Background

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