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Novi oralni antikoagulansi u prevenciji trombembolijskog rizika kod fibrilacije atrija

Novi oralni antikoagulansi u prevenciji trombembolijskog rizika kod fibrilacije atrija. Svjetski dan zdravlja, 7. april 2013. godine Naučni simpozijum ATRIJALNA FIBRILACIJA. UDRUŽENJE KARDIOLOGA BiH Radna grupa za aterosklerozu Radna grupa za naprasnu smrt

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Novi oralni antikoagulansi u prevenciji trombembolijskog rizika kod fibrilacije atrija

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  1. Novi oralni antikoagulansi u prevenciji trombembolijskog rizika kod fibrilacije atrija Svjetski dan zdravlja, 7. april 2013. godine Naučni simpozijum ATRIJALNA FIBRILACIJA UDRUŽENJE KARDIOLOGA BiH Radna grupa za aterosklerozu Radna grupa za naprasnu smrt Radna grupa za bazična istraživanja Udruženje kardiologa HNK/Ž Akademik Doc.dr Emir Fazlibegović, ESC, FESC Mostar 04.04.2013.

  2. Kratka istorija antikoagulanasa UFH: antitrombin zavisna inhibicija FXai thrombinau odnosu 1:1 Parenteral 1930s VKAs: indirektni uticaj na sintezu brojnih od vitamina K-zavisnih faktorakoagulacije Oral 1940s LMWH: antitrombin-zavisna inhibicija FXa >trombin Parenteral 1980s 1990s Parenteral DTIs Parenteral 2000s Indirektni FXa inhibitori Oral DTIs Direktni FXa inhibitori Oral • Oralni warfarin je jedini antikoagulans za hroničnu upotrebu UFH, nefrakcionirani heparin; LMWH, niskomolekularni heparin; DTIs, direktni inhibitori trombina Alban. Eur J Clin Invest 2005; Link. Circulation 1959; Maraganore et al. Biochemistry 1990

  3. Potencijali antikoagulansii njihova ciljna mjesta ORALNI PARENTERALNI TF/VIIa TFPI (tifacogin) TTP889 X IX APC (drotrecoginalfa) sTM (ART-123) IXa VIIIa RivaroxabanApixabanLY517717YM150 DU-176bBetrixaban Va AT Xa FondaparinuxIdraparinux II (trombin) DX-9065aOtamixaban IIa Dabigatran Fibrinogen Fibrin APC, activated protein C; AT, antithrombin; sTM, soluble thrombomodulin; TF, tissue factor; TFPI, tissue factor pathway inhibitor Adapted from Weitz & Bates. J Thromb Haemost 2005

  4. Faktori koji utiču na primjenu antikoagulanasa Starost od 80 i > godina(biološkapremahronološkoj) Procjenarizika od krvarenja(absolutni premarelativni) Mogućnost INR monitoringa(prevoz, udaljenost, cijena) Pacijentove želje(razmotriti životni stil) INR, international normalized ratio

  5. Prosthetic Valves Thromboses

  6. Rizik od krvarenja kod pacijenata sa AIMtretiranih različitim kombinacijama:aspirin, clopidogrel i vitamin K antagonista

  7. CHADS -2 / HAS - BLED SCORE

  8. Nove strategije sa novim antikoagulansima Heparin(s) Fondaparinux Početno odmjeravanje dvije standarne opscije AVK Istraživanje novih oralnih antikoagulanasa Heparin(s) Fondaparinux Dabigatran Jedan lijek u jednoj dozi u dugoroćnoj prevenciji Apixaban, Rivaroxaban

  9. Velike studije sa novom generacijom antikoagulanasa

  10. Primary Endpoint of Stroke or Systemic Embolism: Non-inferiority Analysis Non Inferiority p vswarfarin RE-LY Dabigatran 110 mg 1.53% per year Dabigatran 150 mg 1.11% per year Warfarin 1.69% per year ROCKET AF Rivaroxaban 20mg 1.7% per year Warfarin 2.2% per year ARISTOTLE Apixaban 5 mg 1.27% per year Warfarin 1.60% per year ITT Analysis HR = 0.91 p<0.001 HR = 0.66 p<0.001 Modified ITT HR = 0.79 p<0.001 ITT Analysis HR = 0.79 p<0.001 ROCKET showed non-inferiority in ITT analysis. An on treatment or per-protocol analysis is generally performed in the assessment of non-inferiority. If numerous patients come off of study drug, this biases the trial towards a non-inferior result in an ITT analysis. This is the basis for performing a per-protocol analysis in a non-inferiority assessment. NB: Indirect comparison only. No head to head comparison available. C. Michael Gibson, M.S., M.D. Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011

