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Nuove evidenze sullimpiego di antiaggreganti e anticoagulanti nello STEMI e nelle SCA NSTE Francesco Bovenzi Dipartimento Cardio-Respiratorio U.O. di Cardiologia,

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Presentation on theme: "Nuove evidenze sullimpiego di antiaggreganti e anticoagulanti nello STEMI e nelle SCA NSTE Francesco Bovenzi Dipartimento Cardio-Respiratorio U.O. di Cardiologia,"— Presentation transcript:

1 Nuove evidenze sullimpiego di antiaggreganti e anticoagulanti nello STEMI e nelle SCA NSTE Francesco Bovenzi Dipartimento Cardio-Respiratorio U.O. di Cardiologia, Ospedale Campo di Marte Lucca LUCCA CARDIOLOGIA

2 SYNERGY LMWH ESSENCE 1997 CURE Clopidogrel Ischemic risk GP IIb/IIIa blockers PRISM-PLUS PURSUIT ACUITY TACTICS TIMI-18 Early invasive PCI ~ 5% stents~85% stentsDrug-eluting stents ISAR-REACT 2 Milestones in ACS Management OASIS-5 Fondaparinux Anti-Thrombin Rx Anti-Platelet Rx Treatment Strategy Heparin Aspirin Conservative ICTUS Bivalirudin REPLACE 2 Bleeding risk TRITON Timi 38 Prasugrel CURRENT OASIS-7 PLATO Ticagrenor

3 The result is 80 different combinations! Extreme attention should be paid to the use of drugs or drug combinations and dosages that may favour bleeding

4 Atalanta ACC 2010 Eugene Braunwald I più potenti inibitori delle piastrine sono stati studiati nel TRITON TIMI-38 e nel PLATO che hanno posto le basi per lalba di una nuova era della terapia antipiastrinica. Finora non cè stato nulla di free lunch, perché quando interveniamo sulla coagulazione troveremo associato, in ogni modo, un eccesso di sanguinamento. La nostra futura sfida sarà trovare uno sweet spot nella ricerca di bilanciare lefficacia con la sicurezza.

5 Primary Therapeutic Goal for ACS Prevent the development of occlusive thrombus Arrest procoagulant activity and inflammation Attenuate platelet activation and aggregation Promote platelet disaggregation Facilitate perfusion

6 The Key Platelet Transmembrane Receptors AA ADP PGI 2 IP TXA 2 TP PLC Ca ++ ADP G q + IP 3 Ca ++ Ca ++ AC G S + G i - ATP cAMP + - P2X 1 P2Y 1 ADP P2Y 12 Activation of GPIIb/IIIa Binding of soluble fibrinogen Aggregation PGH2 TAX2 COX TAXS PAR TRAP

7 AA ADP PGI 2 IP TXA 2 TP PLC Ca ++ ADP G q + IP 3 Ca ++ Ca ++ AC G S + G i - ATP cAMP + - P2X 1 P2Y 1 ADP P2Y 12 Activation of GPIIb/IIIa Binding of soluble fibrinogen Aggregation PGH2 TAX2 COX TAXS PAR TRAP Conventional Antiplatelet Agents ASA Clopidrogel Ticlopidina Reopro Tirofiban Eptifibatide

8 AA ADP PGI 2 IP TXA 2 TP PLC Ca ++ ADP G q + IP 3 Ca ++ Ca ++ AC G S + G i - ATP cAMP + - P2X 1 P2Y 1 ADP P2Y 12 Activation of GPIIb/IIIa Binding of soluble fibrinogen Aggregation PGH2 TAX2 COX TAXS PAR TRAP Conventional Antiplatelet Agents ASA Clopidrogel Ticlopidina Reopro Tirofiban Eptifibatide Prasugrel Ticagrelor Cangrelor

9 AA ADP PGI 2 IP TXA 2 TP PLC Ca ++ ADP G q + IP 3 Ca ++ Ca ++ AC G S + G i - ATP cAMP + - P2X 1 P2Y 1 ADP P2Y 12 Activation of GPIIb/IIIa Binding of soluble fibrinogen Aggregation PGH2 TAX2 COX TAXS PAR TRAP Conventional Antiplatelet Agents ASA Clopidrogel Ticlopidina Reopro Tirofiban Eptifibatide Prasugrel Ticagrelor Cangrelor SCH530348

