Edo. Coagulation factor Xa Common ending of drug class of direct Factor Xa inhibitors

Transcription

1 What does the name edoxaban mean? Edo Tokyo Coagulation factor Xa Common ending of drug class of direct Factor Xa inhibitors ban EdoXaban

2 Features of novel oral anticoagulants Dabigatran 1 Rivaroxaban 1,2 Apixaban 1,3 Edoxaban 4 6 Target IIa (thrombin) Xa Xa Xa Hours to Cmax CYP metabolism No Yes (moderate) Yes (moderate) Minimal (<4%) Bioavailability 6% 100% with food 60% 62% Transporters P gp P gp/bcrp P gp/ BCRP P gp Protein binding 35% 93% 87% 50% Half life h 7 11 h 8 15 h h Renal elimination 80%* 33% # 25% # 35% # /50%* Dosing regimen BID OD/BID BID OD BCRP, breast cancer resistance protein CYP, cytochrome P450; P-gp, P-glycoprotein NR, not reported * Of absorbed substance # Of ingested substance 1. Eriksson et al. Clin Pharmacokinet 2009;48:1-22; 2. Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2011; 3. ELIQUIS Summary of Product Characteristics. Bristol Myers Squibb/Pfizer EEIG, UK; 4. Ruff et al. Hot Topics in Cardiology 2009;18:1-32; 5. Matsushima et al. Am Assoc Pharm Sci 2011; abstract; 6. Ogata et al. J Clin Pharmacol 2010;50:743-53

3 Phase II data Atrial Fibrillation

4 Edoxaban study 018: major and clinically relevant nonmajor bleeding 12 ** Bleeding incidence (%) * 2 0 Warfarin Edoxaban 30 mg QD Edoxaban 60 mg QD Edoxaban 30 mg BID Edoxaban 60 mg BID n/n 8/250 7/235 11/234 19/244 19/180 *p<0.05, **p<0.01, vs warfarin QD, once daily; BID, twice daily Weitz et al. Thromb Haemost 2010;104:633-41

5 Edoxaban phase II dose finding study in atrial fibrillation: exposure and bleeding C max AUC C min ng/ml QD 60 QD 30 BID 60 BID Ng*h/mL QD 60 QD 30 BID 60 BID ng/ml QD 60 QD 30 BID 60 BID 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 Bleeding incidence, % QD Edoxaban 60 QD 30 BID 60 BID Weitz et al. Thromb Haemost 2010;104:633-41

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7 Study design: ENGAGE AF TIMI 48 Randomized, double blind, double dummy, event driven study PATIENTS AF on electrical recording within last 12 months Intended oral anticoagulant CHADS 2 2 N=21,105 RANDOMIZATION 1:1:1 randomization is stratified by CHADS 2 score 2 3 versus 4 6 and need for edoxaban dose reduction* Edoxaban 30/15 mg QD regimen Edoxaban 60/30 mg QD regimen Warfarin (INR ) Median duration of follow up 2.8 years *Dose reduced by 50% if CrCl 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 Giugliano et al. N Engl J Med 2013

8 Overall patient characteristics Characteristic Warfarin (n=7,036) Edoxaban 60 mg (n=7,035) Edoxaban 30 mg (n=7,034) Median age [IQR], years 72 [64 78] 72 [64 78] 72 [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) IQR=interquartile range Giugliano et al. N Engl J Med 2013; e pub ahead of print

9 Overall patient characteristics Characteristic CHADS 2, mean±sd, n (%) Dose reduction at randomization*, n (%) Creatinine clearance ml/min Weight 60 kg Verapamil or quinidine Warfarin (n=7,036) 2.8±1.0 5,445 (77.4) 1,591 (22.6) 1,787 (25.4) 1,361 (19.3) 701 (10.0) 243 (3.5) Edoxaban 60 mg (n=7,035) 2.8±1.0 5,422 (77.1) 1,613 (22.9) 1,784 (25.4) 1,379 (19.6) 684 (9.7) 258 (3.7) Edoxaban 30 mg (n=7,034) 2.8±1.0 5,470 (77.8) 1,564 (22.2) 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) Patients could appear in more than one category, therefore percentages may not total 100% *Patients with CrCl 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 2,018 (28.7) 149 (2.1) 799 (11.4) 2,073 (29.5) SD=standard deviation Giugliano et al. N Engl J Med 2013; e pub ahead of print