  11. ITT P-value Hemorrhagic Stroke RELY HR Dabigatran 110 mg 0.12% / yr 0.31 <0.001 Dabigatran 150 mg 0.10% / yr 0.26 <0.001 Warfarin 0.38% / yr ROCKET Rivaroxaban 20 mg 0.26% / yr 0.59 0.012* Warfarin 0.44% / yr ARISTOTLE Apixaban 5 mg 0.24% / yr 0.51 <0.001 Warfarin 0.47% / yr *In an on treatment analysis in Rocket AF Hemorrhagic Stoke rates were 0.26% / yr for rivaroxaban and 0.44% / yr for warfarin, p=0.024. No on treatment analysis is available from RE-LY. NB: Indirect comparison only. No head to head comparison shown. C. Michael Gibson, M.S., M.D. Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011

  12. ITT P-value Ischemic Stroke HR RELY Dabigatran 110 mg 1.34% / yr 1.20 0.35 Dabigatran 150 mg 0.92% / yr 0.76 0.03 Warfarin 1.20% / yr ROCKET Rivaroxaban 20 mg 1.62% / yr 0.99 0.92* Warfarin 1.64% / yr ARISTOTLE Apixaban 5 mg 0.97% / yr 0.92 0.42 Warfarin 1.05% / yr *In an on treatment analysis in Rocket AF Ischemic Stoke rates were 1.34% / yr for rivaroxaban and 1.42% / yr for warfarin, p=0.58. No on treatment analysis is available from RE-LY. NB: Indirect comparison only. No head to head comparison available C. Michael Gibson, M.S., M.D. Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011

  13. Major Bleeding ITT P-value RE-LY HR Dabigatran 110 mg 2.71% / yr 0.8 0.003 Dabigatran 150 mg 3.11% / yr 0.93 0.31 Warfarin 3.36 150 mg Dabigatranvs 110 mg Dabigatran = HR of 1.16 (1.00–1.34) p = 0.052 On Treatment P-value ROCKET Rivaroxaban 20 mg 3.60% / yr 0.92 0.58* Warfarin 3.45% / yr 2 g drop *There is no ITT analysis of safety in Rocket AF. There is no on treatment analysis of safety from RE-LY. P-value ARISTOTLE Apixaban 5 mg 2.13% / yr 0.69 <0.001 Warfarin 3.09% / yr 2 g drop in 24 hours NB: Indirect comparison only. No head to head comparison available. C. Michael Gibson, M.S., M.D. Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011

  14. All Cause Mortality ITT p-value HR RELY Dabigatran 110 mg 3.75% / yr 0.91 0.35 Dabigatran 150 mg 3.64% / yr 0.88 0.051 Warfarin 4.13% / yr ROCKET Rivaroxaban 20 mg 4.52% / yr 0.92 0.152* Warfarin 4.91% / yr ARISTOTLE Apixaban 5 mg 3.52% / yr 0.89 0.01 Warfarin 3.94% / yr 95% CI 0.89 (0.80, 0.998) N=448 events planned, 480 in trial *In an on treatment analysis in Rocket AF mortality rates were 1.87% / yr for rivaroxaban and 2.21% / yr for warfarin, p=0.073. No on treatment analysis is available from RE-LY. NB: Indirect comparison only. No head to head comparison available. C. Michael Gibson, M.S., M.D. Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011

  15. VerifyNowTM (Ultegra rapid platelet function assay) • Turbidimetric based optical detection system – to measure PLT induced aggregation as an increase in light transmission • Simple, rapid report, not require specialized technician • “Point-of-care system”

  16. Impact of Platelet Reactivity on Clinical Outcomes After PCI Failure Rate for Normal and High On-TreatmentPlateletReactivity(P2Y12 reaction unit - PRU > 230) Brar S J Am Coll Cardiol, 2011; 58:1945-1954

