Nuovi Anticoagulanti Orali Stato dell Arte e Nuove Linee Guida

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1 Nuovi Anticoagulanti Orali Stato dell Arte e Nuove Linee Guida Antonio Di Chiara Ospedale di San Daniele-Tolmezzo AAS n.3 Alto Friuli Collinare Medio Friuli

2 ASA none NOAC VKA Modificata da Huisman MV, et al. J Am Coll Cardiol. 2017;69:

3 Agenda Focus su sottogruppi degli studi dei NOACs nella NVAF Anziani Valvulopatie Il problema del sotto dosaggio Indicazioni dei NOACs diverse dalla NVAF Studi in corso Sostenibilità economica 4

4 AGENDA POPOLAZIONE ANZIANA 5

5 AGE >75 yrs 40% 43% 31% 41%

6 Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation. A meta analysis of randomised trials Stroke and Systemic Embolic Events subgroups Major Bleeding subgroups Ruff CT et al. Lancet 2014;383:

7 Risultati di efficacia e sicurezza in relazione all età Pazienti trattati con edoxaban 30 mg con peso 60 kg, compromissione moderata della funzionalità renale o uso concomitante di inibitori della P-gp. Kato ET et al. J Am Heart Assoc. 2016;5:e003432doi: /JAHA

8 Risultati di efficacia e sicurezza nei pazienti con età >85aa Ictus/EES < 85 anni 85 anni Warfarin Incidenza (%/anno) 1,7 3,5 Edoxaban 60/30* Incidenza (%/anno) 1,5 2,5 Edoxaban 60/30* vs Warfarin HR (95% Cl) 0,88 (0,75 1,03) 0,73 (0,40 1,33) P int 0,56 Ictus ischemico < 85 anni 85 anni 1,2 2,4 1,2 1,9 1,01 (0,84 1,22) 0,79 (0,39 1,60) 0,50 Ictus emorragico < 85 anni 85 anni 0,5 0,8 0,3 0,5 0,53 (0,37 0,76) 0,64 (0,18 2,28) 0,78 Sanguinamenti maggiori < 85 anni 85 anni 3,3 8,8 2,7 5,0 0,82 (0,72 0,94) 0,58 (0,35 0,94) 0,17 ICH < 85 anni 85 anni 0,8 1,6 0,4 0,9 0,46 (0,33 0,62) 0,61 (0,20 1,88) 0,62 Sanguinamenti fatali < 85 anni 85 anni 0,4 0,6 0,2 0,6 0,52 (0,33 0,82) 0,99 (0,20 4,91) 0,45 Kato ET et al. J Am Heart Assoc. 2016;5:e003432doi: /JAHA

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10 AGENDA NVAF E VALVULOPATIE 14

11 History of VHD in Pts Randomized in ARISTOTLE, ROCKET AF, and RE LY J Am Heart Assoc. 2016;5:e002776

12 Efficacy and Safety of DOACs Versus Warfarin in Patients With or Without VHD in the ARISTOTLE, ROCKET-AF, and RE-LY Studies J Am Heart Assoc. 2016;5:e

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14 AGENDA SOTTODOSAGGIO 21

15 0 % 21% 4.7% 25%

16 Off-Label Dosing of Non-Vitamin K Antagonist Oral Anticoagulants and Adverse Outcomes: The ORBIT-AF II Registry Steinberg et al. JACC vol.68, no. 24,

17 Large U.S. administrative database, 14,865 patients with AF October September 30, 2015 Use of a standard dose in patients with a renal indication for dose reduction (potential overdosing) Use of a reduced dose when the renal indication is not present (potential underdosing). Among the 1,473 pts with a renal indication for dose reduction, 43.0% were potentially overdosed higher risk of major bleeding (HR 2.19; 95% CI ) no difference in stroke (3 NOACs pooled). Among the 13,392 pts with no renal indication for dose reduction, 13.3% were potentially underdosed higher risk of stroke (HR: 4.87; 95% CI 1.30 to 18.26) but no statistically significant difference in major bleeding in apixaban. No relationships in dabigatran- or rivaroxabantreated patients without a renal indication.

