Pre-treatment with P2Y12 inhibitors in ACS patients: who, when, why and which agent

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1 Pre-treatment with P2Y12 inhibitors in ACS patients: who, when, why and which agent Guerrino Zuin, UOS di UTIC Dipartimento Cardio-Toraco-Vascolare Ospedale dell Angelo Mestre

3 The goal of DAPT is to reduce the risk of ischaemic events such as (re)-infarction and, in patients in whom a PCI is performed, the risk of stent thrombosis

4 The term pre-treatment defines a strategy according to which an antiplatelet drug, usually a P2Y12 inhibitor, is given before coronary angiography is performed. Thus, administration of a P2Y12 inhibitor in the ambulance (pre-hospital setting), in the emergency department, coronary care unit, or even in the catheterization laboratory before coronary angiography is performed can all be appropriately considered to represent pre-treatment. Importantly, the term pretreatment should not be used for administration of P2Y12 inhibitors immediately before a PCI.

7 EYESHOT Registry Pre-Treatment with DAPT 79.3% (1807/2280) 79.5% (1395/1755)

8 EYESHOT Registry Drugs and Devices Before Coronary Angio/During Hospit

Cumulative Hazard Rate CURE Primary End Point - MI/Stroke/CV Death 0.14 0.

00 * In combination with standard therapy 0 3 6 9 12 Months of Follow-Up The

9 Cumulative Hazard Rate CURE Primary End Point - MI/Stroke/CV Death Placebo + ASA* 11.4% 9.3% Clopidogrel + ASA* * In combination with standard therapy Months of Follow-Up The CURE Trial Investigators. N Engl J Med. 2001;345: % RRR P < N = 12,562

8% Clopidogrel + ASA* 0.05 0.0 * In combination with standard therapy 31% RRR P = 0.

10 Cumulative Hazard Rate PCI-CURE Overall Long-Term Results Composite of cardiovascular death or MI from randomization to end of follow-up 0.15 Placebo + ASA* 12.6% % Clopidogrel + ASA* * In combination with standard therapy 31% RRR P = N = Days of follow-up Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001.

11 CURE Only 21% of patients undergoing PCI (82% of stents), Evaluated dual antiplatelet therapy in patients managed medically with a minority undergoing delayed catheterization, often several days (6) after admission

12 NSTEMI Following the CURE and CREDO studies, clopidogrel pretreatment has been generalized for non-st elevation ACS management with a Class I-B recommendation in the European (2011) and US guidelines (2012), with the paradigm that sooner is better.

13 Prasugrel: The ACCOAST Investigators N Engl J Med 2013 Total population.

14 Prasugrel: The ACCOAST Investigators N Engl J Med 2013 PCI Cohort.

15 NSTEMI the ACTION Study Group: Metanalisi BMJ 2014 All Patients with non-stemi ACS and patients undergoing PCI : Mortality: Pretreatment with P2Y inhibitors was not associated with a significant reduction in death (any cause) (odds ratio 0.90 e 0.83, P= NS ) Safety: Pretreatment with P2Y12 inhibitors was associated with a significant increase of major bleeding (odds ratio 1.32 e 1.23, P< e < 0.48 )

16 NSTEMI: The ACTION Study Group: Metanalisi BMJ 2014 with rapid access of patients to the catheterization laboratory (3-4 hrs) and use of modern techniques of revascularization CURRENT study did not confirm the superiority of 600 mg over 300 mg of clopidogrel in the global management of non-st elevation ACS. Because no data are available for ticagrelor, conclusions cannot be drawn for this drug.

17 The concept of systematic and immediate pretreatment with P2Y12 antagonists in patients admitted with non-st elevation ACS needs to be reconsidered. ESC guidelines 2015:

18 NSTEMI ESC Guidelines 2015

19 STEMI ESC GUIDELINES 2012

21 Prehospital Ticagrelor in ST-Segment Elevation Myocardial Infarction. Gilles Montalescot, M.D. for the ATLANTIC Investigators. N Engl J Med 2014.

22 Stable 56% NSTEMI 25% STEMI 19% Cangrelor significantly reduced the rate of ischemic events, including stent thrombosis, during PCI, with no significant increase in severe bleeding the CHAMPION PHOENIX Investigators*, N Engl J Med, 2013

23 DOCUMENTO DI CONSENSO ANMCO, SIC, SICI-GISE E SICCH: APPROCCIO CLINICO AL PRETRATTAMENTO FARMACOLOGICO IN PAZIENTI CANDIDATI A PROCEDURE DI RIVASCOLARIZZAZIONE MIOCARDICA: 2016 Tabella 6. Pretrattamento farmacologico in pazienti con SCA NSTE a rischio molto alto, candidati a strategia invasiva immediata (< 2 ore). Raccomandato Opzionale (SI>no) Opzionale (NO>si) NO Anticoagulanti UFH - - Prasugrel 2 Antiaggreganti per os ASA 1 - Ticagrelor 2 Clopidogrel 2 Antiaggreganti e.v. ASA EBPM Fondaparinux Bivalirudina - Abciximab Eptifibatide Tirofiban EBPM: Eparine a Basso Peso Molecolare

