Risultati delle studio ENGAGE AF TIMI 48 Dott. P. SARTORI IRCCS A Azienda Ospedaliera Universitaria San Martino-IST U.O. Cardiologia – Genova Giovedì 22 OTTOBRE 2016 SAVONA

Fattore della Coagulazione Xa Etimologia Edo Tokyo banEdoXa “Comun ending of direct Factor Xa inhibitors” ban

Edoxaban posizionato nel centro catalitico del Fattore Xa Xa Inibitore diretto del FXa 62% biodisponibilita’ orale Picco plasmatico 1-2h t 1/2 ~10-14h Monosomministrazione ~50% escreto rene Dose ↓ 50% 2 if: - CrCl mL/m - Peso ≤ 60kg - Inibitori forti di P-gp P-gp=p-glycoprotein CrCl=creatinine clearance; FXa=Factor Xa; 2. Salazar DE et al. Thromb Haemost 2012;107: EDOXABAN EDO Xa BAN

N=1146 Weitz et al. Thromb Haemost 2010;104: Study design: Randomized, double blind edoxaban dose regimens, open-label warfarin, parallel treatment groups Primary Objective: Evaluation of safety of four fixed dose-regimens of Edoxaban vs. Warfarin in patients with atrial fibrillation (CHADS 2 ≥ 2) Primary endpoints: Occurrence of major and/or clinically relevant non-major bleeding, elevated hepatic enzymes and/or bilirubin Edoxaban study 018: dose Finding Study in AF Day 1 Screening Edoxaban 60 mg QD Edoxaban 30 mg BID Edoxaban 60 mg BID* Active control (Warfarin, INR 2.0–3.0) 3-month randomized treatment period Follow-up assessment Edoxaban 30 mg QD ≤30 days +30 days after last dose

WarfarinEdoxaban 30 mg QD Edoxaban 60 mg QD Edoxaban 30 mg BID Edoxaban 60 mg BID Bleeding incidence (%) n/N 8/2507/23511/23419/24419/ Edoxaban studio 018: major and clinically relevant non-major bleeding * ** *p<0.05, **p<0.01, vs warfarin QD, once daily; BID, twice daily Weitz et al. Thromb Haemost 2010;104:633-41

Edoxaban phase II dose finding study in af: exposure and bleeding AUC, area under the plasma concentration-time curve from 0 to 24 hours at steady-state; C max, maximum steady-state plasma concentration; C min, minimum steady-state concentration; QD, once daily; BID, twice daily ng/mL 30 QD 60 QD 30 BID 60 BID C max 30 QD 60 QD 30 BID 60 BID Ng*h/mL AUC 30 QD 60 QD 30 BID 60 BID ng/mL C min Bleeding incidence, % 30 QD 60 QD 30 BID 60 BID Edoxaban Weitz et al. Thromb Haemost 2010;104:633-41

n engl j med 369;15 nejm.1406 org october 10, 2013 Hokusai-VTE study

n engl j med 369;22 nejm.org november 28, 2013 Engage AF-TIMI 48

Edoxaban 30/15 mg QD regimen Warfarin (INR 2.0–3.0) Edoxaban 60/30 mg QD regimen PATIENTS AF on electrical recording within last 12 months Intended oral anticoagulant CHADS 2 ≥2 N=21,105 Median duration of follow up 2.8 years Disegno dello studio: ENGAGE AF-TIMI 48 *Dose reduced by 50% if CrCl 30–50 mL/min, body weight ≤60 kg or patient receiving verapamil, quinidine or dronedarone AF=atrial fibrillation; CrCl=creatinine clearance INR=International Normalized Ratio; QD=once daily RANDOMIZATION 1:1:1 randomization is stratified by CHADS 2 score 2–3 versus 4–6 and need for edoxaban dose reduction* Randomized, double-blind, double-dummy, event-driven study Giugliano et al. N Engl J Med 2013 x

