La preparazione alla PTCA nelle sindromi coronariche acute Area Emergenza Urgenza ANMCO

1. La preparazione alla PTCA nelle sindromi coronariche acute Area Emergenza Urgenza ANMCO Roma 20 marzo 2010 La preparazione farmacologica alla PTCA : trattamento antiaggregante/anticoagulante precoce o in sala di emodinamica? Cesare Greco Cardiologia III Ospedale S Giovanni- Roma

2. TACTICS-TIMI 18 Study Design PCI/ CABG Early Invasive Angio Medical Rx ESC NSTE ACS Guidelines 2002 UA/ NSTEMI ASA, Hep,Tirofiban Endpoints Early Conservative Baseline Troponin Medical Rx ETT +ischemia Chest pain Cath/ PCI/ CABG Randomize -24 hrs Hour 0 6 mos 4- 48 108 hrs hrs

3. CGF entro 6 ore (in media 3 ore) Kastrati et al. JAMA. 2006;295:1531-1538

4. ESC NSTE ACS Guidelines 2007 The primary end point was a composite of death, myocardial infarction, or urgent target vessel revascularization occurring within 30 days after randomization; Kastrati et al. JAMA. 2006;295:1531-1538

5. ISAR REACT 2: Subset Analyses Abciximab No./Total (%) Placebo No./Total (%) Relative Risk All Patients 281/1010 (28.0) 234/1012 (23.3) Age 159/527 (30.3) 128/482 (26.6) >67 years 122/483 (25.5) ≤67 years 106/530 (20.2) Sex 71/262 (27.4) Women 51/236 (21.7) 210/748 (28.2) Men 183/776 (23.8) Diabetes 80/284 (28.6) Yes 68/252 (27.1) 201/726 (27.8) 166/760 (22.0) No Troponin >0.03 g/L 178/536 (33.3) 146/513 (28.6) Yes 103/474 (22.0) 88/499 (17.8) No Clopidogrel interval 115/461 (25.1) >3 hours 93/475 (19.8) 166/549 (30.4) 141/537 (26.4) ≤3 hours 0.9 1.0 1.3 1.1 1.2 0.6 0.7 0.8 0.5

6. ACUITY Timing: primary end point results at 30 days Deferred use of IIb/IIIa blockers was associated with a slightly higher rate of ischemic events, but also gave a significantly lower incidence of major bleeding

7. Study design 2 of 3 high-risk criteria: 1. Age > 60 years 2. + CKMB or TnT/I 3. ST  or transient ST  (Or age 50-59, h/o CVD and + CKMB or TnT/I) High Risk NSTE ACS N=10.500 Placebo / delayed provisional Eptifibatide pre PCI Routine early eptifibatide Randomize within 12 hours of presentation Invasive strategy 12 to 96 hours after randomization Primary Endpoint: 96-hr Death, MI, Recurrent ischemia requiring urgent revascularization, or Thrombotic bailout Key Secondary Endpoint: 30-d Death or MI

8. Methods We compared a strategy of early, routine administration of eptifibatide with delayed, provisional administration in 9492 patients who had acute coronary syndromes without ST-segment elevation and who were assigned to an invasive strategy. Sample size reduced to 9500 patients when pooled primary event rate greater than expected late in trial Results Presentation to randomization time was 5.6 hours.Coronary angiography was performed in 97.5% of patients at a median interval of 21.4 hours Giugliano et al. N Engl J Med 2009;360:2176-90

9. Kaplan-Meier Curves for 30-day Death or MI 15 12.4% Delayed provisional eptifibatide 10 11.2% Death or MI (%) Routine early eptifibatide P = 0.079 (stratified for intended early clopidogrel use) 5 0 6 8 10 12 14 16 18 20 22 24 26 28 30 0 2 4 Time Since Randomization (Days)

10. Composite primary end point at 96 hours Giugliano et all N Engl J Med 2009;360:2176-90

11. Key secondary end point : death and MI at 30 days Giugliano et al. N Engl J Med 2009;360:2176-90

12. “Non buttiamo il bambino con l’acqua sporca” Nel gruppo dei 7650 pazienti con positività della troponina l’endpoint secondario di morte ed infarto a 30 giorni veniva ridotto dal trattamento upstream dell’1.4%, con una tendenza che sfiorava la significatività statistica. In un’analisi non pubblicata, ma diffusa dagli stessi investigatori dell’EARLY ACS dei dati raggruppati dell’EARLY ACS e dell’ACUITY Timing vede a favore del trattamento upstream rispetto a quello selettivo un odds ratio di 0.92 (IC 95% 0.82-1.01) che anche in questo caso sfiora la significatività statistica. G Ital Cardiol 2010; 11 (2): 93-95

