21-3-2016

1

John Fanikos

• Consultant

– Boehringer Ingelheim

– Baxalta, Inc

– BD Rx, Inc

• Board of Directors

– North American

Thrombosis Forum (NATF)

– Hospital Quality

Foundation (HQF)

• Family

–Dad (James): CVS

–Brother (Paul): Boehringer

Ingelheim

Disclosures

Harry Büller

• Research support

– None

• Consultant

– Bayer

– Boehringer Ingelheim

– BMS

– Daiichi Sankyo

– Pfizer

– Portola

LIVE VIENNA

FEATURE REPORT

12:10 Leonardo De Luca, Italy

Real-world evidence confirms clinical profile of dabigatran etexilate

LIVE VIENNA

EXPERT ANALYSIS

NOAC dosing regimens to optimize patient protection

12:25 Bernard Vrijens, Belgium

LIVE VIENNA

BREAKING NEWS

First specific reversal agent for a NOAC now available

12:40 Steve Austin, UK

21-3-2016

2

LIVE VIENNA

FINANCIAL FORECAST

Reducing the impact on healthcare resources in anticoagulation care12:55 Ian Menown, UK

Anticoagulation 1.0

The first oral anticoagulant

Anticoagulation 2.0

A new standard in oral anticoagulant therapy

Stroke prevention

in patients

with NVAF

Treatment of

acute DVT/PE

Prevention of VTE

following elective

hip and knee

replacement surgery

Prevention of

recurrence of

DVT/PE

NOACs are a standard therapy in multiple

settings worldwide, including:

Anticoagulation 3.0

The next step in oral anticoagulation care

1. Ansell et al. Chest 2008; 2. Umer Usman et al. J Interv Card Electrophysiol 2008; 3. Khoo et al. Int J Clin Pract 2009;

4. Ruff et al. Lancet 2014

Why are NOACs so popular?

NOACs overcome many of the limitations of

warfarin1–31

Safety and efficacy of NOACs has been

demonstrated in clinical trials vs warfarin42

Dabigatran is the only NOAC with a specific

reversal agent available3

21-3-2016

3

LIVE VIENNA

FEATURE REPORT

12:10 Leonardo De Luca, Italy

Real-world evidence confirms clinical profile of dabigatran etexilate

• Personal fees:

– Astra Zeneca

– Bayer

– Boehringer Ingelheim

– Eli Lilly

– Daiichi Sankyo

– Menarini

– The Medicines Company

Disclosures

Rapid onset of action

Short half-lives compared with warfarin

Predictable and consistent anticoagulant effects

Low potential for drug–drug interactions

No drug–food interactions

No requirement for routine coagulation monitoring

What does this mean?

Simpler anticoagulation management

NOACs overcome many practical limitations

of warfarin

Ansell et al. Chest 2008; Healey et al. Circulation 2012;

Khoo et al. Int J Clin Pract 2009; Pradaxa®: EU SPC, 2016;

Umer Usman et al. J Interv Card Electrophysiol 2008

RE-LY®: pivotal RCT for SPAF and a global

non-inferiority trial of exemplary design

TTR, time in therapeutic range

Ezekowitz et al. Am Heart J 2009;

Connolly et al. N Engl J Med 200916

• Good INR control for warfarin (mean 64% TTR)

• 99.9% patients completed follow-up

Dabigatran 150 mg BID

N=6076

Dabigatran 110 mg BID

N=6015

Warfarin (INR 2.0–3.0)

N=6022

R

Blind dosing Open

AF with ≥1 risk factor for stroke

Absence of contraindications

18 113 patients from 951 centres in 44 countries

Primary endpoint: stroke/SETreatment assignment not based

on patients’ risk profiles

RE-LY® trial sufficiently powered to evaluate two independent doses (large, fully

randomized patient populations)

RE-LY®: at a glance

Connolly et al. N Engl J Med 2010;

Connolly et al. N Engl J Med 2014

Dabigatran 150 mg BID vs warfarin

40%

STROKE/SE

35%

40%similarSTROKE/SE

Dabigatran 110 mg BID vs warfarin

40%

ICH

59% CV

MORTALITY

15%

40%

ICHMAJOR

BLEEDING

20% 70%

40%similarMAJOR

BLEEDING

40%similarCV

MORTALITY

GI BLEEDING

48%

40%similarGI BLEEDING

In the USA, the licensed doses for Pradaxa® are: Pradaxa®

150 mg BID and Pradaxa® 75 mg BID for the prevention of

stroke and systemic embolism in adult patients with NVAF

Clinical practice (n>250 000 patients)

RE-LY®

(n>18 000 patients) FDA Medicare

analysis

(n>134 000)1

US Dept of

Defense

database

(n>25 000)2

Danish

observational

studies

(n>21 000)4,5

US insurance

database

(n>64 000)6

2 US insurance

databases

(n>44 000)3

Real-world experience from >250000 patients confirms

positive safety and efficacy profile of dabigatran

1. Graham et al. Circulation 2015; 2. Villines et al.

Thromb Haemost 2015; 3. Seeger et al. AHA 2015;

