Paolo Verdecchia, F.A.C.C., F.E.S.C., F.A.H.A.Hospital of AssisiDepartment of MedicineVia Valentin Müller, 106081 - Assisi PGE-mail: verdec@tin.it

DabigatranDabigatran

Simposio:Nuovi anticoagulanti orali: dai criteri di scelta all’esperienza sul campo

Simposio:Nuovi anticoagulanti orali: dai criteri di scelta all’esperienza sul campo

Conflict of Interest Disclosure

Travel grants/fee for membership on Advisory Committees and speaking at scientific meetings:

• Boehringer-Inghelheim• Bayer• Daiichi-Sankyo• Stroder

Travel grants/fee for membership on Advisory Committees and speaking at scientific meetings:

• Boehringer-Inghelheim• Bayer• Daiichi-Sankyo• Stroder

No honorarium for today’s talkNo honorarium for today’s talk

DabigatranDabigatran

1. Lo studio RE-LY

2. Le indagini della Food and

Drug Administration (FDA)

3. L’esperienza di Assisi

1. Lo studio RE-LY

2. Le indagini della Food and

Drug Administration (FDA)

3. L’esperienza di Assisi

DabigatranDabigatran

1. Lo studio RE-LY

2. Le indagini della Food and

Drug Administration (FDA)

3. L’esperienza di Assisi

1. Lo studio RE-LY

2. Le indagini della Food and

Drug Administration (FDA)

3. L’esperienza di Assisi

ParametroParametro RELYRELYN = 18 113N = 18 113

ROCKET-AFROCKET-AFN = 14 264N = 14 264

ARISTOTLEARISTOTLEN = 18 201N = 18 201

ENGAGE-AFENGAGE-AFN = 21 105N = 21 105

Disegno dello Disegno dello studio: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

DoseDose Dabigatran: 110 mg b.i.d.; 150 mg b.i.d.

Rivaroxaban: 20 mg o.d.(15 mg o.d. se VFG 30-49 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 Endpoint primarioprimario

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-Durata follow-upup

2.0 anni (mediana) 1.8 anni (mediana) 1.9 anni (mediana) 2.8 anni (mediana)

Endpoint Endpoint primario di primario di sicurezzasicurezza

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)Età (anni) 71.5 (media) 73 (mediana) 70 (mediana) 72 (mediana)

CHADSCHADS22

ScoreScore2.1 3.5 2.1 2.8

TTR (medio%)TTR (medio%) 64 55 62 65

Analisi Analisi statisticastatistica

Intention to treat • Per protocol• Intention to treat

Intention to treat • Per protocol• Intention to treat

BID = 1 somministrazione ogni 12 ore

Connolly SJ et al. N Engl J Med 2010;363:1875–6 6

Anni di osservazione0.0 0.5 1.0 1.5 2.0 2.5

0.01

0.02

0.03

0.05

0.04

Ris

chio

cu

mu

lati

vo

0.00

WarfarinDabigatran

110 mg BID

Dabigatran 150 mg BID

Dabigatran 150 mg BIDvs. warfarin: HR 0.65(95% CI: 0.52–0.81)Non inferiorità: p<0.001 Superiorità: p<0.001

Dabigatran 150 mg BID vs warfarin: -35%

RE-LY: stroke or systemic embolismDabigatran 110 mg BID vs. warfarin: RR 0.90 (95% CI: 0.74–1.10)Non inferiorità: p<0.001Superiorità: p=0.30

Dabigatran 110 mg BID vs warfarin: -10%

Ischaemic StrokeIschaemic Stroke

0

0.2

0.4

0.6

0.8

1

1.2

1.4-24% vs warfarin

P=0.03

1.34 0.92 1.21

WarfarinDabigatran150 mg

Dabigatran110 mg

p = 0.42p = 0.42

0.97 1.05

p = 0.581p = 0.5811.32 1.42

N Engl J Med 2010;363:1875–6N Engl J Med 2010;363:1875–6N Engl J Med 2011;365:883-91N Engl J Med 2011;365:883-91

