A new generation of oral anticoagulants. Is there any place for Edoxaban and Betrixaban?

Transcription

1 A new generation of oral anticoagulants. Is there any place for and Betrixaban? Δημήτρης Ρίχτερ, MD, FESC, FAHA -Διευθυντής Καρδιολογικής Κλινικής Ευρωκλινικής Αθηνών -Γενικός Γραμματέας ΙΜΕΘΑ -Μέλος ΔΣ ΕΛΙΚΑΡ

2 Τα τελευταία τέσσερα έτη έχω λάβει αμοιβή για συμμετοχή σε μελέτες, ab, ή δορυφορικά συμπόσια από AstraZeneca, Bayer, Sanofi, Pfizer, Vianex, MSD, Unilever, Boehringer, Novartis, Abbott, Galenica, Amgen, Specifar, Menarini, Merck, Pharmaswiss, Winmedica

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4 Comparison of the pharmacological characteristics of newer OACs Parameter Dabigatran Rivaroxaban Apixaban Target Thrombin Factor Xa Factor Xa Factor Xa Oral bioavailability 6.5% %* ~66% 50% Plasma protein binding 34 35% 92 95% 87% 40 59% Dosing (for SPAF indication) *After oral ingestion *15 20 mg to be taken with food Fixed, twice daily Fixed, once daily Fixed, twice daily Fixed, once daily Prodrug Yes No No No Half-life (h) (young healthy) (elderly) T max (h) ~ Routine coagulation monitoring No No No No Eriksson BI et al, 2011; Frost et al, 2007; Kubitza D et al, 2005; Kubitza D et al, 2005; Ogata K et al, 2010; Stangier et al, 2005; Raghavan N et al, 2009; Xarelto SmPC 2011; Xarelto PI 2011; Pradaxa SmPC 2011; Eliquis SmPC 2011; Dabigatran PI; ROCKET AF Investigators 2010; Lopes et al, 2010; Ruff et al,

5 Comparison of the pharmacological characteristics of new OACs Parameter Dabigatran Rivaroxaban Apixaban Renal clearance 80% 33%; additional 33% cleared after metabolic degradation to inactive drug Potential drug interactions Rifampicin, quinidine, amiodarone, potent P-gp inhibitors Potent inhibitors of both CYP3A4 and P-gp*, strong inducers of CYP3A4 ~25% 35% Potent CYP3A4 inhibitors* Potent inhibitors of both CYP3A4 and P-gp *CYP, cytochrome P-450 isoenzymes; P-gp, P-glycoprotein. Strong inhibitors of both CYP3A4 and P-gp include azole antifungals (e.g., ketoconazole, itraconazole, voriconazole, posaconazole) and protease inhibitors, such as ritonavir. Eriksson BI et al, 2011; Xarelto Summary of Product Characteristics

6 ENGAGE-AF: study overview N=21,105 patients AF on electrical recording 12 months Intended oral anticoagulation CHADS 2 2 Double blind Double dummy Event-driven: 672 events R Randomization stratified by: 1. CHADS vs Anticipated drug exposure: renal function, body weight, strong P-gp inhibitor use) Low-dose regimen: edoxaban 30 mg od* (n=7034) High-dose regimen: edoxaban 60 mg od* (n=7035) Active control: Warfarin (INR 2 3) (n=7036) Expected median duration of follow-up 24 months Primary endpoint: stroke or SE (non-inferiority margin: 1.38) Secondary endpoint: stroke or SE or cardiovascular/all-cause mortality Principal safety outcome: major bleeding (modified ISTH) *Dose halved in patients at risk of increased drug exposure

7 dosing regimens Two dosing regimens: high (60 mg) and low (30 mg) Data across a fourfold dose range: 60, 30, 15 mg od Can reduce doses during study: 60 to 30 mg od; 30 to 15 mg od Dose adjustment at randomization for 1 of the following: Creatinine clearance ml/min Weight 60 kg Cardiac medications that are strong P-gp inhibitors Continuous dose adjustment after randomization if any of the above characteristics change 30-day transition to open-label VKA at study end: edoxaban 30 mg od and VKA until INR reaches 2.0 or for 2 weeks (whichever comes first) Weitz et al, 2010; ESC 2013; Giugliano et al, 2013