4. Larsen et al. Am J Med 2014a; 5. Larsen Am J Med

2014b; 6. Lauffenburger et al. J Am Heart Assoc 2015

21-3-2016

4

RE-LY®1–4

Warfarin

D150 BID

MEDICARE*5

Warfarin

D150 & D75 BID

combined

RCT

Real-world

data

MORTALITY

EV

EN

T R

AT

E

(% P

ER

YE

AR

)

INC

IDE

NC

E P

ER

100

PE

RS

ON

-YE

AR

S

ISCHAEMIC

STROKEICH

MAJOR

BLEEDING

GI

BLEEDINGMI

HR: 0.76

P=0.04

RR: 0.41

P<0.001

RR: 0.94

P=0.41

RR: 1.48

P=0.001

RR: 1.27

P=0.12

RR: 0.88

P=0.051

HR: 0.80

P=0.02

HR: 0.34

P<0.001

HR: 0.97

P=0.50

HR: 1.28

P<0.001

HR: 0.92

P=0.29

HR: 0.86

P=0.006

5

4

3

2

1

0

5

4

3

2

1

0

Independent FDA analysis confirms the favourable

benefit–risk profile of dabigatran from RE-LY®

1. Connolly et al. N Engl J Med 2009; 2. Connolly et al. N EnglJ Med 2010; 3. Connolly et al. N Engl J Med 2014;

4. Pradaxa®: EU SPC, 2016; 5. Graham et al. Circulation 2015

In the USA, the licensed doses for Pradaxa® are: Pradaxa®

150 mg BID and Pradaxa® 75 mg BID for the prevention of stroke and systemic embolism in adult patients with NVAF

>18000 patients

>134 000 patients

RE-LY®1–4

Warfarin

D150 BID

MEDICARE*5

Warfarin

D150 & D75 BID

combined

RCT

Real-world

data

MORTALITY

EV

EN

T R

AT

E

(% P

ER

YE

AR

)

INC

IDE

NC

E P

ER

100

PE

RS

ON

-YE

AR

S

ISCHAEMIC

STROKEICH

MAJOR

BLEEDING

GI

BLEEDINGMI

HR: 0.76

P=0.04

RR: 0.41

P<0.001

RR: 0.94

P=0.41

RR: 1.48

P=0.001

RR: 1.27

P=0.12

RR: 0.88

P=0.051

HR: 0.80

P=0.02

HR: 0.34

P<0.001

HR: 0.97

P=0.50

HR: 1.28

P<0.001

HR: 0.92

P=0.29

HR: 0.86

P=0.006

5

4

3

2

1

0

5

4

3

2

1

0

Independent FDA analysis confirms the favourable

benefit–risk profile of dabigatran from RE-LY®

In the USA, the licensed doses for Pradaxa® are: Pradaxa®

150 mg BID and Pradaxa® 75 mg BID for the prevention of stroke and systemic embolism in adult patients with NVAF

1. Connolly et al. N Engl J Med 2009; 2. Connolly et al. N EnglJ Med 2010; 3. Connolly et al. N Engl J Med 2014;

4. Pradaxa®: EU SPC, 2016; 5. Graham et al. Circulation 2015

>18000 patients

>134 000 patients

Drastic reduction in ICH with dabigatran

compared with warfarin at any level of TTR

cTTR, centre’s mean time in therapeutic range

Wallentin et al. Lancet 2010

0,280,3

0,13

0,21

0,34

0,42

0,24

0,3

0,64

0,93

0,67

0,77

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

<57.1% 57.1–65.5% 65.5–72.6% >72.6%

Rate

per

100 p

ers

on

-years

cTTR

P (interaction)

vs warfarin

Dabigatran 110 mg BID 0.71

Dabigatran 150 mg BID 0.89

Warfarin

RE-LY®1–4

Warfarin

D150 BID

MEDICARE*5

Warfarin

D150 & D75 BID

combined

RCT

Real-world

data

MORTALITY

EV

EN

T R

AT

E

(% P

ER

YE

AR

)

INC

IDE

NC

E P

ER

100

PE

RS

ON

-YE

AR

S

ISCHAEMIC

STROKEICH

MAJOR

BLEEDING

GI

BLEEDINGMI

HR: 0.76

P=0.04

RR: 0.41

P<0.001

RR: 0.94

P=0.41

RR: 1.48

P=0.001

RR: 1.27

P=0.12

RR: 0.88

P=0.051

HR: 0.80

P=0.02

HR: 0.34

P<0.001

HR: 0.97

P=0.50

HR: 1.28

P<0.001

HR: 0.92

P=0.29

HR: 0.86

P=0.006

5

4

3

2

1

0

5

4

3

2

1

0

Independent FDA analysis confirms the favourable

benefit–risk profile of dabigatran from RE-LY®

In the USA, the licensed doses for Pradaxa® are: Pradaxa®

150 mg BID and Pradaxa® 75 mg BID for the prevention of

stroke and systemic embolism in adult patients with NVAF

1. Connolly et al. N Engl J Med 2009; 2. Connolly et al. N EnglJ Med 2010; 3. Connolly et al. N Engl J Med 2014;

4. Pradaxa®: EU SPC, 2016; 5. Graham et al. Circulation 2015

>18000 patients

>134 000 patients

In patients who experience a major bleed,

dabigatran is associated with improved outcome

Majeed et al. Circulation 2013

*Combined data from dabigatran 150 mg and 110 mg BID treatment groups;