N Engl J Med 2011;365:981-92N Engl J Med 2011;365:981-92

0

0,2

0,4

0,6

0,8

1

1,2

1,4

1,6

1,8

2

WarfarinEdoxaban30 mg

Edoxaban60 mg

1.25 1.77 1.25

N Engl J Med 2013;369:2093-104N Engl J Med 2013;369:2093-104

+41% vs warfarinP<0.001

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

0.5

RE-LY ROCKET-AF ARISTOTLE ENGAGE-AF

WarfarinDabigatran 150 mg

Dabigatran 110 mg ApixabanRivaroxaban Edoxaban 30 mg

Edoxaban 60 mg

Haemorragic Stroke in RE-LY, ROCKET AF, ARISTOTLE, ENGAGE AF

0.760.76

0.100.100.120.12

0.440.44

0.260.26

0.470.47

0.240.24

0.470.47

0.260.26

Rate(x 100

patientsper

year)

Rate(x 100

patientsper

year)

HR 0.26p<0.001

HR 0.51p<0.001

HR 0.33p<0.001

HR 0.54p<0.001

0.160.16

HR 0.59p=0.024

HR 0.31p<0.001

Intracranial bleeding is less with dabigatran than with warfarin at any level

of cTTR

00.10.20.30.40.50.60.70.80.9

1

Dabigatran 110mg BID

Dabigatran 150mg BID

Warfarin

< 57.1%< 57.1% 57.1-65.5%57.1-65.5% 65.5-72.6%65.5-72.6% > 72.6%> 72.6%cTTR:cTTR:

Rate ofintracranial

bleeding(per 100patients

per year)

Rate ofintracranial

bleeding(per 100patients

per year)

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)

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)

Wallentin L et al. Lancet 2010;376:975–83

0

0.5

1

1.5

2

2.5

3

3.5

4

RE-LY ROCKET-AF ARISTOTLE ENGAGE-AF

WarfarinDabigatran 150 mg

Dabigatran 110 mg ApixabanRivaroxaban Edoxaban 30 mg

Edoxaban 60 mg

Major Bleedings in RE-LY, ROCKET AF, ARISTOTLE, ENGAGE AF

3.573.57

3.313.31

2.872.87

3.453.453.603.60

3.093.09

2.132.13

3.433.43

2.752.75

1.611.61

Rate(x 100

patientsper

year)

Rate(x 100

patientsper

year)

HR 0.81p=0.002

HR 0.71p<0.001

HR 0.53p<0.001

HR 0.80p<0.001

Lower with dabigatran 110 mg, apixaban and both doses of edoxaban versus warfarinLower with dabigatran 110 mg, apixaban and both doses of edoxaban versus warfarin

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

RE-LY ROCKET-AF ARISTOTLE ENGAGE-AF

WarfarinDabigatran 150 mg

Dabigatran 110 mg ApixabanRivaroxaban Edoxaban 30 mg

Edoxaban 60 mg

Gastrointestinal Bleedings in RE-LY, ROCKET AF, ARISTOTLE, ENGAGE AF

1.251.25

1.851.85

1.361.36

1.121.12

1.621.62

0.860.860.760.76

1.231.23

1.511.51

Rate(x 100

patientsper

year)

Rate(x 100

patientsper

year)

HR 1.49p<0.001

HR 0.89P=0.37

HR 0.67p<0.001

HR 1.23P=0.03

0.820.82

HR 1.45 P<0.05

HR 1.09P=0.44

Lower only with edoxaban 30 mg versus warfarinLower only with edoxaban 30 mg versus warfarin

Higher with dabigatran 150 mg, rivaroxaban and edoxaban 60 mg versus warfarinHigher with dabigatran 150 mg, rivaroxaban and edoxaban 60 mg versus warfarin

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

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

1 2 3 4 5 6 7

0

0,1

0,2

0,3

0,4

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0,6

0,7

0,8

0,9

1

1 2 3 4 5 6 7

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

1 2 3 4 5 6 7

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

1 2 3 4 5 6 7

Apix

D150

RivaED60

Warf

ED30

D110

D150

ED60Apix Riva D110

Warf

ED30

Stroke/Systemic Embolism Stroke

Ischaemic Stroke Death

D150

ED60Apix

Riva

D110

Warf

ED30

D150ED60

Apix

Riva

D110

Warf

ED30

Apixaban (Apix) Dabigatran (D)

110 mg150 mg

Edoxaban (ED)

30 mg60 mg

Rivaroxaban (Riva) Warfarin (Warf)

