EFFICACY, SAFETY AND SECURITY:

a new data for Dabigatran Etexilate in Primary

SPAF anticoagulation care

Pendrik Tandean
Cardiolgy Division of Internal Medicine
Department, Hasanuddin University
Department of Cardiology and Vascular
Medicine, Hasanuddin University.

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 TOPICS

Burden and Management of Atrial Fibrillation

The goal of OAC therapy
Optimizing usage of NOAC in daily practice
Randomized controlled trial vs daily practice data
Conclusion

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Prevalence of Diagnosed AF
Stratified by Age and Sex

12.0
Women 11.1
Men 10.3
10.0
9.1

8.0 7.3 7.2

6.0
5.0 5.0
x-axis = %
4.0 3.4 y-axis = # of
3.0 men/women
2.0 1.7 1.7
0.9 1.0
0.1 0.2 0.4
0.0
<55 55-59 60-64 65-69 70-74 75-79 80-84 > 85
# Women 530 310 566 896 1498 1572 1291 1132
# Men 1529 634 934 1426 1907 1886 1374 759

Go AS, JAMA. 2001 May 9;285(18):2370-5. Pub Med PMID: 11343485

 STROKE AND ATRIAL FIBRILLATION

Affected AF is associated with a 5-fold higher stroke risk

part of overall1
the brain
AF doubles the risk of stroke when adjusted for
other risk factors2
Without prevention, approximately 1 in 20
patients will have a stroke each year3
Responsible for nearly a third of all strokes5, and
the leading cause of embolic stroke6

1. Savelieva I et al. Ann Med 2007; 39: 371 391; 2. ACC/AHA/HRS focused update guidelines : Fuster V et al. Circulation
2011; 3. Atrial Fibrillation Investigators. Arch Intern Med 1994; 154: 1449-1457; 4. Carlson M. Medscape Cardiol 2004; 8; 5.
Hannon N et al. Cerebrovasc Dis 2010; 29:439; 6. Emmerich J et al. Eur Heart J 2005; 7(Suppl C):C2833

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GOALS FOR ANTICOAGULANT THERAPY IN
AF

I need to
maximize risk
reduction at the
same time as
minimizing harm to
the patient
- PCP CPA Study

92% of AF-Related stroke 8% of AF-Related stroke

are Ischemic are Hemorrhagic

1. Connoly SJ et al. Circulation. 2008; 118 : 2029-2037. 2. Connoly SJ et al. N Engl J Med 2009; 361(12): 1139-1151.

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European Society of Cardiology Guidelines
CHA2DS2-VASc and Stroke Rate

Risk Factors
For Stroke and Thrombo-embolism in Non-valvular AF
Risk Factor Score

Congestive heart failure/LV dysfunction* 1

Hypertension* 1

Age >75** 2

Diabetes Mellitus* 1

Stroke / TIA / Thrombo-embolism** 2

Vascular Disease* 1

Age 65-74* 1

Sex category (i.e. female sex)* 1

Maximum Score 9
Note: maximum score is 9 since age may contribute 0,1, or 2 points
* Clinically relevant non-major risk factor
** Major risk factor

Camm AJ. Europace. 2010 Oct;12(10):1360-420. Pub Med PMID: 20876603.

Bleeding Risk Scores Widely Used in AF

HAEMORRHAGES1
HASBLED2
ATRIA Score3

1.Gage BF, et al. Am Heart J. 2006 Mar;151(3):713-9. PMID: 16504638. Pub Med PMID:16504638.
2.Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. Chest. 2010 Nov;138(5):1093-100. PMID:20299623.
3.Fang MC, et al. J Am Coll Cardiol. 2011 Jul 19;58(4):395-401. Pub Med PMID:21757117.
Bleeding Risk Scores in AF
ATRIA HAS-BLED HEMORR2HAGES

Anemia1 3 Hypertension4 1 Hepatic10 or 1

Renal disease2 1

Severe renal disease2 3 Abnormal Renal5 or 1

Ethanol abuse 1
Liver function6 1
Age 75 yrs 2 Stroke 1 Malignancy 1
Any prior hemorrhage 1 Bleeding 1 Older Age (>75 yrs) 1

