EDOXABAN Lixiana® Non eravamo gia’ abbastanza confusi prima … Nuovi Anticoagulanti orali Dabigatran (Pradaxa®) Rivaroxaban (Xarelto®) Quale usare, su chi Apixaban (Eliquis®) Scenario Warfarin in AF: ↓stroke 64% vs placebo Warfarin ↑bleeding and has well-known limitations 3 NOACs at least as effective; ↓hem. stroke by 51%1 edoxaban 1. Dogliiotti A et al. Clin Cardiol 2013;36:61-7. EDOXABAN EDO Xa BAN Inibitore diretto del FXa Edoxaban seated in Factor Xa catalytic center 62% biodisponibilita’ orale Picco plasmatico1-2h t1/2 ~10-14h Once daily ~50% escreto rene Dose↓ 50%2 if: - CrCl 30-50 mL/m - Peso ≤ 60kg - Inibitori forti di P-gp CrCl=creatinine clearance; FXa=Factor Xa; P-gp=p-glycoprotein 2. Salazar DE et al. Thromb Haemost 2012;107:925-36. Pharmacologic Profiles of Approved and Investigational Oral Anticoagulants Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban Target Vitamin K epaxide Thrombin Xa Xa Xa Administration Once daily Twice daily Once daily Twice daily Once daily Prodrug No Yes No No No Half-life 40 hrs 12-14 hours 9-13 hours 8-15 hours 10-14 hours Bioavailability >95% 6.5% 80% ~66% 62% 80% 30-60% 25% 50% 2 hours 2.5-4 hours 3 hours 1-2 hours No Yes Yes Yes Renal Minor excretion Time to Peak 72-96 hours Plasma Metabolized by Yes CYP3A4 Uchiyama S, et al. J Stroke Cerebrovasc Dis. 2012;21:165-173; Eriksson BI, et al. Annu Rev Med. 2011;62:41-57 Hokusai-VTE study n engl j med 369;15 nejm.1406 org october 10, 2013 Hokusai-VTE study Randomized, double blind, event driven, non-inferiority study Designed to broaden applicability to real world practice, by encouraging physicians to enroll all VTE patients Starting with standard parenteral heparin At least 3 months treatment, duration flexible All patients followed for 12 months Halving the dose for patients perceived to be at higher risk for bleeding Creatinine Clearance 30-50 Body weight < 60 Kg concomitant treatment with potent P-glycoprotein inhibitors). Scopo: valutare se terapia con (LMW)heparin iniziale seguita da edoxaban da solo e’ non inferiore a (LMW)heparin iniziale con sovrapposizione con warfarin, seguita da warfarin da sola nel trattamento di pazienti con tromboembolia venosa acuta sintomatica per la prevenzione delle recidive di tromboembolismo sintomatico durante follow up di 12 mesi Total patients 8292 edoxaban Sham INR Tromboembolia venosa sintomatica R INR warfarin Day 1- 5 Day 6- 12 (LMW)Eparina iniziale placebo warfarin placebo edoxaban 3M 6M 12 M Study Outcomes Efficacy • Primary : symptomatic recurrent VTE in mITT analysis • Secondary: symptomatic recurrent VTE + Death from CV causes + Death from any causes in the on-treatment period Safety • Principal : major bleeding + clinically relevant non-major bleeding on-treatment All outcomes were adjudicated by an independent clinical event committee Baseline characteristics Mean age, years (SD) Edoxaban (N=4118) 56 (16) Warfarin (N=4122) 56 (16) Male gender, n (%) 2360 (57) 2356 (57) Qualifying diagnosis, n (%) DVT PE 2468 (60) 1650 (40) 2453 (60) 1669 (40) 2713 (66) 378 (9) 784 (19) 2697 (65) 393 (10) 736 (18) 733 (18) 719 (17) Clinical presentation and risk factors, n (%) Unprovoked Cancer Previous VTE Dose of 30 mg ( e.g ≤ 60 kg, CrCl≥30 ≤50 ml/min), n (%) Efficacy outcomes Edoxaban (N=4118) Warfarin (N=4122) Hazard ratio (95% CI) P