10 P2Y12 inhibitors AC + G i - ATP cAMP P2Y 12 Ticlopidine and clopidogrel Prodrugs, converted in vivo by the hepatic cytochrome P-450 enzymatic pathway to active metabolites, 85% inactive metabolite Irreversibly inhibiting the receptor Because of the toxicity of ticlopidine (neutropenia, thrombotic thrombocytopenic purpura), ticlopidine has been almost completely replaced by clopidogrel in clinical practice.

11 P2Y12 inhibitors AC + G i - ATP cAMP P2Y 12 Ticlopidine and clopidogrel Prodrugs, converted in vivo by the hepatic cytochrome P-450 enzymatic pathway to active metabolites, 85% inactive metabolite Irreversibly inhibiting the receptor Because of the toxicity of ticlopidine (neutropenia, thrombotic thrombocytopenic purpura), ticlopidine has been almost completely replaced by clopidogrel in clinical practice. Prasugrel Prodrugs, Prasugrel is a thienopyridine with 10-fold more potent anti-P2Y12 receptor inhibitory activity than clopidogrel. Conversion to its active metabolite is less dependence on CYP enzymes than clopidogrel Irreversibly inhibiting the receptor More rapid and consistent inhibitory effects on platelet aggregation than Clopidogrel

12 P2Y12 inhibitors AC + G i - ATP cAMP P2Y 12 Ticlopidine and clopidogrel Prodrugs, converted in vivo by the hepatic cytochrome P-450 enzymatic pathway to active metabolites, 85% inactive metabolite Irreversibly inhibiting the receptor Because of the toxicity of ticlopidine (neutropenia, thrombotic thrombocytopenic purpura), ticlopidine has been almost completely replaced by clopidogrel in clinical practice. Prasugrel Prodrugs, Prasugrel is a thienopyridine with 10-fold more potent anti-P2Y12 receptor inhibitory activity than clopidogrel. Conversion to its active metabolite is less dependence on CYP enzymes than clopidogrel Irreversibly inhibiting the receptor More rapid and consistent inhibitory effects on platelet aggregation than Clopidogrel Ticagrelor Not a prodrug Rapid onset of inhibitory effect Reversibly bound with faster offset of effect and functional recovery of all circulating platelets

13 P2Y12 inhibitors AC + G i - ATP cAMP P2Y 12 Ticlopidine and clopidogrel Prodrugs, converted in vivo by the hepatic cytochrome P-450 enzymatic pathway to active metabolites, 85% inactive metabolite Irreversibly inhibiting the receptor Because of the toxicity of ticlopidine (neutropenia, thrombotic thrombocytopenic purpura), ticlopidine has been almost completely replaced by clopidogrel in clinical practice. Prasugrel Prodrugs, Prasugrel is a thienopyridine with 10-fold more potent anti-P2Y12 receptor inhibitory activity than clopidogrel. Conversion to its active metabolite is less dependence on CYP enzymes than clopidogrel Irreversibly inhibiting the receptor More rapid and consistent inhibitory effects on platelet aggregation than Clopidogrel Ticagrelor Not a prodrug Rapid onset of inhibitory effect Reversibly bound with faster offset of effect and functional recovery of all circulating platelets Cangrelor ATP analogue Reversible binds to and inhibits the P2Y12 ADP receptor Immediately active after i.v. infusion

14 New P2Y12 inhibitors AC + G i - ATP cAMP P2Y 12 Elinogrel Direct-acting, reversible P2Y12 inhibitor that can be administered both intravenously and orally A Phase 2 Safety and Efficacy Study of Elinogrel a Novel Intravenous and Oral P2Y12 Inhibitor in Non- Urgent PCI (INNOVATE-PCI) is a multicenter, randomized, double-blind, triple- dummy,clopidogrel-controlled study of intravenous and oral elinogrel compared with clopidogrel in patients undergoing nonurgent (including elective) PCI. After diagnostic angiography, patients scheduled for nonurgent PCI will be randomized to clopidogrel or 1 of 3 doses of elinogrel. The Early Rapid Reversal of Platelet Thrombosis With Intravenous Elinogrel Before PCI to Optimize Reperfusion in Acute MI (ERASE-MI) is a randomized trial evaluating the safety and tolerability of intravenous elinogrel (10, 20, 40, and 60 mg) before PCI in patients with STEMI