Hypertension3 1 Labile INR8 1 Reduced platelet number 1

or function11
Elderly (>65 yrs) 1 Rebleeding12 2
1.
2.
Hemoglobin <13 g/dl men; <12 g/dl women
Estimated glomerular filtration rate <30 ml/min or dialysis-dependent
Drugs or 9 1
Hypertension4 1
3.
4.
Diagnosed hypertension
Systolic blood pressure >160 mmHg
Alcohol 1
5. Presence of chronic dialysis or renal transplantation or serum creatinine 200 mmol/L
6. Chronic hepatic disease (eg cirrhosis) or biochemical evidence of significant hepatic derangement (eg bilirubin 2 x upper limit of normal,
in association with aspartate aminotransferase/alanine aminotransferase/alkaline phosphatase >3 x upper limit normal, etc.)
Anemia13 1
8. Unstable/high INRs or poor time in therapeutic range (eg <60%)
9.
10.
Concomitant use of drugs, such as antiplatelet agents, non-steroidal anti-inflammatory drugs, or alcohol abuse etc.
Cirrhosis, two-fold or greater elevation of AST or APT, or albumin <3.6 g/dl Genetic factors14 1
11. Platelets <75,000, use of antiplatelet therapy (eg daily aspirin) or NSAID therapy; or blood dyscrasia
12. Prior hospitalization for bleeding
13.
14.
Most recent hematocrit <30 or hemoglobin <10 g/dl
CYP2C9*2 and/or CYP2C9*3
Excessive fall risk15 1
15. Alzheimer's dementia, Parkinson's disease, schizophrenia, or any condition predisposing to repeated falls
Stroke 1
Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. J Am Coll Cardiol 2012;60:000000. 2012 Jul 24. [Epub ahead of print] Online Appendix.
PMID: 22858389.
 WHAT DO THE GUIDELINE SAY ?

In MALE AF PATIENTS with CHA2DS2-VASc

score 2, OAC therapy is RECOMMENDED. In
MALE AF PATIENTS with CHA2DS2-VASc score 1,
OAC therapy should be CONSIDERED

In FEMALE AF PATIENTS with CHA2DS2-VASc

score 3, OAC therapy is RECOMMENDED. In
FEMALE AF PATIENTS with CHA2DS2-VASc score 2,
OAC therapy should be CONSIDERED

Combinations of OAC and Anti Platelets

INCREASE BLEEDING RISK and should be AVOIDED
in patients without another indication for Anti
Platelets

Kirchhof P et al. European Heart Journal 2016:37:2893-2962

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SHOULD ANTICOAGULATION BE WITH WARFARIN OR
NOAC ?
WHAT DO THE GUIDELINE SAY ?

When OAC is initiated in AF PATIENTS

WHO IS ELIGIBLE FOR NOACs:
a direct thrombin inhibitor (DABIGATRAN);
or an oral Factor Xa inhibitor
(e.g. Rivaroxaban, Apixaban)
NOAC IS RECOMMENDED IN PREFERENCE TO
VITAMIN K ANTAGONIST

Kirchhof P et al. European Heart Journal 2016:37:2893-2962

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 RESULTS OF THE STUDIES WITH NOACs
(ISCHEMIC STROKE)

No. of events (%/yr)

NOAC Warfarin HR 95% CI

Dabigatran 159 (1.34) 142 (1.20) 1.11 0.891.40

110 mg (ITT)

Dabigatran 111 (0.92) 142 (1.20) 0.76 0.600.98

150 mg (ITT)

Rivaroxaban 149 (1.34) 161 (1.42) 0.94 0.751.17

(Safety AT)
Apixaban* 162 (0.97) 175 (1.05) 0.92 0.741.13
(ITT)
Apixaban** 140 (1.54) 136 (1.50) 1.02 0.811.29
(ITT)
0.0 0.5 1.0 1.5 2.0
Favours NOAC Favours Warfarin
1. Connolly SJ et al. N Engl J Med 2009;361:113951; 2. Pradaxa.Local Product Information. 2016; 3. Patel MR et al. N Engl J Med
2011;365:88391(appendix); 4. Granger CB et al. N Engl J Med 2011;365:98192; 5. Lopes RD et al. Lancet 2012; 380:174958Q
Not head-to-head comparison for illustrative purposes only adapted from references 15
* Unknown type of stroke occurred in 14 patients in the Apixaban group and 21 patients in the warfarin group. Among the patients
with ischemic strokes, hemorrhagic transformation occurred in 12 patients with Apixaban and 20 patients with warfarin
** Revised data; re-categorized following original publication GPM-PXS-0006-ID
 RESULTS OF THE STUDIES WITH NOACs
(INTRACRANIAL BLEEDING)

