"WORKSHOP FCSA" Milano, 29 maggio 2015 GLI ANTICOAGULANTI DIRETTI (DOAC): I DOAC NEL TROMBOEMBOLISMO VENOSO E NUOVE POSSIBILI INDICAZIONI

Transcript

1 "WORKSHOP FCSA" Milano, 29 maggio 2015 GLI ANTICOAGULANTI DIRETTI (DOAC): I DOAC NEL TROMBOEMBOLISMO VENOSO E NUOVE POSSIBILI INDICAZIONI (Cardioversione, FA valvolari, Neoplasie, Pediatria) Luigi Ria U.O.C. di Medicina Interna Centro Trombosi ed Emostasi P.O. S.Cuore di Gesù Gallipoli ASL LECCE

2 Treatment for VTE Initial (0 to 7 days) LMWH/FDX Long-term (7 days to 3-6 months) VKA Extended (3-6 months to indefinite) VKA or NO TX

3

4 Two possible ways Rivaroxaban/ Apixaban Dabigatran/ Edoxaban

5

6

7 DOACs compared with VKA for acute venous thromboembolism: evidence from phase 3 trials VTE Recurrence or VTE-related death DOACs vs VKAs HR 0.90 (95%CI 0.77,1.06) van Es N. et al. Blood 2014; 124 (12):

8 DOACs compared with VKA for acute venous thromboembolism: evidence from phase 3 trials Major Bleeding DOACs vs VKAs HR 0.61 (0.45,0.83) van Es N. et al. Blood 2014; 124 (12):

9 DOACs compared with VKA for acute venous thromboembolism: evidence from phase 3 trials Other End Point DOACs vs VKAs van Es N. et al. Blood 2014; 124 (12):

10 Indirect comparison of Dabigatran, Rivaroxaban, Apixaban and Edoxaban for the treatment of acute VTE Mantha S et al. J Thromb Thrombolysis 2015; 39:

11 The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in patients Cumulative incidence of recurrent thromboembolism separately in patients with idiopathic (unprovoked) and secondary VTE Prandoni P et al. Haematologica 2007; 92:

12 Treatment for VTE Initial (0 to 7 days) LMWH/FDX Long-term (7 days to 3-6 months) VKA Extended (3-6 months to indefinite) VKA or NO TX

13

14 Efficacy and Safety of New Oral Anticoagulants for Extended Treatment of Venous Tromboembolism: Systematic Review and Meta-Analyses of Randomized Controlled Trials Recurrent symptomatic VTE and VTE-related deaths DOACs vs Placebo Dabigatran vs VKAs Sardar P et al. Drugs 2013; 73(11):

15 Efficacy and Safety of New Oral Anticoagulants for Extended Treatment of Venous Tromboembolism: Systematic Review and Meta-Analyses of Randomized Controlled Trials Major bleeding DOACs vs Placebo Dabigatran vs VKAs Sardar P et al. Drugs 2013; 73(11):

16 Efficacy and Safety of New Oral Anticoagulants for Extended Treatment of Venous Tromboembolism: Systematic Review and Meta-Analyses of Randomized Controlled Trials Major or Clinically Relevant Nonmajor Bleeding DOACs vs Placebo Dabigatran vs VKAs Sardar P et al. Drugs 2013; 73(11):

17 Efficacy and Safety of New Oral Anticoagulants for Extended Treatment of Venous Tromboembolism: Systematic Review and Meta-Analyses of Randomized Controlled Trials All-cause mortality DOACs vs Placebo Dabigatran vs VKAs Sardar P et al. Drugs 2013; 73(11):

18 Overview of NOAC trials in VTE Initial (0 to 7 days) LMWH/FDX Long-term (7 days to 3-6 months) VKA Extended (3-6 months to indefinite) VKA or NO TX LMWH/ FDX LMWH/ FDX DABIGATRAN (RE-COVER and RE-COVER II) EDOXABAN (HOKUSAI VTE) DABIGATRAN (RE-SONATE + RE-MEDY) RIVAROXABAN (EINSTEIN DVT and PE) RIVAROXABAN (EINSTEIN EXTENSION) APIXABAN (AMPLIFY) APIXABAN 2.5 or 5 mg bid (AMPLFY - EXTENSION)

19 NOACs: nuove possibili indicazioni Cardioversione Fibrillazione Atriale Valvolare Profilassi del TEV in Medicina Interna Neoplasie Pediatria

20 ESC 2012 update: cardioversion recommendations Recommendation Class Level For patients with AF of 48 hours duration, or when the duration of AF is unknown, OAC therapy (e.g. VKA with INR 2 3 or dabigatran) is recommended for 3 weeks prior to and for 4 weeks after cardioversion, regardless of the method (electrical or oral/i.v. pharmacological) I B In patients with risk factors for stroke or AF recurrence, OAC therapy, whether with dose-adjusted VKA (INR 2 3) or a NOAC, should be continued lifelong irrespective of the apparent maintenance of sinus rhythm following cardioversion I B Camm AJ et al. Europace 2012; 14:

