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Antiagregaciona terapija u kardiovaskularnim bolestima

Antiagregaciona terapija u kardiovaskularnim bolestima. Doc . dr. Neboj ša Tasić Institut za Kardiovaskularne bolesti “Dedinje” Medicinski fakultet Beograd. Ciljevi inhibicije trombocita. x. SCH 530348 E5555. ASPIRIN. TERUTROBAN. HEPARINS FONDAPARINUX BIVALIRUDIN RIVAROXABAN

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Antiagregaciona terapija u kardiovaskularnim bolestima

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  1. Antiagregacionaterapija u kardiovaskularnimbolestima Doc. dr. Nebojša Tasić Institut za Kardiovaskularne bolesti “Dedinje” Medicinski fakultet Beograd

  2. Ciljevi inhibicije trombocita x SCH 530348 E5555 ASPIRIN TERUTROBAN HEPARINS FONDAPARINUX BIVALIRUDIN RIVAROXABAN APIXABAN DABIGATRAN x 5HT 5HT Thromboxane TICLOPIDINE CLOPIDOGREL PRASUGREL A Coagulation Collagen ADP ADP ADP 2 x x ATP ATP GPVI 5HT Thrombin P2Y 2A 1 TP a P2X ACTIVE METABOLITE 1 PAR4 PAR1 x Dense AZD6140 CANGRELOR granule PLATELET P2Y 12 Thrombin generation ACTIVATION Amplification Shape change Alpha granule x x Aggregation a b IIb 3 a b a b IIb 3 IIb 3 Fibrinogen Coagulation factors Inflammatory mediators GP IIb/IIIa ANTAGONISTS PAR = protease-activated receptor; TP = thromboxane A2 / prostaglandin H2. Storey RF. Curr Pharm Des. 2006;12:1255-1259. 10

  3. Antitrombocitnaterapija u KVB

  4. Klopidogrel u kardiovaskularnimbolestima Primenaklopidogrela u KVB • Šlog • NSTEMI/ACS • STEMI • PCI: BMS/DES • Rizik: benefit profil

  5. TXA 2 Mehanizam delovanja klopidogrela CLOPIDOGREL C ADP ADP Collagen thrombin TXA GPllb/llla (fibrinogen receptor) Activation 2 ASA COX COX=cyclo-oxygenase 1. Jarvis B et al. Drugs 2000; 60: 347–377.

  6. CAPRIE study Lancet 1996, 348: 1329-1339 • N = 19,185, multicentre double-blind trial • Clopidogrel reduces the risk of death/MI/stroke in patients with previous MI, stroke or PVD by RRR 8.7% compared to high-dose aspirin • For every 1000 patients treated 5 combined end points would be prevented • NNT 200 patients • A/E: diarrhoea, rash • Increased cost to NHS £200,000 • Super aspirin will save your life

  7. Ringleb, P. A. et al. Stroke 2004;35:528-532

  8. Florijan, Vršac 65-godine, muškarac Jak bol u grudima dok je muzao krave Nema dijabetes, Otac umro od IM u 48 godini, Bivši pušač (prestao <12 meseci) BP 160/90 mmHg Bolnica: troponin T 8,1, CK 350, CK-MB 45 O2, NTG, aspirin, ACE, Mo • Hitna pomoć stigla za 50min od poziva

  9. Kako lečiti Florijana ? Fibrinoliza? Primarna PCI?

  10. Nakon 3 sata jak bol

  11. PatogenezaAkutnogKoronarnogSindroma Ruptura/erozijaplaka Adhezija trombocita Aktivacija trombocita Parcijalna okluzija/tromboza arterija & nestabilna angina Mikroembolizacija & MI sa non-ST elevacijom Potpuna okluzija arterija/tromboza & ST elevacija MI Adapted from Davies MJ. Circulation. 1990; 82 (supl II): 30-46.

  12. ACS sa perzistentnom ST-segment elevacijom ACS bez perzistentne ST-segment elevacije Adapted from Michael Davies Adapted from Michael Davies Troponin povišen ili ne CK- MB ili Troponin

  13. Anti-Thrombin Rx Heparin LMWH Bivalirudin [ Fondaparinux ] Anti-Platelet Rx GP IIb/IIIa blockers Aspirin Clopidogrel Treatment Strategy Conservative Early invasive PRISM-PLUS REPLACE 2 OASIS-5 PURSUIT CURE ESSENCE TACTICS TIMI-18 PCI ~ 5% stents ~85% stents Drug-eluting stents Prekretnice u lečenju ACS ICTUS ISAR-REACT 2 ACUITY SYNERGY 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Ischemic risk Bleeding risk Adapted from and with the courtesy of Steven Manoukian, MD

  14. ASPIRIN VS PLACEBO ESC guidelines for the management of NSTE-ACS. Eur Heart J 2007; 28: 1598–660.

  15. RR 19% 26% 32% 13% 23% KOJA DOZA ASPIRINA? Kontrola bolja Aspirin bolji 500-1000 mg 160-325 mg 75-150 mg <75 mg Bilo koja doza 0.4 0.6 0.8 1.0 1.2 1.4 ATT Colaborators. B Med J2002;96: 123–131.