10 Treatment Study drug was administered to 21,026 (99.6%) of randomized patients 5,330 (25.3%) of these patients received a reduced dose of edoxaban/placebo at randomization After randomization further dose reductions occurred in 7.1% of patients and dose increases occurred in 1.2% of patients Rates were similar across groups Median duration of treatment exposure was 907 days excluding interruptions, and median follow up was 1022 days (2.8 years) The median time in therapeutic range (TTR) for warfarin was 68.4%, (interquartile range %) and the mean time was 64.9±18.7% * *Time in therapeutic range (TTR) was calculated using the method of Rosendaal et al. A slide in the Back Up section explains the method in more detail Giugliano et al. N Engl J Med 2013; e pub ahead of print Rosendaal et al. Thromb Haemost 1993;69:

11 Study design: ENGAGE AF TIMI 48 Randomized, double blind, double dummy, event driven study PATIENTS AF on electrical recording within last 12 months Intended oral anticoagulant CHADS 2 2 N=21,105 RANDOMIZATION 1:1:1 randomization is stratified by CHADS 2 score 2 3 versus 4 6 and need for edoxaban dose reduction* Edoxaban 30/15 mg QD regimen Edoxaban 60/30 mg QD regimen Warfarin (INR ) *Dose reduced by 50% if CrCl ml/min, body weight 60 kg patient receiving verapamil, quinidine or dronedarone Median duration of follow up 2.8 years Giugliano et al. N Engl J Med 2013

12 Edoxaban: Dosaggio raccomandato

13 Efficacy endpoints: stroke or SEE ITT and mitt on treatment analysis Treatment N n Incidence (%/yr) HR (97.5% CI) P value Warfarin (median TTR 68.4%) 7, Edoxaban 60/30 mg (mitt) 7, ( ) P<0.001 a Edoxaban 60/30 mg (ITT) 7, ( ) 0.08 b Hazard ratio (97.5% CI) mitt 0.79 P<0.001 a ITT 0.87 P=0.08 b Edoxaban better Warfarin better a non inferiority; b superiority Giugliano et al. N Engl J Med 2013;369:

14 Stroke or systemic embolic event (%) Kaplan Meier of primary efficacy outcome ITT population Warfarin Edoxaban 60/30 mg (HR=0.87, ) Median TTR=68.4% Years No.at risk Warfarin Edoxaban /30 mg Giugliano et al. N Engl J Med 2013;369:

15 Primary efficacy outcome Outcome Warfarin (n=7,036) Edoxaban 60/30 mg (n=7,035) Edoxaban 60/30 mg versus warfarin n %/yr n %/yr HR (95% CI) P Stroke or SEE mitt, on treatment ITT Post study transition ( ) Δ 0.87 ( ) Δ <0.001 * 0.08 Stroke Hemorrhagic Ischemic Non disabling, nonfatal Disabling or fatal Fatal SEE ( ) 0.54 ( ) 1.00 ( ) 0.80 ( ) 0.97 ( ) 0.92 ( ) 0.65 ( ) 0.11 < Data are from the ITT cohort during the overall study period with 95% CI and P values for superiority, unless otherwise stated; Δ 97.5% CI *Non inferiority analysis. P values for superiority were 0.02 for high dose edoxaban vs warfarin. CI=confidence intervals; ITT=Intent To Treat mitt=modified Intent To Treat; SEE=systemic embolic event Giugliano et al. N Engl J Med 2013;369:

16 Major bleeding Safety on treatment analysis Treatment N n Incidence (%/yr) HR (95% CI) P value Warfarin 7, Edoxaban 60/30 mg 7, ( ) <0.001 Hazard ratio (95% CI) P for superiority Edoxaban 60 /30mg vs warfarin 0.80 P< Edoxaban better Warfarin better Giugliano et al. N Engl J Med 2013;369:

17 Kaplan Meier of principal safety outcome Warfarin Edoxaban 60/30 mg (HR=0.80, ) Major bleeding (%) Median TTR=68.4% Years No.at risk Warfarin Edoxaban /30 mg Giugliano et al. N Engl J Med 2013;369:

18 Safety outcomes Outcome Warfarin (n=7,012) Edoxaban 60/30 mg (n=7,012) Edoxaban 60/30 mg versus warfarin n %/yr n %/yr HR (95% CI) P Major bleeding ( ) <0.001 Life threatening bleeding ( ) <0.001 CRNM bleeding Minor bleeding 1, , ( ) 0.84 ( ) < Major or CRNM bleeding 1, , ( ) <0.001 Any overt bleeding 2, , ( ) <0.001 Data are from the Safety cohort during the on treatment period CRNM=clinically relevant non major Giugliano et al. N Engl J Med 2013;369:

19 Net clinical outcomes Warfarin (n=7,012) Edoxaban 60/30 mg (n=7,012) Edoxaban 60/30 mg versus warfarin n %/yr n %/yr HR (95% CI) P Primary Composite of stroke, SEE, major bleeding, and all cause mortality Secondary Composite of disabling stroke, life threatening bleed, and all cause mortality Tertiary Exploratory composite of stroke, SEE, life threatening bleed, and all cause mortality 1, , ( ) ( ) , ( ) Data are from the overall treatment period SEE=systemic embolic event Giugliano et al. N Engl J Med 2013;369:

20 Summary of key outcomes Stroke and SEE: mitt on treatment 0.79 Stroke and SEE: ITT 0.87 Hemorrhagic stroke: ITT 0.54 Ischemic stroke: ITT 1.00 Major bleed: safety cohort 0.80 CRNM bleed: safety cohort Death: ITT CV death: ITT Stroke, SEE, major bleed, death: ITT Edoxaban 60/30 mg better Warfarin better Giugliano et al. N Engl J Med 2013;369:

21 Relationship between edoxaban dose, concentration, anti factor Xa activity, and outcomes in the ENGAGE AF TIMI 48 trial Christian T. Ruff, MD, MPH On behalf of the Executive Committee and investigators TIMI Study Group Brigham and Women s Hospital Harvard Medical School Boston, MA

22 ENGAGE AF: Stroke or SEE (%/Year) 2,5 HD Edoxaban vs. Warfarin No DR: HR 0.78 ( ) DR: HR 0.81 ( ) P int =0.85 2,21 Stroke/SEE (%/year) 2,0 1,5 1,0 0,5 0,0 Edox Conc. (ng/ml) Anti-FXa (IU/mL) 1,29 Warfarin 1.00 No dose reduction NA NA HD Edox 60 mg Warfarin 1,79 HD Edox 30 mg Dose reduction NA NA DR, dose reduction; HD, high dose; LD, low dose; SEE, systemic embolic event Ruff et al., Lancet, 2015

23 ENGAGE AF: Major bleed (%/Year) 6,0 5,0 HD Edoxaban vs. Warfarin No DR: HR 0.88 ( ) DR: HR 0.63 ( ) P int =0.02 4,85 Major bleed (%/year) 4,0 3,0 2,0 1,0 0,0 Edox Conc. (ng/ml) Anti-FXa (IU/mL) 3,02 Warfarin 2,66 No dose reduction NA NA HD Edox 60 mg Warfarin 3,05 HD Edox 30 mg Dose reduction NA NA DR, dose reduction; HD, high dose; LD, low dose; SEE, systemic embolic event Ruff et al., Lancet, 2015

24 Summary 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 Dose reduction by 50% based on clinical feature reduced mean edoxaban exposure 29 35% and anti FXa activity 20 25% compared to the population who were not dose reduced * Dose reduced by 50%: CrCl ml/min, weight 60 kg, Strong P gp inhibitor C. Ruff poster presented at ESC 2014

25 Efficacy and Safety of Edoxaban in Elderly Patients With Atrial Fibrillation in the ENGAGE AF TIMI 48 Trial Eri Toda Kato, MD, PhD; Robert P. Giugliano, MD, SM; Christian T. Ruff, MD, MPH; Yukihiro Koretsune, MD, PhD; Takeshi Yamashita, MD, PhD; Robert Gabor Kiss, MD, PhD; Francesco Nordio, PhD; Sabina A. Murphy, MPH; Tetsuya Kimura, MS; James Jin, PhD; Hans Lanz, MD; Michele Mercuri, MD, PhD; Eugene Braunwald, MD; Elliott M. Antman, MD

26 Patient Characteristics <65 years (n=5,497) years (n=7,134) 75 years (n=8,474) Female (%) Dyslipidemia (%) Warfarin TTR (%) CHADS 2 score (mean) Congestive heart failure (%) Hypertension (%) Median Age (yr) Diabetes (%) Prior stroke or TIA (%) HAS BLED score 3 (%) Median CrCl (ml/min) Median weight (kg) Dose reduction at rando (%) All P<0.001 except dyslipidemia P=0.007