7,012 included in mITT and Safety analysis 807 did not complete the end date visit 746 Died # 61 Withdrew consent 0 Were lost to follow-up Warfarin (n=7,036; ITT) Edoxaban 30 mg (n=7,034; ITT) 7,002 included in mITT and Safety analysis 7,012 included in mITT and Safety analysis 6,228 included in Completed end date visit 6,250 included in Completed end date visit 6,157 included in Completed end date visit 783 did not complete the end date visit 720 Died # 62 Withdrew consent 1 Was lost to follow-up 879 did not complete the end date visit 811 Died # 68 Withdrew consent 0 Were lost to follow-up Edoxaban 60 mg (n=7,035; ITT) N=24 did not receive study drug N=23 did not receive study drug N=32 did not receive study drug 21,105 randomized # deaths before the study end date was announced Giugliano et al. N Engl J Med 2013; e-pub ahead of print

Characteristic Warfarin (n=7,036) Edoxaban 60 mg (n=7,035) Edoxaban 30 mg (n=7,034) Median age [IQR], years72 [64–78] Female sex, n (%)2,641 (37.5)2,669 (37.9)2,730 (38.8) Region, n (%) North America Latin America Western Europe Eastern Europe Asia Pacific and South Africa 1,562 (22.2) 888 (12.6) 1,078 (15.3) 2,381 (33.8) 1,127 (16.0) 1,559 (22.2) 886 (12.6) 1,079 (15.3) 2,383 (33.9) 1,128 (16.0) 1,560 (22.2) 887 (12.6) 1,079 (15.3) 2,380 (33.8) 1,128 (16.0) Paroxysmal atrial fibrillation, n (%)1,778 (25.3)1,753 (24.9)1,835 (26.1) Qualifying risk factors, n (%) Age ≥75 years Prior stroke or transient ischemic attack Chronic heart failure Diabetes mellitus Hypertension requiring treatment 2,820 (40.1) 1,991 (28.3) 4,048 (57.5) 2,521 (35.8) 6,588 (93.6) 2,848 (40.5) 1,976 (28.1) 4,097 (58.2) 2,559 (36.4) 6,591 (93.7) 2,806 (39.9) 2,006 (28.5) 3,979 (56.6) 2,544 (36.2) 6,575 (93.5) Caratteristiche cliniche IQR=interquartile range Giugliano et al. N Engl J Med 2013; e-pub ahead of print

Characteristic Warfarin (n=7,036) Edoxaban 60 mg (n=7,035) Edoxaban 30 mg (n=7,034) CHADS 2, mean±SD, n (%) ≤3 4–6 2.8±1.0 5,445 (77.4) 1,591 (22.6) 2.8±1.0 5,422 (77.1) 1,613 (22.9) 2.8±1.0 5,470 (77.8) 1,564 (22.2) Dose reduction at randomization*, n (%) Creatinine clearance 30–50 mL/min Weight ≤60 kg Verapamil or quinidine 1,787 (25.4) 1,361 (19.3) 701 (10.0) 243 (3.5) 1,784 (25.4) 1,379 (19.6) 684 (9.7) 258 (3.7) 1,785 (25.4) 1,334 (19.0) 698 (9.9) 260 (3.7) Previous vitamin K antagonist for ≥60 days, n (%)4138 (58.8)4140 (58.8)4163 (59.2) Medications at time of randomization, n (%) Aspirin Thienopyridine Amiodarone Digoxin or digitalis preparations 2,092 (29.7) 164 (2.3) 827 (11.8) 2,176 (30.9) 2,070 (29.4) 174 (2.5) 866 (12.3) 2,078 (29.5) 2,018 (28.7) 149 (2.1) 799 (11.4) 2,073 (29.5) Patients could appear in more than one category, therefore percentages may not total 100% *Patients with CrCl 30–50 mL/min, body weight ≤60 kg or those receiving concomitant strong P-gp inhibitors (verapamil, quinidine or dronedarone) at randomization received a 50% reduction in the dose of edoxaban to maintain similar exposure to the patient with out these factors SD=standard deviation Giugliano et al. N Engl J Med 2013; e-pub ahead of print

I risultati dello studio Engage-AF TIMI-48 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 Hemorrhagic stroke Ischemic stroke