8 Study design and inclusion ROCKET AF 1 RE-LY 2 ARISTOTLE 3,4 ENGAGE AF 5 No. of patients 14,264 18,113 18,201 21,105 Statistical objective Non-inferiority Non-inferiority Non-inferiority Non-inferiority No. study arms Study drug Double-blind rivaroxaban Two doses of double-blind dabigatran Double-blind apixaban Two doses* of double-blind edoxaban Control Double-blind warfarin (INR 2 3) Open-label warfarin (INR 2 3) Double-blind warfarin (INR 2 3) Double-blind warfarin (INR 2 3) AF type of pts included Non-valvular Non-valvular All except mechanical valves Non-valvular 1. Patel MR et al, 2011; 2. Connolly SJ et al, 2009; 3. Lopes RD et al, 2010; 4.Granger CB et al, 2011; 5. Giugliano R at al, 2013 * Dose reduced by 50% in selected Patients

9 Study endpoints ROCKET AF 1 RE-LY 2 ARISTOTLE 3 AVERROES 4 ENGAGE AF- TIMI 48 5 Study drug Rivaroxaban Dabigatran Apixaban Apixaban Primary efficacy Stroke and systemic embolism Primary safety Composite of major and non-major clinically relevant bleeding Major bleeding 1. Patel MR et al, 2011; 2. Connolly SJ et al, 2009; 3. Lopes RD et al, 2010; 4. Connolly SJ et al, 2011; 5. Ruff CT et al,

10 ENGAGE-AF: key inclusion and exclusion criteria Key inclusion criteria Documented history of AF with planned anticoagulation CHADS 2 score 2 (congestive heart failure, hypertension, age 75 years, diabetes mellitus = 1 point each; history of stroke or transient ischaemic attack = 2 points) Key exclusion criteria AF owing to a reversible disorder CrCl <30 ml/min High bleeding risk Use of dual antiplatelet therapy Moderate/severe mitral stenosis Other indications for anticoagulant therapy ACS, coronary revascularization or stroke within 30 days before randomization

11 Inclusion criteria: risk factors ROCKET AF 1 RE-LY 2 ARISTOTLE 3 AVERROES 4 ENGAGE AF-TIMI 48 5 Rivaroxaban Dabigatran Apixaban Apixaban Prior stroke/tia or systemic embolism Or 2 of the following:* CHF or LVEF 35% Hypertension Age 75 years Diabetes mellitus 1 of the following: Prior stroke/tia or systemic embolism Symptomatic CHF or LVEF 40% Age 75 years Age 65 years and one of the following: i. Diabetes mellitus ii. CAD iii. Hypertension 1 of the following: Prior stroke/tia or systemic embolism Age 75 years Symptomatic CHF or LVEF 40% Diabetes mellitus Hypertension requiring pharmacological treatment 1 of the following: Prior stroke/ TIA Age 75 years CHF NYHA class 2 or LVEF 35% Diabetes mellitus Hypertension on treatment Documented PAD Prior stroke/tia or systemic embolism Or 2 of the following: CHF Hypertension Age >75 years Diabetes mellitus *Enrolment of patients without prior stroke, TIA, or systemic embolism and only two factors capped at 10% 1. Patel MR et al, 2011; 2. Connolly SJ et al, 2009; 3. Lopes RD et al, 2010; 4. Connolly SJ et al, 2011; 5. Ruff CT et al,