15 I ragionevoli dubbi con terapia anticoagulante e antiaggregante Quale è il rischio e limpatto degli eventi aterotrombotici nelle SCA? Quale è il rischio e loutcome dei sanguinamenti nelle SCA? Esiste un compromesso clinico tra rischio emorragico e beneficio della doppia antiaggregazione? Quanto incide la biodiversità sulle scelte? Quale è il timing del rischio di sanguinamento Come affrontare il rischio di sanguinamento correlato ad altre procedure invasive Partiamo dalle evidenze dei tre ultimi grandi trial

16 Factorial Randomized Trial (2X2) of Optimal Clopidogrel and Aspirin Dosing in Patients with ACS Undergoing an Early Invasive Strategy with Intent For PCI Non ancora pubblicato! OASIS ESC 2009

17 Study Design, Flow and Compliance 25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%) Planned Early (<24 h) Invasive Management with intended PCI Ischemic ECG Δ (80.8%) or cardiac biomarker (42%) 25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%) Planned Early (<24 h) Invasive Management with intended PCI Ischemic ECG Δ (80.8%) or cardiac biomarker (42%) PCI 17,232 (70%) Angio 24,769 (99%) Angio 24,769 (99%) No PCI 7,855 (30%) No Sig. CAD 3,616CABG 1,809 CAD 2,430 Randomized to receive (2 X 2 factorial): CLOPIDOGREL: Double-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg then 75 mg/d) ASA: High Dose ( mg/d) vs Low dose ( mg/d) Efficacy Outcomes:CV Death, MI or stroke at day 30 Stent Thrombosis at day 30 Safety Outcomes:Bleeding (CURRENT defined Major/Severe and TIMI Major) Key Subgroup: PCI v No PCI Complete Follow up 99.8%

18 Clopidogrel: Double vs Standard Dose Primary Outcome and Components StandardDoubleHR95% CIPIntn P CV Death/MI/Stroke PCI (2N=17,232) No PCI (2N=7855) Overall (2N=25,087) MI PCI (2N=17,232) No PCI (2N=7855) Overall (2N=25,087) CV Death PCI (2N=17,232) No PCI (2N=7855) Overall (2N=25,087) Stroke PCI (2N=17,232) No PCI (2N=7855) Overall (2N=25,087)

19 Days Cumulative Hazard Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients Clopidogrel Standard Clopidogrel Double HR % CI P= % RRR CV Death, MI or Stroke

20 Days Cumulative Hazard Clopidogrel Standard Dose Clopidogrel Double Dose 42% RRR HR % CI P=0.001 Clopidogrel: Double vs Standard Dose Definite Stent Thrombosis (Angio confirmed)

21 Conclusions Clopidogrel Dose Comparison 1.Double-dose clopidogrel significantly reduced major CV events in PCI (CV death, MI or stroke) and stent thrombosis 2.In patients not undergoing PCI double dose clopidogrel was not significantly different from standard dose 3.There was a modest excess in CURRENT- defined major bleeds but no difference in severe: TIMI major bleeds, ICH, fatal bleeds or CABG-related bleeds

22 Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolisis in MI

23 TRITON-TIMI 38: Balance of efficacy and safety events HR 0.81 ( ) p= NNT=46 35 events HR 1.32 ( ) p=0.03 NNH=167 Wiovitt SD et al. NEJM 2007 (6795 pts) (6813 pts)

24 Diabetic Subgroup HR 0.70 P<0.001 Days Endpoint (%) CV Death / MI / Stroke TIMI Major NonCABG Bleeds NNT = 20 (46) N= Prasugrel Clopidogrel Prasugrel Clopidogrel

