NUOVI ANTICOAGULANTI ORALI (NAO): risultati ottenuti e studi in corso. Dabigatran. Marco Moia

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1 NUOVI ANTICOAGULANTI ORALI (NAO): risultati ottenuti e studi in corso Dabigatran Marco Moia Centro Emofilia e Trombosi A. Bianchi Bonomi Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico di Milano FCSA - Bologna, 8 Novembre 2013

2 Dabigatran etexilate Prodrug of dabigatran, which reversibly inhibits the active site of thrombin Oral bioavailability of 6%, rapidly and completely converted to dabigatran by esterases Plasma levels peak 2 hours after administration Half-life of 14 to 17 hours: once- or twice-daily administration 80% of the drug is excreted unchanged by the kidneys

3 The dabigatran prodrug concept Dabigatran is not absorbed due to its polar molecular structure For oral administration, the prodrug dabigatran etexilate was developed

4 The dabigatran prodrug concept Dabigatran is not absorbed due to its polar molecular structure For oral administration, the prodrug dabigatran etexilate was developed N CH 3 O N N NH 2 H 3 C O N H O N O N O CH 3 No Cyt P450 involved No intermediate in plasma Plasma esterases CH 3 N O N N NH 2 HO N H NH O N Dabigatran

5 Dabigatran: indicazioni attualmente registrate in Italia Profilassi primaria del TEV in: protesi elettiva di anca o ginocchio Profilassi degli eventi ischemici nella FANV

6 Phase III Randomized Controlled Trials of DOAC for Indications Other Than VTE Prevention One study on prosthetic heart valves: RE-ALIGN (dabigatran vs warfarin)

7 FANV

8 N Engl J Med 2009;361

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14 Circulation. 2013;127: Concomitant antiplatelet drugs appeared to increase the risk for major bleeding in RE-LY without affecting the advantages of dabigatran over warfarin

15 The Long Term Multi-Center Observational Study of Dabigatran Treatment in Patients with Atrial Fibrillation: (RELY-ABLE) Study Connolly SJ et al, Circulation, published online June 14, 2013 Patients enrolled in RELY continued to receive the double-blind dabigatran dose for up to 28 months of follow up 5851 patients enrolled (48% of patients originally randomized and 86% of RELY- ABLE-eligible patients) Mean follow up for RELY+ RELY-ABLE receiving dabigatran was 4.3 years

16 RELY-ABLE, annual rates of: Stroke or Systemic Embolism

17 RELY-ABLE, annual rate of: Major Bleeding

18 RELY-ABLE Mortality rates

19 Results Stroke or systemic embolism Dabigatran 150 bid: 1.46 %/year Dabigatran 110 bid: 1.60 %/year Major hemorrhage (hemorrhagic stroke) Dabigatran 150 bid: 3.74 (0.13) %/year Dabigatran 110 bid: 2.99 (0.14) %/year

20 Conclusion During 2.3 years continued treatment with dabigatran after RE-LY, there was a higher rate of major bleeding with dabigatran 150 mg twice daily compared to 110 mg, and similar rates of stroke and death

21 Aderenza: problema critico nelle malattie croniche L aderenza alle terapie a lungo termine per malattie croniche non supera in media il 50% Ne consegue: distorsione sull efficacia, paragonata al risultato degli studi clinici incremento dei costi per gestione complicanze ripercussioni negative sui sistemi sanitari

22 Adherence to anticoagulant treatment with dabigatran in a real-world setting Shulmann S et al, JTH 2013;11: In our clinical practice adherence to the twicedaily dabigatran regimen was generally good, although 12% of the patients had an inadequate adherence

23 Limitations of this study 103 patients only, single-center study (specialized anticoagulation clinic) Short follow-up (mean 1 year) Adherence is likely to decrease with time Actions to counteract this decrease annual discussions on the importance of preventing stroke longer-term evaluation of the adherence routine feedback from the pharmacies

24 TEV

25 RE-COVER N Engl J Med 2009;361:

26 RE-COVER, N Engl J Med 2009;361:

27 N Engl J Med 2013;368: Conclusions: Dabigatran was effective in the extended treatment of VTE and carried a lower risk of major or clinically relevant bleeding than warfarin but a higher risk than placebo

28 Tanti successi, ma anche un insuccesso

29 Eikelboom JW et al, N Eng J Med, September 2013 Conclusions no benefit and an excess risk in patients with mechanical heart valves

30 Complicanze emorragiche nei pazienti anticoagulati per FA (Clinical trials, fase III)

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32 Aim and design Aim: to compare the management and prognosis of major bleeding in patients treated with dabigatran or warfarin Methods: two independent investigators reviewed bleeding reports from 1,034 individuals with 1,121 major bleeds enrolled in 5 phase III trials comparing dabigatran with warfarin in 27,419 patients treated for 6 to 36 months

33 Main results Patients with major bleeds on dabigatran, than those on warfarin: Were older Had lower creatinine clearance More frequently used aspirin or NSAID The 30-day mortality after the first major bleed tended to be lower in the dabigatran group (9.1%) than in the warfarin group (13.0%)

34 Conclusions Patients who experienced major bleeding on dabigatran, compared with those who had major bleeding on warfarin: required more red cell transfusions received less plasma required a shorter stay in intensive care had a trend to lower mortality

35 Dabigatran and Postmarketing Reports of Bleeding Southworth MR et al DOI: /NEJM p The Mini-Sentinel assessment suggests that bleeding rates associated with dabigatran are not higher than those with warfarin, a finding that is consistent with the results of RE-LY

36 Da questi studi, dabigatran appare efficace e sicuro, nel FANV e nel TEV? Sì!

37 Blood. 2013;121(18):