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Dipartimento Cardio-Respiratorio U.O. di Cardiologia, Ospedale “ Campo di Marte” Lucca

LUCCA. CARDIOLOGIA. Nuove evidenze sull’impiego di antiaggreganti e anticoagulanti nello STEMI e nelle SCA NSTE Francesco Bovenzi. Dipartimento Cardio-Respiratorio U.O. di Cardiologia, Ospedale “ Campo di Marte” Lucca. Anti-Thrombin Rx. Heparin. LMWH. Bivalirudin. Fondaparinux.

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Dipartimento Cardio-Respiratorio U.O. di Cardiologia, Ospedale “ Campo di Marte” Lucca

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  1. LUCCA CARDIOLOGIA Nuove evidenze sull’impiego di antiaggreganti e anticoagulanti nello STEMI e nelle SCA NSTEFrancesco Bovenzi Dipartimento Cardio-Respiratorio U.O. di Cardiologia, Ospedale “Campo di Marte” Lucca

  2. Anti-Thrombin Rx Heparin LMWH Bivalirudin Fondaparinux Anti-Platelet Rx GP IIb/IIIa blockers Prasugrel Aspirin Ticagrenor Clopidogrel Treatment Strategy Conservative Early invasive PRISM-PLUS REPLACE 2 OASIS-5 TRITON Timi 38 PURSUIT PLATO CURE ESSENCE TACTICS TIMI-18 PCI ~ 5% stents ~85% stents Drug-eluting stents Bleeding risk Milestones in ACS Management ICTUS ISAR-REACT 2 CURRENT OASIS-7 ACUITY SYNERGY 1994 1995 1996 1997 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2010 1990 Ischemic risk

  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 l’alba di una nuova era della terapia antipiastrinica. Finora non c’è 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 l’efficacia 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. ++ Ca The Key Platelet Transmembrane Receptors ADP TRAP ADP TXA2 ADP PGI2 P2Y12 P2X1 TP P2Y TAX2 IP PAR 1 AA AC - + PLC G G G q i S COX ++ ATP Ca + - + ++ PGH2 Ca cAMP IP 3 TAXS Activation of GPIIb/IIIa Binding of soluble fibrinogen Aggregation

  7. ++ Ca Conventional Antiplatelet Agents Clopidrogel Ticlopidina ADP TRAP ADP TXA2 ADP PGI2 P2Y12 P2X1 TP P2Y TAX2 IP PAR 1 AA AC - + PLC G G G q i S COX ++ ATP Ca + - + ++ PGH2 Ca cAMP IP 3 ASA TAXS Activation of GPIIb/IIIa Reopro Tirofiban Eptifibatide Binding of soluble fibrinogen Aggregation

  8. ++ Ca Conventional Antiplatelet Agents Prasugrel Ticagrelor Cangrelor Clopidrogel Ticlopidina ADP TRAP ADP TXA2 ADP PGI2 P2X1 TP P2Y P2Y12 TAX2 IP PAR 1 AA AC - + PLC G G G q i S COX ++ ATP Ca + - + ++ PGH2 Ca cAMP IP 3 ASA TAXS Activation of GPIIb/IIIa Reopro Tirofiban Eptifibatide Binding of soluble fibrinogen Aggregation

  9. ++ Ca Conventional Antiplatelet Agents Prasugrel Ticagrelor Cangrelor Clopidrogel Ticlopidina SCH530348 ADP TRAP ADP TXA2 ADP PGI2 P2X1 TP P2Y P2Y12 TAX2 IP PAR 1 AA AC - + PLC G G G q i S COX ++ ATP Ca + - + ++ PGH2 Ca cAMP IP 3 TAXS ASA Activation of GPIIb/IIIa Reopro Tirofiban Eptifibatide Binding of soluble fibrinogen Aggregation

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

  11. P2Y12 inhibitors • Prasugrel • Prodrugs, Prasugrel is a thienopyridine with 10-fold more potentanti-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 • 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. P2Y12 AC - + i G ATP cAMP

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

  15. I ragionevoli dubbi con terapia anticoagulante e antiaggregante Quale è il rischio e l’impatto degli eventi aterotrombotici nelle SCA? Quale è il rischio e l’outcome 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. ESC 2009 2007 2009 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-7

