I DOAC sono tutti uguali per efficacia e sicurezza? Indicazioni e appropriatezza prescrittiva degli anticoagulanti ad azione diretta (DOAC) I DOAC sono tutti uguali per efficacia e sicurezza? provocazione…. A me non piacciono le classifiche tra i nao… non ci credo, credo invece nel valore aggiunto della capacità di utilizzo di questi farmaci… Vorrei portare l’attenzione non tanto sul nao stesso ma sul cardiologo e quindi su cosa fa il cardiologo di fronte a determinati pazienti… in quest’ambito vorrei cercare di parlarvi di apixaban e del suo possibile utilizzo in alcuni sottogruppi di pazienti…. Dott. Sergio Agosti Dirigente Medico Responsabile UTIC SOC Cardiologia Ospedale Novi Ligure Recco (GE), 26 Ottobre 2016 Hotel La Villa Manuelina

Assume that NAOs have been on the market for 5 year A new drug comes to the market. Compared to NAOs, the new drug has: - cheaper - antidote - requirement for monthly monitoring to adjust dose - many food and drug interactions - 25% increased relative risk of stroke/systemic embolism - nearly 50% increased relative risk of major bleeding - approx. 2.5 times the rate of ICH - 10% increased relative risk of mortality Would Warfarin be approved by regulatory authorities now?

TAO e NAO nell’FA in Italia Warfarin: 1960 Dabigatran (Pradaxa): giugno 2013 Rivaroxaban (Xarelto): agosto 2013 Apixaban (Eliquis): gennaio 2014 Edoxaban (Lixiana): settembre 2016 rimborsabilità

An effective antithrombotic treatment could combine in any single patient ….. Efficacy at preventing stroke in AF and at treating DVT or PE Adherence taken as instructed for the prescribed period of time Convenience easy to take and to administer i.e. number of doses Treatment goal Safety/tolerability profile similar to control treatment 4 4

Assorbimento e metabolismo dei NAO Dabigatran Rivaroxaban Apixaban Bio-disponibilità 3-7% 66% (senza cibo), 100% con il cibo 50% Pro-farmaco Si No Clearance renale 80% 35% 27% Metabolismo epatico(CYP3A4 involved) Si (eliminazione) Si (eliminazione, contributo minimo del CYP3A4) Assorbimento con il cibo Nessun effetto +39% Assunzione con il cibo raccomandata Mandatoria Assorbimento con H2B/PPI –12–30% Etnia Asiatica +25% Tollerabilità GI Dispepsia 5–10% Nessun problema Emivita di eliminazione 12–17 ore 5–9 ore (giovani), 11–13 ore (anziani) 12 ore Ricavata da Heidbuchel et al. Europace. 2013;15:625–651. 1. Heidbuchel et al. Europace. 2013;15:625–651.

Lancet, published online December 4, 2013 Mostrate ieri dal prof alperine Lancet, published online December 4, 2013

STROKE OR SYSTEMIC EMBOLISM NNT 173 NOACs associated with a RRR of 19% compared to Warfarin Ruff CT, Lancet, December 4, 2013

NOACs associated with a non significant RRR of 14% MAJOR BLEEDING No head to head comparisons NOACs associated with a non significant RRR of 14% compared to Warfarin Ruff CT, Lancet, December 4, 2013

EFFICACY AD SAFETY SECONDARY ENDPOINTS ICH NNT 141 NNT PER ICH è 140, linea di indipendenza ICH NNT 141 Ruff CT, Lancet, December 4, 2013

Adapted from European Heart Journal doi:10.1093/eurheartj/ehs253 SINTESI: efficacia e sicurezza dei nuovi anticoagulanti orali nella fibrillazione atriale non valvolare

60% RRR Haemorrhagic stroke Inibitori del p2y12 Intracranial hemorrhage risk with the new oral anticoagulants: a systematic review and meta analysis Daniel Caldeira et al. J Neurol 2014