Only first major bleed included; Analysis not adjusted for covariates

Reduced risk of death with dabigatran vs warfarin during 30 days after the bleeding

(P=0.052) in the absence of a specific reversal agent*

Mort

alit

y r

ate

(%

)

0

0.1

0.2

5 10 15 20 25 30 35

Warfarin

Dabigatran

Time (days)

5 Phase III trials comparing

dabigatran with warfarin in 27419

patients treated for 6 to 36 months

RE-LY®1–4

Warfarin

D150 BID

MEDICARE*5

Warfarin

D150 & D75 BID

combined

RCT

Real-world

data

MORTALITY

EV

EN

T R

AT

E

(% P

ER

YE

AR

)

INC

IDE

NC

E P

ER

100

PE

RS

ON

-YE

AR

S

ISCHAEMIC

STROKEICH

MAJOR

BLEEDING

GI

BLEEDINGMI

HR: 0.76

P=0.04

RR: 0.41

P<0.001

RR: 0.94

P=0.41

RR: 1.48

P=0.001

RR: 1.27

P=0.12

RR: 0.88

P=0.051

HR: 0.80

P=0.02

HR: 0.34

P<0.001

HR: 0.97

P=0.50

HR: 1.28

P<0.001

HR: 0.92

P=0.29

HR: 0.86

P=0.006

5

4

3

2

1

0

5

4

3

2

1

0

Independent FDA analysis confirms the favourable

benefit–risk profile of dabigatran from RE-LY®

In the USA, the licensed doses for Pradaxa® are: Pradaxa®

150 mg BID and Pradaxa® 75 mg BID for the prevention of

stroke and systemic embolism in adult patients with NVAF

1. Connolly et al. N Engl J Med 2009; 2. Connolly et al. N EnglJ Med 2010; 3. Connolly et al. N Engl J Med 2014;

4. Pradaxa®: EU SPC, 2016; 5. Graham et al. Circulation 2015

>18000 patients

>134 000 patients

21-3-2016

5

Graham et al. Circulation 2015

Age group

(n)

Men

HR (95% CI)

Women

HR (95% CI)

65–74 (55 761) = =

75–84 (57 345) = +

>85 (21 308) + ++

The vast majority of Medicare patients (≈84%) received

the 150 mg BID dose of dabigatran

GI bleeding in the FDA analysis of Medicare patientsFavourable benefit–risk profile of dabigatran in

real-world: independent Danish registry

Larsen et al. Am J Med 2014*Adjusted HR: age, components of CHA2DS2-VASc, HAS-BLED, months since August 2011

11 315 first-time dabigatran users (7063 VKA-naïve)

vs 22 630 matched warfarin users (14126 VKA-naïve)

VKA-naïve stratum HR* (95% CI)

Dabigatran 110 mg BID

vs warfarin

Any 0.72 (0.59–0.88)

Major 0.93 (0.74–1.16)

Fatal 0.52 (0.28–0.95)

GI 0.50 (0.27–0.94)

ICH 0.30 (0.17–0.54)

Dabigatran 150 mg BID

vs warfarin

Any 0.68 (0.55–0.84)

Major 0.67 (0.53–0.85)

Fatal 0.70 (0.33–1.52)

GI 1.45 (0.84–2.50)

ICH 0.33 (0.17–0.66)

Favours dabigatran Favours warfarin

0.10 0.50 1.00 2.00 5.00

RE-LY®1–4

Warfarin

D150 BID

MEDICARE*5

Warfarin

D150 & D75 BID

combined

RCT

Real-world

data

MORTALITY

EV

EN

T R

AT

E

(% P

ER

YE

AR

)

INC

IDE

NC

E P

ER

100

PE

RS

ON

-YE

AR

S

ISCHAEMIC

STROKEICH

MAJOR

BLEEDING

GI

BLEEDINGMI

HR: 0.76

P=0.04

RR: 0.41

P<0.001

RR: 0.94

P=0.41

RR: 1.48

P=0.001

RR: 1.27

P=0.12

RR: 0.88

P=0.051

HR: 0.80

P=0.02

HR: 0.34

P<0.001

HR: 0.97

P=0.50

HR: 1.28

P<0.001

HR: 0.92

P=0.29

HR: 0.86

P=0.006

5

4

3

2

1

0

5

4

3

2

1

0

Independent FDA analysis confirms the favourable

benefit–risk profile of dabigatran from RE-LY®

1. Connolly et al. N Engl J Med 2009; 2. Connolly et al. N EnglJ Med 2010; 3. Connolly et al. N Engl J Med 2014;

4. Pradaxa®: EU SPC, 2016; 5. Graham et al. Circulation 2015

In the USA, the licensed doses for Pradaxa® are: Pradaxa®

150 mg BID and Pradaxa® 75 mg BID for the prevention of

stroke and systemic embolism in adult patients with NVAF

>18000 patients

>134 000 patients

Camm et al. Eur Heart J 2012;

