mg LD/ 10 mg MD CLOPIDOGREL 300 mg LD/ 75 mg MD 1 o endpoint: CV death, MI, Stroke 2 o endpoints:CV death, MI, Stroke, Rehosp-Rec Isch CV death, MI, UTVR Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleeds Key Substudies: Pharmacokinetic, Genomic Median duration of therapy - 12 months N= 13,608 NEJM: 2009 NEJM 2007

52 HR 0.81 ( ) P= Prasugrel Clopidogrel HR 0.80 P= HR 0.77 P= Days Primary Endpoint (%) 12.1 (781) 9.9 (643) TRITON TIMI 38 Primary Endpoint: CV Death, MI, Stroke NNT= 46 Days NEJM: 2009 NEJM 2007

53 TRITON TIMI 38: Stent Thrombosis (Definite + Probable) HR 0.48 P < Prasugrel Clopidogrel 2.4 (142) NNT= (68) Days Endpoint (%) Any Stent at Index PCI N= 12,844 NEJM 2007

54 B OVERALL No GPI GPI DES BMS DM No DM > <65 Female Male STEMI UA/NSTEMI Prasugrel BetterClopidogrel Better HR Age Reduction in risk (%) P inter = NS TRITON TIMI 38: CV Death, MI, Stroke Major Subgroups CrCl > 60 CrCl < NEJM 2007

55 TRITON TIMI 38 (STEMI: 3534 pt) CVD + nf MI + nf StrokeCVD +nf MI + Urg target v revas. Stent thrombosis TIMI Major bleeding Lancet 2009

56 TRITON TIMI 38: Bleeding Events % Events P=0.03 Clopidogrel Prasugrel P=0.01 P=0.23 P=0.74P=0.002 ICH in Pts w Prior Stroke/TIA (N=518) Clop 0 (0) % Pras 6 (2.3)% (P=0.02) NEJM: 2007 NEJM 2007

57 PLATO study design Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding 6–12-month exposure Clopidogrel If pre-treated, no additional loading dose; if naive, standard 300 mg loading dose, then 75 mg qd maintenance; (additional 300 mg allowed pre PCI) Ticagrelor 180 mg loading dose, then 90 mg bid maintenance; (additional 90 mg pre-PCI) NSTE-ACS (mod-to-high risk) STEMI 37% (if primary PCI) Clopidogrel-treated or -naive; randomised within 24 hours of index event (N=18,624) NEJM: 2009

58 Wallentin L et al. N Engl J Med 2009; PLATO: Risultati end-point primario (CVD+MI+Stroke) 8,688 8, Cumulative incidence (%) Clopidogrel Ticagrelor HR 0.88 (95% CI 0.77–1.00), p=0.045 No. at risk Clopidogrel Ticagrelor 9,291 9,333 8,875 8,942 8,763 8,827 Days after randomisation Clopidogrel Ticagrelor ,688 8,673 8,286 8,397 6,379 6,480 Days after randomisation * HR 0.80 (95% CI 0.70–0.91), p< ,437 8,543 6,945 7,028 4,751 4,822 Cumulative incidence (%) *Excludes patients with any primary event during the first 30 days NEJM: 2009

59 Clopidogrel Ticagrelor 9,186 9,235 7,305 7,246 6,930 6,826 6,6705,209 5,129 3,841 3,783 3,479 3, Clopidogrel Ticagrelor ,545 HR 1.04 (95% CI 0.95–1.13), p=0.434 K-M estimated rate (% per year) PLATO: Time to major bleeding – primary safety event NEJM: 2009

60 PLATO-STEMI 18,758 patients enrolled in PLATO 134 patients not randomized 18,624 patients randomized NSTEMI/UA/other: 10,194 patients STEMI: 8,430 patients Randomized to ticagrelor: efficacy population N= 4,201 Randomized to clopidogrel: efficacy population N= 4,229 No intake of study medication: 36 patients No intake of study medication: 48 patients Safety population N=4,165 Safety population N=4,181

61 PLATO-STEMI Primary endpoint: CV death, MI or stroke Months HR: 0.85 (95% CI = 0.74–0.97), p= Clopidogrel Ticagrelor K-M estimated rate (% per year) Steg PG: ESC 2009

62 PLATO: Stent thrombosis NEJM: 2009 PLATO-STEMI : Stent thrombosis Steg PG: ESC 2009

63 K-M estimated rate (% per year) Months Clopidogrel Ticagrelor HR 0.96 (95% CI = 0.83–1.12), p=0.63 PLATO-STEMI Primary safety event: major bleeding Steg PG: ESC 2009

64 PCI Recommendations – Class I (Classe I – Evidenza C) 2008

65 Ancillary Therapy to Reperfusion (2004) Unfractionated heparin (UFH) should be given intravenously in: Patients undergoing PCI or surgical revascularization After alteplase, reteplase, tenecteplase After streptokinase, anistreplase, urokinase in patients at high risk for systemic emboli.

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67 La PTCA va considerata sempre e comunque un trattamento Farmaco-invasivo Forse è meglio abbandonare i termini Facilitata e Rescue perché potentially misleading labels: as-soon-as-possible o timely dovrebbero diventare il nuovo parametro di riferimento. La trombolisi rimane una buona scelta nei pazienti che si presentano presto con un tempo D2B lungo, con valutazione angiografica as-soon-as-possible Il calcolo del rischio emorragico deve assumere la stessa rilevanza del calcolo del rischio ischemico

68 Considerazioni finali (2) Le Linee Guida forniscono elementi utilissimi per la preparazione corretta e linvio alla PTCA, ma… …limplementazione delle stesse va coniugata sempre con… Condizioni logistiche Fruibilità di risorse adeguate (SUEM 118, Emodinamica H24 ecc) Condizioni del paziente (classe Killip), insorgenza e durata dei sintomi, sede dellinfarto, età, rischio emorragico, comorbilità.

69 GRAZIE Ospedale Giovanni Paolo II – Lamezia Terme Lamezia Terme U. O. CARDIOLOGIA con UTIC


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