Quando (e come) inziare; se (e quando) cambiare. Maddalena Lettino Humanitas Research Hospital, Rozzano Milano, Italy

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1 Quando (e come) inziare; se (e quando) cambiare i P2Y12 nelle SCA Maddalena Lettino Humanitas Research Hospital, Rozzano Milano, Italy

2 Disclosure Speaker fee: Aspen, Astra Zeneca, BMS, Boehringer, Eli Lilly, Daichii Sankio, Bayer, Pfizer, Sanofi Advisory board member: AZ, Eli Lilly, Daiichi Sankyo, BMS, Pfizer, Sanofi, Bayer

3 Overview Pre-treatment: the concept Evidences for NSTE-ACS and for STEMI Is pre-treatment still needed with new drugs? Switching: when and why

4 Pre-trattamento nella SCA sottoposta a PCI: Obiettivi principali Ricanalizzazione farmacologica, detrombosi Prevenzione trombosi hardware, embolizzazione distale, no-reflow Prevenzione riocclusione, recidive eventi ischemici/trombotici Primo contatto medico <120 min tempo PCI primaria Breve intervallo di tempo per il pre-trattamento

5 Pre-hospital treatment with antiplatelet agents: what is the aim? To sort an immediate action on the ongoing thrombus formation and reopen the vessel? To prevent distal embolization during PCI? To prevent stent thrombosis after the procedure?

6 Blood flow (% decrease) Synergistic Action of Clopidogrel on top of ASA in Thrombus Formation Experimental model Clopidogrel plus ASA (10 mg/kg plus 10 mg/kg) Time (minutes) Clopidogrel (10 mg/kg) ASA (10 mg/kg) Placebo 1. Herbert JM et al. Thromb Haemost 1998; 80:

7 NIH-PA Author Manuscript NIH-PA Author Ma NIH-PA Author Manuscript NIH-PA Aut Silvain et al. Page 17 Old fibrin-rich thrombi and fresh platelet-rich thrombi Silvain et al. Page 13 Clopidogrel pre-treatment was administered in 66% of patients: and did not induce any significant change in platelet composition, when compared to patients without pre-h inhibition of the P2Y12 receptor Page Figure 6. Evolution of the percent thrombus composition for each component in % (Y axis) Figure 2 bis. Scanning electron micrograph at 3000x magnification This portion is mainly composed of platelet aggregates with a few cholesterol crystals (in yellow) relative to ischemic time (min) (X axis) 288 consecutive STEMI pts; 45 intra-coronary thrombi Lines represent linear regression for correlation with ischemic time.

8 The CURE trial: early pretreatment effect Yusuf S et al. Circulation 2003; 107:

9 Mortality Pre-trattamento con clopidogrel nella SCA Major bleeding Bellemain-Appaix a, et al. BMJ 2013; 349: g6269 & TCT 2013 JAMA 2012; 308(23):

10 NSTE ACS ESC guidelines Linea guida Statement Class/LOE 2002 In ACS patients clopidogrel is recommended for acute treatment and for longer term treatment I B For all patients an immediate 300 mg loading dose of clopidogrel is recommended A P2Y12 Inhibitor should be added as soon as possible and maintained I A I A

11 Pre-trattamento con Clopidogrel in STEMI Studio CIPAMI Intervallo carico clopidogrel PCI primaria: 47 minuti Zeymer U, et al. Clin Res Cardiol 2012; 101: Bellmain-Appaix A et al, TCT 2013

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14 Study population and design

15 Definite Stent Thrombosis up to 30 Days after Ticagrelor in the Modified Intention-to-Treat Population 24 hr P= days P=0.023 Montalescot G, et al. N Engl J Med 2014;371:

16 ESC NSTE ACS guidelines 2015 ESC STEMI guidelines 2017 Ticagrelor or prasugrel over clopidogrel ESC DAPT guidelines 2017

17 Cangrelor: the CHAMPION platform Steg PG, et al.lancet 2013; 382:

18 Perche cambiare il P2Y12? Per una sopraggiunta complicanza o controindicazione Per modulare il rischio emorragico o trombotico del paziente Per sottoporsi ad un intervento chirurgico

19 ESC DAPT guidelines 2017

20 TROPICAL ACS Sibbing D et al, Lancet 2017; 390:

21 BRIDGE Therapy Low dose aspirin continued throughout START cangrelor* STOP cangrelor Surgery RESUME cangrelor** STOP prasugrel STOP clopidogrel ticagrelor RESUME clopidogrel*** Day *Initiate within 72 hours from P2Y 12 inhibitor discontinuation at a dose of 0.75 mg/kg/min for a minimum of 48 hours and a maximum of 7 days h 0 **If thrombotic risk is high, bleeding risk is acceptable, and oral administration is not feasible +4-6 h Follow-up until discharge ***With mg loading dose, as soon as oral administration possible. Prasugrel or ticagrelor discouraged Excessive CABGsurgery related bleeding 11.8% vs 10.4% (p= 0.763) Angiolillo D et al, JAMA 2012; 307(3):

22 Cangrelor: switch con clopidogrel e ticagrelor Ticagrelor did not attenuate the pharmacodynamic effect of cangrelor. Also the pharmacodynamic effects of ticagrelor were preserved Steinhubl SR et al. Thromb Res 2008; 121: 527 SchneiderDJ et al. JACC Cardiovasc Int 2014; 7: 435

23 ESC DAPT guidelines 2017