18 NOACs Stroke non emorragico Edoxaban 30/15 mg daily Ruff CT et al. Lancet 2014;383:

19 Popolazione con aggiustamento della posologia in base ai criteri prespecificati Nello studio Engage i pazienti arruolati nel braccio 60/30 che hanno ridotto il dosaggio per insufficienza renale, basso peso corporeo o uso concomitante di inibitori delle pgp sono stati Di questi: 1306 pazienti per CrCl ml/min (60%) 684 pazienti per peso corporeo 60Kg (31%) 227 pazienti per utilizzo concomitante di inibitori delle pgp (<10%) 424 pazienti presentavano più di un criterio *Pazienti trattati con edoxaban 30 mg con peso 60 kg, compromissione moderata della funzionalità renale o uso concomitante di inibitori della P-gp. Ruff CT et al. Lancet 2015;385 (9984):

20 Endpoint di efficacia e sicurezza in base alla riduzione del dosaggio nei pazienti con caratteristiche prespecificate Ruff CT et al. Lancet 2015;385

21 AGENDA INDICAZIONI DIVERSE DA NVAF 31

22 Anticoagulant VKA Low-Shear Stress Thrombosys Antiplatelet High-Shear Stress Thrombosys ESUS (embolic stroke unknown origin) NVAF Protesi valvolari biologiche DVT/PE Protesi Valvolari Meccaniche Sindrome Anticorpi Antifosfolipidi Fibrillazione Atriale Reumatica Ictus (aterosclerosi grandi arterie) Sindromi coronariche acute Trombosi di stent 32

23 Stroke. 1993;24: WARFARIN 3/7 hyperaggr. 3/7 normal 1/7 inhibition ASPIRIN 7/17 partial 10/17 complete

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25 Wienen W et al. Thromb Haemost 2007; 98:

26 NAVIGATE ESUS ESUS R Rivaroxaban 15 mg once daily Aspirin 100 mg once daily

27 RESPECT ESUS ESUS R Dabigatran 150/110 mg twice daily Aspirin 100 mg once daily

28 ATTICUS ESUS R Apixaban 5/2.5 mg twice daily Aspirin 100 mg once daily

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30 Pioneer AF-PCI Primary Safety End Point major bleeding or minor bleeding [TIMI criteria] or requiring medical attention N Engl J Med 2016;375:

31 Pioneer AF-PCI Secondary Efficacy End Point death from cardiovascular causes, myocardial infarction, or stroke N Engl J Med 2016;375:

32 Study Design: Multicenter, randomized, open-label trial following a PROBE design Paroxysmal, persistent or permanent NVAF ACS successfully treated by PCI and BMS or DES Stable CAD successfully treated by elective PCI and BMS or DES R Dabigatran 150 mg BID + P2Y12 inhibitor Dabigatran 110 mg BID + P2Y12 inhibitor Warfarin (INR ) + P2Y12 inhibitor + ASA 6-month minimum treatment duration with visits every 3 months for the first year, then visits and telephone contact alternating every 3 months and a 1-month post-treatment visit Mean duration of follow-up: ~14 months N=2725 Randomization 120 hours post-pci* Dabigatran (110 or 150 mg) P2Y12 inhibitor Warfarin P2Y12 inhibitor 1 month of ASA (BMS) 3 months of ASA (DES) *Study drug should be administered 6 hours after sheath removal and no later than 120 hrs post-pci ( 72 hrs is preferable). PROBE, prospective, randomized, open, blinded end-point; R, randomization; BMS, bare metal stent; DES, drug-eluting stent. ClinicalTrials.gov: NCT ; Cannon et al. Clin Cardiol 2016

33 Probability of event (%) Primary Endpoint: Time to first ISTH major or clinically relevant non-major bleeding event HR: 0.52 (95% CI: ) Non-inferiority P< P< Warfarin triple therapy HR: 0.72 (95% CI: ) Non-inferiority P< P=0.002 Warfarin triple therapy Dabigatran 110 mg dual therapy Dabigatran 150 mg dual therapy Time to first event (days) Time to first event (days) Full analysis set presented. HRs and Wald CIs from Cox proportional-hazard model. For the dabigatran 110 mg vs warfarin comparison, the model is stratified by age, non-elderly vs elderly (<70 or 70 in Japan and <80 or 80 years old elsewhere). For the dabigatran 150 mg vs warfarin comparison, an unstratified model is used, elderly patients outside the USA are excluded. Non-inferiority P value is one sided (alpha=0.025). Wald two-sided P value from (stratified) Cox proportional-hazard model (alpha=0.05)