12 ENGAGE-AF: study metrics Complete information on primary endpoint: 99.5% of all potential patient-years of follow-up 1 patient lost to follow-up; 244 patients withdrew consent After randomization: Dose reduction (60 mg 30 mg or 30 mg 15 mg): 7.1% of patients Dose increase (30 mg 60 mg or 15 mg 30 mg): 1.2% of patients Similar rates of dose change across all three treatment arms Median treatment exposure: 907 days Median follow-up: 1022 days (2.8 years) Warfarin arm, for the treatment period: Median (IQR) TTR: 68.4% ( %) Mean (± SD) TTR: 64.9% (± 18.7%)

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14 ENGAGE-AF: patient characteristics (3) Characteristic 30 mg od (N=7034) 60 mg od (N=7035) Warfarin (N=7036) Dose reduction at randomization, % CrCl 50 ml/min Weight 60 kg Concomitant P-gp inhibitors Medications randomization, % Thienopyridine Amiodarone Digitoxin or digitalis

15 ENGAGE-AF: primary efficacy endpoint Stroke or systemic embolism Patients with event (%) No. of patients at risk Edox. 30 mg od Edox. 60 mg od Warfarin ITT population Warfarin Time since randomization (years) Low-dose edoxaban High-dose edoxaban 30 mg od vs warfarin: HR 1.13 (97.5% CI ); p (sup.) = mg od vs warfarin: HR 0.87 (97.5% CI ); p (sup.) = 0.08

16 ENGAGE-AF: primary efficacy endpoint Stroke/SE on treatment (mitt) Stroke/SE in overall study period (ITT) 30 mg od %/year (N=7034) 60 mg od %/year (N=7035) Warfarin %/year (N=7036) 30 mg od vs warfarin HR, p-value* ( ) # p= ( ) # p=0.10 Stroke ( ) p=0.12 Ischaemic ( ) p<0.001 Haemorrhagic ( ) p<0.001 Fatal ( ) p=0.27 Systemic embolism ( ) p= mg od vs warfarin HR, p-value* 0.79 ( ) # p< ( ) # p= ( ) p= ( ) p= ( ) p< ( ) p= ( ) p=0.19 *p-values are non-inferiority for mitt analysis and superiority for all others; # 97.5% CI; all others are 95% CI

17 Efficacy of the NOACs for SPAF vs. VKAs Outcome Dabigatran 110 mg bid Dabigatran 150 mg bid Rivaroxaban 20 mg od Apixaban 5 mg bid 60mg 30mg Stroke / SEE -10% (ns) -34% (s) -21% (ns) -21% (s) -21% (ns) +7% (ns) Ischemic strokes +11% (ns) -24% (s) -6% (ns) -8% (ns) 0% +41% (s) Hemorrhagic strokes -69% (s) -74% (s) -41% (s) -49% (s) -46% (s) -67% (s) All Cause Mortality -9% (ns) -12% (ns) -15% (ns) -11% (s) -8% (ns) -13% (s) ns=non-significant s= significant Connolly SJ et al. N Engl J Med 2009;361: Patel MR et al. N Engl J Med 2011;365: Granger CB et al. N Engl J Med 2011;365: Giugliano R at al. N Engl J Med 2013.DOI: /NEJMoa

18 ENGAGE-AF: principal safety outcome Major bleeding (ISTH) Patients with event (%) Time since randomization (years) No. of patients at risk Edox. 30 mg od Edox. 60 mg od Warfarin Safety population High-dose edoxaban Warfarin Low-dose edoxaban mg od vs warfarin: HR 0.80 (95% CI ); p (sup.) < mg od vs warfarin: HR 0.47 (95% CI ); p (sup.) <0.001

19 ENGAGE-AF: safety outcomes (all bleeding events) 30 mg od %/year (N=7002) 60 mg od %/year (n=7012) Warfarin %/year (N=7012) 30 mg od vs warfarin HR, p-value* Major bleeding ( ) p<0.001 Life-threatening bleeding Non-major clinically relevant bleeding ( ) p< ( ) p<0.001 Minor bleeding ( ) p< mg od vs warfarin HR, p-value* 0.80 ( ) p< ( ) p< ( ) p< ( ) p=0.002 Safety population; *p-values are for superiority