Primary Endpoint: Stroke / SEE (907 days median treatment) (2.8 years median f/u) Non inferiority Analysis (mITT, On Treatment ) Edoxaban 60* mg QD vs warfarin Edoxaban 30* mg QD vs warfarin P Values Non-inferioritySuperiority P< P=0.005 Hazard ratio (97.5% CI) P=0.017 P=0.44 Superiority Analysis (ITT, Overall) 0.87 P=0.08 P=0.10 Hazard ratio (97.5% CI) P Value for Superiority Edoxaban 60* mg QD vs warfarin Edoxaban 30* mg QD vs warfarin Warfarin TTR 68.4 % *Dose reduced by 50% in selected pts edoxaban superior edoxaban inferior edoxaban noninferior 1,50 % 1,18% 1,61% Warfarin TTR 68.4% 1,80% 1,57% 2,04%

ENGAGE AF: Stroke or SEE (%/Year) Edox Conc. (ng/mL) Anti-FXa (IU/mL) No dose reductionDose reduction Warfarin HD Edox 60 mg LD Edox 30 mg Warfarin HD Edox 30 mg LD Edox 15 mg NA NA HD Edoxaban vs. Warfarin No DR: HR 0.78 (0.61–0.99) - DR: HR 0.81 (0.58–1.13) P int =0.85 LD Edoxaban vs. Warfarin No DR: HR 1.07 (0.86–1.34) - DR: HR 1.07 (0.79–1.46) P int =0.99 DR, dose reduction; HD, high dose; LD, low dose; SEE, systemic embolic event Poster presented at ESC 2014

Warfarin TTR 68.4% Hem. Stroke Ischemic Stroke 2° EP: Stroke, SEE, CV death Death or ICH All-cause mortality CV death Myocardial infarction Key Secondary Outcomes HR (95% CI) Edoxaban 60* mg QD vs warfarin Edoxaban 30* mg QD vs warfarin P vs edoxaban superior * Dose reduced by 50% in selected pts edoxaban inferior warfarin E-60E-30 < < < ,47% Vs 0,26% Vs 0,16% 1,25% Vs 1,25% Vs 1,77% 4,43 Vs 3,85% Vs 4,23% 4,88% Vs 4,27% Vs 4,03% 4,35% Vs 3,99% Vs 3,80% 3,17% Vs 2,74% Vs 2,71% 0,75% Vs 0,70% Vs 0,89%

ENGAGE AF: Major bleed (%/Year) Edox Conc. (ng/mL) Anti-FXa (IU/mL) No dose reductionDose reduction Warfarin HD Edox 60 mg LD Edox 30 mg Warfarin HD Edox 30 mg LD Edox 15 mg NA NA HD Edoxaban vs. Warfarin No DR: HR 0.88 (0.76–1.03) - DR: HR 0.63 (0.50–0.81) P int =0.02 LD Edoxaban vs. Warfarin No DR: HR 0.55 (0.46–0.65) - DR: HR 0.31 (0.23– 0.42) P int = DR, dose reduction; HD, high dose; LD, low dose; SEE, systemic embolic event Poster presented at ESC 2014

Summary of key outcomes Stroke and SEE: ITT Major bleed: safety cohort CRNM bleed: safety cohort Death: ITT Stroke, SEE, major bleed, death: ITT 1.50 CV death: ITT Edoxaban 60/30 mg betterWarfarin better Stroke and SEE: mITT on-treatment Ischemic stroke: ITT 0.00 Hemorrhagic stroke: ITT 0.54 Giugliano et al. N Engl J Med 2013;369:2093–2104

ENGAGE AF: Stroke o EES (%/Year) No dose reductionDose reduction Warfarin HD Edox 60 mg Warfarin HD Edox 30 mg HD Edoxaban vs. Warfarin No DR: HR 0.78 (0.61–0.99) DR: HR 0.81 (0.58–1.13) P int =0.85 DR, dose reduction; HD, high dose; LD, low dose; SEE, systemic embolic event Ruff et al., Lancet, 2015

ENGAGE AF: Sanguinamenti Maggiori (%/Year) 48.5 Edox Conc. (ng/mL) 0.85 Anti-FXa (IU/mL) No dose reductionDose reduction Warfarin HD Edox 60 mg Warfarin HD Edox 30 mg NA NA HD Edoxaban vs. Warfarin No DR: HR 0.88 (0.76–1.03) DR: HR 0.63 (0.50–0.81) P int =0.02 DR, dose reduction; HD, high dose; LD, low dose; SEE, systemic embolic event Ruff et al., Lancet, 2015

ng/mL IU/mL HD EdoxabanLD Edoxaban No DR 30 mg No DR 60 mg DR 30 mg DR 15 mg HD EdoxabanLD Edoxaban No DR 30 mg No DR 60 mg DR 30 mg DR 15 mg Mean edoxaban trough concentration (N=6780) Mean trough anti-FXa activity (N=2865) HD = High dose LD = low dose DR = dose reduction ENGAGE AF: Edoxaban concentration and anti-FXa activity Poster presented at ESC 2014