21 RE-LY sottoanalisi cardioversione: Ictus o Embolia Sistemica (entro 30 giorni dalla CV) 1.8 Ictus/embolia sistemica (%) RR 1.28 (95% CI: ) 0.77 P=0.71 Dabigatran 110 mg BID RR 0.49 (95% CI: ) 0.30 P=0.40 Dabigatran 150 mg BID 0.60 Warfarin Eventi/numero: 5/647 2/672 4/664 BID = due volte al giorno; CI = intervallo di confidenza; RR = rischio relativo Nagarakanti R et al. Circulation 2011;123:

22 RE-LY sottoanalisi cardioversione: Ictus o Embolia Sistemica con o senza TEE 2.5 TEE prima della cardioversione Senza TEE prima della cardioversione Ictus/embolia sistemica (%) Dabigatran 110 mg BID P= Dabigatran 150 mg BID P= Warfarin 0.83 Dabigatran 110 mg BID P= Dabigatran 150 mg BID P= Warfarin Percentuali analoghe di ictus o embolia sistemica con/senza TEE prima della cardioversione BID = due volte al giorno; TEE = ecocardiogramma transesofageo Nagarakanti R et al. Circulation 2011;123:

23 RE-LY sottoanalisi cardioversione: sanguinamenti maggiori Sanguinamenti maggiori (%) RR 2.82 (95% CI: ) 1.70 P=0.06 Dabigatran 110 mg BID RR 0.99 (95% CI: ) P= Dabigatran 150 mg BID Warfarin Eventi/numero: 11/647 4/672 4/664 Sanguinamenti maggiori <30 giorni dopo cardioversione sono stati poco frequenti in tutti i gruppi BID = due volte al giorno; TEE = ecocardiogramma transesofageo Nagarakanti R et al. Circulation 2011;123:

24 Piccinni JP et al. JACC 2013; 61 (19): Flaker G. et al. JACC 2014; 62 (11):

25 Design: randomized, open-label, parallel-group, active-controlled multicentre study Inclusion criteria: Age 18 years, non-valvular AF lasting >48 h or unknown duration, scheduled for cardioversion Cardioversion strategy Early # Delayed R 2:1 R 2:1 Rivaroxaban 20 mg od* 1-5 days VKA Rivaroxaban 20 mg od* 21 days (max 56 days) VKA Cardioversion Cardioversion Rivaroxaban 20 mg od* 42 days VKA Rivaroxaban 20 mg od* 42 days VKA End of study treatment OAC 30-day follow-up *15 mg if CrCl ml/min; VKA with INR ; # protocol recommended only if adequate anticoagulation or immediate TEE Modificata da Ezekowitz MD, et al. Am Heart J 2014;167(5):646-52;

26 primary efficacy and safety endpoints Cappato R, et al. Eur Heart J 2014: doi: /eurheartj/ehu367.

27 NOACs: nuove possibili indicazioni Cardioversione Fibrillazione atriale valvolare Profilassi del TEV in Medicina Interna Neoplasie Pediatria

28 Definition of valvular versus non-valvular AF in trials on NOACs based on exclusion criteria RCT NOACs Criteria for defining a valvular AF RE-LY ROCKET-AF ARISTOTLE ENGAGE AF-TIMI 48

29 Definitions of valvular versus non-valvular AF according to international consensus guidelines Guideline on AF Text with the definition ESC 2010 ESC 2012 Focused update ACC/AHA/ ESC 2011 AHA/ACC/ HRS 2014

30 Esclusione di FA valvolare RE-LY Rocket-AF Aristotle Engage AF Dabigatran Rivaroxaban Apixaban Edoxaban Protesi meccanica E E E E Stenosi mitralica moderata-severa VP severa da operare Protesi biologica E E E E E E I Riparazione valvolare (+anello/plastica) I I I I

31 SVD: considerata significativa dal medico che arruolava per i riflessi sulla pratica clinica RE-LY Ezekowitz MD et al. ACC 2014 Abs Rocket AF Breithardt G et al. EHJ 2014 Tot. trials Aristotle Avezum A et al. ESC 2013 Abs Tot. SVD ,8% ,1% ,4% Insuff. Mitralica ,5% ,7% ,3% Insuff. Aortica ,7% ,3% ,4% Stenosi Aortica ,9% ,7% 384 8,0% Insuff.Tricusp ,8% ,2% St.Mitralica lieve Precedenti procedure su valvole 193 4,9% 131 2,7% 106 5,3% 251 5,2%

