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Ugo Limbruno

I nuovi antiaggreganti piastrinici: alla ricerca di una maggiore efficacia e di un minore rischio emorragico. Ugo Limbruno. Cardiology Unit ASL 9 Grosseto, Italy. Farmaci antitrombotici nelle SCA. enoxaparin fondaparinux bivalirudin. ASA. +UFH. +Thyenop. + IIb/III a

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Ugo Limbruno

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  1. I nuovi antiaggreganti piastrinici: alla ricerca di una maggiore efficacia e di un minore rischio emorragico Ugo Limbruno Cardiology Unit ASL 9 Grosseto, Italy

  2. Farmaci antitrombotici nelle SCA enoxaparin fondaparinux bivalirudin ASA +UFH +Thyenop. +IIb/IIIa inhib. berlin 1960 2007

  3. thrombotic risk bleeding risk Adverse events (outcome) Antithrombotic therapy intensity

  4. PCI thrombotic risk bleeding risk “optimal” therapy Adverse events (outcome) Antithrombotic therapy intensity

  5. Tienopiridine ASA Inib. GP IIb/IIIa

  6. ASA/tienopiridine: principali limiti Clopidogrel ASA -30% control ASA 325mg Montalescot et al. J Am Coll Cardiol. 2006;48:931 Malinin et al, Blood Coag Fibrin 2004;15;295.

  7. ASA/tienopiridine: principali limiti Clopidogrel ASA pts resistance: 8% resistance: up to 45%! control ASA 325mg Malinin et al, Blood Coag Fibrin 2004;15;295. Jernberg et al, Eur Heart J 2006;27;1166

  8. Clop 600 mg Pras 60 mg Pras 60 mg latenza d’azione IPA (%) Clop 300 mg hours Payne CD et al. Presented at TCT 2006

  9. Tienopiridine: principali limiti • Ridotta potenza antiaggregante • (problema per DES) • Resistenza/risposta individuale variabile • Profarmaci Latenza azione • (problema per PCI urgenti) • Inibitori irreversibili P2Y12Durata azione • (problema per CABG)

  10. i nuovi antipiastrinici… • Prasugrel • AZD6140 • Cangrelor • TRA-SCH 530348

  11. Prasugrel AZ6140 Cangrelor SCH-530348

  12. Tienopiridine: 3 generazioni Ticlopidine (1st generation) • Inibitori irreversibili • del rec. P2Y12 • Profarmaci Clopidogrel (2nd generation) Prasugrel (3rd generation)

  13. O CH3 O C O N N O O C S S F Cl C H 3 O O N N HOOC O * HS S F F Pro-drug Clopidogrel Prasugrel 85% Inactive Metabolites metabolismo + efficiente! Active metabolite

  14. Prasugrel: un nuova, più potente tienopiridina prasugrel clopidogrel Jernberg et al, Eur Heart J 2006;27;1166-1173.

  15. Prasugrel: meno non-responders acuto cronico Jernberg et al, Eur Heart J 2006;27;1166-1173.

  16. Prasugrel: trials JUMBO-TIMI26 (900 pts) Phase 2 (dose ranging) TRITON-TIMI38 (13.000 ACS pts) Phase 3

  17. Prasugrel: TRITON-TIMI 38 TIMI 38. N Engl J Med 2007;357:2001

  18. Prasugrel: TRITON-TIMI 38 Prasugrel non indicato in: - paz. con prec. stroke - età>75aa, <65Kg TIMI 38. N Engl J Med 2007;357:2001

  19. AZD 6140 • Non è una tienopiridina • Non è un profarmaco • Inibitore reversibile • del rec. P2Y12 rapido “offset” Breve latenza d’azione Minor variabilità azione

  20. AZD6140: trials DISPERSE DISPERSE-2 (990 pts) Phase 2 PLATO (18.000 ACS pts) Phase 3

  21. AZD 6140: DISPERSE trial AZD6140 100 mg bid Clopidogrel Day 1 Day 14 Day 1 Day 14 100 100 80 80 Mean % inhibition Mean % inhibition 60 60 40 40 20 20 2 4 8 12 2 4 8 12 24 2 4 8 12 2 4 8 12 24 Time ( hours) Time (hours) Husted S et al. Eur Heart J. 2006;27:1038

  22. AZD 6140: DISPERSE-2 trial 990 ACS pts: bleedings at 30 days Minor Major 12 9.8 10 8.0 8.1 8 Total Bleeding Rate, % 6 4 2 0 AZD6140 90 mg bid AZD6140 180 mg bid Clopidogrel 75 mg qd Cannon CP et al. J Am Coll Cardiol 2007;50:1844

  23. AZD 6140: DISPERSE-2 trial Ventricular pauses >2.5 sec 12 9.9% 10 8 5.6% % 6 4.8% 4.4% 3.2% 4 2 0 AZD6140 AZD6140 Study A Study B Clop 90 mg 180 mg Clopidogrel in 2 different early ACS trials Patients from DISPERSE2 Cannon CP et al. J Am Coll Cardiol 2007;50:1844

  24. Cangrelor • Analogo ATP • Inibitore reversibile • del rec. P2Y12 • uso endovena Farmaco “ideale” per PCI: rapido onset-offset d’azione

  25. Cangrelor: phase 2 trial start cangrelor n=105 stop abcximab n=94 Greenbaum A et al. Am Heart J 2006;151:689

  26. Clopidogrel SCH-530348 + VS Prasugrel AZD6140 (Cangrelor) ASA

  27. SCH-530348: trials Inibitore del recettore per la trombina PAR-1 (on top of ASA+clopidogrel) TRA-PCI (573 pts) Phase 2 TRA-ACS (10.000 ACS pts) TRA 2P-TIMI 50 (19.500 ATS pts) Phase 3

  28. Conclusioni • ASA-Tienopiridine, gli “unmet needs”: • insufficiente azione antiaggregante (problema DES). • variabilità di effetto, non-responders. • latenza d’azione (PCI urgenti). • Nuovi antiaggreganti: • Prasugrel: + rapido, + potente, - nonresp, + emorragie! • AZD6140, Cangrelor, SCH-530348: solo trials fase 2.

  29. Conclusioni E’ cruciale che il trattamento antipiastrinico del futuro offra un corretto bilanciamento tra effetti anti-trombotici e pro-emorragici in tutti i pazienti.

  30. PCI Transradial ! thrombotic risk bleeding risk “optimal” therapy Adverse events (outcome) Adverse events (outcome) Antithrombotic therapy intensity

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