STEMI PREPARAZIONE ALLA ANGIOPLASTICA NEGLI OSPEDALI SENZA EMODINAMICA PAF 2010 La preparazione alla PTCA nelle SCA PREPARAZIONE FARMACOLOGICA ALLA PTCA: DALLE LINEE GUIDA AI DATI DEGLI STUDI E DEI REGISTRI STEMI PREPARAZIONE ALLA ANGIOPLASTICA NEGLI OSPEDALI SENZA EMODINAMICA Francesco Chiarella Ospedale S.Corona Pietra Ligure

1 UTIC / 136.500 ab. 1 letto UTIC / 21.816 ab. CENSIMENTO 2005 COMINCIAMO COL DIRE CHE IN iTALIA 5° Censimento Federativo Strutture Cardiologiche

BLITZ-3: provenienza ricoveri UTIC DA SPOKE AD HUB SOLO 15% ! HUB 177 3

PREPARAZIONE FARMACOLOGICA A PTCA OSPEDALI SENZA EMODINAMICA: DALLE LINEE GUIDA AI DATI DEGLI STUDI E DEI REGISTRI Linee Guida: rielaborazioni annuali su STEMI e PCI da Comitati Congiunti di 5 Società Scientifiche

IMPRESCINDIBILITA’ DI PROTOCOLLI CONDIVISI Ogni comunità deve sviluppare un protocollo (“sistema di cure”) per lo STEMI Team multidisciplinare Sistema Emergenza Territoriale Ospedale/i no Cath-Lab (“Spoke”) Ospedale/i con Cath Lab (“Hub”) UPDATE 2009 I IIa IIb III C ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 5

A ciascun Pz il suo percorso A ciascun Pz il suo trattamento QUALE FARMACO? ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update A ciascun Pz il suo percorso A ciascun Pz il suo trattamento

Pathway: Triage and Transfer for PCI (in STEMI) STEMI patient who is a candidate for reperfusion Initially seen at a non-PCI capable facility Initially seen at a PCI capable facility Initial Treatment with fibrinolytic therapy (Class 1, LOE:A) Send to Cath Lab for primary PCI (Class I, LOE:A) Transfer for primary PCI (Class I, LOE:A) Tempo da angor < 3 h Tempo al pallone > 1 h Basso score rischio / no rischio emorr. Tempo da angor > 3 h Tempo al pallone < 1 h Alto score di rischio / rischio emorragico HIGH RISK Transfer to a PCI facility is reasonable for early diagnostic angio & possible PCI or CABG (Class IIa, LOE:B), High-risk patients as defined by 2007 STEMI Focused Update should undergo cath (Class 1: LOE B) NOT HIGH RISK Transfer to a PCI facility may be considered (Class IIb, LOE:C), especially if ischemic symptoms persist and failure to reperfuse is suspected Prep antithrombotic (anticoagulant plus antiplatelet) regimen Diagnostic angio Medical therapy only PCI CABG 2009 STEMI Focused Update. Appendix 5 7

A tutti prima possibile: Update 2009 La dose di carico di tienopididine è raccomandata per tutti STEMI I IIa IIb III C Clopidogrel almeno 300 – 600 mg appena possibile a tutti i pazienti avviati a PCI primaria o non primaria. Studi di dose finding hanno dimostrato che aumentando il dosaggio si inibiscono PTL più rapidamente, 300600900, ma la sicurezza e l’efficacia clinica non sono ancora rigorosamente stabilite, ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 8 8

MODIFIED Recommendation STEMI: PREPARAZIONE ALLA ANGIOPLASTICA NEGLI OSPEDALI SENZA EMODINAMICA entra PRASUGREL MODIFIED Recommendation STEMI  PCI primaria I IIa IIb III B Prasugrel 60 mg should be given as soon as possible for primary PCI. Limitazioni: età > 75 storia di TIA o stroke, “active bleeding” urgente BPAC anticoagulanti peso < 60 Kg 9

TRITON-TIMI 38 ACS (STEMI or UA/NSTEMI) & Planned PCI ASA N= 13,600 Wiviott SD et al AHJ 152: 627,2006 Adapted with permission from E.Antman TRITON-TIMI 38 ACS (STEMI or UA/NSTEMI) & Planned PCI ASA N= 13,600 Double-blind CLOPIDOGREL 300 mg LD/ 75 mg MD PRASUGREL 60 mg LD/ 10 mg MD Median duration of therapy - 12 months 1o endpoint: CV death, MI, Stroke 2o 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 10 10 10