Ictus emorragico (TF receptor) Tissue factor (TF) is a transmembrane receptor for Factor VII/VIIa (FVII/VIIa). It is constitutively expressed by cells surrounding blood vessels. The endothelium physically separates this potent "activator" from its circulating ligand FVII/FVIIa and prevents inappropriate activation of the clotting cascade. Breakage of the endothelial barrier leads to exposure of extravascular TF and rapid activation of the clotting cascade. TF is also expressed in certain tissues, such as the heart and brain, and provides additional hemostatic protection to these tissues. Mackmann, Anesth Analg. 2009 May; 108(5):1447-52 The role of tissue factor and factor VIIa in hemostasis.

Quali pazienti Il paziente anziano Il paziente con Insufficienza Renale Il paziente con valvulopatia apixaban a chi…

Apixaban nel paziente anziano

Il rischio di stroke nella FA aumenta con l’età Warfarin è particolarmente sottoutilizzato nei pazienti anziani Halvorsen et al. Eur Hear J. 2014;35(28):1864–72; 2

Apixaban vs Warfarin nei pazienti > 80 anni Halvorsen et al. Eur Hear J. 2014;35(28):1864–72; 2

Apixaban nel paziente con insufficienza renale

IRC è comune tra i pazienti con FA IRC aumenta il rischio di stroke, sanguinamento e morte per tutte le cause nei pazienti con FA Olesen et al. N Engl J Med 2012;367:625–35.

Apixaban è eliminato attraverso multiple vie di escrezione

Apixaban è stato più efficace e si è associato a minori sanguinamenti maggiori vs Warfarin nei pazienti con IR Hohnloser et al. Eur Heart J 2012;22:2821–30.

Raccomandazioni dell’EHRA nei pazienti con IR (2015)

Apixaban nel paziente con valvulopatia

Definizione di FA non valvolare (FAVN) Updated EHRA Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with NVAF: Heidbuchel, August 31, 2015

ESC Congress 2013, Dr Alvaro Avezum, Duke Clinical Research Institute VHD in ARISTOTLE 4808 (26,4%) patients had a history of VHD at baseline Any VHD* 4.808 100.0% Any mitral valve disease 3.578 74.4 Mitral regurgitation 3.526 73.3 Mitral stenosis 131 2.7 Any aortic valve disease 1.150 23.9 Aortic stenosis 887 18.4 Aortic regurgitation 384 8.0 Tricuspidal regurgitation 2.124 44.2 Prior valve surgery 251 5.2 ESC Congress 2013, Dr Alvaro Avezum, Duke Clinical Research Institute

NAO in numeri…. 180000 pz nei trials 8000 articoli - studi clinici (PUBMED) Almeno 350000 pz nei registri Anticoagulante che ha più analisi post hoc, registri e articoli e pz trattati nel mondo…. Oltre 20 milioni di pz trattati nel mondo

Real-world Comparison of Major Bleeding Risk Among Non-valvular Atrial Fibrillation Patients Initiated on Apixaban, Dabigatran, Rivaroxaban, or Warfarin: A Propensity Score Matched Analysis Lip GYH1, Keshishian A2, Kamble S3, Pan X3, Mardekian J4, Horblyuk R4, Hamilton M3 1University of Birmingham Institute of Cardiovascular Sciences, City Hospital, Birmingham, United Kingdom, Aalborg Thrombosis Research Unit, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; 2STATinMED Research, Ann Arbor, MI, USA; 4Bristol-Myers Squibb Company, Princeton, NJ, USA; 4Pfizer, Inc., New York, USA

