Impatto delle nuove linee guida. miocardica nelle. Angelo Sante Bongo. Angelo Sante Bongo

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1 Impatto delle nuove linee guida nell attività ità interventistica: ti ti Rivascolarizzazione miocardica nelle SCA

2 Trattamento antitrombotico in corso di IMA Rischio trombotico Rischio emorragico

3 Farmaci antitrombotici nelle SCA Enoxaparin Fundaparinux Bivalirudin ASA +UFH +Thyenop. +IIb/IIIa inhib. berlin

4 Landmark Practice Advances in Acute Coronary Syndromes STEMI VIENNA REGISTRY PRIMARY PCI ABCIXIMAB BIVALIRUDIN SK SK+ ASPIRIN r-tpa TNK Pre-H lysis Morrison CLOPIDOGREL REACT CARESS ASPIRIN + HEPARIN NSTE-ACS TROPONIN UPSTREAM GP IIb/IIIa ENOXAPARIN CLOPIDOGREL EARLY INVASIVE ABCIXIMAB IN CATH LAB FONDAPARINUX BIVALIRUDIN

5 The 3 Most Important Advances in Antiplatelet Therapy for ACS Aspirin i ADP antagonists Platelet GP IIb/IIIa receptor antagonists

6 Meadows TA, Bhatt DL. Circ Res ;100:1261

7 O O CH C 3 O S N Cl Pro-drug O C O S N F Clopidogrel CH 3 Prasugrel 85% Inactive Metabolites O O CH 3 C O S N Cl O S N F O C O CH 3 O S N Cl O OCH 3 HOOC N * HS Cl Active metabolite O HOOC N *HS F

8 ADP-receptor antagonists major drawbacks Clopidogrel is only slightly more effective than aspirin As with aspirin, clopidogrel binds irreversibly to platelets In some patients there is resistance to clopidogrel treatment

9 GPIIb/IIIa-receptor antagonists major drawbacks Can only be administered by intravenous injection or infusion and are complicated to manufacture Oral drugs have been investigated but were not effective and have therefore not reached the market

10 Antiplatelet Therapy in ACS 108 ASA ASA + Clopidogrel ASA + Prasugrel -22% Reduction in -20% Ischemic Events -19% 0 +60% +38% +32% Placebo APTC CURE TRITON-TIMI 38 Single Dual Antiplatelet Rx Antiplatelet Rx Higher IPA Increase in Major Bleeds

11 What is the Problem? We Always Mix Antiplatelet Agents Thrombin generation ASPIRIN 5HT Thromboxane Coagulation Collagen Thrombin PAR1 PAR4 A 2 TPa x GPVI 5HT 2A PLATELET ACTIVATION ADP P2Y 1 ATP P2X 1 5HT ADP ATP Dense granule ADP TICLOPIDINE CLOPIDOGREL PRASUGREL ACTIVE METABOLITE x AZD6140 CANGRELOR P2Y 12 Shape change Alpha granule Coagulation factors Inflammatory mediators Storey RF. Curr Pharm Des. 2006;12: Amplification a IIb b 3 a IIb b 3 Fibrinogen x Aggregation a IIb b 3 GP IIb/IIIa ANTAGONISTS

12 Tienopiridine: principali p limiti Ridotta potenza antiaggregante (problema per DES) Resistenza/risposta individuale variabile Profarmaci Latenza azione (problema per PCI urgenti) Inibitori irreversibili P2Y12 (problema per CABG) Durata azione

13 i nuovi antipiastrinici Prasugrel AZD6140 Cangrelor TRA-SCH

14 Antiplatelet therapies in ACS ADP-antagonists Oral Clopidogrel l indirect agent, dosing trials Prasugrel indirect agent AZ-6310 direct competitive agent IV Cangrelor direct competitive agent Glycoprotein IIb/IIIa inhibitors PAR (thrombin) receptor antagonist (TRA)

15 Antiplatelet therapies in ACS ADP-antagonists Oral Clopidogrel l indirect agent, dosing trials Prasugrel indirect agent AZ-6310 direct competitive agent IV Cangrelor direct competitive agent Glycoprotein IIb/IIIa inhibitors PAR (thrombin) receptor antagonist (TRA)

16 ) End point (% Balance of efficacy and safety events Clopidogrel 12.1 HR 0.81 CV death / MI / stroke ( ) P = NNT = 46 Prasugrel 5 TIMI major Prasugrel NonCABG bleeds Clopidogrel Days 35 events HR 1.32 ( ) P = 0.03 NNH = 167