  17. Gene-Matrix Trial 4000 PCI patients Standard of care vs Customized antiplatelet treatmentaccording to platelet FunctionTesting and genotyping for CYP450 2C19*2 and ABCB1 C

  18. Whatis cooking behind the scene ? • New regimens / applications • Accoast • Atlantic • Pegasus • Euromax (bivalirudin vs SOC STEMI) • Brave 4 (prasugrel + bivalirudin vs SOC in STEMI) • AAA (dabigatran in Afib & ACS) • Re-Align (Dabigatran in mechanicalheart valves) • New antiplatelet agents • Elinogrel / Cangrelor / Vorapaxar • New anticoagulants (verymany)

  19. New Parenteral Anticoagulants under Investigation • Idrabiotaparinux, • ultra-low-molecular-weight heparins, re-engineered UFH [M118]), • Direct FIIa inhibitors , flovagatran sodium, pegmusirudin, NU172, HD1-22), • Direct FXIa inhibitors (BMS-262084, antisense oligonucleotides targeting FXIa, clavatadine), • FIXa inhibitors (RB-006), • FVIIIa inhibitors (TB-402), • FVIIa/tissue factor inhibitors (tifacogin, NAPc2, PCI-27483, BMS-593214), • FVa inhibitors (drotrecogin alpha activated, ART-123) • Dual thrombin/FXa inhibitors (EP217609, tanogitran).

  20. jednom dnevno Predvidljivefarmakokinetikeifarmakodinamike Visoka oralna bioraspoloživpost Brzo djelovanje Fiksna doza Ne zatijeva monitoring koagulacije Rivaroxaban:novi oralni, direktni inhibitorFaktora Xa Rivaroxaban Rivaroxaban se veže direktno za aktivno mjesto Faktora Xa (Ki 0.4 nM) Roehrig et al. 2005; Perzborn et al. 2005; Kubitza et al. 2005; 2006; 2007

  21. Pacijenti sa svježim akutnim koronarnim sy. Stabilizacija 1–7 dana od početka događaja Aspirin 75–100 mg N ~3,500 MD odluka za liječenjeclopidogrelom NE DA STRATUM 1 STRATUM 2 *Doze od 5, 10 i 20 mg Placebo Placebo Rivaroxabandvaput/dan 3 doze* Rivaroxabandvaput/dan 3 doze* Rivaroxabanjednom /dan 3 doze* Rivaroxabanjednom/dan 3 doze* Tretman tokom 6 mjeseci Primarnicilj:TIMI značajno krvarenje

  22. Pacijenti sa AF + ≥2 riziko faktora: CHF, hipertension, ≥75 god., diabetes ili ICV, TIA ili sistemskaembolija n ~14,000 Rivaroxaban Warfarin 20 mg dnevno 15 mg za CrCl 30–49 INR ciljni 2.5 (2.0–3.0 ) Monthly monitoring and adherence to standard of care guidelines Mjesečni monitoring prema prihvaćenim standardima liječenja Primarnicilj: ICV ili ne-CNS sistemski embolizam TIA, tranzitorna ishemijska ataka;ICV:moždani udar;CHF:hronična srčana slabost CrCl, kreatininklirens

  23. Sprovedena u 45 zemalja, 1178 centara, na 14 264 pacijenta

  24. Primarni rezultati efikasnosti kod moždanog udara i ne-CNS embolije

  25. ROCKET-AF: Primarni rezultat efikasnosti

  26. Primarni rezultati - sigurnost

  27. ROCKET-AF: Krvarenja

  28. Ključni sekundarni rezultati efikasnosti

  29. Sumarni rezultati ROCKET AF studije Rivaroxaban : Warfarin (Čikago,15.Nov 2010.) Efikasnost: Rivaroxaban nije bio slabiji od warfarina u prevenciji ICV i drugih embolizama. Rivaroxaban je bio bolji od warfarina kod pacijenata koji su uzeti u studiju sa lijekom. Na početku tretmana, rivaroxaban nije bio slabiji niti mnogo bolji od warfarina Sigurnost: Sličnost u broju krvarenja i dodatnih događanja Manje ICH i fatalnih krvarenja sa rivaroxabanom. Zaključak: Rivaroxaban može biti alternativa warfarinu kod srednje do visokorizičnih pacijenata sa AF.