25 Montalescot G et al. Lance t 2008;372:1-9; Wiviott SD, N Engl J Med 2007;357(20):

26 TRITON-TIMI 38: Timing of benefit Days 0 Loading Dose Maintenance Dose Primary Endpoint (%) Wiovitt SD et al. NEJM 2007 (6795 pts) (6813 pts)

27 TRITON-TIMI 38: Stent Thrombosis (ARC Definite + Probable) Days Endpoint (%) Wiovitt SD et al. NEJM 2007

28 TRITON-TIMI 38: Bleeding Events (%) TIMI Major Bleeds ARD 0.6% HR 1.32 p=0.03 NNH=167 Life Threatening ARD 0.5% HR 1.52 p=0.01 Non fatal ARD 0.2% p=0.23 Fatal ARD 0.3% p=0.002 ICH ARD 0% p=0.74 Wiovitt SD et al. NEJM 2007

29 OVERALL >=60 kg < 60 kg < 75 >=75 No Yes Prior Stroke / TIA Age Wgt Risk (%) Prasugrel BetterClopidogrel Better HR P int = P int = 0.18 P int = 0.36 Wiovitt SD et al. NEJM 2007 TRITON-TIMI 38: Bleeding risk subgroups

30 Safety Significant increase in serious bleeding (32% increase) Avoid in pts with prior CVA/TIA Efficacy 1. A significant reduction in: CV Death/MI/Stroke 19% Stent Thrombosis52% uTVR 34% MI 24% 2. An early and sustained benefit 3. Across ACS spectrum Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD Higher IPA to Support PCI Net clinical benefit significantly favored Prasugrel Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the benefit: risk balance

31 Bleeding Risk Subgroups Therapeutic Considerations Significant Net Clinical Benefit with Prasugrel 80% MD 10 mg Reduced MD Guided by PK Age > 75 or Wt < 60 kg 16% Avoid Prasugrel Prior CVA/TIA 4% Antman EM, AHA 2007

32 Study of Platelet Inhibition and Patient Outcomes: PLATO Study Design

33 Days after randomisation Cumulative incidence (%) PLATO: Primary efficacy endpoint (CV death,MI or stroke) Wallentin L et al. NEJM (9.291 pts) (9.333 pts)

34 Days after randomization Cumulative incidence (%) Myocardial InfarctionCardiovascular death PLATO: Secondary efficacy endpoints Wallentin L et al. NEJM 2009

35 K-M estimated rate (% per years) Days from first IP dose Wallentin L et al. NEJM 2009 PLATO: Primary safety event (total major bleeding) (9.235 pts) (9.186 pts)

36 Non-CABG TIMI major bleeding Non-CABG PLATO major bleeding* CABG PLATO major bleeding* CABG TIMI major bleeding K-M estimated rate (% per years) PLATO: Non CABG and CABG major bleeding Wallentin L et al. NEJM 2009 *Bleeding with clinically significant disability or associated with hemoglobin declive at least 3.0 g/dl but less 5.0 g/dl trasfusion of 2 to 3 units

37 No. at risk Clopidogrel Ticagrelor 6,676 6,732 6,157 6,268 6,062 6,173 5,917 Days after randomization 4,849 4,924 3,706 3,766 2,987 3, Cumulative incidence (%) Clopidogrel Ticagrelor , Clopidogrel Ticagrelor ,676 6,732 6,376 6,439 6,332 6,375 6,209 Days after randomization 5,114 5,141 3,917 3,591 3,164 3,2336,241 Myocardial infarction Cardiovascular death Cumulative incidence (%) HR 0.80 (95% CI = 0.69–0.92), p=0.002 HR 0.82 (95% CI = 0.68–0.98), p=0.025 PLATO-invasive Cannon PC et al. Lancet 2010

38 Ticagrelor Clopidogrel NS 0 K-M estimated rate (% per year) PLATO major bleeding* TIMI major bleeding GUSTO severe bleeding* Non-CABG CABG PLATO-invasive: Non-CABG and CABG-related major bleeding Cannon PC et al. Lancet 2010 *Bleeding with clinically significant disability or associated with hemoglobin declive at least 3.0 g/dl but less 5.0 g/dl trasfusion of 2 to 3 units