17 Prasugrel: un nuova, più potente tienopiridina idina prasugrel clopidogrel Jernberg et al, Eur Heart J 2006;27;

18 Prasugrel: meno non-responders acuto cronico Jernberg et al, Eur Heart J 2006;27;

19 Antiplatelet therapies in ACS ADP-antagonists Oral Clopidogrel l indirect agent, dosing trials Prasugrel indirect agent AZ-6310 direct competitive agent IV Cangrelor direct competitive agent Glycoprotein IIb/IIIa inhibitors PAR (thrombin) receptor antagonist (TRA)

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24 Antithrombotic treatment options Elective PCI N-STEMI ACS STEMI To maximize the effectiveness of therapy and reduce the hazard of bleeding, ischaemic and bleeding risks should be evaluated on an individual basis European Angelo Heart Sante Journal Bongo ;doi: /eurheartj/ehq277

25 Antithrombotic treatment options Elective PCI N-STEMI ACS STEMI European Angelo Heart Sante Journal Bongo ;doi: /eurheartj/ehq277

26 Antiplatelet therapy ELECTIVE PCI ASA mg per os or 250 ( 500) mg bolus i.v. followed by mg per os daily Clopidogrel 300 (600)-mg loading dose followed by 75 mg daily for all patients 300 mg at least 6 h before PCI 600 mg at least 2 h before PCI GPIs European Angelo Heart Sante Journal Bongo ;doi: /eurheartj/ehq277 Should be used only in bail-out situations (thrombus, slow flow, vessel closure, very complex lesions)

27 Anticoagulation therapy ELECTIVE PCI UFH Enoxaparin IU/kg i.v. bolus without GPIs IU/kg with GPIs European Angelo Heart Sante Journal Bongo ;doi: /eurheartj/ehq277

28 Antithrombotic treatment options Elective PCI N-STEMI ACS STEMI European Angelo Heart Sante Journal Bongo ;doi: /eurheartj/ehq277

29 N-STEMI ACS High ischaemic risk is associated with ST-segment changes, elevated troponin, diabetes, and a GRACE score >140. A high bleeding risk is associated with female sex, age >75 years, bleeding history, GFR <30 ml/min, and use of femoral access. European Heart Journal ;doi: /eurheartj/ehq277

30 Antiplatelet therapy N-STEMI ACS European Heart Journal ;doi: /eurheartj/ehq277

31 Antiplatelet therapy N-STEMI ACS ASA Clopidogrel GPIs mg per os or 250 ( 500) mg i.v. bolus followed by mg daily 600 mg loading dose, followed by 75 mg daily, Prasugrel 60 mg loading dose, followed by 10 mg daily, Ticagrelor 180 mg loading dose, followed by 90 mg twice daily Should be used only in bail-out out situations (thrombus, slow flow, vessel closure, very complex lesions) Recent trials did not demonstrate additional benefit of GPIs after a clopidogrel loading dose of 600 mg Severe bleeding complications increase with prasugrel use, specifically in patients with a history of stroke and TIA, in the elderly ( 75 years), and in underweight patients (60 kg) European Heart Journal ;doi: /eurheartj/ehq277

32 ISAR-REACT 2 N-STEMI ACS Kastrati et al, JAMA. 2006;295:(doi: /jama joc60034)

33 Anticoagulation therapy before cath lab N-STEMI ACS GOLDEN RULES: Avoid crossover especially between UFH and low molecular weight heparin (LMWH) To discontinue antithrombins after PCI except in specific individual situations (e.g. thrombotic complication) RISK STRATIFICATION European Heart Journal ;doi: /eurheartj/ehq277

34 Anticoagulation therapy N-STEMI ACS Very high risk of ischemia (persistent angina, haemodynamic instability, refractory arrhythmia) UFH Bivalirudin (monotherapy) high h bleeding risk pts 60 IU/kg i.v. bolus, followed by infusion until PCI 0.75 mg/kg bolus followed by 1.75 mg/kg/h European Heart Journal ;doi: /eurheartj/ehq277

35 Anticoagulation therapy N-STEMI ACS Medium to high risk of ischemia (troponin positive,recurrent angina, dynamic ST changes) (invasive strategy is planned within 24 ( 48) UFH Enoxaparin Fondaparinux Bivalirudin UFH 60 IU/kg i.v. bolus, then infusion until PCI (ACT tritation) 1 mg/kg subcutaneous (s.c.) twice daily until PCI (0,75 mg/kg in pts > 75 y.o.) 2.5 mg daily s.c. until PCI 0.1 mg/kg bolus followed by 0.25 mg/kg/h European Heart Journal ;doi: /eurheartj/ehq277