  16. CURE - DIZAJN STUDIJE Clopidogrel 300mg udarnadoza n = 12,562 28 zemalja Clopidogrel75mg o.d.(n = 6,259) ASA 75–325 mg o.d. Pacijentisa akutnimkoronarnimsindromom R Duplo-slepolečenjedo 12 meseci (nestabilna angina ili non-Q infarktmiokarda) ASA 75–325 mg o.d. Placebo 1 tab o.d.(n = 6,303) Dan 1 Placebo udarna doza Vizita na otpustu Poseta 12. mesecfinalna Poseta 1. mesec Poseta 3. mesec Poseta 6. mesec Poseta 9. mesec R = Randomizacija The CURE Study Investigators. Eur Heart J 2000; 21: 2033–41.

  17. CURE - REZULTATI Kumulativnidogađaji (Infarkt miokarda, šlog, ilikardiovaskulrna smrt) Placebo*(n = 6,303) Clopidogrel* (n = 6,259) 20% relativnaredukcija rizika p = 0.00009 The CURE Study Investigators. Eur Heart J 2000; 21: 2033–41.

  18. Placebo*(n = 6,303) Clopidogrel*(n = 6,259) Događaj p vrednost • Značajnokrvarenje1 • Životno ugrožavajuće • Druga velika krvarenja • Transfuzijeviše od 2 jedinice krvi1 • Minornakrvarenja1 • Značajnakrvarenja poTIMI definiciji2 • Značajnakrvarenja poGUSTO definiciji3 2.7% 1.8% 0.9% 2.2% 2.4% 1.2% 1.1% 3.7% 2.2% 1.5% 2.8% 5.1% 1.1% 1.2% 0.001 NS 0.002 0.02 < 0.001 0.70 0.48 CURE – HEMORAGIJA The CURE Study Investigators. Eur Heart J 2000; 21: 2033–41.

  19. HEMORAGIJA VS DOZA ASA 6.0% 4.9% 5.0% 4.0% 4.0% 3.5% Stopa krvarenja (%) 3.0% 2.6% Placebo* 2.3% 2.0% Clopidogrel* 2.0% 1.0% 0.0% 100 mg 100–200 mg > 200 mg ASA doza 75–325 mg The CURE Study Investigators. Eur Heart J 2000; 21: 2033–41.

  20. ESC PREPORUKE ZA LEČENJE NSTEMI - 2007 • ASA svim bolesnicima bez kontraindiakcija (160-325mg udarno, 75-100mg odrzavanje) • Klopidogrel - udarna doza 300 mg po • Doza održavanja 75 mg po • Nastaviti 12 meseci od indeksnog događaja ukoliko je rizik krvarenja mali

  21. ALBION – DA LI JE 300MG DOVOLJNO Randomizovana, otvorenastudijasa slepom centralizovanom laboratorijskomprocenom kod pacijenataod 1885 godinasa UA/NSTEMI (unutar 48 h) Clopidogrel 300 mg LD zatim 75 mg qd D2 n=35 LD Clopidogrel 600 mg LD zatim 75 mg qd D2 Kliničko praćenje 30 dana R n=34 Clopidogrel 900 mg LD zatim 75 mg qd D2 n=34 0 1/2 1 2 3 4 5 6 24 Montalescot G. J Am Coll Cardiol2006; 48: 931–38.

  22. ALBION - INHIBICIJA TROMBOCITA Montalescot G. J Am Coll Cardiol2006; 48: 931–38.

  23. ALBION – POVEĆANJE TROPONINA I p=ns Montalescot G. J Am Coll Cardiol2006; 48: 931–38.

  24. ALBION – UČESTALOST MACE Montalescot G. J Am Coll Cardiol2006; 48: 931–38.

  25. ALBION – UČESTALOST KRVARENJA Montalescot G. J Am Coll Cardiol2006; 48: 931–38.

  26. LečenjeRana terapija • Reperfuzija: što je pre moguće • Trombolitička terapija • PrimarnaPCI • Hitna CABG • Refraktorna ishemija • Kardiogeni šok • Koronarna vaskulatura nije pogodna za PCI ili procedura nije uspela • Akutne mehanićke komplikacije AMI (ruptura papilarnog mišića, VSD, ruptura zida LK)

  27. PrimarnaPCI • Sa iskusnim timom (vrata-do-balonavreme<90minuta), superiorna u odnosu na fibrinolitičku terapiju • Brza procena funkcije LK • Procena drugih bolesnih krvnih sudova

  28. “Spašavajuća”PCI • PCI procedura koja se sprovodi kod bolesnika bez adekvatnog odgovora na trombolizu (50% ST segment rezolucija) • Nema adekvatnih podataka o sniženju mortaliteta ili naknadnogMI

  29. Dugotrajni ishod kod bolesnika lečenih sa primarnom PCI ili trombolitičkom terapijom p<0.0001 Keeley Lancet 2003;361:13 Frequency (%) p<0.0001 p=0.0019 p=0.0053 p<0.0001 Recurrent ischaemia Death, non-fatal re-MI, or stroke Non-fatal MI Death Death, excl. SHOCK data