Value 130 (3.2) 146 (3.5) 0.89 (0.70-1.13) <0.001 First recurrent VTE - no. (%) Overall study period Patients with index DVT* 83 (3.4) 81 (3.3) Patients with index PE** 47 (2.8) 65 (3.9) 66 (1.6) 80 (1.9) On-treatment period Subgroup severe PE (RV dysfunction ProBNP) n/N (%) * ** 15/454 (3.3) 30/485 ( 6.2) Noninferiority 1.02 (0.75-1.38) 0.73 (0.50-1.06) 0.82 (0.60-1.14) 0.52 (0.28 - 0.98) Denominator is number of patients with index DVT: 2468 and 2453 in edoxaban and warfarin group respectively Denominator is number of patients with index PE : 1650 and 1669 in edoxaban and warfarin group respectively <0.001 noninferiority) Primary Efficacy Outcome hep / edoxaban hep / warfarin HR (n / N) (95% CI) 130 / 4,118 146 / 4,122 0.89 3.2% 3.5% (0.70–1.13) 66 / 4,118 80 / 4,122 0.82 1.6% 1.9% (0.60-1.14) (n / N) mITT Overall mITT On-Rx Overall On-Rx Warfarin TTR : 63.5% 0.70 0 1.13 1.00 Edoxaban superior 11 0.89 Hazard Ratio 1.50 Edoxaban non-inferior Safety outcomes First major or clinically relevant non major – no. (%) Major – no. (%) Fatal Intracranial Non-Fatal in Critical Sites Intracranial Non-Fatal in Non-Critical Sites Clinically Relevant NonMajor– no. (%) Edoxaban (N=4118) Warfarin (N=4122) Hazard ratio (95% CI) P Value 349 (8.5) 423 (10.3) 0.81 (0.71-0.94) 0.004 56 (1.4) 66 (1.6) 2 (<0.1) 10 (0.2) 0 13 (0.3) 5 (0.1) 41 (1.0) 298 (7.2) 0.84 (0.59-1.21) superiority 0.35 superiority 6 (0.1) 25 (0.6) 12 (0.3) 33 (0.8) † 368 (8.9) 0.80 (0.68-0.93) 0.004 superiority Principal Safety Outcome hep / edoxaban hep / warfarin HR (n / N) (95% CI) 349 / 4,118 423 / 4,122 0.81 8.5% 10.3% (0.71–0.94) (n / N) On Rx 0.71 0.81 0 0.94 Hazard Ratio 1.00 Edoxaban superior 1.50 Edoxaban inferior Relative Efficacy/ Safety in 30 mg dose group Edoxaban N = 733 (%) Warfarin N = 719 (%) Hazard ratio First recurrent VTE 22 (3.0) 30 (4.2) 0.73 (0.42-1.26) Clinically relevant non major or major bleeding 58 (7.9) 92 (12.8) 0.62 (0.44-0.86) (95 % CI) Hokusai-VTE study (LMW)heparin/edoxaban regimen non-inferior to standard therapy for preventing recurrent VTE consistent efficacy in patients with DVT and PE clinically significant reduction in recurrent VTE in right ventricular dysfunction subgroup less clinically relevant bleeding dose adaptation (30 mg) effective and safer Paziente random dopo il trattamento Engage AF-TIMI 48 n engl j med 369;22 nejm.org november 28, 2013 Study Design 21,105 PATIENTS AF on electrical recording within last 12m CHADS2 ≥2 RANDOMIZATION 1:1:1 randomization is stratified by CHADS2 score 2–3 versus 4–6 and need for edoxaban dose reduction* Double-blind, Double-dummy Warfarin (INR 2.0–3.0) High-dose Edoxaban 60* mg QD Low-dose Edoxaban 30* mg QD *Dose reduced by 50% if: - CrCl 30–50 mL/min 1º Efficacy EP = Stroke or SEE - weight ≤60 kg 2º Efficacy EP = Stroke or SEE or CV mortality - strong P-gp inhibitor 1º Safety EP = Major Bleeding (ISTH criteria) Non-inferiority Upper 97.5% CI <1.38 Ruff CR et al. Am Heart J 2010; 160:635-41. Baseline Characteristics Median age [IQR] 72 [64, 78] Female sex 38% Paroxysmal atrial fibrillation 25% CHADS2 (mean + SD) CHADS2 ≥ 3 CHADS2 ≥ 4 2.8 ± 1.0 53% 23% Prior CHF Hypertension Age ≥ 75 years Diabetes mellitus Prior stroke or TIA 57% 94% 40% 36% 28% Dose reduced at randomization 25% Prior VKA experience 59% Aspirin at randomization 29% Amiodarone