  30. PrimarnaICH15% % of Patients with Ischemic Stroke Ishemična73% Subdural / Subarahnoidalna12% Nakon D/Cwarfarinn=44 (55%) NawarfarinINR <2.0n=17 (21%) KontrolnaAFn=25 (31%) AFFIRM: CNS događanja kod pacijenata koji su prevedeni uSR AFFIRM Investigators. New Engl J Med. 2002;347:1825-1833.

  31. Kontrola odgovora: DCKardioverzijakod PerzistentneAF u RACE Study • 522 pacijenta saperzistentnomAF/AFl 24 hdo1 grandomizirano je premakontrola odgovora/ritma • 90%iz grupe sa kontrolom odgovora,a91% sa kontrolom ritma je imalo1 ili višerizikofaktoraza moždani udar • kontrola odgovora u miru<100/min • kontrola ritma sa DC konverzijom ili antiaritmicima • praćenje2 godine • Primarni rezultat: uzrok smrti zbogkardiovaskularnihi drugih događanja, pacemaker implantacija i antiaritmici Van Gelder et al. N Engl J Med. 2002;347:1834-1840.

  32. Zanemarenost antikoagulantne terapije u AF* Oko polovine pacijenata sa AF uzima warfarin 13 opštih bolnica 21 kliničkih bolnica Warfarin therapy No warfarin therapy 53% 47% 53% 47% *US population January–December 2002AF, atrial fibrillation Waldo et al. J Am Coll Cardiol 2005

  33. Optimlna dozawarfarinau prevenciji ICVu AF Prothrombin time ratio >2.0 (INR of 3.7 to 4.3) increases the risk of bleeding Odds ratio of stroke by INR Bleeding Stroke 18.2 11.2 10 15 8 10 6 Odds ratio for stroke Odds ratio for ICH 4 5 3 2 1 0 0 0 1.4 1.6 1.8 2 2.3 2.7 1.0 1.5 2.0 3.0 4.0 7.0 Prothrombin time ratio INR AF, atrial fibrillation; ICH, intracranial haemorrhage; INR, international normalized ratio Hylek & Singer. Ann Intern Med 1994; Hylek et al. N Engl J Med 1996

  34. Optimal intensity for warfarin for stroke prevention in AF 20 15 Ischaemic stroke Intracranial bleeding Odds ratio 10 5 1 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 INR AF, atrial fibrillation; INR, international normalized ratio Fuster et al. Circulation 2006

  35. Tretman AF prema starosti Antikoagulansi i rizik za ICV Stroke rate Unmet need Probability Warfarin use Age AF, atrial fibrillation White et al. Am J Med 1999; Wolf et al. Arch Intern Med 1987

  36. Ograničenja za upotrebu antagonista vitamina K (3) • Otpor u propisivanju antagonista vitamina K • Posebno starijim pacijentima zbog visokog pretpostavljenog rizika naspram mogućeg benefita • Bojazan od intrakranijalnog krvarenja, najteže komplikacije krvarenja

  37. Karakteristike‘idealnog’ antikoagulansa Doziranje jednom dnevno Širok terapeutski prozor Fiksna doza Da ne stupa u interakciju sa hranom i lijekovima Brzo postizanje i brz prekid aktivnosti Predvidljivafarmakokinetikaifarmakodinamika Brzi reverziblniefekt Bez potrebnog monitoringa primjene

  38. Rezultati ROCKET studije • Efikasnost • Rivaroxaban nije bio inferiorniji od varfarina u prevenciji moždanog udara i ne-CNS embolije • Sigurnost • Sličan nivo pojave krvarenja i neželjenih efekata • Manje intrakranijalnih krvarenja i smrtnih krvarenja sa rivaroxabanom • Zaključak RIVAROXABAN JE DOKAZANA ALTERNATIVA VARFARINU ZA SREDNJE ILI VISOKO RIZIČNE PACIJENTE SA ATRIJALNOM FIBRILACIJOM

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