Simposio:
Nuovi anticoagulanti orali:
dai criteri di scelta
all’esperienza sul campo
Dabigatran
Paolo Verdecchia, F.A.C.C., F.E.S.C., F.A.H.A.
Hospital of Assisi
Department of Medicine
Via Valentin Müller, 1
06081 - Assisi PG
E-mail: [email protected]
Conflict of Interest Disclosure
Travel grants/fee for membership on
Advisory Committees and speaking at
scientific meetings:
• Boehringer-Inghelheim
• Bayer
• Daiichi-Sankyo
• Stroder
No honorarium for today’s talk
Dabigatran
1. Lo studio RE-LY
2. Le indagini della Food and
Drug Administration (FDA)
3. L’esperienza di Assisi
Dabigatran
1. Lo studio RE-LY
2. Le indagini della Food and
Drug Administration (FDA)
3. L’esperienza di Assisi
Parametro
RELY
ROCKET-AF
ARISTOTLE
ENGAGE-AF
N = 18 113
N = 14 264
N = 18 201
N = 21 105
Disegno dello
studio:
Multicentrico (951
centri), randomizzato,
warfarin in aperto,
dabigatran in doppia
cecità (PROBE)
Multicentrico (1178
centri), randomizzato,
doppia cecità,
double dummy
Multicentrico (1030 centri),
randomizzato, doppia
cecità, double dummy
Multicentrico (1393 centri),
randomizzato, doppia
cecità, double dummy
Dose
Dabigatran: 110 mg
b.i.d.; 150 mg b.i.d.
Rivaroxaban: 20 mg o.d.
(15 mg o.d. se VFG 3049 cc/min)
Apixaban: 5 mg b.i.d.
(2.5 mg o.d. se età > 80,
peso <60 o creatininemia
> 1.5 mg/dl)
Edoxaban: 60 mg od; 30
mg od. Dosi dimezzate
se: VFG 30-50; peso <60,
verapamil e/o chinidina
Endpoint
primario
Composito di ictus
(ischemico / emorragico)
ed embolia sistemica
Composito di ictus
(ischemico / emorragico)
ed embolia sistemica
Composito di ictus
(ischemico ed emorragico)
ed embolia sistemica
Composito di ictus
(ischemico ed emorragico)
ed embolia sistemica
Durata follow-up
2.0 anni (mediana)
1.8 anni (mediana)
1.9 anni (mediana)
2.8 anni (mediana)
Endpoint
primario di
sicurezza
Sanguinamenti maggiori
(inclusi i sanguinamenti
pericolosi per la vita e
quelli fatali)
Composito di
sanguinamenti maggiori e
non maggiori
clinicamente rilevanti
Sanguinamenti maggiori
(criteri ISTH)
Sanguinamenti maggiori
(criteri ISTH)
Età (anni)
71.5 (media)
73 (mediana)
70 (mediana)
72 (mediana)
CHADS2
Score
2.1
3.5
2.1
2.8
TTR (medio%)
64
55
62
65
Analisi statistica
Intention to treat
• Per protocol
• Intention to treat
Intention to treat
• Per protocol
• Intention to treat
RE-LY: stroke or systemic embolism
Rischio cumulativo
0.05
0.04
Dabigatran 110 mg BID
vs. warfarin:
RR 0.90
(95% CI: 0.74–1.10)
Non inferiorità: p<0.001
Superiorità: p=0.30
Dabigatran 150 mg BID
vs. warfarin:
HR 0.65
(95% CI: 0.52–0.81)