Real-world Comparison of Major Bleeding Risk Among Non-valvular Atrial Fibrillation Patients Initiated on Apixaban, Dabigatran, Rivaroxaban, or Warfarin: A Propensity Score Matched Analysis Objective To compare the risk of major bleeding among newly-anticoagulated non-valvular atrial fibrillation (NVAF) patients initiating on warfarin, rivaroxaban, dabigatran, or apixaban using propensity score matching (PSM)* Study design Retrospective cohort study using the Truven MarketScan® Commercial Claims and Encounter and Medicare Supplemental and Coordination of Benefits Databases Study period Jan 1, 2012 – Dec 31, 2014 Study population Adult (≥18 years) patients with NVAF diagnosis (ICD-9-CM codes: 427.31 or 427.32) newly initiated on OAC (warfarin, dabigatran, rivaroxaban, and apixaban) between Jan 1, 2013 and Dec 31, 2014 and continuously enrolled in medical and pharmacy benefits for at least 12 months prior to the index date# Patients with an OAC prescription claim prior to the index date were excluded Patients with evidence of transient AF (thyrotoxicosis, pericarditis), cardiac surgery, venous thromboembolism (VTE), valvular heart disease, or pregnancy were also excluded Final sample included 45 361 patients; the index medication was apixaban in 7438 (16.4%), dabigatran in 4661 (10.3%), rivaroxaban in 17 801 (39.2%), and warfarin in 15 461 (34.1%) patients Analyses Patients were classified into 1:1 PSM cohorts: Apixaban-warfarin (n=6964) Dabigatran-warfarin (n=4515) Rivaroxaban-warfarin (n=12 625) Major bleeding was defined as bleeding requiring hospitalization during or within 30 days of drug use period Cox proportional hazard models were used to estimate relative risk of major bleeding with 95% CIs Sensitivity analysis was conducted to assess the treatment effect associated with risk of major bleeding among patients prescribed the standard dose for all OACs (warfarin, apixaban 5 mg BID, rivaroxaban 20 mg QD, or dabigatran 150 mg BID) Apixaban-dabigatran (n=4407) Apixaban-rivaroxaban (n=7399) Dabigatran-rivaroxaban (n=4657)

Real-world Comparison of Major Bleeding Risk Among Non-valvular Atrial Fibrillation Patients Initiated on Apixaban, Dabigatran, Rivaroxaban, or Warfarin: A Propensity Score Matched Analysis Apixaban initiators had a significantly lower risk of major bleeding compared to warfarin initiators (HR: 0.53; 95% CI: 0.39-0.71) In sensitivity analysis (standard dose), results were similar to main analysis (HR: 0.55; 95% CI: 0.39-0.77) Dabigatran initiators had a significantly lower risk of major bleeding compared to warfarin initiators (HR: 0.69; 95% CI: 0.50-0.96) In sensitivity analysis (standard dose), dabigatran 150 mg initiators had a non-significant difference in major bleeding risk compared to warfarin initiators (HR: 0.71; 95% CI: 0.49-1.05) Rivaroxaban initiators had a statistically non-significant difference in major bleeding risk compared to warfarin initiators (HR: 0.98; 95% CI: 0.83-1.17) In sensitivity analysis (standard dose), results were similar to main analysis (HR: 0.97; 95% CI: 0.80-1.18) Warfarin N = 6,964 (Reference) Apixaban Major Bleeding Incidence Rate (per 100 person-years) Warfarin N = 4,515 (Reference) Dabigatran Major Bleeding Incidence Rate (per 100 person-years) Warfarin N = 12,625 (Reference) Rivaroxaban Major Bleeding Incidence Rate (per 100 person-years)

Conclusioni Necessario conoscere le varie molecole di NAO per migliorare il loro utilizzo, individualizzando la terapia Apixaban è un farmaco efficace e sicuro e che garantisce un’ottima compliance e maneggevolezza Apixaban mantiene un beneficio clinico netto favorevole anche in diverse sottopopolazioni di pazienti fragili (anziani, IRC) Apixaban può essere utilizzato anche nei pazienti con valvolupatia

Karl Link 1941

GRAZIE PER L’ATTENZIONE Mail: agostisergio@virgilio.it