LA TERAPIA ANTIAGGREGANTE PRIMA E DOPO STENT Francesco Bellandi

1. IL DIVENIRE CLINICO IN CARDIOLOGIA Firenze 31 Ottobre 2008 LA TERAPIA ANTIAGGREGANTE PRIMA E DOPO STENT Francesco Bellandi U.O. Cardiologia - Ospedale di Prato

2. RIDUZIONE DEL RISCHIO DI EVENTI ISCHEMICI POSTPROCEDURALI RIDUZIONE DEL RISCHIO DI TROMBOSI DELLO STENT RISCHIO EMORRAGICO

3. Antiplatelet Therapy ASA ASA +Clopidogrel ASA +Prasugrel ISCHEMIC EVENTS NET CLINICAL BENEFIT Reduction inIschemicEvents - 22% - 20% - 19% BLEEDINGS Increase in Major Bleeds + 32% + 38% + 60% Single Antiplatelet Rx Dual Antiplatelet Rx Higher IPA

4. Periprocedural Bleeding and 1-Year Outcome After Percutaneous Coronary Interventions OR: 3.7; P < 0.001 OR: 4.7; P < 0.001 Ndrepepa G et al; JACC 2008: 690-697

5. ASA TIENOPIRIDINE INIBITORI GLICOPROTEINE DOPPIA ANTIAGGREGAZIONE

6. Antiplatelets treatment • Main open issues: • Need of pretreatment • Loading Dose • Length and Dose of long term therapy • Clopidogrel low responsiveness • Perioperative Management in patients with stents • Dual antiplatelet therapy and Chronic oral Anticoagulation

7. Antiplatelets treatment • Main open issues: • Need of pretreatment • Loading Dose • Length and Dose of long term therapy • Clopidogrel low responsiveness • Perioperative Management in patients with stents • Dual antiplatelet therapy and Chronic oral Anticoagulation

8. MACE a 30 giorni (morte, infarto e stroke) TOTALE 6336 pz Riduzione 29% Dal 5.8% al 4.1% P = 0.004 SABATINE MS et al, Am Heart J 2008: 910-917

9. TIMI major or minor bleeding TOTALE 6336 pz Dal 1.9% al 2.3% OR: 1,21 P = 0.29 SABATINE MS et al, Am Heart J 2008: 910-917

10. CREDO Study: Optimal timing for the initiation of pre-treatment with 300mg clopidogrel before PCI. Steinhubl S, J Am Coll Cardiol 2006; 47:939-43

11. PCI – ESC 2005 Pretrattamento in caso di PCI Dose 300 mg almeno 6 ore prima della PCI programmata per CAD stabile e idealmente il giorno prima

12. Antiplatelets treatment • Main open issues: • Need of pretreatment • Loading Dose • Length and Dose of long term therapy • Clopidogrel low responsiveness • Perioperative Management in patients with stents • Dual antiplatelet therapy and Chronic oral Anticoagulation

13. Faster Onset of Action and Higher Level of Platelet Inhibition (Dose-Effect): ALBION Trial Maximum Inhibition of Platelet Aggregation (ADP 5 mol/L) 300 mg LD 600 mg LD 900 mg LD 40 35 30 25 20 15 10 5 0 Inhibition (%) Shortened time to reach the highest Level of inhibition of the 300 mg LD P < 0.05 vs. 300 mg LD 1 2 3 4 5 6 24 Time (Hours) Montalescot G, et al. JACC 2006

14. ISAR REACT II: 2022 NSTE ACS pts *Death, MI; TVR to 30 d P = 0.041 Kastrati A et at; JAMA 2005

15. ISAR-REACT II Study: Optimal timing for the initiation of pre-treatment with 600 mg clopidogrel before PCI Clopidogrel interval (hours) ≤3 h one - year Death/MI/TVR 30.4% ≤ 3 h > 3 h 26.4% 25.1% > 3 h 19.8% Abciximab Placebo Ndrepepa G, Eur Heart J 2007

16. ARMYDA–2: Randomized Trial of Clopidogrel Loading Dose 4-8 Hours Before PCI *Death, MI; TVR to 30 d P = 0.041 Composite 1° Endpoint (%)* 600 mg 300 mg (n = 126) (n = 129) Patti G, et al. Circulation. 2005;111:2099-106.

17. PCI – ESC 2005 PCI URGENTE o Dose carico 600 mg immediatamente dopo il primo PCI ad hoc per CAD stabile contatto medico, se clinicamente giustificabile ARMYDA 2

18. PCI – AHA 2007 update Classe IIa If clopidogrel is given at the time of procedure, supplementation with GP IIb/IIIa receptor antagonists can be beneficial. (Level of Evidence: B).