Non inferiorità: p<0.001
Superiorità: p<0.001
Warfarin
Dabigatran
110 mg BID
0.03
Dabigatran
150 mg BID
0.02
0.01
0.00
0.0
0.5
1.0
Dabigatran 150 mg BID vs warfarin:
-35%
Dabigatran 110 mg BID vs warfarin:
-10%
1.5
2.0
2.5
Anni di osservazione
BID = 1 somministrazione ogni 12 ore
Connolly SJ et al. N Engl J Med 2010;363:1875–6
6
Ischaemic Stroke
1.4
1.4
-24% vs warfarin
P=0.03
1.2
1.2
1
1
0.8
0.8
0.2
1.34
0.92
1.21
0
Dabigatran Dabigatran Warfarin
110 mg
150 mg N Engl J Med 2010;363:1875–6
2
+41% vs warfarin
P<0.001
1,8
1
1,4
0.8
1,2
1
0.6
0,8
0.4
0,6
0,2
0
Rivaroxaban
Warfarin
N Engl J Med 2011;365:883-91
1.2
1,6
0,4
1.42
0.4
0.4
0
p = 0.581
0.6
0.6
0.2
1.32
p = 0.42
0.97
1.05
Apixaban
Warfarin
0.2
1.25
Edoxaban
60 mg
1.77
1.25
0
Edoxaban Warfarin
30 mg N Engl J Med 2013;369:2093-104
N Engl J Med 2011;365:981-92
Haemorragic Stroke
in RE-LY, ROCKET AF, ARISTOTLE, ENGAGE AF
Warfarin
Dabigatran 150 mg
0.5
Dabigatran 110 mg
Rivaroxaban
Apixaban
Edoxaban 30 mg
0.47
0.47
0.45
0.4
Edoxaban 60 mg
0.44
0.76
0.35
Rate
(x 100 0.3
patients 0.25
per
0.2
year)
0.26
HR 0.59
p=0.024
0.05
HR 0.51
p<0.001
HR 0.54
p<0.001
0.16
0.15
0.1
0.24
0.26
0.12
0.10
HR 0.33
p<0.001
HR 0.31
p<0.001
HR 0.26
p<0.001
0
RE-LY
ROCKET-AF
ARISTOTLE
ENGAGE-AF
Intracranial bleeding is less with dabigatran
than with warfarin at any level of cTTR
cTTR:
Rate of
intracranial
bleeding
(per 100
patients
per year)
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
< 57.1%
57.1-65.5%
65.5-72.6%
> 72.6%
cTTR < 57.1%
D 110 mg vs warfarin: HR 0.43 (0.19-1.00)
D 150 mg vs warfarin: HR 0.53 (0.25-1.15)
cTTR 57.1-65.5%
D 110 mg vs warfarin: HR 0.31 (0.15-0.66)
D 150 mg vs warfarin: HR 0.45 (0.24-0.88)
cTTR 65.5-72.5%
D 110 mg vs warfarin: HR 0.20 (0.07-0.58)
D 150 mg vs warfarin: HR 0.35 (0.15-0.82)
cTTR > 72.6%
D 110 mg vs warfarin: HR 0.27 (0.11-0.66)
D 150 mg vs warfarin: HR 0.39 (0.18-0.84)
Dabigatran 110
mg BID
Wallentin L et al. Lancet 2010;376:975–83
Dabigatran 150
mg BID
Warfarin
Major Bleedings
in RE-LY, ROCKET AF, ARISTOTLE, ENGAGE AF
Warfarin
Dabigatran 150 mg
4
3.5
3
Dabigatran 110 mg
0.5
Rivaroxaban
Apixaban
Edoxaban 30 mg
3.60
3.57
3.43
3.45
3.31
3.09
2.87
2.75
HR 0.81
p=0.002
Rate 2.5
(x 100
patients
2
per
year) 1.5
1
Edoxaban 60 mg
HR 0.80
p<0.001
2.13
HR 0.71
p<0.001
1.61
HR 0.53
p<0.001
Lower with dabigatran 110 mg, apixaban
and both doses of edoxaban versus warfarin
0
RE-LY
ROCKET-AF
ARISTOTLE
ENGAGE-AF
Gastrointestinal Bleedings
in RE-LY, ROCKET AF, ARISTOTLE, ENGAGE AF
Warfarin
Dabigatran 150 mg
2
Dabigatran 110 mg