20 ENGAGE-AF: safety outcomes (components of major bleeding) 30 mg od %/year (N=7002) 60 mg od %/year (n=7012) Warfarin %/year (N=7012) 30 mg od vs warfarin HR, p-value* Major bleeding ( ) p<0.001 Fatal ( ) p< mg od vs warfarin HR, p-value* 0.80 ( ) p< ( ) p=0.006 Critical organ or area ( ) p< ( ) p<0.001 Any ICH ( ) p<0.001 Fatal ICH ( ) p<0.001 Gastrointestinal ( ) p< ( ) p< ( ) p= ( ) p=0.03 Safety population; *p-values are for superiority

21 ENGAGE-AF: secondary efficacy outcomes Stroke, systemic embolism or CV death Stroke, systemic embolism or all-cause death 30 mg od %/year (N=7034) 60 mg od %/year (N=7035) Warfarin %/year (N=7036) 30 mg od vs warfarin HR, p-value* ( ) p= ( ) p=0.13 CV death ( ) p=0.008 All-cause death ( ) p=0.006 Myocardial infarction ( ) p= mg od vs warfarin HR, p-value* 0.87 ( ) p= ( ) p= ( ) p= ( ) p= ( ) p=0.60 *p-values are for superiority

22 Definition of major bleeding ROCKET AF 1 RE-LY 2 ARISTOTLE 3 & AVERROES 4 ENGAGE AF-TIMI 48 5 Rivaroxaban Dabigatran Apixaban Clinically overt bleeding associated with any of the following: Bleeding associated with any of the following: Acute or subacute clinically overt bleeding with any of the following: Clinically overt bleeding with any of the following: A decrease in Hb level of 2 g/dl A transfusion of 2 U of packed red blood cells or whole blood Fatal bleeding Critical organ bleeding Reduction in Hb level of 2 g/dl Transfusion of 2 U of blood Fatal bleeding Symptomatic critical organ bleeding A decrease in Hb-level of 2 g/dl over a 24-hour period A transfusion of 2 U of packed red blood cells Fatal bleeding Critical organ bleeding A decrease in Hb-level of 2 g/dl A transfusion of 2 U of packed red blood cells Fatal bleeding Symptomatic critical organ bleeding 1. Patel MR et al, 2011; 2. Connolly SJ et al, 2009; 3. Lopes RD et al, 2010; 4. Connolly SJ et al, 2011; 5. Ruff CT et al,

23 Major Bleeding with edoxaban in NVAF High-dose edoxaban vs warfarin Low-dose edoxaban vs warfarin The reduction in major bleeding with edoxaban as compared with warfarin was significantly greater among patients who received a dose reduction at randomization than among those who did not receive a dose reduction (Fig. S4 in the Supplementary Appendix). Giugliano R at al. N Engl J Med 2013.DOI: /NEJMoa

24 ENGAGE-AF: events during 30-day transition period Stroke or systemic embolism Major bleeding

25 ENGAGE-AF: summary Compared with warfarin, edoxaban 60 mg and 30 mg od showed: Non-inferiority for the composite of stroke or SE in AF patients at moderate/high risk of stroke Significant reductions in major bleeding Significant improvements in net clinical outcomes (stroke, SE, major bleeding or all-cause death) Both doses of edoxaban are viable alternatives to warfarin for stroke prevention in patients with non-valvular AF

26 Phase III studies for VTE treatment Trial name Design Initial treatment with LMWH/ fondaparinux Treatment duration (months) Long-term treatment regimen 26 Active comparator Rivaroxaban EINSTEIN DVT Open label No 3, 6 or 12 od LMWH/VKA EINSTEIN PE Open label No 3, 6 or 12 od LMWH/VKA EINSTEIN EXT Double blind No 6 or 12 od Placebo Dabigatran RE-COVER Double blind Yes* 6 bid Warfarin RE-COVER II Double blind Yes 6 bid Warfarin RE-MEDY Double blind No 18 bid Warfarin RE-SONATE Double blind No 6 bid Placebo Apixaban AMPLIFY Double blind No 6 bid LMWH/warfarin AMPLIFY-EXT Double blind No 12 bid Placebo Hokusai-VTE Double blind Yes 12 od # Heparin/warfarin *Median=9 days; # two 30 mg tablets