39 - Inibisce in modo diretto la trombina legata al coagulo e circolante con uno specfico legame bivalente ai due siti - Non richiede la presenza dell'antitrombina - Inibisce la trombina mediata dall'attivazione piastrinica - Ha un'emivita plasmatica di 25 minuti - Non richiede monitoraggio Luci e ombre della bivaliridina Fibrina Sito catalitico Trombina Bivalirudina 1 2 Sito esterno

40 Study Design – Patient Flow Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy UFH/Enox + GP IIb/IIIa (N=4,603) Bivalirudin + GP IIb/IIIa (N=4,604) Bivalirudin Alone (N=4,612) R* GPI upstream (N=2294) GPI CCL for PCI (N=2309) GPI upstream (N=2311) GPI CCL for PCI (N=2293) Aspirin in all Clopidogrel dosing and timing per local practice Aspirin in all Clopidogrel dosing and timing per local practice Moderate- high risk ACS ACUITY

41 Primary Endpoint Measures (ITT) UFH/Enoxaparin + GPI vs. Bivalirudin Alone 11,7% 7,3% 5,7% 3,0% 10,1% 7,8% Net clinical outcome Ischemic composite Major bleeding 30 day events (%) UFH/Enoxaparin+GPI (N=4603)Bivalirudin alone (N=4612) P NI < P Sup = P NI = P Sup = 0.32 P NI < P Sup < ACUITY Stone GW et al. N Engl J Med. 2006;355:2203–2216.

42

43 3602 randomized pts undergoing primary PCI Use of the polymer-based slow- release paclitaxel-eluting TAXUS stent will safely reduce the 1-year rate of ischemia- driven TLR Hypothesis: Use of the polymer-based slow- release paclitaxel-eluting TAXUS stent will safely reduce the 1-year rate of ischemia- driven TLR Bivalirudin compared to UFH + routine IIb/IIIa will reduce the composite rate of death, reinfarction, TVR, stroke and major bleeding at 30-days Hypothesis: Bivalirudin compared to UFH + routine IIb/IIIa will reduce the composite rate of death, reinfarction, TVR, stroke and major bleeding at 30-days HORIZONS AMI Trial UFH + IIb/IIIainhibitorBivalirudin+bail-outIIb/IIIa Randomize 1:1 Target vessel stenting TAXUSstent Bare metal Express stent Randomize 3:1 Anti-thrombotic therapy

44 Harmonizing Outcomes with Revascularization and Stents in AMI UFH + GP IIb/IIIa N=1802 Bivalirudin Monotherapy N=1800 R 1:1 Randomized 30 day FU* * Range ±7 days ITT population N=1778 (98.7%) N=1777 (98.7%) N=1802N=1800 Withdrew Withdrew Lost to FU Lost to FU pts with STEMI

45 Diff = Diff = 0.0% [-1.6, 1.5] RR = 0.99 [0.76, 1.30] P sup = 1.00 Primary Outcome Measures Diff = Diff = -3.3% [-5.0, -1.6] RR = RR = 0.60 [0.46, 0.77] P NI P sup Diff = Diff = -2.9% [-4.9, -0.8] RR = RR = 0.76 [0.63, 0.92] P NI P sup = endpoint Stone GW, et al. N Engl J Med. 2008;358(21):

46 Conclusioni - I nuovi farmaci che bloccano il recettore P2Y12 (prasugrel, ticagrelor) sono risultati più efficaci del clopidogrel grazie ad una migliore farmacocinetica e farmacodinamica. Ad essi si associa tuttavia un certo grado di rischio emorragico. - La bivalirudina riduce i sanguinamenti locali e dorgano nei pazienti con SCA sottoposti a PCI, soprattutto in quelli a maggior rischio emorragico (anziani), ma per unefficace copertura anti-ischemica deve essere associata ad un regime di doppia anti-aggregazione piastrinica. - Lanalisi di efficacia e di rischio in particolari sottogruppi di pazienti con SCA potrà permettere di utilizzare il farmaco più vantaggioso per quel dato contesto clinico.


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