  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%) Randomized to receive (2 X 2 factorial): CLOPIDOGREL: Double-dose(600 mg then150 mg/d x 7d then 75 mg/d) vsStandard dose (300 mg then 75 mg/d) ASA: High Dose (300-325 mg/d) vsLow dose (75-100 mg/d) Angio 24,769 (99%) PCI 17,232 (70%) No PCI 7,855 (30%) No Sig. CAD 3,616 CABG 1,809 CAD 2,430 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 DosePrimary Outcome and Components

  19. Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients CV Death, MI or Stroke Clopidogrel Standard 15% RRR 0.04 Clopidogrel Double 0.03 Cumulative Hazard 0.02 HR 0.85 95% CI 0.74-0.99 P=0.036 0.01 0.0 Days 0 3 6 9 12 15 18 21 24 27 30

  20. Clopidogrel: Double vs Standard Dose Definite Stent Thrombosis (Angio confirmed) Clopidogrel Standard Dose 0.012 42% RRR 0.008 Cumulative Hazard Clopidogrel Double Dose 0.004 HR 0.58 95% CI 0.42-0.79 P=0.001 0.0 0 3 6 9 12 15 18 21 24 27 30 Days

  21. ConclusionsClopidogrel Dose Comparison Double-dose clopidogrel significantly reduced major CV events in PCI (CV death, MI or stroke) and stent thrombosis In patients not undergoing PCIdouble dose clopidogrel was not significantly different from standard dose There was a modest excess in CURRENT-defined major bleedsbut 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 15 138 events HR 0.81 (0.73-0.90) p=0.0004 NNT=46 (6795 pts) 12.1 9.9 10 (6813 pts) 5 35 events HR 1.32 (1.03-1.68) p=0.03 NNH=167 2.4 1.8 0 0 30 60 90 180 270 360 450 Wiovitt SD et al. NEJM 2007

  24. Diabetic Subgroup N=3146 18 Clopidogrel 17.0 16 CV Death / MI / Stroke 14 12.2 12 HR 0.70P<0.001 Endpoint (%) Prasugrel 10 NNT = 20 (46) 8 6 TIMI Major NonCABG Bleeds Clopidogrel 4 2.6 2.5 2 Prasugrel 0 0 30 60 90 180 270 360 450 Days

  25. Montalescot G et al. Lancet 2008;372:1-9; Wiviott SD, N Engl J Med 2007;357(20):2001-15

  26. 8 6 Primary Endpoint (%) 4 2 0 0 2 3 30 1 0 60 90 180 270 360 450 Days Loading Dose Maintenance Dose TRITON-TIMI 38: Timing of benefit (6795 pts) (6813 pts) Wiovitt SD et al. NEJM 2007

  27. TRITON-TIMI 38: Stent Thrombosis (ARC Definite + Probable) 3 2 Endpoint (%) 1 0 60 90 180 270 360 30 0 450 Days Wiovitt SD et al. NEJM 2007

  28. TRITON-TIMI 38: Bleeding 4 2 Events (%) 0 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. TRITON-TIMI 38: Bleeding risk subgroups Risk (%) + 37 Yes Prior Stroke / TIA -16 No Pint = 0.006 -1 >=75 Age -16 Pint = 0.18 < 75 +3 < 60 kg Wgt Pint = 0.36 -14 >=60 kg -13 OVERALL 0.5 1 2 Prasugrel Better Clopidogrel Better HR Wiovitt SD et al. NEJM 2007

  30. Efficacy 1. A significant reduction in: CV Death/MI/Stroke 19% Stent Thrombosis 52% uTVR 34%       MI 24% 2. An early and sustained benefit 3. Across ACS spectrum Safety Significant increase in serious bleeding(32% increase)Avoid in pts with prior CVA/TIA Higher IPA to Support PCI Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD 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 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 Antman EM, AHA 2007

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

  33. PLATO: Primary efficacy endpoint(CV death,MI or stroke) 11.7 12 (9.291 pts) 10 9.8 8 (9.333 pts) 6 Cumulative incidence (%) 4 2 0 60 240 300 0 120 180 360 Days after randomisation Wallentin L et al. NEJM 2009