27 Event Rate by Age (warfarin only) 6,0 Stroke/ SEE P<0.001 Ischaemic Stroke P<0.001 ISTH Major Bleeding P<0.001 ICH P< ,0 4.8 Event rate (%/ pt yrs) 4,0 3,0 2,0 1,0 1,1 1,8 2,3 0,9 1,1 1, ,0 < < Age (yr) < < Kato ET et al. J Am Heart Assoc. 2016;5: e003432

28 No Evidence of Effect Modification HD Edoxaban vs Warfarin HR, 95% CI HD Warfarin Edoxaban Event rate (%/ pt yr) Stroke/ SEE Ischemic stroke <65 yr yr yr P interaction: all >0.05 <65 yr yr 75 yr Major Bleeding ICH <65 yr yr 75 yr <65 yr yr 75 yr Favours Edoxaban Favours Warfarin Kato ET et al. J Am Heart Assoc. 2016;5: e003432

29 last accessed Nov. 2014

30 End Points by Age > 85 yrs P interaction: all >0.05 Kato ET et al. J Am Heart Assoc. 2016;5: e003432

31 Summary The risk of stroke/see, ischemic stroke, ISTH major bleeding, and ICH increased with age (p<0.001), but more markedly so for ISTH major bleeding and ICH. There was no effect modification by age when comparing edoxaban with warfarin. Edoxaban reduced the absolute rates of major bleeding, and ICH. Edoxaban provided superior net clinical benefit over warfarin by decreasing the bleeding risk, particularly in the elderly. Oral Comunication at American Heart Association, November, 2014 Chicago

32 Conclusion The efficacy and safety profile of edoxaban compared to warfarin is consistent regardless of age in patients with AF. Due to the higher risk of both stroke and particularly bleeding across all treament, the absolute benefits of edoxaban trended to be greater in the elderly. Oral Comunication at American Heart Association, November, 2014 Chicago

33 Concomitant Use of Antiplatelet Therapy with Edoxaban or Warfarin in Patients with Atrial Fibrillation: Analysis from the ENGAGE AF TIMI 48 Trial Haiyan Xu, Christian T. Ruff, Robert P. Giugliano, Sabina A. Murphy, Indravadan Patel, Minggao Shi, Michele Mercuri, Elliott M. Antman, Eugene Braunwald TIMI Study Group, Brigham and Women s Hospital Nov 18 th, 2014 AHA Chicago

34 Baseline Characteristics Variables Not on Antiplatelet On Antiplatelet Therapy P value Therapy (N=14997) (N=4912) Age, yr, median (IQR) 72 (64, 77) 72 (64, 78) 0.52 Female 40% 32% <0.001 CHADS 2 score 4 22% 24% <0.001 HAS BLED score 3 35% 79% <0.001 Diabetes 35% 41% <0.001 Prior MI 9% 18% <0.001 Prior coronary revascularization 8% 26% <0.001 Peripheral arterial disease 3% 6% <0.001 Carotid artery disease 5% 9% <0.001 Prior stroke or TIA 28% 28% 0.87 Prior non ICH bleeding history 9% 12% <0.001 Dose reduced at randomization 26% 25% 0.07 Oral Comunication at American Heart Association, November, 2014 Chicago

35 Efficacy of Edoxaban vs. Warfarin Stratified by Antiplatelet Therapy Annualized Event Rate (%/yr) HD Edox vs. Warf Efficacy Edo Warf HR(95%CI) P int Stroke/SEE No antiplatelet Antiplatelet ( ) 0.70( ) 0.14 Ischemic stroke No antiplatelet Antiplatelet ( ) 0.73( ) 0.08 Hemorrhagic stroke No antiplatelet Antiplatelet ( ) 0.66( ) 0.33 MI No antiplatelet Antiplatelet ( ) 0.85( ) 0.87 CV death No antiplatelet Antiplatelet ( ) 0.83( ) 0.83 Oral Comunication at American Heart Association, November, 2014 Chicago 0, HD Edox better Warf better