at randomization 12% CHF=congestive heart failure; IQR=interquartile range; TIA=transient ischemic attack; VKA=vitamin K antagonist 6 Primary Endpoint: Stroke / SEE (907 days median treatment) (2.8 years median f/u) Noninferiority Analysis (mITT, On Treatment) Hazard ratio (97.5% CI) 1,50% Warfarin TTR 68.4% 1,18% Edoxaban 60* mg QD vs warfarin 1,61% Edoxaban 30* mg QD vs warfarin 0.50 0.79 P Values Non-inferiority Superiority P<0.0001 P=0.017 1.07 P=0.005 1.00 1.38 P=0.44 2.0 edoxaban noninferior Superiority Analysis (ITT, Overall) 1,80% Warfarin TTR 68.4% 1,57% Edoxaban 60* mg QD vs warfarin 2,04% Edoxaban 30* mg QD vs warfarin 0.50 *Dose reduced by 50% in selected pts Hazard ratio (97.5% CI) P Value for Superiority 0.87 P=0.08 1.13 P=0.10 1.00 2.0 edoxaban superior edoxaban inferior Key Secondary Outcomes Warfarin TTR 68.4% Edoxaban 60* mg QD vs warfarin Edoxaban 30* mg QD vs warfarin E-60 0.54 0.33 Hem. Stroke HR (95% CI) P vs warfarin E-30 <0.001 <0.001 0,47% Vs 0,26% Vs 0,16% 1.00 1.41 Ischemic Stroke 0.97 <0.001 0.005 0.32 1,25% Vs 1,25% Vs 1,77% 2° EP: Stroke, SEE, CV death 4,43 Vs 3,85% Vs 4,23% 0.87 0.82 Death or ICH 4,88% Vs 4,27% Vs 4,03% 0.004 <0.001 0.92 0.87 All-cause mortality 4,35% Vs 3,99% Vs 3,80% 0.86 0.85 CV death 3,17% Vs 2,74% Vs 2,71% 0.94 Myocardial infarction 0.25 0.08 0.006 0.013 0.008 0.60 0.13 1.19 0,75% Vs 0,70% Vs 0,89% *Dose reduced by 50% in selected pts 0.87 0.95 0.5 edoxaban superior 1.00 2.0 edoxaban inferior Main Safety Results - Safety Cohort on Treatment Warfarin TTR 68.4% Edoxaban 60* mg QD vs warfarin Edoxaban 30* mg QD vs warfarin 0.80 ISTH Major Bleeding P<0.001 P<0.001 0.47 3,43% Vs 2,75% Vs 1,61% 0.55 Fatal Bleeding 0,38% Vs 0,21% Vs 0,13% Intracranial Hemorrhage HR (95% CI) P=0.006 P<0.001 0.35 0.47 P<0.001 P<0.001 0.30 0,85% Vs 0,39% Vs 0,26% 1.23 Gastrointestinal Bleeding 0.67 1,23% Vs 1,51% Vs 0,82% *Dose reduced by 50% in selected pts 0.25 P Value vs warfarin 0.5 edoxaban superior 1.0 P=0.03 P<0.001 2.0 edoxaban inferior Safety cohort=all patients who received at least 1 dose by treatment actually received Types of stroke by treatment group Engage-AF TIMI-48 Hemorrhagic stroke Ischemic stroke Kaplan–Meier curves for hemorrhagic stroke (A) and ischemic stroke (B) are shown for the 3 treatment arms in the intention-to-treat (ITT) cohort during the entire study period Net Clinical Outcomes Warfarin TTR 68.4% Edoxaban 60* mg QD vs warfarin Hazard ratio P Value vs warfarin (95% CI) Edoxaban 30* mg QD vs warfarin 0.89 Stroke, SEE, death, major bleeding 8,11% Vs 7,26% Vs 6,79% P=0.003 0.83 P<0.001 0.88 Disabling stroke, life-threatening bleeding, death P=0.008 0.83 5,23% Vs 4,64% Vs 4,38% P<0.001 0.88 Stroke, SEE, life-threatening bleeding, death P=0.003 0.89 P=0.007 6,02% Vs 5,30% Vs 5,37% *Dose reduced by 50% in selected pts SEE=systemic embolic event 0.5 0.71 edoxaban superior 1.0 edoxaban inf Alleggeriamo un po’ Della serie: certe volte i trials non servono… Relationship between edoxaban dose, concentration, anti-factor Xa activity, and outcomes in the ENGAGE AF-TIMI 48 trial Trough plasma samples 1-mo. Post randomization*: Edoxaban concentration (N=6780) Anti-FXa activity (N=2865 Substudy) Quintiles Bioanalytical and ADME Labs Rotachrome Heparin Assay Stago STAR Evolution Platform Correlated edoxaban dose, concentration, and