24 DOCUMENTO DI CONSENSO ANMCO, SIC, SICI-GISE E SICCH: APPROCCIO CLINICO AL PRETRATTAMENTO FARMACOLOGICO IN PAZIENTI CANDIDATI A PROCEDURE DI RIVASCOLARIZZAZIONE MIOCARDICA: 2016 Tabella 7. Pretrattamento farmacologico in pazienti con SCA NSTE a rischio alto, candidati a strategia invasiva precoce (< 24 ore) e a rischio moderato, candidati a strategia invasiva elettiva (< 72 ore). Anticoagulanti Raccomandato Opzionale* (SI>no) Fondaparinux Enoxaparina) Opzionale!(NO>si) UFH 1 Bivalirudina 2 NO Altre&EBPM Antiaggreganti)per)os ASA Ticagrelor 3 Clopidogrel 3 Prasugrel Antiaggreganti)e.v. " " " Anti"ischemici " Betabloccanti! NTG Verapamil! Diltiazem Abciximab! Eptifibatide! Tirofiban) " Statina Atorvastatina " " "

25 DOCUMENTO DI CONSENSO ANMCO, SIC, SICI-GISE E SICCH: APPROCCIO CLINICO AL PRETRATTAMENTO FARMACOLOGICO IN PAZIENTI CANDIDATI A PROCEDURE DI RIVASCOLARIZZAZIONE MIOCARDICA: 2016

26 Conclusioni Nella SCA NSTE del tratto ST, in assenza di trial randomizzati che ne abbiano dimostrato un vantaggio, il pretrattamento con inibitori del recettore P2Y 12, pur se molto diffuso, è da considerare opzionale

27 Conclusioni Nella SCA NSTE la probabilità di un vantaggio del pretrattamento va valutata nel singolo paziente e in rapporto alla tempistica di esecuzione della coronarografia. Proponiamo quindi un pretrattamento selettivo, guidato dalle condizioni di rischio ischemico, di rischio emorragico e del tempo previsto all esecuzione della coronarografia. Gran parte delle problematiche inerenti questo tema sarebbero risolte da un più precoce accesso alla coronarografia, soprattutto per i pazienti a maggior rischio.

28 Conclusioni Nella SCA STEMI per quanto riguarda il secondo antiaggregante orale, preferenzialmente prasugrel o ticagrelor, pur non essendo dimostrata la superiorità dell utilizzo in pretrattamento, se ne ritiene consigliabile la somministrazione precoce se l'organizzazione territoriale lo consente e soprattutto se il trasporto del paziente impiega oltre 30 minuti.

29 Conclusioni Nella SCA STEMI la somministrazione di clopidogrel (dose da carico 600 mg, dose di mantenimento 75 mg per os/die) va riservata ai casi in cui prasugrel e ticagrelor sono controindicati o non disponibili.

31 GRAZIE PER L ATTENZIONE

32 Conclusioni Nella SCA STEMI è raccomandato pretrattare il paziente con aspirina al primo contatto medico (sul territorio o in ambulanza)

34 Cumulative Incidence Mortality ( %) In Brief: Optimal Use of Dual Antiplatelet Therap Pooled TIMI Trials: All Cause Mortality Through 1 Year After ACS in Patients With Diabetes STEMI Diabetes No Diabetes UA/NSTEMI Diabetes No Diabetes 11 TIMI trials, N > 62,000 pts n = 10,613 with diabetes (17.1%) P <.0001 P <.0001 STEMI Diabetes No Diabetes Days After ACS Number at Risk , , , , , , , UA/NSTEMI Diabetes No Diabetes P <.0001 STEMI P <.0001 UA/NSTEMI , Slide 2 Donahoe SM, et al. JAMA. 2007;298: Reproduced with permission.

36 CURE: Outcomes With Clopidogrel in Various Subgroups Characteristic Percentage of Patients With Event No. of Clopidogrel + Placebo Patients ASA + ASA Relative Risk (95% CI) Overall 12, Associated MI No associated MI Male sex Female sex < 65 yr old > 65 yr old ST segment deviation No ST segment deviation Enzymes elevated at entry Enzymes not elevated at entry Diabetes No diabetes Low risk Intermediate risk High risk History of revascularization No history of revascularization 10, Revascularization after randomization No revascularization after randomization Clopidogrel Better Yusuf S, et al. N Engl J Med. 2001;345: Reproduced with permission Placebo Better

38 Endpoint (%) TRITON TIMI 38: Patients With Diabetes (N = 3146) Slide 10 CV death/mi/stroke Clopidogrel Prasugrel TIMI major bleeding Prasugrel Days Wiviott SD, et al. Circulation. 2008;118: Adapted with permission. HR 0.70 P < % 12.2% NNT = 21 Clopidogrel 2.6% 2.5% P =.81

41 G Montalescot ACTION Study Group: BMJ 2014, patients with NSTEMI

42 SPOKE HUB EYESHOT Registry STEMI: Strategies and Timing STEMI n=1066 PCI 919 (86.2%) Thrombolysis: 54 (5.1%) followed by PCI in 26 (48.1%) 1022 (95.9%) Coro CABG 13 (1.2%) 44 (4.1%) Medical Rx 90 (8.4%) Medical Rx 134 (12.6%)

43 SPOKE HUB EYESHOT Registry NSTE-ACS: Strategies and Timing NSTE-ACS n=1519 PCI 831 (54.7%) 1258 (82.8%) Coro CABG 39 (2.6%) 261 (17.2%) Medical Rx 388 (25.5%) Medical Rx 649 (42.7%)

44 Pretrattamento (n=2037) no Pretrattamento (n=1996) The ACCOAST Investigators.

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