13. Efficacy (adjusted) Adjusted OR (95% CI) Death/MI/RIUR/TBO at 96 hours Upstream Clopidogrel 0.93 (0.79 – 1.10) No Clopidogrel 0.94 (0.72 – 1.22) p for interaction = 0.99 Death/MI at 30 days Upstream Clopidogrel 0.85 (0.73 – 0.99) No Clopidogrel 1.02 (0.80 – 1.30) p for interaction = 0.23 0 1 2 3 Early eptifibatide better Provisional eptifibatide better

14. Design of TIMACS Obiective Optimal timing of coronary intervention in patients with NSTE ACS Randomization Early intervention : angiography < 24 hours (1503) Delayed : angiography >36 hours (1438) Implementation Early intervention (median) : angiography 98% in 14 hours Delayed ( median) : angiography 98% in 50 hours

15. TIMACS Kaplan–Meier Cumulative Risk of the Primary Outcome, stratified according to GRACE Risk Score at baseline. 3031 patients Mehta et al. N Engl J Med 2009;360:2165-75.

16. IN-ACS Outcome 3682 SCA-NSTE

17. High-RiskACS Patients Study Design Randomize(n = 10,000) Enoxaparin IV Heparin …enoxaparin or unfractionated heparin was given immediately after enrollment according to the patient’s randomly assigned treatment. 60 U/kg  12 U/kg/hr (aPTT 50-70 sec) 1 mg/kg SC Q12H Early invasive strategy Other therapy per AHA/ACC Guidelines (ASA, -blocker, ACE, clopidogrel, GP IIb/IIIa) Primary endpoint: Death or MI at 30 days

18. Can the results of clinical trials be transferred to the real world? – NRMI 4 In-hospital mortality by early use of GPIIb/IIIa inhibitor In-hospital mortality for patients treated with a glycoprotein (GP) IIb/IIIa inhibitor versus those not treated, by the National Registry of Myocardial Infarction non–ST-elevation myocardial infarction (NRMI-NSTEMI) risk score. JACC 2003;42:45-53

19. Study Design TRITON TIMI 38 ACS (STEMI or UA/NSTEMI) & Planned PCI N= 13,600 ASA ASA N=13.600 Double-blind PRASUGREL 60 mg LD/ 10 mg MD CLOPIDOGREL 300 mg LD/ 75 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 bleedsKey Substudies: Pharmacokinetic, Genomic

20. Balance of Efficacy and Safety in Patients <75 Yrs, ≥60 kg, and Without TIA/Stroke 1 6 CV Death / NF MI / NF Stroke 1 4 NNT37 Clopidogrel 11% 1 2 Hazard Ratio, 0.75 (95% CI, 0.66-0.84) P<0.001 1 0 Endpoint (%) 8 Prasugrel 8.4% 6 Non-CABG TIMI Major Bleeding Hazard Ratio, 1.240 (95% CI, 0.91-1.69) P=0.17 NNH222 4 Prasugrel 1.95% 2 Clopidogrel 1.50% 0 180 270 0 30 90 180 270 360 450 Days Adapted from Wiviott SD et al NEJM 357: 2001, 2007 Presented at TCT 2009, San Francisco, CA

21. Timing of Benefit(Landmark Analysis) TRITON TIMI 38 8 6.9 Clopidogrel Clopidogrel 5.6 5.6 6 Primary Endpoint (%) 4.7 4 Prasugrel Prasugrel HR 0.82P=0.01 HR 0.80P=0.003 2 1 0 0 1 2 3 0 30 60 90 180 270 360 450 Days Loading Dose Maintenance Dose Antman EM, J Am Coll Cardiol. 2008. 51(21):2028-33.

22. ACC/AHA STEMI/PCI Update Guidelines 2009

23. Documento di consenso SCA NSTE Federazione Italiana Cardiologia • Quanto più è levato il rischio del paziente, tanto più urgente è la CGF • Un approccio invasivo precoce deve essere accompagnato da una terapia • farmacologica appropriata: • - Tutti ASA, e clopidogrel • - strategia invasiva urgente preferiti UHF ed abciximab • - strategia invasiva precoce se CGF entro 24 ore e rischio emorragico • basso upstream ; se CGF molto precoce (entro 12-24) ore e rischio • emorragico alto downstream • - strategia invasiva entro 72 ore: più opzioni in rapporto a rischio e tempo • nei trattamenti antitrombotici ed antiaggreganti upstream prasugrel o clopidogrel 6-12 ore GIC 2009