anti-Fxa activity Compared efficacy and safety outcomes with warfarin stratified by dose reduction status *Samples excluded if values < lower limit of detection, handling errors, drawn outside protocol time window, endpoint occurred before sample drawn ENGAGE AF: Edoxaban concentration and anti-FXa activity Mean edoxaban trough concentration (N=6780) ng/mL 60 48.5 ± 45.8 HD = High dose LD = low dose DR = dose reduction 34.6 ± 30.9 40 24.5 ± 22.7 20 0 No DR 60 mg DR 30 mg HD Edoxaban No DR 30 mg 16.0 ± 14.5 DR 15 mg LD Edoxaban Mean trough anti-FXa activity (N=2865) 1.00 0.85 ± 0.76 IU/mL 0.64 ± 0.54 0.44 ± 0.37 0.50 0.00 No DR 60 mg DR 30 mg HD Edoxaban No DR 30 mg 0.35 ± 0.28 DR 15 mg LD Edoxaban Poster presented at ESC 2014 ENGAGE AF: Stroke or SEE (%/Year) HD Edoxaban vs. Warfarin No DR: HR 0.78 (0.61–0.99) - DR: HR 0.81 (0.58–1.13) Pint=0.85 2.5 LD Edoxaban vs. Warfarin No DR: HR 1.07 (0.86–1.34) - DR: HR 1.07 (0.79–1.46) Pint=0.99 2.36 Stroke/SEE (%/year) 2.21 2.0 1.5 1.79 1.38 1.29 1.00 1.0 0.5 0.0 Edox Conc. (ng/mL) Anti-FXa (IU/mL) Warfarin HD Edox 60 mg LD Edox 30 mg Warfarin No dose reduction NA NA 48.5 0.85 DR, dose reduction; HD, high dose; LD, low dose; SEE, systemic embolic event 24.5 0.44 HD Edox 30 mg LD Edox 15 mg Dose reduction NA NA 34.6 0.64 Poster presented at ESC 2014 16.0 0.35 ENGAGE AF: Major bleed (%/Year) Major bleed (%/year) 6.0 HD Edoxaban vs. Warfarin No DR: HR 0.88 (0.76–1.03) - DR: HR 0.63 (0.50–0.81) Pint=0.02 LD Edoxaban vs. Warfarin No DR: HR 0.55 (0.46–0.65) - DR: HR 0.31 (0.23–0.42) Pint=0.002 4.85 5.0 4.0 3.0 3.02 3.05 2.66 2.0 1.0 0.0 Edox Conc. (ng/mL) Anti-FXa (IU/mL) 1.65 Warfarin HD Edox 60 mg LD Edox 30 mg 1.50 Warfarin No dose reduction NA NA 48.5 0.85 DR, dose reduction; HD, high dose; LD, low dose; SEE, systemic embolic event 24.5 0.44 HD Edox 30 mg LD Edox 15 mg Dose reduction NA NA 34.6 0.64 16.0 0.35 Poster presented at ESC 2014 ENGAGE AF: Summary Compared to well-managed warfarin TTR (68.4%) once-daily edoxaban: Non-inferior for stroke/SEE (both regimens) - High dose ↓stroke/SEE on Rx (trend ITT) Both regimens significantly reduced: - Major bleeding (20%/53%) - ICH (53%/70%) - Hem. stroke (46%/67%) - CV death (14%/15%) Superior net clinical outcomes ENGAGE AF: Summary (2) Patients meeting clinical criteria for edoxaban dose reduction were at high risk*: Increase in stroke and bleeding events in warfarin patients (placebo edoxaban dose reduction Dose reduction of edoxaban compared with warfarin: Preserved relative efficacy Provided even greater safety Tailoring the dose based on clinical features alone: Prevented excess edoxaban drug levels Dose modification of edoxaban in ENGAGE AF-TIMI 48: Helped optimize the balance between ischemic and bleeding events without measuring drug levels or anticoagulation activity * Dose reduced by 50%: CrCl 30–50 mL/min, weight ≤60 kg, Strong P-gp inhibitor Observations High study drug discontinuation rate (33%) Similar rates among groups Low-dose edoxaban 30mg QD likely not tenable Met criteria for noninferiority Primary endpoint: warfarin 1.5%/yr vs. low-dose 1.61%/yr Significant increased risk of ischemic stroke vs. warfarin Warfarin: 1.25%/yr - Low-dose edoxaban: 1.77%/yr HR 1.41 (95% CI: 1.19-1.67, P<0.001) Grazie per l’attenzione EDOXABAN Eravamo gia’ confusi prima … La medicina