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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
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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
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