Balance of Efficacy and Safety TIMI Major NonCABG Bleeds TRITON: Results 15 138 events The number of subjects who would need to be treated to result in one excess major bleed (NNH) was 167 Clopidogrel HR 0.81 (0.73-0.90) P=0.0004 12.1 CV Death / MI / Stroke 9.9 10 NNT = 46 Endpoint (%) Prasugrel Trattare 46 x prevenire un evento 35 events 5 TIMI Major NonCABG Bleeds Prasugrel HR 1.32 (1.03-1.68) P=0.03 2.4 1.8 Clopidogrel NNH = 167 30 60 90 180 270 360 450 Trattare 167 x causare un bleeding Adapted with permission from Wiviott SD et al NEJM 357:2007 Days 11 11

TIMI Major NonCABG Bleeds STEMI Cohort N=3534 TRITON TIMI-38 15 CV Death / MI / Stroke Clopidogrel 12.4% 9.5% 10.0% 10 HR 0.79 Percent (%) (0.65-0.97) 6.5% Prasugrel P=0.02 NNT = 42 HR 0.68 (0.54-0.87) 5 P=0.002 TIMI Major NonCABG Bleeds Prasugrel 2.4 2.1 Clopidogrel 30 60 90 180 270 360 450 Days From Randomization Montalescot et al Lancet 2008.Adapted with permission from Antman EM. 12 12

Timing of Benefit (Landmark Analysis - 3 days) beneficio nei primi 3 gg e nei 18 mesi Timing of Benefit (Landmark Analysis - 3 days) TRITON TIMI-38 8 6.9 Clopidogrel Clopidogrel 6 5.6 5.6 Primary Endpoint (%) 4.7 4 Prasugrel Prasugrel HR 0.82 P=0.01 HR 0.80 P=0.003 2 1 1 2 3 30 60 90 180 270 360 450 Loading Dose Days Maintenance Dose Adapted with permission from Antman EM JACC 2008. 13 13 13

For STEMI undergoing non-primary PCI carico prasugrel dopo coronarografia pre-PTCA ( entro 1 h) the following regimens are recommended: MODIFIED Rec If the patient did not receive fibrinolytic therapy… …either a loading dose of 300-600 mg of clopidogrel should be given or, once the coronary anatomy is known and PCI is planned, a loading dose of 60 mg of prasugrel should be given promptly and no later than 1 hour after the PCI. I IIa IIb III B ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update 14

Ticagrelor ! antagonist of recettore adenosinico P2Y12 PLATO: 18.624 STEMI e NSTEMI random ticagrelor vs clopidogrel (180-mg loading dose, 90 mg twice daily thereafter) (300-to-600-mg loading dose, 75 mg daily thereafter). NEJM, 361:1045-1057 2009 15

PCI “facilitata” e “rescue”: termini obsoleti (molto attuali) I termini “facilitated PCI” e “rescue PCI” non dovrebbero più essere usati “ Contemporary therapeutic choices leading to reperfusion for pts with STEMI can be described without these potentially misleading labels” confondenti rispetto a obiettivo riperfusione Cambio concettuale: la riperfusione è l’obiettivo, non si parlerà più di “facilitazione” e di “rescue”, termini giudicati confondenti e obsoleti che siamo invitati a mandare in cantina ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update

FINESSE CARESS Transfer-AMI > > per testare per testare STEMI alto rischio CARESS Transfer-AMI FINESSE Combined Abciximab REteplase Stent Study in AMI per testare fibrinolisi+PCI subito vs fibrinolisi + PCI rescue > Trial of Routine ANgioplasty and Stenting after Fibrinolysis to Enhance Reperfusion in nAMI (TRANSFER-AMI) per testare ½ fibrinolisi + ABCX + PCI >

CARESS-IN-AMI: DISEGNATO ALLA RICERCA DEL MIGLIORE TRATTAMENTO PER I PZ CON STEMI NEGLI OSPEDALI NO CATH-LAB “Not a trial of facilitated angioplasty opposed to primary angioplasty” 600 STEMI <75 years old > 1 high risk feature RETEPLASE ½ dose, ABCX, heparin, ASA Randomizzazaione a trasferimento immediato x pci o trasferimento x rescue o differito 18