36 Safety of Edoxaban vs. Warfarin Stratified by Antiplatelet Therapy Annualized Event Rate (%/yr) HD Edox vs. Warf Efficacy HD Edox Warf HR(95%CI) P int Major bleeding No antiplatelet Antiplatelet ( ) 0.82( ) 0.91 Fatal Bleeding No antiplatelet Antiplatelet ( ) 0.34( ) 0.17 Life threatening bleeding No antiplatelet Antiplatelet ( ) 0.56( ) 1.00 Intracranial bleeding No antiplatelet Antiplatelet ( ) 0.46( ) ,1 1 Oral Comunication at American Heart Association, November, 2014 Chicago HD Edox better Warf better

37 Summary and Conclusions Addition of antiplatelet to anticoagulant did increase bleeding risk The relative efficacy and safety of both doses of edoxaban compared to well managed warfarin were consistent regardless of concomitant antiplatelettherapy Oral Comunication at American Heart Association, November, 2014 Chicago

38 AF e HF

39 Baseline characteristics in AF trials RE LY (Dabigatran) 1 ROCKET AF (Rivaroxaban) 3 ARISTOTLE (Apixaban) 4 ENGAGE AF (Edoxaban) 5 N 18,113 14,264 18,201 21,105 Concurrent aspirin use, % Ø VKA naïve, % Median CrCl [IQR], ml/min [52 88] Δ NR Comorbid conditions, % Prior stroke, TIA CHF Hypertension Diabetes Prior MI # # Ø Previous aspirin use; #I Includes prior systemic embolism; CrCl ml/min was largest proportion of patients in J-ROCKET (51%) and ARISTOTLE (42%); CHF=chronic heart failure; CrCl=creatinine clearance; IQR=interquartile range; MI=myocardial infarction; NR=not recorded; TIA=transient ischemic attack; VKA=vitamin K antagonist 1. Connolly et al. N Engl J Med 2009;361: ; 2. FDA Advisory Committee Briefing Document 27 August Committee/UCM pdf. Last accessed 15 th October 2013; 3. Patel et al. N Engl J Med 2011;365: Granger et al. N Engl J Med 2011;365: ; 5. Giugliano et al. N Engl J Med 2013; e-pub ahead of print

40 Efficacy and Safety in Patients with Prior CHF Stroke/SEE HDE W No HF HF, NYHA I II HF, NYHA III IV Ischemic Stroke No HF HF, NYHA I II HF, NYHA III IV Hemorrhagic stroke Higher Dose Edoxaban vs. Warfarin HR 95% CI Annualized Annualized event rate Ev (yr/%)(%/yr No HF HF, NYHA I II HF, NYHA III IV Annualized event rate (yr/%) Favors HDE Favors W P int > 0.05 for all Magnani G, AHA 2014, Chicago, USA

41 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:

42 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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44 HOKUSAI VTE Great Wave at Kanagawa. Katsushika Hokusai (25.4 x 37.1 cm) color woodblock print from Hokusai's series Thirty six Views of Mount Fuji, which are the high point of Japanese prints. The Hokusai VTE Investigators. N Engl J Med 2013 Hokusai VTE clinical study protocol. Version 5.0, 16 April Daiichi Sankyo

45 N=8, sites in 37 countries Hokusai VTE: study design Randomized, double blind, event driven study Edoxaban 60 mg (30 mg) * Objectively confirmed VTE Stratified randomization: DVT / PE Dose of edoxaban Risk factors R Sham INR INR All patients followed for 12 months regardless of treatment duration Day 1 5 Day 6 12 Warfarin (INR ) 3 mo 12 mo Edoxaban Placebo Edoxaban Warfarin Placebo Warfarin Low molecular weight heparin / UFH *Dose was halved to 30 mg in patients perceived to be at higher risk for bleeding due to potential overanticoagulation by predefined criteria During days 6 12 edoxaban or placebo edoxaban was started once heparin was stopped Raskob et al. J Thromb Haemost 2013;11: The Hokusai VTE Investigators. N Engl J Med 2013

46 Kaplan Meier curves of efficacy outcomes overall analysis Edoxaban Warfarin Overall On Rx TTR : 63.5% Number at Risk: Edoxaban Overall Warfarin Overall Edoxaban On tx Warfarin On tx The Hokusai VTE Investigators. N Engl J Med 2013