36 Anticoagulation therapy Low risk of ischemia (troponin negative, no ST-segment changes) N-STEMI ACS fondaparinux mg s.c. daily enoxaparin UFH 1 mg/kg s.c. twice daily (0.75 mg in patients 75 years) 60 IU/kg i.v. bolus followed by infusion (aptt controlled). European Heart Journal ;doi: /eurheartj/ehq277

37 Anticoagulation therapy during cath lab N-STEMI ACS UFH Enoxaparin Fondaparinux Bivalirudin Continue infusion, ACT target range: s with GPIs s without GPIs less than 8 h since last s.c. appl.: no additional bolus; within 8 12 h of last s.c. appl.: add 0.30 mg/kg i.v. bolus; >12 h since last s.c. appl.: 0.75 mg/kg i.v. bolus. Add UFH IU/kg when PCI is performed. Add an additional i.v. bolus of 0.5 mg/kg and increase the infusion rate to 1.75 mg/kg/h before PCI. European Heart Journal ;doi: /eurheartj/ehq277

38 Antithrombotic treatment options Elective PCI N-STEMI ACS STEMI European Heart Journal ;doi: /eurheartj/ehq277

39 Antithrombotic treatment options High ischaemic risk is associated with ST-segment changes, elevated troponin, diabetes, and GRACE score > 140 High bleeding risk is associated with female sex, age > 75 years, bleeding history, GFR < 30 ml/min, and use of femoral access European Heart Journal ;doi: /eurheartj/ehq277

40 Antiplatelet therapy STEMI ACS European Heart Journal ;doi: /eurheartj/ehq277

41 Antiplatelet therapy STEMI ACS ASA DAPT GPIs mg per os or 250 ( 500) mg i.v. bolus followed by mg daily Prasugrel 60 mg loading dose, followed by 10 mg daily, Ticagrelor 180 mg loading dose, followed by 90 mg twice daily Clopidogrel 600 mg loading dose, followed by 75 mg daily (if other not available) The controversial literature data, the negative outcome of the only prospective RCT, and the beneficial effects of faster acting and more efficacious ADP receptor blockers in primary PCI do not support prehospital or pre-catheterization use of GPIIb IIIa inhibitors. European Heart Journal ;doi: /eurheartj/ehq277

42 TRITON TIMI - 38 STEMI ACS N Engl J Med 2007;357:

43 De Luca, G. et al. JAMA 2005;293: METANALISI - Abciximab Primary Mortality at 30 days Mortality at 6 and 12 months Secondary Reinfarction at 30 days STEMI ACS

44 HORIZONS - AMI STEMI ACS N Engl J Med 2008;358:

45 Anticoagulation therapy STEMI ACS UFH 60 IU/kg i.v. with GPIs 100 IU/kg i.v. without GPIs Bivalirudin 0.75 mg/kg bolus followed by 1.75 mg/kg/h A recent study suggested bivalirudin monotherapy as an alternative to UFH plus a GPIIb IIIa inhibitor.255 Significantly lower severe bleeding rates led to a beneficial net clinical outcome indicating that bivalirudin may be preferred in STEMI patients at high risk of bleeding. One-year outcome of the HORIZONS RCT confirmed the beneficial action of bivalirudin monotherapy vs. UFH and a GPIIb IIIa inhibitor. European Heart Journal ;doi: /eurheartj/ehq277

46 Impatto delle nuove linee guida nell attività interventistica: Conclusioni Rivascolarizzazione miocardica nelle SCA 1. La doppia antiaggregazione è un trattamento assodato e irrinunciabile 2. Le nuove tienopiridine offrono vantaggi sul fronte antitrombotico ma possono incrementare il rischio emorragico 3. Dobbiamo abituarci,prima dell'avvio del trattamento antitrombotico, a stratificare il rischio emorragico del paziente 4. Gli inibitori glicoproteine devono essere usati nei paziento con alto rischio trombotico ti e trombosi evidente, in bail out ma non in upstream. 5. Non embricare tipi diversi di eparina 6. Considerare l'uso di bivalirudina come alternativa all'eparina nei pazienti ad altro rischio emorragico

47 Impatto delle nuove linee guida nell attività interventistica: Conclusione Rivascolarizzazione miocardica nelle SCA