27 for the Treatment of Acute Symptomatic Venous Thromboembolism the HOKUSAI-VTE study On behalf of the HOKUSAI -VTE Investigators Breaking Wave Off Kanagawa. Katsushika Hokusai 1831 (25.4 x 37.1 cm) colour woodblock print from Hokusai's series Thirty-six Views of Fuji, which are the high point of Japanese prints. The original is at the Hakone Museum in Japan.

28 Oral direct factor Xa inhibitor with a rapid onset of action and halflife of hours 60 mg once daily dose was selected based on phase II data Dose of 30 mg in case of moderate renal impairment (CrCl 30-50mL/min) low body weight, i.e., 60 Kg concomitant use of P-gp inhibitors

29 Aim: To evaluate whether initial (LMW)heparin followed by edoxaban only is non-inferior to initial (LMW)heparin overlapping with warfarin, followed by warfarin only in the treatment of subjects with acute symptomatic venous thromboembolism for the prevention of symptomatic recurrent venous thromboembolism during a 12-month study period edoxaban Sham INR Symptomatic confirmed VTE event R INR warfarin Day 1-5 Day M 6 M 12 M initial (LMW)Heparin placebo warfarin placebo edoxaban

30 Baseline characteristics (N=4118) Warfarin (N=4122) Mean age, years (SD) 56 (16) 56 (16) Male gender, n (%) 2360 (57) 2356 (57) Qualifying diagnosis, n (%) DVT PE 2468 (60) 1650 (40) 2453 (60) 1669 (40) Clinical presentation and risk factors, n (%) Unprovoked Cancer Previous VTE 2713 (66) 378 (9) 784 (19) 2697 (65) 393 (10) 736 (18) Dose of 30 mg ( e.g 60 kg, CrCl ml/min), n (%) 733 (18) 719 (17)

31 Primary Efficacy Outcome hep / edoxaban (n / N) hep / warfarin (n / N) HR (95% CI) mitt Overall 130 / 4, % 146 / 4, % 0.89 ( ) Overall mitt 66 / 4, / 4, On-Rx 1.6% 1.9% ( ) On-Rx TTR : 63.5% Hazard Ratio superior non-inferior

32 Safety outcomes (N=4118) Warfarin (N=4122) Hazard ratio (95% CI) P Value First major or clinically relevant non major no. (%) 349 (8.5) 423 (10.3) 0.81 ( ) superiority Major no. (%) 56 (1.4) 66 (1.6) 0.84 ( ) 0.35 superiority Fatal 2 (<0.1) 10 (0.2) Intracranial 0 6 (0.1) Non Fatal in Critical Sites 13 (0.3) 25 (0.6) Intracranial 5 (0.1) 12 (0.3) Non Fatal in Non Critical Sites 41 (1.0) 33 (0.8) Clinically Relevant Non- Major no. (%) 298 (7.2) 368 (8.9) 0.80 ( ) some patients have more than 1 bleeding superiority

33 Principal Safety Outcome hep / edoxaban (n / N) 349 / 4, % hep / warfarin (n / N) 423 / 4, % HR (95% CI) 0.81 ( ) Number of patients at risk warfarin edoxaban