  30. Lečenje AKS Anti-ishemijsko lečenje Antitrombocitni lekovi Antikoagulansi Revaskularizacija/Reperfuzija/Tromboliza Dugotrajno lečenje/sekundarna prevencija

  31. Klopidogrel – tienopyridin izbora doza? pre-lečenje? Trajanje lečenja?

  32. P=0.005 NS Safety (major bleed, neutropenia, thrombocytopenia, early drug discontinuation) Efficacy (Cardiac death, MI, TVR) CLASSICS - clopidogrel vs. ticlopidin posle koronarnog stentinga Circulation 2000;102:624

  33. PCI-CURE: Dizajn studije CURE PCI-CURE N=2,658 patients undergoing PCI Pretreatment Otvoreni protokol-tienopiridin PLACEBO + ASA N = 1345 Praćenje (do 12 mes. nakon rand.) 30 d. post PCI* PCI R Otvoreni protokol tienopiridin CLOPIDOGREL + ASA N = 1313 Pretreatment *1oIshod:CV smrt, MI, urgentna revaskularizacija Mehta SR et al. Lancet 2001:358:527-33

  34. 0.08 Placebo 0.06 Kumulativnastopa rizika 0.04 Clopidogrel RR 0.70 95% CI 0.50-0.97 P=0.03 0.02 0.0 5 10 15 20 25 30 Daninakon PCI Primarniishod:KVsmrt, IM, hitna revaskularizacija Mehta SR et al. Lancet 2001:358:527-33

  35. Placebo 0.10 0.08 0.06 Kumulativnastopa rizika Clopidogrel 0.04 RR 0.75 95% CI 0.56-1.00 P=0.047 0.02 0.0 0 100 200 300 400 Dani nakon PCI KV smrt, IM:Od PCI do krajaperioda praćenja Mehta SR et al. Lancet 2001:358:527-33

  36. Hemoragijske komplikacije Mehta SR et al. Lancet 2001:358:527-33

  37. CREDO: Dizajn studije PCI 28 Dana 12 Meseci Pretretman Clopidogrel# Clopidogrel* Clopidogrel Arm LDClopidogrel# R Placebo* Clopidogrel # Placebo # Placebo Arm • LD=loading doza, PT= Pretretman, R= Randomizcija • # pored standardne terapijeuključujući ASA (325 mg) • pored standardne terapijeuključujući ASA (81-325 mg) JAMA, November 20, 2002 – Vol 288, No 19: 2411 – 2420

  38. 8.5% KOMBINOVANI ISHOD DOGAĐAJA (%) Placebo* Clopidogrel* 0 3 6 9 12 MESECI OD RANDOMIZACIJE Dugoročna korist clopidogrelakod PCI pacijenata 1 godišnji rezultati (IM, Šlog, iliSmrt) 11.5% 27% RRR p = 0.02 *Standardna terapij uključujući ASA JAMA, November 20, 2002 – Vol 288, No 19: 2411 – 2420

  39. Rani efektiudarne dozeclopidogrela pre PCI(pretretman) (Smrt, IM, UrgTVR) 8.3% 18.5 % RRR p = 0.23 6.8% KOMBINOVANI ISHOD DOGAĐAJA (%) PT- Clopidogrel* No-PT * 0 7 14 21 28 DANI OD RANDOMIZACIJE *Od PCI do 28. dana, standardnaterapija uključujući ASA (325mg odrandomizacijedo 28. dana) PT= Pretretman JAMA, November 20, 2002 – Vol 288, No 19: 2411 – 2420

  40. Ukupni bezbednosni ishodi • Nisuopservirana fatalna krvarenja ili intrakranijalnehemoragije • Kada jeclopidogreldavan čitavu godinunije bilo statističkiznačajnog porastau velikim krvarenjima (8.8% vs. 6.7 %, p=0.07), i stope malih krvarenja su bile približno jednake • Približno 2/3 svih velikih krvarenja se dogodio kod pacijenata podvrgnutih CABG: • CABG bolesnici u obe grupesu iskusili visoku incidencuvelikih krvarenja JAMA, November 20, 2002 – Vol 288, No 19: 2411 – 2420

  41. 20µmol ADP-induced platelet aggregation (%) Ticlopidine 2x 500mg, then 250 bd (n=10) 100 Clopidogrel 300mg, then 75mg od (n=10) 80 Clopidogrel 600mg, then 75mg bd (n=10) 60 40 20 0 0 4 24 48 Time after administration (hours) Clopidogrel loading doza – više je bolje? Müller Heart 2001;85;92-3

  42. PCI-CLARITY Dizajn studije 3491 Patients Randomized into CLARITY-TIMI 28 1739 assigned placebo 1752 assigned clopidogrel 300 mg  75 mg/d (NO PRETREATMENT) (CLOPIDOGREL PRETREATMENT) A n g i o g r a p h y Open-label clopidogrel w/ loading dose recommended 930 underwent PCI during index hosp. 933 underwent PCI during index hosp. 30-day clinical follow-up

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