e’ in continuo aggiornamento e cambiamento Bisogna adeguarsi al cambiamento I tempi cambiano Quale usare, quando, su chi Slides di Back-up ENGAGE AF: Correlation of trough edoxaban concentration and anti-FXa activity R = 0.96 HD Edoxaban no DR (60mg) Trough Anti-FXa Activity [IU/mL] 4 P<0.0001 3 3 2 2 1 1 0 0 LD Edoxaban no DR (30mg) 4 3 2 2 1 1 0 0 25 50 75 100 125 150 LD Edoxaban DR (15mg) 4 3 0 HD Edoxaban DR (30mg) 4 0 25 50 75 100 125 150 Trough edoxaban concentration [ng/mL] AF, atrial fibrillation; DR, dose reduction; FXa, factor Xa; HD, high dose; LD, low dose poster presented at ESC 2014 PatientswithEvent(%) 8 -- low-dose edoxaban -- warfarin -- high-dose edoxaban 6 4 2 0 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years Guigliano et al., NEJM 2013 12 -- warfarin -- high-dose edoxaban -- low-dose edoxaban PatientswithEvent(%) 10 8 6 4 2 0 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years Guigliano et al., NEJM 2013 ENGAGE - Methods Endpoints Primary efficacy: time to first stroke or systemic embolism Primary safety: major bleeding Analysis Modified ITT Noninferiority: upper boundary of 97.5% CI could not exceed 1.38 vs. warfarin Superiority testing: if met noninferiority criteria Power: If 672 endpoints, >87% power ENGAGE - Methods Inclusion criteria Age ≥21 years ECG tracing of Afib within previous 12 months CHADS2 of 2 or greater Exclusion criteria ACS or stroke within past 30 days Afib due to reversible disorder Est Clcr <30 ml/min Use of dual antiplatelets “High risk” of bleeding Vantaggi • • • • • • Nuovi Anticoagulanti Orali Dose – risposta prevedibile : dose fissa giornaliera Non necessità di monitoraggio del grado di anticoagulazione Elevata efficacia e sicurezza Significativa riduzione del rischio emorragico Inizio e termine d’azione rapidi gestione bridging therapy Minime interazioni farmacologiche e assenza di interazioni alimentari Potenziali Svantaggi • Necessità di “nuovi” test laboratoristici da eseguire in casi particolari (esempio : eventi emorragici o trombotici) • Difficoltà di valutare l’aderenza del paziente alla terapia • Mancanza di antidoto in caso di sovradosaggio o emorragie • Inizio e termine d’azione rapidi: potenziale svantaggio nei pazienti con bassa aderenza terapeutica • Possibile ridotta consapevolezza della terapia da parte del paziente • Costo elevato ENGAGE - Results 21,105 patients randomized Reduced dose: 25% of patients Warfarin: mean TTR 68% Antidoto - PRT064445 (Portola Pharmaceuticals) • Analogo ricombinante del Fxa – cui manca il dominio Gla che si lega alle membrane plasmatiche, per cui non può formarsi la protrombinasi – il cui sito attivo • è reso inattivo • permette ancora di legare substrati o inibitori come rivaroxaban, apixaban, betrixaban, ecc. • È in corso uno studio clinico di Fase 2 sulla reversione dei test di coagulazione con anti-FXa2 1Hutchaleelaha A. Eur Heart J 2012 2http://clinicaltrials.gov/ct2/show/NCT01758432 1 BAY1110262 (Bayer) antidoto specifico rivaroxaban neutralizza effetto sul FXa2 Interazioni farmacologiche dei NACO Induzione o inibizione della P-glicoproteina (P-gp) Induzione o inibizione del CYP-3A4 Pg p I dati del registro danese Tolerability and Adverse Events % pts % pts % pts *Dose reduced by 50% in selected pts P <0.001 for each edoxaban dose vs warfarin P=NS P=NS 13