Edoxaban 60 mg
Rivaroxaban
HR 1.49
p<0.001
1.62
1.6
Rate
(x 100 1.2
patients
1
per
0.8
year)
Edoxaban 30 mg
1.85
1.8
1.4
Apixaban
1.36
1.25
HR 1.09
P=0.44
1.51
HR 1.45
P<0.05
HR 1.23
P=0.03
1.23
1.12
0.86
0.76
HR 0.89
P=0.37
0.6
0.82
HR 0.67
p<0.001
0.4
Lower only with edoxaban 30 mg versus warfarin
0.2
Higher with dabigatran 150 mg, rivaroxaban and edoxaban 60
mg versus warfarin
0
RE-LY
ROCKET-AF
ARISTOTLE
ENGAGE-AF
Quindi, rispetto al warfarin, il
dabigatran:
• Riduce significativamente l’end-point primario
e l’ictus ischemico (150 mg), o è equivalente al
warfarin (110 mg)
• Riduce drasticamente le emorragie
endocraniche e l’ictus emorragico (110 mg e
150 mg)
• Riduce significativamente le emorragie
maggiori (110 mg), o è equivalente al warfarin
(150 mg)
• Aumenta le emorragie gastrointestinali (150
mg), o è equivalente al warfarin (110 mg)
0,9
Stroke/Systemic Embolism
D150
ED30
0,8
Warf
0,7
0,6
0,5
ED60
0,4
Apix
Riva
D110
0,3
0,2
0,1
Probability of each rank
Probability of each rank
1
1
2
3
4
5
6
ED30
Stroke
D150
0,8
Warf
0,7
0,6
Apix
0,5
0,4
Riva
ED60
D110
0,3
0,2
0,1
Ischaemic Stroke
0,9
ED30
D150
0,7
D110
0,6
0,5
Warf
0,4
Apix
ED60
Riva
0,3
1
7
Probability of each rank
1
Probability of each rank
0,9
0
0
0,8
1
0,2
0,1
2
0,8
3
4
5
6
7
Warf
Death
0,7
0,6
0,5
0,4
0,3
ED30
D150
ED60
0,2
Apix
D110
0,1
Riva
0
0
1
2
3
Apixaban (Apix)
4
5
6
Dabigatran (D)
110 mg
150 mg
7
Edoxaban (ED)
30 mg
60 mg
1
2
3
4
Rivaroxaban (Riva)
5
6
7
Warfarin (Warf)
Verdecchia P, Lip GYH, et al. Expert Opin Drug Saf. 2014
Oct 14:1-14. [Epub ahead of print]
Major Bleeding
ED30
0,9
Apix
0,8
D150
0,7
0,6
ED60
0,5
Warf
D110
Riva
0,4
0,3
0,2
Probability of each rank
Probability of each rank
1
Warf
0,8
0,7
0,6
D110
0,5
ED60
ED30
0,4
D150
Apix
3
4
0,3
0,2
0
0
2
3
4
5
6
Gastrointestinal Bleeding
ED30
0,9
0,8
Apix
0,7
Riva
Warf
ED60
0,6
D150
D110
0,5
0,4
0,3
0,2
2
1
7
Probability of each rank
1
Probability of each rank
Riva
0,9
0,1
0,1
1
Intracranial Bleeding
1
6
5
7
Myocardial Infarction
0,7
Riva
0,6
Warf
0,5
ED30
D110
D150
Apix
0,4
ED60
0,3
0,2
0,1
0,1
0
0
1
2
3
Apixaban (Apix)
4
5
6
Dabigatran (D)
110 mg
150 mg
7
Edoxaban (ED)
30 mg
60 mg
1
2
3
4
Rivaroxaban (Riva)
5
6
7
Warfarin (Warf)
Verdecchia P, Lip GYH, et al. Expert Opin Drug Saf. 2014
Oct 14:1-14. [Epub ahead of print]
Dabigatran
1. Lo studio RE-LY
2. Le indagini della Food and
Drug Administration (FDA)
3. L’esperienza di Assisi
Event Rates with Dabigatran (75 mg or 150 mg bid) vs
Warfarin in 134 000 patients with AF aged ≥ 65 years
Event
Dabigatran