  34. PLATO: Secondary efficacy endpoints Myocardial Infarction Cardiovascular death 7 7 6 6 5 5 4 4 Cumulative incidence (%) Cumulative incidence (%) 3 3 2 2 1 1 0 0 0 60 120 180 240 300 360 0 60 120 180 240 300 360 Days after randomization Days after randomization Wallentin L et al. NEJM 2009

  35. 15 10 5 0 60 120 0 180 300 240 360 PLATO: Primary safety event (total major bleeding) (9.235 pts) (9.186 pts) K-M estimated rate (% per years) Days from first IP dose Wallentin L et al. NEJM 2009

  36. PLATO: Non CABG and CABG major bleeding 9 8 7 6 5 K-M estimated rate (% per years) 4 3 2 1 0 Non-CABG PLATO major bleeding* Non-CABG TIMI major bleeding CABG PLATO major bleeding* CABG TIMI major bleeding *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 Wallentin L et al. NEJM 2009

  37. PLATO-invasive Cardiovascular death Myocardial infarction 8 8 Clopidogrel 6.6 6 6 5.3 Cumulative incidence (%) Clopidogrel Cumulative incidence (%) Ticagrelor 4.3 4 4 3.4 Ticagrelor 2 2 HR 0.80 (95% CI = 0.69–0.92), p=0.002 HR 0.82 (95% CI = 0.68–0.98), p=0.025 0 0 0 60 120 180 240 300 360 0 60 120 180 240 300 360 Days after randomization Days after randomization No. at risk 6,732 6,439 6,375 6,241 5,141 3,591 3,233 Ticagrelor 6,732 6,268 6,173 6,010 4,924 3,766 3,078 6,676 6,376 6,332 6,209 5,114 3,917 3,164 Clopidogrel 6,676 6,157 6,062 5,917 4,849 3,706 2,987 Cannon PC et al. Lancet 2010

  38. PLATO-invasive: Non-CABG and CABG-related major bleeding NS 13 Ticagrelor Clopidogrel 11.6 11.5 12 4.7 11 10 NS 4.1 9 Non-CABG 8.0 8.0 8 7 2.3 K-M estimated rate (% per year) 2.8 6 5 NS 4 3.2 CABG 2.9 3 1.7 2 1.9 1 0 PLATO major bleeding* TIMI major bleeding GUSTO severe bleeding* *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 Cannon PC et al. Lancet 2010

  39. Luci e ombre della bivaliridina 2 1 Trombina Trombina Sito catalitico Sito esterno Trombina Trombina Bivalirudina Fibrina • - 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

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

  41. UFH/Enoxaparin+GPI (N=4603) Bivalirudin alone (N=4612) PNI <0.0001 PSup = 0.015 PNI = 0.011 PSup = 0.32 PNI <0.0001 PSup <0.0001 30 day events (%) 11,7% 10,1% 7,8% 7,3% 5,7% 3,0% Net clinical Ischemic Major bleeding outcome composite ACUITY Primary Endpoint Measures (ITT) UFH/Enoxaparin + GPI vs. Bivalirudin Alone Stone GW et al. N Engl J Med. 2006;355:2203–2216.

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

  43. 3602 pts with STEMI Bivalirudin Monotherapy N=1800 Randomized 9 15 • • • Withdrew • • • • • • Lost to FU • • • 10 13 N=1778 (98.7%) N=1777 (98.7%) 30 day FU* ITT population N=1802 N=1800 * Range ±7 days Harmonizing Outcomes with Revascularization and Stents in AMI R 1:1 UFH + GP IIb/IIIa N=1802

  44. Primary Outcome Measures Diff = -2.9% [-4.9, -0.8] RR = 0.76 [0.63, 0.92] PNI ≤ 0.0001 Psup = 0.006 Diff = -3.3% [-5.0, -1.6] RR = 0.60 [0.46, 0.77] PNI ≤ 0.0001 Psup ≤ 0.0001 Diff = 0.0% [-1.6, 1.5] RR = 0.99[0.76, 1.30] Psup = 1.00 1 endpoint 1 endpoint Stone GW, et al. N Engl J Med. 2008;358(21):2218-2230.

  45. Conclusioni • L’analisi 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. - 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 d’organo nei pazienti con SCA sottoposti a PCI, soprattutto in quelli a maggior rischio emorragico (anziani), ma per un’efficace copertura anti-ischemica deve essere associata ad un regime di doppia anti-aggregazione piastrinica.

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