January et al. J Am Coll Cardiol 2014;

Verma et al. Can J Cardiol 2014

Guidelines recommend dabigatran for SPAF in

patients with one or more risk factors

Dabigatran has been rigorously studied

through a well-designed and highly representative

clinical trials1–31

Guidelines recommend dabigatran for SPAF

in patients with one or more risk factors4–62

Dabigatran is supported by a wealth of independent

clinical practice evidence, unparalleled among

the NOACs7–123

Summary

1. Connolly et al. N Engl J Med 2009; 2. Connolly et al. N Engl J Med 2013; 3. Connolly et al. N Engl J Med 2014;

4. Camm et al. Eur Heart J 2010; 5. January et al. J Am Coll Cardiol 2014; 6. Verma et al. Can J Cardiol 2014;

7. Graham et al. Circulation 2015; 8. Villines et al. Thromb Haemost 2015; 9. Seeger et al. AHA 2015;

10. Larsen et al. Am J Med 2014a; 11. Larsen et al. Am J Med 2014b; 12. Lauffenburger et al. J Am Heart Assoc 2015

21-3-2016

6

LIVE VIENNA

EXPERT ANALYSIS

NOAC dosing regimens to optimize patient protection

12:25 Bernard Vrijens, Belgium

I am a full-time employee of WestRock Healthcare

Disclosures

EU-sponsored research

Vrijens et al. Br J Clin Pharmacol 2012

Medication adherence is the process by which patients take their medications as prescribed

time Initiate Implement Persist

Patient does not initiate treatment

Binary (yes/no)

Patient delays, omits or takes extra doses

Dosing history

Patient discontinues

treatment

Time to event

Vrijens et al. Expert Rev Clin Pharmacol 2014

Dose taken

Dose missed

03:00

24/4/2003 12/5/2003 30/5/2003 17/6/2003 5/7/2003 23/7/2003

Dosin

g tim

e

06:00

09:00

12:00

15:00

18:00

21:00

00:00

02:591

Management of patient adherence differs based on the pattern of non-adherence

03:00

24/4/2003 12/5/2003 30/5/2003 17/6/2003 5/7/2003 23/7/2003

Do

sin

g t

ime

06:00

09:00

12:00

15:00

18:00

21:00

00:00

02:59

BID, twice daily; Vrijens et al. Expert Rev Clin Pharmacol 2014

Management of patient adherence differs based on the pattern of non-adherence

Dose taken

Dose missed

1

Do

sin

g t

ime

2/12/1993 20/12/1993 7/1/1994 25/1/1994 12/2/1994 2/3/1994

03:00

06:00

09:00

12:00

15:00

18:00

21:00

00:00

02:59

2

26/11/2002

03:00

06:00

09:00

12:00

15:00

18:00

21:00

00:00

02:59

Do

sin

g t

ime

28/8/2002 15/9/2002 3/10/2002 21/10/2002 8/11/2002

3

Tre

atm

ent d

iscontin

uatio

n

Do

sin

g t

ime

03:00

06:00

09:00

12:00

15:00

18:00

21:00

00:00

02:59

8/2/2000 25/2/2000 13/3/2000 30/3/2000 16/4/2000 3/5/2000

4

Each of the four patients on a BID regimen took 75% of prescribed doses during a 3-month period

Decrease in adherence

due to non-implementation

Decrease in adherence

due to discontinuation

of treatment (non-persistence)

16 907 participants from 95 clinical studies ranging from 30–1400 days

Blaschke et al. Annu Rev Pharmacol Toxicol 2012

Extent of non-adherence

Percentage of patients

who dosed correctly

Percentage of patients

engaged with the dosing

regimen

Perfect adherence

0 300200100

50

60

70

80

90

100

Pro

po

rtio

n o

f p

atie

nts

(%

)

Time (days)

21-3-2016

7

Half-lives of all NOACs are similar, but dosing regimens in AF differ

*The approved dosing regimen of rivaroxaban is OD for stroke prevention in patients with nonvalvular AF, prevention of VTE

after orthopaedic surgery, and long-term secondary prevention of VTE. Rivaroxaban is administered as a BID regimen for

the initial treatment of VTE and secondary prevention after acute coronary syndromes (Xarelto: EU SPC, 2015)

Heidbuchel et al. Europace 2015

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24Time (hours)

Dabigatran (12–17 hrs)

Apixaban (12 hrs)

Edoxaban (10–14 hrs)

Rivaroxaban* (elderly: 11–13 hrs)

Twice

daily

(BID)

Rivaroxaban*

(adults: 5–9 hrs)

Once

daily

(OD)

Dabigatran BID dosing resulted in more consistent plasma levels than OD dosing

150 mg BID Peak–trough ratio ~ 2/1

300 mg OD Peak–trough ratio ~ 5/1

Predicted median concentration vs time at steady state after oral administration of dabigatran; data simulated for the

average RE-LY® patient with AF (male, 72 years old, 80 kg)