CARESS-IN-AMI: Primary Outcome STEMI con immediata PCI: minor numero di eventi avversi a 30 gg Non differenze significative di sanguinamenti RETEPLASE ½ dose, ABCX, heparin, ASA 10.7% 4.4% immediata pci Di Mario et al. Lancet 2008;371. CARESS: legittima reteplase metà dose, ABCX, eparina, ASA e poi trasferire

TRANSFER-AMI Studio di strategia farmacoinvasiva in 1059 STEMI alto rischio giunti entro 12 ore da esordio ad ospedale senza cathlab PCI RISULTERA’ DISEGNO: TNK STANDARD E PCI ENTRO 24 H VERSUS TTNK STANDARD E PCI DIFFERITA > 24 H 2.8 hrs 32 hrs A tutti: - TNK standard-dose, ASA, UFH or enoxaparin Clopidogrel loading 300 mg for pts < 75 age 75 mg for pts >75 age Giunti nel Centro con CathLab: GP IIb/IIIa receptor antagonists according to institutions’ standard practice 2b 3a solo negli osp con cathlab Cantor et al. N Eng J Med 2009;360:26. 20

TRANSFER-AMI: efficacia e sicurezza Kaplan Meier Curves for Primary Endpoint 17 % Cumulative Incidence 11 % pharmaco-invasive EARLY PCI p=0.004 Cantor et al. N Engl J Med 2009;360:26 Days RR= 0.64, 95 CI% (0.47-0.87) Severe bleeding (GUSTO criteria) : no differenze tra i due gruppi Mild bleeding (GUSTO criteria) : higher incidence in the pharmaco-invasive group (13.0% vs 9.%, p=0.036). TRANSFER AMI legittima TNK dose standard, ASA, clopidogrel, eparina poi trasferire 21

TRANSFER-AMI: CONCLUSIONI In STEMI ad alto rischio che si presentano a Ospedale Spoke: - fibrinolisi con TNK dose standard , clopidogrel - trasferimento a Hub per eseguire subito angiografia e PCI “without waiting to determine whether reperfusion has occurred” . via libera a PCI dopo TNK ! Cantor et al. N Eng J M 2009;360:26.

Recommendations for the Use of Glycoprotein IIb/IIIa Receptor Antagonists in STEMI

Modified Recommendation Use of Glycoprotein IIb/IIIa Receptor Antagonists in STEMI Modified Recommendation E’ RAGIONEVOLE INIZIARE IL TRATTAMENTO CON ANTI IIb/IIIa AL MOMENTO DI ANGIOPLASTICA (CON O SENZA STENTING) abciximab tirofiban, eptifibatide I IIa IIb III A IIb IIIa in sala I IIa IIb III B

Modified Recommendation Use of Glycoprotein IIb/IIIa Receptor Antagonists in STEMI la sentenza: pre Cath-Lab incerta utilità Modified Recommendation L’UTILITA’ DI ANTI IIb/IIIa COME STRATEGIA FARMACOLOGICA DI PREPARAZIONE ALLA ANGIOPLASTICA prior to arrival in the cardiac catheterization laboratory for angiography and PCI is uncertain. I IIa IIb III B

finesse = ABCX pre-PCI ½ -dose lytic + ABCX pre-PCI ABCX alone ABCX at time of PCI I risultati del FINESSE pubblicati dopo le Linee Guida riaccendono la disputa

finesse = ABCX FINESSE: Study design Treatment Pre-PCI treatment with ½ -dose lytic plus abciximab, pre-PCI abciximab alone, and abciximab at time of PCI Inclusion Suspected acute MI (ST change or LBBB) within 6 h of symptom onset Exclusion Low risk (<60 yo, localized inferior infarct) high risk for bleeding 1° OUTCOMES Death, VF after 48 hours, shock, CHF within 90 days FINESSE design Ellis et al. N Eng J Med. 2008;358:2205-2217.

Considerando solo “alto rischio, tempo < 4 ore” FINESSE a 1 anno N = 397 N = 2452 Considerando solo “alto rischio, tempo < 4 ore” STEMI alto rischio a centro spoke entro 4h 1/2 RETEPLASE + ABCX TORNA E VINCE Meno morti a 1 anno !