32 Clinical characteristics and outcomes in AF and native mitral and aortic valve disease in the ROCKET AF trial Efficacy: Stroke or systemic embolism Breithardt G et al. EHJ 2014: 35:

33 Secondo i criteri di inclusione nei megatrial, i risultati di efficacia dei NOACs sono stati osservati anche in un gran numero di pazienti con: Valvulopatie non emodinamicamente significative, che non necessitano di intervento cardiochirurgico Valvulopatie anche severe, ma differenti dalla stenosi mitralica (2 trial su 3) Interventi di riparazione valvolare senza sotituzione, a differenza di quanto schematizzato nelle linee-guida americane (AHA/ACC 2014)

34 NOACs e VALVULOPATIE Protesi valvolare X meccanica Stenosi mitralica severa Valvulopatia con intervento CCH pianificato Protesi valvolare biologica Pregressa plastica valvolare + anello TAVI o mitral clip? Valvulopatia moderata + severa (esclusa SM) senza intervento pianificato Ok!

36 NEJM 2011; 365: Apixaban 2.5 mg BID for 30 d. vs Enoxaparin 40 mg OD for 14 d.

37 NEJM 2013; 368: Rivaroxaban 10 mg OD for 35 ±4 d. vs Enoxaparin 40mg OD for 10±4 d. Day Relative risk ratio p= for non-inferiority (one-sided)

38 NEJM 2013; 368: Rivaroxaban 10 mg OD for 35 ±4 d. vs Enoxaparin 40mg OD for 10±4 d. Day ARR 1.3%, RRR 22.9% Relative risk ratio p= for superiority (two-sided)

39 NOACs: profilassi del TEV in Medicina Interna Studio di fase 3 MARINER (Efficacy and safety of Rivaroxaban vs placebo in the prevention of symptomatic VTE and VTErelated death post-hospital discharage in high risk, medically ill patients)

41 MAGELLAN and ADOPT: Cancer Patients Gerotziafas GT et al. Ther Clin Risk Manag 2014;10:423-36

42 MAGELLAN and ADOPT: Cancer Patients Gerotziafas GT et al. Ther Clin Risk Manag 2014;10:423-36

43 Pazienti con Cancro Trials con i DOACs in VTE 1058/30989 (3.3%) Wharin C. Blood Rev 2014; 28 (1):1-8

44 NOACs in Acute VTE: Cancer Patients VTE recurrence NOACs vs VKAs Vedovati MC et al. CHEST 2015;147(2):

45 NOACs in Acute VTE: Cancer Patients Major Bleeding NOACs vs VKA Vedovati MC et al. CHEST 2015;147(2):

46

48 Dietrich K. et al. Thromb Res 2015; 135:

49 Rivaroxaban ed età pediatrica FASE IIa somministrazione compresse o sciroppo (20 mg/die) per 30 giorni dopo almeno 2 mesi di trattamento standard Popolazione con VTE di età compresa tra i 6 anni < 18 anni (completata la coorte 12-18, ora aperta la coorte 6 anni < 12 anni) Fine arruolamento: Novembre 2015

50 Rivaroxaban ed età pediatrica fase IIa: obiettivi The primary objective of the study is: to investigate the occurrence of major bleeding and clinically relevant non-major bleeding The secondary objectives of the study are: to characterize the safety and PK/PD profile of a 30-day treatment of rivaroxaban tablets or oral suspension to investigate the occurrence of recurrent venous thromboembolism

51 Overall Study Design Prior standard of care treatment for at least 60 days Pediatric subjects aged 6 years to <18 years with documented prior venous thromboembolism R Baseline Day 0 N=20 Interim Visit Day 15 +/-3 days Rivaroxaban 20 mg once daily s.c.lmwh or VKA Day 30 +/- 3 days End of study treatment Day 60+/- 7 days Follow-up visit N=20 Screening Day-60 to -15 Observational Period Approx.30 days V1 Screening Day-60 to -15 V2 Randomization Day 0 V3 Interim Day 15 +/-3 days V4 End of treatment 30 +/- 3 days V5 Follow-up 60 +/- 7 days

52 NOACs: Take home messages I NOACs hanno efficacia analoga ai VKAs nel trattamento del TEV acuto, ma sono più sicuri Nel trattamento esteso del TEV sono associati ad un basso rischio emorragico Limitate evidenze nei pazienti con cancro Pari sicurezza vs warfarin nei pazienti sottoposti a cardioversione Possibile impiego in alcune valvulopatie escluse le protesi valvolari meccaniche, la stenosi mitralica e le valvulopatie severe con intervento CCH pianificato Non indicazione nella profilassi primaria del paziente con patologia internistica acuta Al momento non ci sono evidenze per l impiego in pediatria