Pro

ba

bili

ty o

f e

ach

ra

nk

Pro

ba

bili

ty o

f e

ach

ra

nk

Pro

ba

bili

ty o

f e

ach

ra

nk

Pro

ba

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ty o

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ach

ra

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Verdecchia P, Lip GYH, et al. Expert Opin Drug Saf. 2014 Oct 14:1-14. [Epub ahead of print]

Verdecchia P, Lip GYH, et al. Expert Opin Drug Saf. 2014 Oct 14:1-14. [Epub ahead of print]

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

1 2 3 4 5 6 7

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

1 2 3 4 5 6 7

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

1 2 3 4 5 6 7

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

1 2 3 4 5 6 7

ApixD150

Riva

ED60

Warf

ED30

D110

D150

ED60

Apix

RivaD110

Warf

ED30 Major Bleeding Intracranial Bleeding

Gastrointestinal Bleeding Myocardial Infarction

D150ED60

Apix Riva

D110

Warf

ED30

D150

ED60

Apix

Riva

D110

WarfED30

Apixaban (Apix) Dabigatran (D)

110 mg150 mg

Edoxaban (ED)

30 mg60 mg

Rivaroxaban (Riva) Warfarin (Warf)

Pro

ba

bili

ty o

f e

ach

ra

nk

Pro

ba

bili

ty o

f e

ach

ra

nk

Pro

ba

bili

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Verdecchia P, Lip GYH, et al. Expert Opin Drug Saf. 2014 Oct 14:1-14. [Epub ahead of print]

Verdecchia P, Lip GYH, et al. Expert Opin Drug Saf. 2014 Oct 14:1-14. [Epub ahead of print]

DabigatranDabigatran

1. Lo studio RE-LY

2. Le indagini della Food and

Drug Administration (FDA)

3. L’esperienza di Assisi

1. Lo studio RE-LY

2. Le indagini della Food and

Drug Administration (FDA)

3. L’esperienza di Assisi

Event(x 100 patient-years)

Dabigatran(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

3,42 2,65 1.28 (1.14-1.44)

Acute Myocardial Infarction

1,57 1,69 0.92 (0.78-1.08)

Death 3,26 3,78 0.86 (0.77-0.96)

Event Rates with Dabigatran (75 mg or 150 mg bid) vs Warfarin in 134 000 patients with AF aged ≥ 65 years

Graham DJ et asl. Circulation 2014; October 30Graham DJ et asl. Circulation 2014; October 30

Graham DJ et asl. Circulation 2014; October 30Graham DJ et asl. Circulation 2014; October 30

-20%Adjusted HR:0.80 (0.67-0.96); p=0.02

-20%Adjusted HR:0.80 (0.67-0.96); p=0.02

-66%Adjusted HR:0.34 (0.26-0.46); p<0.001

-66%Adjusted HR:0.34 (0.26-0.46); p<0.001 -14%

Adjusted HR0.86 (0.77-0.96); p=0.006

-14%Adjusted HR0.86 (0.77-0.96); p=0.006

+28%Adjusted HR:1.28 (1.14-1.44); p=0.006

+28%Adjusted HR:1.28 (1.14-1.44); p=0.006

DabigatranDabigatran

1. Lo studio RE-LY

2. Le indagini della Food and

Drug Administration (FDA)

3. L’esperienza di Assisi

1. Lo studio RE-LY

2. Le indagini della Food and

Drug Administration (FDA)

3. L’esperienza di Assisi

L’esperienza di AssisiL’esperienza di Assisi

Maria Gabriella Molini Francesca Valecchi Paolo VerdecchiaClaudia Bartolini Adolfo Aita

Letizia Di GiacomoStefania Martone

Maria Gabriella Molini Francesca Valecchi Paolo VerdecchiaClaudia Bartolini Adolfo Aita

Letizia Di GiacomoStefania Martone

www.umbriafa.itwww.umbriafa.it

Number 115

Age (years) 78.3 (8)

Weight (Kg) 75.6 (13)

Height (cm) 166.3 (10)

Sex (% women) 53Classification of AF (N, %) - New-onset 24 (21%) - Paroxysmal 12 (10%) - Persistent 30 (26%) - Permanent 49 (43%)

Main Characteristics of Patients (1)

Verdecchia P et al. Curr Op Drug Saf 2014 (in press)Verdecchia P et al. Curr Op Drug Saf 2014 (in press)