47 Primary efficacy outcome (recurrent VTE) Outcome All patients, n (%) Overall study period On treatment period Edoxaban (N=4118) 130 (3.2) 66 (1.6) Warfarin (N=4122) 146 (3.5) 80 (1.9) Patients with index DVT, n (%) 2468 (59.9) 2453 (59.5) Overall study period On treatment period 83 (3.4) 48 (2.0) 81 (3.3) 50 (2.0) Patients with index PE, n (%) 1650 (40.1) 1669 (40.5) Overall study period On treatment period 47 (2.8) 18 (1.1) 65 (3.9) 30 (1.8) Relative risk (95% CI) 0.89 ( ) * 0.82 ( ) * 1.02 ( ) 0.96 ( ) 0.73 ( ) 0.60 ( ) * P<0.001 for non inferiority The Hokusai-VTE Investigators. N Engl J Med 2013

48 Kaplan Meier curves of principal safety outcome Cumulative Event Rate (%) Edoxaban Warfarin Time to Event (days) Number of patients at risk warfarin edoxaban The Hokusai-VTE Investigators. N Engl J Med 2013

49 Principal safety outcomes Outcome First major or clinically relevant non major bleeding, n (%) Major bleeding, n (%) Fatal Non fatal in critical sites Non fatal in non critical sites Edoxaban (N=4118) Warfarin (N=4122) Relative risk (95% CI) 349 (8.5) 423 (10.3) 0.81 ( ) * 56 (1.4) 2 (<0.1) 13 (0.3) 41 (1.0) 66 (1.6) 10 (0.2) 25 (0.6) 33 (0.8) 0.84 ( ) # Clinically relevant non major bleeding, n (%) 298 (7.2) 368 (8.9) 0.80 ( ) * Any bleeding, n (%) 895 (21.7) 1056 (25.6) 0.82 ( ) * P=0.004, # P=0.35, P<0.001 for superiority The Hokusai-VTE Investigators. N Engl J Med 2013

50 Subgroup analysis: 30 mg Efficacy outcomes # Characteristic Edoxaban (N=733) Warfarin (N=719) Relative risk (95% CI) Efficacy Recurrent VTE 22 (3.0) 30 (4.2) 0.73 ( ) # At randomization and for overall (12-month) treatment period regardless of treatment duration Safety outcomes Characteristic Edoxaban (N=733) Warfarin (N=719) Relative risk (95% CI) Safety Primary: First major or clinically relevant non major bleeding, n 58 (7.9) 92 (12.8) 0.62 ( ) (%) Major bleeding, n (%) 11 (1.5) 22 (3.1) 0.50 ( ) Clinically relevant non major bleeding, n (%) 47 (6.4) 70 (9.7) The Hokusai-VTE Investigators. N Engl J Med 2013

51 Subgroup of patients with pulmonary embolism

52 Subgroup analysis in Hokusai VTE Approximately 90% of PE patients had a baseline NT probnp level measured In PE patients with NT probnp levels 500 pg/ml recurrent VTE occurred in 15 of 454 patients (3.3%) who received edoxaban and in 30 of 484 patients (6.2%) given warfarin (HR 0.52 [ ]) Of the 1002 random sample of patients measured by CT, approximately 35% had RV dysfunction Similar results were observed in patients with RV dysfunction on CT as in those with NT probnp levels 500 pg/ml (HR 0.42 [ ]) The Hokusai VTE Investigators. N Engl J Med 2013

53 Subgroup analysis in PE patients with NT probnp 500 pg/ml 7 6 HR=0.52 (95% CI, ) 6.2% Patients (%) % Edoxaban Warfarin /454 30/484 VTE recurrence The Hokusai VTE Investigators. N Engl J Med 2013

54 Conclusioni Nello studio HOKUSAI edoxaban ha dimostrato: non inferiorità vs warfarin nella prevenzione delle ricorrenze di VTE riduzione significativa dei sanguinamenti risultati consistenti in un ampio spettro di pazienti inclusi: pazienti che hanno ridotto il dosaggio a 30 mg pazienti con EP più estesa The Hokusai VTE Investigators. N Engl J Med 2013

55 HOKUSAI VTE IMPLICAZIONI PRATICHE Unico NOAC SEMPRE in Monosomministrazione strategia flessibile (più aderente alla pratica clinica) per dosaggio e durata del trattamento Utilizzo di eparina che riflette la pratica clinica Unico con dati di riduzione dosaggio in pz selezionati (fragili) Confronto diretto con warfarin fino a 12 mesi di trattamento