Clemens et al. Curr Med Res Opin 2012

Dabigatran 150 mg BID resulted in a lower peak–trough plasma ratio over 24 hours than the same dose (300 mg) given OD

Schematic illustration of theoretical drug exposure in the therapeutic window

Therapeutic range and biologic variability for anticoagulants

Day

Co

nce

ntr

atio

n

5 6 7 8 9 10

Bleeding

Thrombosis

Simulations using the same agent; T1/2 = 12 hrs; Tmax = 3 hrs

Vrijens & Heidbuchel. Europace 2015

Trade-off between better daily implementation and increased forgiveness

OD

BID

Steady state One missed BID dose

One missed OD dose = 3 missed BID doses One extra dose

*OD and BID dosing for same agent and the same total daily dose; assuming T1/2 = 12 hrs; Tmax = 3 hrs

Vrijens & Heidbuchel. Europace 2015

BID regimen increases forgiveness for similar deviations in adherence

OD* BID*

Dosing times (day)

Do

sin

g t

ime

03:00 06:00 09:00 12:00 15:00 18:00 21:00 24:00 03:00

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95

Dosing times (day)

03:00 06:00 09:00 12:00 15:00 18:00 21:00 24:00 03:00

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95100 100

Bleeding risk

Thrombosis risk

Bleeding risk

Thrombosis risk

Do

sin

g t

ime

Co

ncentr

atio

n

Co

ncentr

atio

n

• 15% missed doses

• 15 OD missed doses vs 30 BID missed doses over 100 days

Dose taken

Dose missed Rivaroxaban should be taken with food for stroke prevention in AF (Xarelto: EU SPC, 2015)

Typical daily regimen for an elderly patient with AF, hypertension, and type 2 diabetes

BREAKFAST LUNCH DINNER

Metformin

Rivaroxaban

Diuretic

Beta blocker

Calcium channel blocker

Metformin

Sulphonylurea

Metformin

Statin

21-3-2016

8

Dabigatran can be taken with or without food (Pradaxa®: EU SPC, 2016)

Typical daily regimen for an elderly patient with AF, hypertension, and type 2 diabetes

Metformin

Dabigatran

MetforminDiuretic

Beta blocker

Calcium channel blocker

Metformin

Sulphonylurea

Dabigatran

BREAKFAST LUNCH DINNER

Statin

Summary

In AF patients, BID dosing offers consistent 24-hr protection

and may minimize the effect of a missed dose vs OD

dosing5,63

1. Lip et al. Thromb Haemost 2014; 2. Granger et al. N Engl J Med 2011; 3. Patel et al. N Engl J Med 2011;

4. Giugliano et al. N Engl J Med 2013; 5. Clemens et al. Curr Med Res Opin 2012; 6. Vrijens & Heidbuchel. Europace 2015

Clinical trials with NOACs have shown non-inferior or

superior efficacy vs warfarin,1–4 but adherence to the

prescribed regimen is of great importance for translating

trial results into clinical practice

1

BID dosing with dabigatran resulted in more consistent

plasma levels than OD dosing and was selected for

dabigatran to provide patients with improved stroke

prevention5

2

LIVE VIENNA

BREAKING NEWS

First specific reversal agent for a NOAC now available

12:40 Steve Austin, UK

• Advisory Bureau and Speaker fees

• Boehringer Ingelheim, Bayer, Baxalta, Octopharma, Pfizer, Sobi, BPL,

Grifols, Alexion, Novartis, Novo Nordisk

• Educational support

• Boehringer Ingelheim, Bayer, Octapharma, Novartis, Pfizer, Grifols,

Novo Nordisk

• Research support

• Grifols, Pfizer

Disclosures Idarucizumab is now approved

2016 2017 2018

Idarucizumab is not approved in all countries. Please check your local prescribing information for details.

1. US FDA 2015. 2. European Commission Community Register of Medicinal Products for Human Use 2015;

3. New Zealand Gazette 2015; 4. Boehringer Ingelheim, Data on file

Available in >1000 hospitals in Europe

and >2000 hospitals in the USA

21-3-2016

9

Idarucizumab is now approved

Available in >1000 hospitals in Europe

Idarucizumab is not approved in all countries. Please check your local prescribing information for details.

1. US FDA 2015. 2. European Commission Community Register of Medicinal Products for Human Use 2015; 3. New

Zealand Gazette 2015; 4. Boehringer Ingelheim, Data on file; 5. ClinicalTrials.gov Identifier: NCT02329327; 6. Portola

Pharmaceuticals, Inc. Press Release, 18 Dec 2015; 7. Portola Pharmaceuticals, Inc. Analyst & Investor Day, 19 Nov 2015

Reversal agent for FXa inhibitors

(andexanet alfa) in development:5

expected European availability: late 2017/early 20186,7

2015

Idarucizumab:

available in

Europe

2016 2017 2018

Adapted from Schiele et al. Blood 2013; Stangier et al. ISTH 2015

Idarucizumab was designed as a specific reversal

agent for the anticoagulant activity of dabigatran

Idarucizumab

Dabigatran

Thrombin

IV administration,

immediate onset of action

No intrinsic procoagulant

or anticoagulant activity

Short half-life

(initial t1/2 ~45 min)