19. Oasis – 7CURRENT study Clopidogrel optimal loading dose Usage to Reduce Recurrent EveNTs Randomized, multinational, double-blind, comparing a high loading dose regimen of Clopiodgrel versus standard dose in pts with NSTEMI managed with an early invasive strategy .

20. Antiplatelets treatment • Main open issues: • Need of pretreatment • Loading Dose • Length and Dose of long term therapy • Clopidogrel low responsiveness • Perioperative Management in patients with stents • Dual antiplatelet therapy and Chronic oral Anticoagulation

21. TROMBOSI DELLO STENTdefinizione e classificazione Classificazione temporale acuta tardiva (“late”) “very late” subacuta PCI 24 ore 1 mese 1 anno Definizione ARC (Academic Research Consortium) • Trombosi definita = sindrome coronarica acuta con evidenza angiografica o • autoptica di trombosi o occlusione dello stent • Trombosi probabile = 1) qualsiasi morte non altrimenti spiegabile entro 30 dalla • dalla procedura; • 2) infarto miocardico acuto nel territorio dell’arteria coronica • trattata senza conferma angiografica • Trombosi possibile = qualsiasi morte non altrimenti inspiegabile oltre 30 giorni • dalla procedura

22. Stent metallici →endotelizzazione completata in 9-12 giorni→terapia antitrombotica per 3-4 settimane dopo impianto di stent

24. PCI – AHA 2007 update Classe I For post-PCI patients receiving a BMS, clopidogrel should be given for a minimum of 1 month (level of Evidence: A) and ideally up to 12 months (unless the patient is at increased risk of bleeding; then it should be given for a minum of 2 weeks (Level of Evidence: B)

25. Stent medicati →azione antiproliferativa→endotelizzazione ritardata→durata terapia antitrombotica ?

26. TROMBOSI DELLO STENTQUAL’E’ LA DIMENSIONE DELPROBLEMA? NEI VARI TRIALS RANDOMIZZATI L’INCIDENZACUMULATIVA AD UN FOLLOW-UP DI 9-12 MESI ERA: 0.7 – 1.2% Ma nei vari registri, più rappresentativi della pratica clinica quotidiana, vengono riportate incidenza 2-3 volte superiori Una differenza sostanziale rispetto agli stents metallici è il PATTERNTEMPORALE della trombosi che non infrequentemente viene osservata oltre i 12 mesi dalla procedura (vey late) Kaul S et al; JACC 2007

27. DES THROMBOSIS (follow-up 4 years) 0,4-0,6% year Wenaweser MS et al, Am Heart J 2008: 910-917 Wenaweser P et al; JACC 2008: 1134-1140

28. 6-month OUTCOMES Ninety-two (80%) of these STs presented as STEMI 20.9% vs 10.2% 31.4% vs 17.3% MACCE: major adverse cardiovascular and cerebrovascular events Chechi T et al; JACC 2008: 2396-2402

29. Riperfusione efficace STEMI with ST STEMI without ST Chechi T et al; JACC 2008: 2396-2402

30. INDICAZIONI ALL’USO DEI DES

31. PCI 2005 Classe I In patients who have undergone PCI, clopidogrel 75 mg daily should be given for at least 3 months after sirolimus stent implantation, and 6 months after paclitaxel stent implantation, and ideally up to 12 months in patients who are not at high risk of bleeding.(Level of Evidence: B) PCI UPDATE 2007 Classe I For all post-PCI stented patients receiving a DES, clopidogrel 75 mg daily should be given for at least 12 months if patients are not at high risk of bleeding. (Level of Evidence: B)

32. PCI 2007 update Classe IIb Continuation of clopidogrel therapy beyond 1 year may be considered in patients undergoing DES placement (Level of Evidence: C) For patients with clinical features associated with stent thrombosis, such as renal insufficiency, diabetes, or procedural characteristics such as left main, bifurcating left main, single patent coronary vessel, multiple stents or treatment of a bifurcation lesion, extended DAT beyond 1 year may be reasonable.

33. DES THROMBOSISOPEN ISSUES Se l’interruzione della doppia antiaggregazione rappresenta il fattore predittivo indipendente di maggior peso per la trombosi dello stent, occorre ricordare che una percentuale variabile da un terzo alla metà dei casi avviene sotto doppia antiaggregazione (Holmes DR et al; JACC 2007)

34. Antiplatelets treatment • Main open issues: • Need of pretreatment • Loading Dose • Length and Dose of long term therapy • Clopidogrel low responsiveness • Perioperative Management in patients with stents • Dual antiplatelet therapy and Chronic oral Anticoagulation

35. Variability in platelet responsiveness to 300 mg loading dose of clopidogrel among 544 individuals.Serebruany VL et al, JACC 2005;45:246-51.