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35 EXPLORE-Xa A Phase 2, Randomized, Parallel Group, Dose-Finding, Multicenter, Multinational Study of the Safety, Tolerability and Pilot Efficacy of Three Blinded Doses of the Oral Factor Xa Inhibitor Betrixaban Compared With Open-Label Dose- Adjusted Warfarin in Patients With Non-Valvular Atrial Fibrillation (EXPLORE-Xa) Steering Committee Stuart J. Connolly, MD, FRCPC (Chairman) Population Health Research Institute McMaster University Hamilton, Ontario, Canada Rafael Diaz, MD Dept. of Cardiology and Clinical Research Instituto Cardiovascular de Rosario Rosario, Argentina Michael D. Ezekowitz, MD, PhD Lankenau Institute for Medical Research Thomas Jefferson Medical College Wynnewood, Pennsylvania, United States Stefan H. Hohnloser, MD, FESC, FACC Dept. of Clinical Electrophysiology Johann Wolfgang Goethe University Frankfurt, Germany Paul Dorian, MD Dept. of Medicine University of Toronto Toronto, Ontario, Canada Study Sponsored by Portola Pharmaceuticals, Inc. and Merck 35

36 Characteristics of Betrixaban Orally-active and selective fxa inhibitor Oral bioavailability 34%, Ki 117 pm Peak to trough concentration profile 2.5 : 1 ~20 hour effective half-life No dose adjustment expected for renal impairment Excreted mostly unchanged through bile with minimal renal excretion (<5%) Antidote in development No major drug interactions expected Not substrate for CYP450 system Substrate for efflux proteins including P-glycoprotein 36

37 Study Objectives Primary Objective Safety and tolerability of oral betrixaban at doses of 40, 60 and 80 mg once a day compared with dose-adjusted warfarin in patients with non-valvular atrial fibrillation or atrial flutter Primary Endpoint Time to major and clinically relevant non-major bleeding Secondary Endpoints Time to any bleeding, death, stroke, MI or systemic embolism Secondary Objective Pharmacokinetics (PK) and pharmacodynamics (PD) of betrixaban 37

38 Patient Disposition and Follow-Up N=561 Patients Screened N=508 Patients Randomized N=53 Patients Not Randomized N=127 Betrixaban 40 mg N=127 Betrixaban 60 mg N=127 Betrixaban 80 mg N=127 Open-Label Warfarin N=116 Completed N=115 Completed N=116 Completed N=119 Completed Minimum follow-up 3 months; Maximum 12 months; Median 4.9 months 38

39 Baseline Characteristics of Patients All Betrixaban Warfarin Total N=381 N=127 N=508 Median Age (years) Age 75 years 47.2% 47.2% 47.2% Male 65.4% 70.1% 66.5% White 97.4% 99.2% 97.8% Weight > 90 kg 45.1% 48.8% 46.1% Country US 72.4% 73.2% 72.6% Canada 24.9% 25.2% 25.0% Germany 2.6% 1.6% 2.3% Baseline CHADS2 score % 29.1% 28.3% % 33.1% 38.2% % 37.8% 33.5% Mean CHADS2 score Baseline GFR (Cockcroft-Gault) < 40 ml/min 9.2% 4.7% 8.1% ml/min 38.6% 37.8% 38.4% > 70 ml/min 52.2% 57.5% 53.5% Concurrent Aspirin Use < 162 mg 38.6% 38.6% 38.6% No Vitamin K Antagonist Experience 12.6% 14.2% 13.0% 39

40 Major Bleeding or Clinically Relevant Non-Major Bleeding Cumulative Hazard Rates Betrix Low Betrix Med Betrix High Warfarin *P= W Days of Follow-up Overall TTR = 64% 40

41 Bleeds, strokes and deaths 41

42 Type of G-I Adverse Events by Treatment 42

43 Conclusions Bleeding was significantly less for betrixaban 40 mg vs.warfarin Bleeding at 60 and 80 mg was comparable to warfarin The number of strokes were within the range expected for warfarin (0-1 per group) All 3 doses were well tolerated D-dimer shows activity across dose spectrum with a trend toward a dose response Compared to well-treated experienced warfarin patients there was a dose dependent effect on the primary endpoint of major and clinically relevant non-major bleeding 43

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