Humanized Fab fragment

Binding affinity for dabigatran ~350× higher than dabigatran to thrombin

dTT, diluted thrombin time; ECT, ecarin clotting time

Glund et al. Lancet 2015

dTT and ECT are appropriate laboratory markers

of the anticoagulant effect of dabigatran

0

An

tico

ag

ula

tio

n a

cti

vit

y (

dT

T)

Unbound dabigatran plasma concentration (ng/mL)

100

150

200

250

0 40 80 120 160 200 28024020 60 100 140 180 260220

0

An

tico

ag

ula

tio

n a

cti

vit

y (

EC

T)

Unbound dabigatran plasma concentration (ng/mL)

100

150

200

250

0 40 80 120 160 200 28024020 60 100 140 180 260220

dTT and ECT show linear correlations with a wide range of

dabigatran concentrations

Idarucizumab is not approved in all countries. Please check your local prescribing information for details.

AE, adverse event; dTT, diluted thrombin time; ECT, ecarin clotting time; Glund et al. Presented at ASH 2014

Idarucizumab provided immediate, complete, and sustained

reversal of dabigatran anticoagulation

Upper limit of normal

Mean baseline

90

85

80

75

70

65

60

55

50

45

40

35

30

25

-2 0 30 60 90 120 4 8 12 16 20 24

Time after end of infusion (hrs)Min

An

tic

oa

gu

lati

on

ac

tiv

ity

(d

TT

)

Idarucizumab

65–80 yr, dabigatran 220 mg

+ idarucizumab 5 g

Placebo

No serious drug-related AEs reported in >200 volunteers

*Other than bleeding; dTT, diluted thrombin time; ECT, ecarin clotting time; Pollack et al. Thromb Haemost 2015

RE-VERSE AD™: multicentre, ongoing,

single-arm, open-label, Phase III study

Primary endpoint:

dabigatran reversal within

4 hours based on dTT or ECT

5 g idarucizumab

(two separate

infusions of 2.5 g)

Sample size:

N=500

Group A:

Life-threatening

bleeding +

dabigatran-treated

Group B:

Emergency surgery

or procedure* +

dabigatran-treated

21-3-2016

10

RE-VERSE AD™ interim results: immediate reversal of dabigatran anticoagulation with idarucizumab based on dTT

Group A:

Life-threatening bleeding

Idarucizumab

2×2.5 g

130

110

70

60

50

40

30

20

120

100

90

80

1 h 2 h 4 h 12 h 24 hBaseline Between

vials

10–30

minTime post-idarucizumab

Group B:

Emergency surgery or procedure

0

An

tic

oa

gu

lati

on

ac

tivit

y (

dT

T)

Idarucizumab is not approved in all countries. Please check your local prescribing information for details.

Assay upper limit of normal; interim analysis includes data for the first 90 patients; Box and whisker plots – box shows

median, 25th, and 75th percentiles, whiskers show 10th and 90th percentiles; Adapted from: Pollack et al. N Engl J Med 2015

Idarucizumab

2×2.5 g

An

tic

oa

gu

lati

on

ac

tivit

y (

dT

T)

130

110

70

60

50

40

30

20

120

100

90

80

1 h 2 h 4 h 12 h 24 hBaseline Between

vials

10–30

min

0

Time post-idarucizumab

No idarucizumab-related safety concerns identified to date

Idarucizumab is not approved in all countries. Please check your local prescribing information for details.

FFP, fresh frozen plasma; PCC, prothrombin complex concentrate; rFVIIa, recombinant activated Factor VII

Praxbind®: EU SPC, 2015

Idarucizumab: indications for use

for emergency surgeryor urgent intervention

in life-threatening or uncontrolled bleeding

Contraindications: None to date

Idarucizumab can be used in conjunction with standard supportive

measures (e.g. FFP, PCC, rFVIIa)

Vials must be

refrigerated (2–8°C)

Idarucizumab is not approved in all countries. Please check your local prescribing information for details.*Restricted to hospital use only; Praxbind®: EU SPC, 2015

Idarucizumab is easy to use and store

\\\\\\ Shelf life: 24 months

Infuse intravenously Inject intravenously

The complete 5 g dose

should be given as

two consecutive IV

infusions over 5–10

minutes each

Give the

complete 5 g dose

in two separate

consecutive bolus

injections

Idarucizumab dose is 5 g IV*

Idarucizumab is administered as a fixed dose,

regardless of the clinical situation

Vials contain a ready-mixed solution for administration

Idarucizumab is not approved in all countries. Please check your local prescribing information for details.