34 Patients with outcome event (%) Rate of intracranial haemorrhage 1,5 1 HR: 0.30 (95% CI: ) P= % HR: 0.12 (95% CI: ) P= % 0,5 0 ARR: 0.7% 0.3% Dabigatran 110 mg dual therapy (n=981) Warfarin triple therapy (n=981) ARR: 0.9% 0.1% Dabigatran 150 mg dual therapy (n=763) Warfarin triple therapy (n=764) Wald two-sided P value from (stratified) Cox proportional-hazard model (alpha=0.05)

35 Additional individual thromboembolic endpoints Dabigatran 110 mg dual therapy (n=981) n (%) Warfarin triple therapy (n=981) n (%) All-cause death 55 (5.6) 48 (4.9) Stroke 17 (1.7) 13 (1.3) D110 DT vs warfarin TT Dabigatran 150 mg dual therapy (n=763) Warfarin triple therapy (n=764) D150 DT vs warfarin TT HR (95% CI) P value HR (95% CI) P value n (%) n (%) 1.12 ( ) 1.30 ( ) (3.9) 35 (4.6) 0.83 ( ) (1.2) 8 (1.0) 1.09 ( ) 0.85 Unplanned revascularization 76 (7.7) 69 (7.0) 1.09 ( ) (6.7) 52 (6.8) 0.96 ( ) 0.83 MI 44 (4.5) 29 (3.0) Stent thrombosis 15 (1.5) 8 (0.8) 1.51 ( ) 1.86 ( ) (3.4) 22 (2.9) 1.16 ( ) (0.9) 7 (0.9) 0.99 ( ) 0.98 Results presented are times to event. Stent thrombosis is time to definite stent thrombosis

36 Apixaban Versus Warfarin in Patients with AF and ACS or PCI: The AUGUSTUS Trial Inclusion AF (prior, persistent, or >6 hrs duration) Physician decision that oral anticoag is indicated ACS and/or PCI with planned P2Y12 inhibitor for 6 months Randomize n =4,600 Patients Exclusion Contraindication to DAPT Other reason for warfarin (prosthetic valve, mod/sev MS) Apixaban Warfarin P2Y12 inhibitor for all patients x 6 months ASA placebo ASA placebo Primary outcome: major/clinically relevant bleeding (through 6 months) Secondary objective: Death, MI, stroke, stent thrombosis

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41 APPRAISE-2 STUDY Engl J Med 365;8. August 25, 2011

42 AGENDA STUDI IN CORSO 55

43 Protesi valvolari cardiache. Meccaniche 2013 Re-Align Dabigatran vs VKA studio negativo Nessuno studio in corso Rheumatic Valvuar Heart Disease A prospective, phase 3, randomized, open-label superiority trial in RVHD comparing rivaroxaban to aspirin in high risk patients either with AF and unsuitable for VKA or without AF and with high risk factors 56

44 Protesi valvolari cardiache Biologiche RIVER A Phase 2, Randomized, Open Label, Non-Inferiority Clinical Trial to Explore the Safety and Efficacy of Rivaroxaban Compared With Vitamin K Antagonism in Patients With Atrial Fibrillation With Bioprosthetic Mitral Valves ATLANTIS A phase IIIb randomised study assenssing efficacy (superiority) and safety of Apixaban versus Standard of Care (DAPT or VKA) following successful TAVR GALILEO Phase III open-label, randomised, study assessing the safety and efficacy of a rivaroxaban-based anticoagulation regimen versus an antiplatelet regimen following successful TAVR 57

45 AGENDA SOSTENIBILITÀ ECONOMICA 58

46 VKAs vs DOACs AAS3 Alto Friuli-Collinare-Medio Friuli Pazienti in TAO per mese Pazienti in NAO per mese

47 Nuovi Anticoagulanti Orali. Spesa Sanitaria in FVG 60

48 Unmet needs Protesi valvolari meccaniche Fibrillazione atriale parossistica: a che livello di AF burden iniziamo a trattare? Fibrillazione atriale secondaria Ictus criptogenetico (Embolic Stroke Unknown Source) Pazienti con Cirrosi epatica e NVAF 61