(x 100 patient-years)
(N=67 207)
Warfarin
(reference)
(N=67207)
Adjusted HR
(95% CI)
Ischemic stroke
1.13
1.39
0.80 (0.67-0.96)
Intracranial
hemorrhage
0.33
0.96
0.34 (0.26-0.46)
Major Gastrointestinal
bleeding
Acute Myocardial
Infarction
3,42
2,65
1.28 (1.14-1.44)
1,57
1,69
0.92 (0.78-1.08)
Death
3,26
3,78
0.86 (0.77-0.96)
Graham DJ et asl. Circulation 2014; October 30
-20%
Adjusted HR:
0.80 (0.67-0.96); p=0.02
-66%
Adjusted HR:
0.34 (0.26-0.46); p<0.001
Graham DJ et asl. Circulation 2014; October 30
+28%
Adjusted HR:
1.28 (1.14-1.44); p=0.006
-14%
Adjusted HR
0.86 (0.77-0.96); p=0.006
Dabigatran
1. Lo studio RE-LY
2. Le indagini della Food and
Drug Administration (FDA)
3. L’esperienza di Assisi
L’esperienza di Assisi
Maria Gabriella Molini
Claudia Bartolini
Francesca Valecchi
Adolfo Aita
Letizia Di Giacomo
Stefania Martone
Paolo Verdecchia
www.umbriafa.it
Main Characteristics of Patients (1)
Number
115
Age (years)
78.3 (8)
Weight (Kg)
75.6 (13)
Height (cm)
166.3 (10)
Sex (% women)
53
Classification of AF (N, %)
- New-onset
24 (21%)
- Paroxysmal
12 (10%)
- Persistent
30 (26%)
- Permanent
49 (43%)
Verdecchia P et al. Curr Op Drug Saf 2014 (in press)
Distribution of CHA2DS2VASc
35
31
30
28
25
Per cent 20
of 15
Patients
10
16
10
10
5
3
1
0
2
3
4
5
6
7
8
CHA2DS2VASc Group
Verdecchia P et al. Curr Op Drug Saf 2014 (in press)
Terapie antitrombotiche/antiaggreganti
assunte in precedenza
Nulla
21%
Warfarin
52%
18%
Aspirina
9%
Eparina
Verdecchia P et al. Curr Op Drug Saf 2014 (in press)
Sospensione Definitiva Trattamento
Totale: 115 pazienti
Sospeso
Continuato
N = 18
(16%)
Cause sospensione definitiva:
N = 97
(84%)
Sospensione definitiva by Dabigatran dose:
11 su 76 pazienti (14%) con Dabigatran 110 mg
7 su 39 pazienti (18%) con Dabigatran 150 mg
Sospensione definitiva:
In media, 76 giorni dopo l’inizio del trattamento
• Distress epigastrico:
• Sanguinamento GI:
• VFG < 30 ml/min:
• Prurito intenso:
• By pass aorto-coronarico:
• Polmonite:
Totale
10 pazienti
1 paziente
3 pazienti
1 paziente
2 pazienti
1 paziente
18 pazienti
Dopo la sospensione:
Warfarin:
7 pazienti;
Altro NAO:
7 pazienti
Né anticoagulanti né ASA: 4 pazienti
Verdecchia P et al. Curr Op Drug Saf 2014 (in press)
Tollerabilità
Distress epigastrico
Presente
(N=25
21,7%)
Assente
(N=90)
Diarrea
Sanguinamenti Minori
Presenti
(N=9;
7,8%)
Assente
(N=106)
Sanguinamenti Maggiori
Presente
(N=3
2,6%)
Presenti
(N=2;
1,7%)
Assente
(N=112)
Assenti
(N=113)
Verdecchia P et al. Curr Op Drug Saf 2014 (in press)
A che punto
siamo con
l’antidoto ?