0

5

10

15

20

25

30

35

2 3 4 5 6 7 8

CHA2DS2VASc GroupCHA2DS2VASc Group

Per centof

Patients

Distribution of CHA2DS2VASc

1010

28283131

1616

1010

33 11

Verdecchia P et al. Curr Op Drug Saf 2014 (in press)Verdecchia P et al. Curr Op Drug Saf 2014 (in press)

21%21%

18%18%

9%9%

52%52%

Terapie antitrombotiche/antiaggreganti assunte in precedenza

Terapie antitrombotiche/antiaggreganti assunte in precedenza

WarfarinWarfarin

NullaNulla

EparinaEparina

AspirinaAspirina

Verdecchia P et al. Curr Op Drug Saf 2014 (in press)Verdecchia P et al. Curr Op Drug Saf 2014 (in press)

Sospeso Continuato

Sospensione Definitiva Trattamento

N = 97(84%)

N = 18(16%)

Sospensione definitiva by Dabigatran dose:11 su 76 pazienti (14%) con Dabigatran 110 mg7 su 39 pazienti (18%) con Dabigatran 150 mg

Sospensione definitiva:In media, 76 giorni dopo l’inizio del trattamento

Cause sospensione definitiva:

• Distress epigastrico: 10 pazienti

• Sanguinamento GI: 1 paziente

• VFG < 30 ml/min: 3 pazienti• Prurito intenso: 1

paziente• By pass aorto-coronarico: 2 pazienti• Polmonite: 1

paziente

Totale 18 pazienti

Totale: 115 pazienti

Dopo la sospensione:Warfarin: 7 pazienti;Altro NAO: 7 pazientiNé anticoagulanti né ASA: 4 pazienti

Verdecchia P et al. Curr Op Drug Saf 2014 (in press)Verdecchia P et al. Curr Op Drug Saf 2014 (in press)

Tollerabilità

Distress epigastrico

Diarrea

Sanguinamenti Minori

Sanguinamenti Maggiori

Assente(N=90)

Presente(N=2521,7%) Assente

(N=106)

Presenti(N=9; 7,8%)

Assente(N=112)

Presente(N=32,6%)

Assenti(N=113)

Presenti(N=2;1,7%)

Verdecchia P et al. Curr Op Drug Saf 2014 (in press)Verdecchia P et al. Curr Op Drug Saf 2014 (in press)

A che punto siamo con l’antidoto ?

A che punto siamo con l’antidoto ?

Sept 2014

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

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

Fully humanized antibody fragment

(Fab)

Fully humanized antibody fragment

(Fab)

Sept 2014

Healthy volunteer study: immediate, complete, and sustained reversal of dabigatran anticoagulation

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

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)

29

End of idarucizumab injection (5 min infusion)

Dabigatran + placebo

–2

Time after end of infusion (hours)

dTT (

s)

DabigatranAntidote

70

65

60

55

50

45

40

35

30

0 2 4 6 8 10 12 24 36 48 7260

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

Idarucizumab is currently in development and is not approved for use in any country. The information presented here is intended for medical education purposes onlyNCT02104947: Available at http://www.clinicaltrials.gov/ct2/show/NCT02104947; Accessed August 2014

30

Started in April 2014, currently recruiting in >35 countries worldwide

Grazie per la vostra attenzione

Grazie per la vostra attenzione

2.8

4.84.6

6.3

2.6

4.4 4.3

5.5

2.2

3.93.8

5.4

Rateof

MajorBleeding

(% peryear)

Concomitant Use of Antiplatelet Therapy with Dabigatran or Warfarin

Dans M et al. Circulation 2013;127:634-640

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).

Graham DJ et asl. Circulation 2014; October 30Graham DJ et asl. Circulation 2014; October 30

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

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

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 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

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.

Limitations1. Lack of adjustment for confounders2. Lack of detailed medical records review

Limitations1. Lack of adjustment for confounders2. Lack of detailed medical records review

Southworth MR et al. N Engl J Med 2013Southworth 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

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;63:321–8Reilly PA et al. J Am Coll Cardiol 2014;63:321–8

Italia:60.600.000 individui

Umbria:897.000 individui(1,5% della popolazioneItaliana)

2.730/135.000piani terapeutici = 2.0%(rispetto ad 1,5% atteso)