*If patient is clinically stable and adequate haemostasis has been achieved; Praxbind®: EU SPC, 2015

Anticoagulation can be resumed soon after

administration of idarucizumab

Dabigatran can be

re-started 24 hours after

administration

Any antithrombotic

treatment (e.g. heparin)

can be initiated at any

time after administration

of idarucizumab

Idarucizumab is not approved in all countries. Please check your local prescribing information for details. This

information is presented for medical education purposes only. aPTT, activated partial thromboplastin time; dTT, diluted

thrombin time; TT, thrombin time; Adapted from: Eikelboom et al. Circulation 2015

Proposed algorithm for management of dabigatran-treated

patients in rare emergency situations

Emergency event

Institute local bleeding management protocol Proceed immediately to surgery

or invasive procedure

If time permits, measure aPTT

and/or TT (dTT)

Administer idarucizumab* 5 g

Mild to moderate bleedingLife-threatening or

uncontrolled bleeding

Requires urgent surgery or invasive procedure in next

8 hours

• Confirm dabigatran presence (patient records, relatives, prescriptions)• If possible, determine degree of anticoagulation (time of last dose, aPTT/TT/dTT)

Reintroduce anticoagulation appropriately after event, depending on thrombotic/bleeding risk

Ensure your local

protocols have been

updated to include

idarucizumab

C AL L TO AC T I O N !

21-3-2016

11

1. Pollack et al. N Engl J Med 2015; 2. Stangier et al. ISTH 2015; 3. Praxbind®: EU SPC, 2015

Summary

Dabigatran is the only NOAC with a specific

reversal agent available1

Idarucizumab reverses the anticoagulant effects

of dabigatran within minutes,1 and has no

procoagulant effect22

Idarucizumab is easy to use, easy to store, and

can be used in a broad patient population33

LIVE VIENNA

FINANCIAL FORECAST

Reducing the impact on healthcare resources in anticoagulation care12:55 Ian Menown, UK

• Honoraria, conference support and/or research grant

to institution from:

– Bayer

– Boehringer Ingelheim

– BMS/Pfizer

– Daichii Sankyo

Disclosures

Strokes are caused directly by AF annually

in the UK4

12 500AF-related strokes that

could be prevented annually in the UK by

appropriate management4

7100

1. Zoni-Berisso et al. Clin Epidemiol 2014; 2. Camm et al. The Route Map for Change & the European Atlas on the

Prevention of AF-Related Stroke. Nov 2014; 3. Cowie et al. NOACs: Innovation in anticoagulation. Mar 2014

~10 000 000People are affected by AF

in Europe1

Total cost of stroke annually in Europe3

€38bn

Acute hospitalization

accounts for the bulk of AF-related

stroke costs in the UK4

Strokes are caused directly by AF annually in Europe2

~360 000

NOACs must be made available for prescribing within

their licensed indications, and should be automatically

included in local formularies1

1. NICE consensus statement on the use of NOACs. Available at:

https://www.nice.org.uk/guidance/cg180/resources/nic-consensus-statement-on-the-use-of-noacs-243733501;

2. NICE TA249, 2012; 3. NICE TA256, 2012; 4. NICE TA275, 2013; 5. NICE TA355, 2015

UK National Institute for Health and Care Excellence (NICE)

21-3-2016

12

What evidence is available for the

cost-effectiveness of dabigatran

vs other NOACs or warfarin?

QALY, quality-adjusted life years

Zheng et al. Clin Ther 2014

UK study showed dabigatran is more

cost-effective than other NOACs or warfarin

Driven by greater effectiveness in reducing both haemorrhagic AND ischaemic strokes with dabigatran vs other OACs

Total cost (£) QALYs

Dabigatran 23342 7.68

Apixaban 24014 7.63

Edoxaban – –

Rivaroxaban 25220 7.47

Warfarin 24680 7.36

*Adjusted for RE-LY® parameters; NMB, net monetary benefit; WTP, willingness to pay

Zheng et al. Clin Ther 2014

Dabigatran had the highest incremental

net monetary benefit

16 000

14 000

12 000

10 000

8000

6000

4000

0

Willingness to pay (£)

Ne

t m

on

eta

ry b

en

efi

t (£

)

2000

Dabigatran combined

Rivaroxaban*

Apixaban*

Warfarin

At NICE WTP threshold of £25000, incremental NMB vs warfarin

Dabigatran: £9217

Apixaban: £7203

Rivaroxaban: £2100

Increasing

savings

What clinical trial and real-world

evidence is available for healthcare

resource utilization with dabigatran

vs warfarin?

Majeed et al. Circulation 2013

Shorter ICU stay after a major bleed with

dabigatran vs warfarin in RE-LY®

Shorter ICU stay benefits patients and may be cost-effective for hospitals

0

1

2

3

Dabigatran Warfarin

P=0.001

(D150 and D110 combined)

Me

an

IC

U s

tay (

nig

hts

)

1.6

2.7

0

5000

10000

15000

Dabigatran Warfarin

Retrospective cohort study using administrative claims data from the US Dept. of Defense (DoD) Health System

Francis et al. Curr Med Res Opin 2015

US DoD study demonstrated significantly lower

medical costs for dabigatran vs warfarin

P<0.001

N=1102

(D150 and D75 combined)

N=1102

To

tal

me

dic

al c

os

ts

pe

r p

ati

en

t ($

)

