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

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

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

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

INIBITORI GLICOPROTEINE ASA TIENOPIRIDINE INIBITORI GLICOPROTEINE DOPPIA ANTIAGGREGAZIONE

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

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

P = 0.004 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

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

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

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

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

Faster Onset of Action and Higher Level of Platelet Inhibition (Dose-Effect): ALBION Trial Maximum Inhibition of Platelet Aggregation (ADP 5 mol/L) 40 35 30 25 20 15 10 5 300 mg LD 600 mg LD 900 mg LD 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

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

Clopidogrel interval (hours) 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

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.

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

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).

Oasis – 7 CURRENT 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 .

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

TROMBOSI DELLO STENT definizione e classificazione Classificazione temporale acuta subacuta tardiva (“late”) “very late” 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

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

2,9% 0,5% 2,7% - 0,8% 5,4% ASA ASA + Ticlopidina ASA + Warfarin Stent thrombosis STARS 2,9% 0,5% 2,7% ISAR - 0,8% 5,4%

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)

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

TROMBOSI DELLO STENT QUAL’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 PATTERN TEMPORALE della trombosi che non infrequentemente viene osservata oltre i 12 mesi dalla procedura (vey late) Kaul S et al; JACC 2007

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

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

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

INDICAZIONI ALL’USO DEI DES

patients who are not at high risk of bleeding. (Level of Evidence: B) 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)

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.

DES THROMBOSIS OPEN 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)

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

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

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

ISAR-CHOICE 2 Randomization 150mg for 30 d 75mg for 30 d 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

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 75mg for 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 1.6 2 1.3 All MI TVR death major bleed trasfusion Han Y, TCT 2007

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).

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 Guarda se nuovi dati e letteratura dopo novembre

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

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

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

Bleeding Risk Subgroups Therapeutic Considerations Reduced MD Guided by PK Age > 75 or Wt < 60 kg Avoid Prasugrel Prior CVA/TIA 16% 4% Significant Net Clinical Benefit with Prasugrel 80% MD 10 mg 44 44

TIMI Major NonCABG Bleeding Antman EM et al, JACC 2008

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

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

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

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

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

ACCP 2008 In patients with a bare metal coronary stent (BMS) who require surgery within 6 weeks of stent placement, we recommend continuing aspirin and clopidogrel in the perioperative period (Grade 1C). In patients with a drug-eluting coronary stent (DES) who require surgery within 12 months of stent placement, we recommend continuing aspirin and clopidogrel in the perioperative period (Grade 1C). In patients with a coronary stent who have interruption of antiplatelet therapy before surgery, we suggest against the routine use of bridging therapy with UFH, LMWH, direct thrombin inhibitors, or glycoprotein IIb/IIIa inhibitors (Grade 2C). 51

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

2,9% 0,5% 2,7% - 0,8% 5,4% ASA ASA + Ticlopidina ASA + Warfarin Stent thrombosis STARS 2,9% 0,5% 2,7% ISAR - 0,8% 5,4%

Khurram Z et al J Invasive Cardiol 2006 Combination therapy with aspirin, clopidogrel and warfarin following coronary stenting is associated with a significant risk of bleeding A + W + C A + W A A = ASA; W = WARFARIN; C = CLOPIDOGREL Khurram Z et al J Invasive Cardiol 2006 54

TROMBOSI DELLO STENT DES ed anticoagulazione (LG FA 2006)

STENTS e WARFARIN Clopidogrel + ASA + warfarin per 4 settimane AD ELEVATO RISCHIO EMBOLICO + BMS ACCP 2008 (Grado 2 C) Clopidogrel + ASA + warfarin per 4 settimane Warfarin + ASA successivamente (con INR target 2-2,5) 2) A RISCHIO EMBOLICO BASSO o MODERATO + BMS (+ DES) ASA + Clopidogrel per 4 settimane (1 anno se DES) ASA successivamente 3) ELEVATO RISCHIO EMBOLICO + DES ACCP 2008 (Grado 2C) ASA + CLOPIDOGREL + WARFARIN (9-12 mesi)

TROMBOSI DELLO STENT DES ed anticoagulazione (LG FA 2006) CLASSE IIb; livelllo di evidenza: C Gli autori ritengono che il clopidogrel sia il farmaco più importante per il mantenimento della pervietà dello stent. 2. l’aggiunta di aspirina alla terapia anticoagulante comporta più rischi che benefici. 3. La terapia di mantenimento dovrebbe consistere nell’associazione tra clopidogrel (75 mg/die) + warfarin (con INR tra 2 e 3) per 9-12 mesi 4. Dopo 9-12 mesi, sospensione del clopidogrel e proseguimento del warfarin come monoterapia

VI RINGRAZIO PER LA BONTA’

PCI – AHA 2007 update (ASA) Classe I Patients already taking daily long-term aspirin therapy should take 75 mg to 325 mg of aspirin before PCI is performed. (Level of Evidence: A). Patients not already taking daily longterm aspirin therapy should be given 300 mg to 325 mg of aspirin at least 2 hours and preferably 24 hours before PCI is performed. (Level of Evidence: C)

PCI – AHA 2007 update Classe IIa For patients with an absolute contraindication to aspirin, it is reasonable to give a 300-mg to 600-mg loading dose of clopidogrel, administered at least 6 hours before PCI, and/or GP IIb/IIIa antagonists, administered at the time of PCI. (Level of Evidence: C)

ACCP 2008 For patients undergoing PCI with a DES, we recommend aspirin (75–100 mg/d) plus clopidogrel (75 mg/d for at least 12 months) [Grade 1A for 3 to 4 months; Grade 1B for 4 to 12 months].

PCI – AHA 2007 update (ASA) Classe I Classe IIa (Level of Evidence: B). After PCI, in patients without allergy or increased risk of bleeding, aspirin 162 mg to 325 mg daily should be given for at least: 1 month after BMS implantation, 3 months after sirolimus-eluting stent implantation, and 6 months after paclitaxel-eluting stent implantation, after which daily long-term aspirin use should be continued indefinitely at a dose of 75 mg to 162 mg. Classe IIa In patients for whom the physician is concerned about risk of bleeding, a lower dose of 75 mg to 162 mg of aspirin is reasonable during the initial period after stent implantation. (Level of Evidence: C)

Porpora trombotica trombocitopenica (raro) Ticlopidina Azione ritardata (fino a 3 giorni) Duplice somministrazione giornaliera Effetti collaterali (10.6% CLASSICS): Rush cutanei, disturbi gastrointestinali Depressione midollare con trombocitopenia e neutropenia (2%) → nei primi 3 mesi (controllo emocromo ogni 2 settimane) Porpora trombotica trombocitopenica (raro)

Ticlopidina e clopidogrel hanno efficacia antitrombotica simile CLASSICS (2000): Ticlopidina e clopidogrel hanno efficacia antitrombotica simile Clopidogrel con più bassa frequenza di effetti collaterali (5.3% vs. 10.6% ticlopidina)

Clopidogrel - vantaggi Rapido ed elevato livello di antiaggregazione dopo carico orale Bassa incidenza di depressione midollare Bassa incidenza di effetti collaterali cutanei e gastrointestinali Monosomministrazione giornaliera