Favors EdoxabanFavors Warfarin Additional Safety Endpoints by Exploratory CrCl Subgroups CI = confidence interval; CrCl = creatinine clearance; GI = gastrointestinal; HR = hazard ratio Bohula EA, et al. Circulation. 2016; 134(1): n/N (%/year) Edoxaban vs WarfarinHR (95% CI)P-valueP int Warfarin Edoxaban 60/30 mg Fatal bleeding 0.76 CrCl 30–50 mL/min 19/1356 (0.7)9/1372 (0.3)0.48 (0.22–1.07) CrCl >50–95 mL/min 34/4130 (0.4)18/4047 (0.2) 0.54 (0.31–0.96)0.036 CrCl >95 mL/min 6/1526 (0.2)5/1593 (0.1) 0.83 (0.26–2.68)0.76 Intracranial bleeding 0.47 CrCl 30–50 mL/min 36/1356 (1.4)17/1372 (0.7 ) 0.46 (0.26–0.82)0.009 CrCl >50–95 mL/min 88/4130 (0.9)37/4047 (0.4) 0.43 (0.29–0.63)<0.001 CrCl >95 mL/min 8/1526 (0.2)7/1593 (0.2) 0.86 (0.31–2.38)0.77 GI bleeding 0.02 CrCl 30–50 mL/min 43/1356 (1.7)51/1372 (2.0) 1.17 (0.78–1.76)0.44 CrCl >50–95 mL/min 109/4130 (1.2) 155/4047 (1.7) 1.47 (1.15–1.87)0.002 CrCl >95 mL/min 38/1526 (1.0)26/1593 (0.7) 0.67 (0.40–1.10)0.11 Minor bleeding 0.40 CrCl 30–50 mL/min 150/1356 (6.3) 120/1372 (4.9) 0.79 (0.62–1.01)0.055 CrCl >50–95 mL/min 434/4130 (5.0) 382/4047 (4.5) 0.90 (0.78–1.03)0.12 CrCl >95 mL/min 130/1526 (3.7) 102/1593 (2.8) 0.75 (0.58–0.97)0.030

* Dose ridotta del 50%: * Dose ridotta del 50%: CrCl 30–50 mL/min, peso ≤60 kg, forti inibitori P-gp Riassunto I pazienti che presentano i criteri clinici per ridurre il dosaggio sono pazienti ad alto rischio: –Gli eventi di stroke e di sanguinamento aumentano nei pazienti trattati con warfarin (che hanno ricevuto il placebo di edoxaban ridotto) La riduzione del dosaggio di Edoxaban rispetto al warfarin: –Mantiene l’efficacia –Garantisce una sicurezza ancora maggiore La riduzione del dosaggio del 50% basata su caratteristiche cliniche riduce l’esposizione media di Edoxaban del 29% rispetto alla popolazione che non ha ridotto il dosaggio Ruff et al., Lancet, 2015

ENGAGE AF Conclusioni 1/2 Edoxaban alla dose di 60/30 mg ha dimostrato la non inferiorità rispetto a warfarin nella prevenzione di stroke/SEE in pz con FA In confronto a warfarin edoxaban 60/30 mg ha dimostrato una riduzione significativa dei sanguinamenti maggiori, intracranici e del net clinical outcome La riduzione di dosaggio a 30 mg in pz ben definiti mantiene l’efficacia e migliora il profilo di safety Edoxaban 60/30mg mantiene il suo profile di efficacia e di sicurezza indipendentemente dall’età Giugliano et al. N Engl J Med 2013;369:

ENGAGE AF Conclusioni 2/2 E’ lo studio che ha arruolato il maggior numero di pazienti; con la durata maggiore; il TTR più alto; la maggiore flessibilità di trattamento (giusto dosaggio per il giusto paziente); più aderente alla realtà clinica

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