$7610

$13 909

In the 12 months following initiation of anticoagulation, mean medical costs for

patients initiated on dabigatran were significantly lower vs warfarin

Largely due to fewer hospitalizations

21-3-2016

13

* P <0.05

Newly diagnosed adults with NVAF, newly treated with dabigatran or warfarin. Followed for up to 12 months after

initiation of anticoagulant; Propensity score matched for demographics, stroke risks, bleeding risks, comorbidities; †Monthly hospitalization data in DoD study derived from 12-month data

1. Sussman et al. AMCP 2014, 2. Sussman et al. Manuscript submitted; 3. Reynolds et al. Manuscript submitted;

4. Francis et al. ACPM 2013; 5. Bancroft et al. Clin Ther 2016; 6. Fu et al. ACPM 2014; 7. Limone et al. ACPM 2015

0,090,08

0,06 0,06

0,08

0,28

0,10,09

0,07 0,07

0,09

0,31

0

0,05

0,1

0,15

0,2

0,25

0,3

0,35

Humedica Humana DoD† Optum HealthCore Truven

Dabigatran

Warfarin

* *

(n=3890)1,2 (n=2220)3 (n=1738)5 (n=1648)6 (n=142)7

*

(n=1264)4

Mean h

ospitalization r

ate

(per

patient

per

month

)

US database studies demonstrated ~10–20%

fewer hospitalizations for dabigatran vs warfarin

What is the clinical and economic

impact of idarucizumab?

Idarucizumab will facilitate urgent surgery/procedures

and control of life-threatening bleeding

Fractures, accidents, falls, trauma

ICH

Lumbar puncture

Acute ischaemic

stroke management

Urgent neurosurgery

ICH

Urgent neurosurgery

Lumbar puncture

Other urgent

surgical

intervention

(e.g. acute

abdomen) or

management

of bleed

Urgent CABG

Urgent cardiac

surgery

Heart transplant

Ablation

complications

PCI

complications

Where might idarucizumab have an impact

on cost-effectiveness?

Avoid delay before urgent

surgery/procedures

Potential for fewer

bleeding

complications

Decreased length of stay in hospital

Decreased

consumption of

blood components

and blood products

1. Zoni-Berisso et al. Clin Epidemiol 2014; 2. Camm et al. The Route Map for Change & the European Atlas on the

Prevention of AF-Related Stroke. Published Nov 2014; 3. Cowie et al. NOACs: Innovation in anticoagulation.

Published Mar 2014; 4. Zheng et al. Clin Ther 2014

Summary

AF-related stroke is associated with substantial economic

cost and personal burden1–31

Dabigatran is less costly than apixaban or rivaroxaban vs

warfarin42

Idarucizumab, by reducing delay to urgent/emergency

procedures and by helping management of life-threatening

bleeding, may improve clinical outcomes and provide

further cost savings

3

21-3-2016

14

What is the impact of NOACs

and reversal agents on my

clinical practice and my patients’ lives?

CVA, cerebrovascular accident; HTN, hypertension; INR, international normalized ratio;

PCC, prothrombin complex concentrate; ROM, range of movement

Examination

• Tenderness over left elbow with

decreased ROM

• Abrasions on left temple and

left patella

History

• AF

• Arthritis

• Dyslipidaemia

• Benign essential HTN

• Diabetes mellitus

• Malignant neoplasm of colon

• CVA (cerebral infarction)

Medications

• Dabigatran 150 mg BID

• Amlodipine, quinapril, metoprolol,

and atorvastatin

Recommendations

• Reverse oral anticoagulation with

idarucizumab or PCC

• Surgical fixation of elbow fracture

• Repeat head CT at 6-hr intervals

Imaging

• Head CT: 4 mm acute

interhemispheric subdural

haematoma. No midline shift or

mass effect

• X-rays: displaced elbow fracture,

no patella fracture

Labs– Glucose 131

– Haemoglobin 13.2

– Platelet count 129

– Prothrombin time 14.6

– INR 1.2

83-yr-old female admitted after fall ‘onto her face’

Dabigatran anticoagulation reversed with idarucizumab;

led to normal haemostasis during surgery

4 days

post-surgery

Patient

discharged

On

admission

Dabigatran

held

Dabigatran

restarted

XIdarucizumab

given

2 days

post-surgery

Before

surgerySurgery

Surgical

fixation of

elbow

fracture

NORMAL

HAEMOSTASIS

Serial head CTs:

no haematoma

growth

1. Graham et al. Circulation 2015; 2. Villines et al. Thromb Haemost 2015; 3. Seeger et al. AHA 2015;

4. Larsen et al. Am J Med 2014a; 5. Larsen et al. Am J Med 2014b; 6. Lauffenburger et al. J Am Heart Assoc 2015

Safety and efficacy of dabigatran is supported by a wealth of independent clinical practice evidence, unparalleled among the NOACs1–6

Dabigatran is the only NOAC with a specific reversal agent available

Idarucizumab is widely available, easy to use, and may improve clinical outcomes and provide cost savings

Please complete your evaluation form

21-3-2016

15