36. Impact of Platelet Reactivity After Clopidogrel Administration on Drug-Eluting Stent Thrombosis Incidence ST: 8.6% NR vs 2.3% R, p=0,001 Buonamici P et al, JACC 2007

37. ISAR-CHOICE 2 A double-blind, randomized study on platelet aggregation in pts treated with a daily dose of 150 or 75mg of clopidogrel for 30 days. 60 stable pts, < 12 h from PCI pretreated with 600mg CLO Randomization 150mg for 30 d 75mg for 30 d Platelet function testing 5 µM ADP-aggregation (%) P <0.001 65±12 45±20 Von Beckerath, E Heart J 2007; 28:1814-1819

38. High Clopidogrel maintaining dosage improves long-term clinical outcomes in Pts with ACS undergoing DES implantation 634 ACS pts, PCI + DES pretreated with 600mg CLO Randomization 150mg for 30 d 75mg for 30 d 75mg for 12 mo 75mgfor 12 mo Clinical evaluation (mean 18mo) 20.2 P <0.001 P <0.001 P <0.001 14.7 13 9 ns 8.1 ns ns 4.2 3.7 2.7 2.3 2 1.6 1.3 All MI TVR death major bleed trasfusion Han Y, TCT 2007

39. PCI – AHA 2005 Classe IIb For patients in whom subacute thrombosis may be catastrophic (unprotected left main, bifurcating left main, or single patent coronary vessel), it is reasonable to perform platelet aggregation studies, and if < 50% platelet inhibition, consider 150 mg/day (clopidogrel).

40. Novel platelet receptor antagonist ADP P2Y12 TP (TXA2/PGH2) PAR1 (Trombina) • Prasugrel • AZD6140 • Cangrelor • BMS-180291 • BS 13.177 • GR 32191 • TERUTROBAN(S188886) • SCH 30348 • E5555

41. Comparison with Higher Dose Clopidogrel IPA (%; 20 mM ADP) IPA (%; 20 mM ADP) P<0.0001 N=201 P<0.0001 for each Prasugrel 60 mg Clopidogrel 600 mg Clopidogrel 150 mg Prasugrel 10 mg Hours 14 Days Wiviott et al Circ 2007

42. Balance of Efficacy and Safety TRITON-TIMI 38N Engl J Med 2007 15 138 events Clopidogrel HR 0.81(0.73-0.90)P=0.0004 12.1 CV Death / MI / Stroke RR – 24% 9.9 10 NNT = 46 Prasugrel Endpoint (%) 5 35 events TIMI Major NonCABG Bleeds Prasugrel 2.4 RR + 32% HR 1.32(1.03-1.68)P=0.03 1.8 Clopidogrel 0 NNH = 167 0 30 60 90 180 270 360 450 Days

43. Balance of Efficacy and Safety TRITON-TIMI 38N Engl J Med 2007 15 138 events Clopidogrel NET CLINICAL BENEFIT favours PRASUGREL P 12,2% vs C 13,9% P = 0,004 HR 0.81(0.73-0.90)P=0.0004 12.1 CV Death / MI / Stroke RR – 24% 9.9 10 NNT = 46 Prasugrel Endpoint (%) 5 35 events TIMI Major NonCABG Bleeds Prasugrel 2.4 RR + 32% HR 1.32(1.03-1.68)P=0.03 1.8 Clopidogrel 0 NNH = 167 0 30 60 90 180 270 360 450 Days

44. Bleeding Risk SubgroupsTherapeutic Considerations Reduced MDGuided by PKAge > 75 or Wt < 60 kg Avoid PrasugrelPrior CVA/TIA 16% 4% Significant Net Clinical Benefit with Prasugrel80% MD 10 mg

45. TIMI Major NonCABG Bleeding Antman EM et al, JACC 2008

46. Antiplatelets treatment • Main open issues: • Need of pretreatment • Loading Dose • Length and Dose of long term therapy • Clopidogrel low responsiveness • Perioperative Management in patients with stents • Dual antiplatelet therapy and Chronic oral Anticoagulation

47. ACC/AHA 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery

48. ACC/AHA 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery Class IIa; level of evidence: C 2 day after 5 day before 0 Restart clopidogrel Stop clopidogrel Surgery Room ASA 80 mg/d Holmes DR et al; JACC 2007

49. Interventi chirurgici a maggior rischio di sanguinamento 7 day before start LMWH STOP 3 day after 1 day after 5 day before 3 day before 0 Surgery Room Restart ASA Stop ASA Stop clopidogrel Restart clopidogrel GISE 2008

50. Interventi chirurgici a basso rischio di sanguinamento 7 day before start LMWH STOP 1 day after 3 day before 0 Restart clopidogrel Stop clopidogrel Surgery Room ASA 80 mg/d GISE 2008