Use of Parenteral Anticoagulants in Patients with STEMI Recommendations for Use of Parenteral Anticoagulants in Patients with STEMI

Use of Parenteral Anticoagulants in STEMI Modified Recommendation IL TRATTAMENTO ANTICOAGULANTE RACCOMANDATO NEGLI STEMI PTCA PRIMARIA INCLUDE: I IIa IIb III C UN BOLO AGGIUNTIVO DI EPARINA NON FRAZIONATA PER I PZ CHE GIA’ LA ASSUMEVANO per mantenere un adeguato regime di scoagulazione (misurare ACT) BIVALIRUDINA , CON O SENZA PRECEDENTE EPARINA I IIa IIb III B entra bivalirudina ! Enoxaparin and fondaparinux unchanged from 2007 STEMI Focused Update

HORIZONS-AMI: Design Emergency angiography Emergency angiography Endpoints: Composite of net adverse clinical events (NACE) Included major bleeding plus MACE (a composite of CVD death, reinfarction, target-vessel revascularization for ischemia, and stroke within 30 days) Stone et al. N Eng J Med. 2008;358:2218-30.

HORIZONS-AMI: Time-to-Event Curves through 30 days: Net Adverse Clinical Events 3602 patients with STEMI & symptom onset ≤ 12 hours randomized 1802 HR=0.75, (0.62-0.92); p=0.006] 1800 Meno eventi avversi a 30 gg con bivalirudina da sola piuttosto che con eparina non frazionata + anti IIb/IIIa Stone et al. N Eng J Med. 2008;358:2218-30. QS STUDIO MOTIVA INDICAZIONE CLASSE I

HORIZONS-AMI: Time-to-Event Curves through 30 days: Major Bleeding p<0.0001 bleeding - 40% a 30 gg Meno sanguinamenti a 30 gg con bivalirudina da sola piuttosto che con eparina non frazionata + anti IIb/IIIa Stone et al. N Eng J Med. 2008;358:2218-30.

HORIZONS-AMI: Results (cont.) Treatment with bivalirudin compared with UFH plus GP IIb/IIa inhibitors resulted in significantly lower: 30-day death rates from cardiac causes (1.8% vs. 2.9%; RR 0.62; 95% CI 0.40 to 0.95; p=.03), & 30-day death from all causes (2.1% vs. 3.1%; RR 0.66; 95% CI 0.44 to 1.00; p=0.047) At one year, MACE rates were identical, but there was a decrease in all-cause mortality with bivalirudin (3.4% versus 4.8%, p=0.03). bivalirudina - morti a 30 gg - morti a 1 anno

Use of Parenteral Anticoagulants in STEMI IL TRATTAMENTO ANTICOAGULANTE RACCOMANDATO NEGLI STEMI PTCA PRIMARIA INCLUDE: Modified Recommendation BIVALIRUDINA I IIa IIb III B Enoxaparin and fondaparinux unchanged from 2007 STEMI Focused Update

Enoxaparin and fondaparinux unchanged from 2007 Unfractionated heparin (UFH) administration guided by: Therapeutic activated clotting time (ACT) levels Prior administration of GP IIb/IIIa receptor antagonists Enoxaparin, if the last subcutaneous dose was administered at least 8 to 12 hours earlier, an IV (intravenous) dose of 0.3 mg/kg of enoxaparin should be given; if the last subcutaneous dose was administered within the prior 8 hours, no additional enoxaparin should be given. (Level of Evidence: B) Fondaparinux, administer additional intravenous treatment with an anticoagulant possessing anti-IIa activity, taking into account whether GP IIb/IIIa receptor antagonists have been administered. (Level of Evidence: C) 36

STEMI PREPARAZIONE ALLA ANGIOPLASTICA NEGLI OSPEDALI SENZA EMODINAMICA TRITRON TIMI 38 TRANSFER-AMI CARESS FINESSE HORIZONS AMI TIENOPIRIDINE (Clopid. 300, Pras 60) TNK + EPARINA + IIbIIIa in sala RETEPLASE ½ + ABCX RETEPLASE ½ + ABCX o solo ABCX o ABCX in cathLab BIVALIRUDINA