Idarucizumab
An Antidote Specific to Dabigatran
 Restoration of coagulation
 Potent binding affinity ~350 times
higher than the binding of dabigatran to
thrombin
 No procoagulant or anticoagulant
effects
 Short half-life
Fully humanized
antibody fragment
(Fab)
 Easy and rapid administration
 IV administration, immediate onset of
action
 Low risk of adverse reactions
– No Fc receptor binding
– No endogenous targets
Idarucizumab is currently in development and is not approved for use in any country.
The information presented here is intended for medical education purposes only
Glund S et al. AHA 2013; abstract 17765;
van Ryn J. AHA 2012; Presentation 9928; van Ryn J et al. Circulation 2012;126:A9928
Sept 2014
Healthy volunteer study: immediate, complete, and
sustained reversal of dabigatran anticoagulation
End of idarucizumab injection (5 min infusion)
70
Dabigatran plus:
Placebo (n=9)
1 g idarucizumab (day 4) (n=9)
2 g idarucizumab (day 4) (n=9)
4 g idarucizumab (day 4) (n=8)
Normal upper reference limit (n=86)
Mean baseline (n=86)
65
dTT (s)
60
55
Dabigatran + placebo
50
45
40
35
30
–2
Dabigatran
0
2
4
6
8
10
12
24
36
48
60
72
Time after end of infusion (hours)
Antidote
Idarucizumab is currently in development and is not approved for use in any country.
The information presented here is intended for medical education purposes only
‘Normal upper reference limit’ refers to (mean+2SD) of 86 predose measurements from a total of 51 subjects
Glund S et al. AHA 2013; abstract 17765
29
Sept 2014
First patient trial of a NOAC-specific antidote
Study to evaluate reversal of the anticoagulant effects of dabigatran with
idarucizumab in:
Bleeding patients – overt bleeding judged by the physician to
require a reversal agent
Surgical patients – require an emergency surgery or procedure for
a condition other than bleeding
Started in April 2014, currently recruiting in >35 countries worldwide
Idarucizumab is currently in development and is not approved for use in any country. The
information presented here is intended for medical education purposes only
NCT02104947: Available at http://www.clinicaltrials.gov/ct2/show/NCT02104947; Accessed August 2014
30
Sept 2014
Grazie
per la vostra
attenzione
Concomitant Use of Antiplatelet Therapy
with Dabigatran or Warfarin
6.3
5.5
4.8
Rate
of
Major
Bleeding
(% per
year)
4.6
4.4
5.4
4.3
3.9
2.8
3.8
2.6
2.2
Of 18 113 patients, 6952 (38.4%) received concomitant aspirin or clopidogrel, or
both, at some time during the study (in 1 out of 5 for the total study duration).
Dans M et al.
Circulation 2013;127:634-640
La dose 75 mg bid (pazienti con VFG < 30 ml/min) è equivalente al warfarin per
ictus ischemico, sanguinamenti GI e mortalità, ma pur sempre migliore del warfarin
per emorragie endocraniche
La dose 150 mg bid (pazienti con VFG > 30 ml/min) è migliore del warfarin per
ictus ischemico, emorragie endocraniche e mortalità, e peggiore del warfarin per
emorragie gastrointestinali
Graham DJ et asl. Circulation 2014; October 30
Limitations
1. Lack of adjustment for confounders
2. Lack of detailed medical records review
Drug-safety investigation,
focused on the occurrence
of bleeding, promoted by
Food and Drug
Administration (FDA) over
the period October 19, 2010
to December 31, 2011.
Southworth MR et al. N Engl J Med 2013
Effect of Dabigatran Plasma Concentrations
and Patient Characteristics on Ischemic Stroke
and Major Bleeding in AF Patients
Reilly PA et al. J Am Coll Cardiol 2014;63:321–8
Italia:
60.600.000 individui
Umbria:
897.000 individui
(1,5% della popolazione
Italiana)
2.730/135.000
piani terapeutici = 2.0%
(rispetto ad 1,5% atteso)