No. of events (%/yr)

NOAC Warfarin HR 95% CI

Dabigatran 110 27 (0.23) 87 (0.74) 0.31 0.200.47

mg (ITT)

Dabigatran 150 36 (0.30) 87 (0.74) 0.40 0.270.60

mg(ITT)

Rivaroxaban 55 (0.5) 84 (0.7) 0.67 0.470.93

(safety AT)

Apixaban 52 (0.33) 122 (0.80) 0.42 0.300.58

(ITT)

0.0 0.5 1.0 1.5 2.0

Favors NOAC Favors Warfarin

Not head-to-head comparison for illustrative purposes only adapted from references 15
1. Connolly SJ et al. N Engl J Med 2009;361:113951; 2. Pradaxa.Local Product Information. 2017; 3. Patel MR et al. N Engl J Med
2011;365:88391(appendix); 4. Granger CB et al. N Engl JMed 2011;365:98192; 5. Lopes RD et al. Lancet 2012; 380:174958Q
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 IN RELY, BOTH DOSES OF DABIGATRAN ASSOCIATED
WITH SIGNIFICANT SAFETY AND EFFICACY BENEFITS VS.
WARFARIN

Dabigatran 150 mg BID Dabigatran 110 mg BID

24%
40% 74% 40%
similar 69%
40%
ISCHEMIC HEMORRHAGIC HEMORRHAGIC
ISCHEMIC STROKE
STROKE STROKE vs warfarin
STROKE
vs warfarin vs warfarin vs warfarin

RE-LY was a PROBE (Prospective, Randomized, Open-label with Blinded Endpoint evaluation) study

Connolly SJ et al. N Engl J Med 2009;361:113951; Pradaxa Local Product Information. 2017
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PREVENTION OF ISCHEMIC AND HEMORRHAGIC STROKE
IS THE PRIORITY FOR ALL PATIENTS

Dabigatran Dabigatran Apixaban Rivaroxaban

150 mg BID 110 mg BID 5/2.5 mg BID 20/15 mg OD
(RE-LY)12 (RE-LY)12 (ARISTOTLE)3,4 (ROCKET AF)5

Superior protection against
Ischemic stroke vs VKA
achieved in a Phase III trial? 24%
RRR

Superior protection against
Hemorrhagic stroke vs VKA
achieved in a Phase III trial? 74%
RRR

Dabigatran 150 mg BID PROVIDES SUPERIOR PROTECTION from

BOTH ISCHEMIC AND HEMORRHAGIC STROKE vs warfarin in a Phase III trial

Not head-to-head comparison no clinical conclusions can be drawn adapted from references 15
RE-LY was a PROBE (Prospective, Randomized, Open-label with Blinded Endpoint evaluation) study

1. Connolly SJ et al. N Engl J Med 2009;361:113951; 2. Pradaxa.Local Product Information. 2017; 3.Granger CB et al. N Engl JMed
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2011;365:98192; 4. Lopes RD et al. Lancet 2012; 380:174958Q; 5. Patel MR et al. N Engl J Med 2011;365:88391 (appendix)
ALL NOACs HAVE A RELATIVELY SHORT MEAN HALF LIFE

PLASMA HALF LIFE

18
12-17 hours

11-13 hours
14 12 hours
5-9 hours
9
Max
Min
5

0
Dabigatran Rivaroxaban Rivaroxaban Apixaban
(young) (elderly)

Dabigatran: 1217 hours3,4

Rivaroxaban: 59 hours (young patients), 1113 hours (elderly patients)3; Apixaban: ~12 hours3

1. Camm AJ et al. Eur Heart J 2012;33:271047; 2. ACCF/AHA/HRS Focused Update Guidelines: Fuster V et al.
J Am Coll Cardiol 2011;57:e10198; 2012; 3. Heidbuchel H et al. Europace 2013;15:62551; 4. Pradaxa Local Product
Information. 2017
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DABIGATRAN ETEXILATE BPOM APPROVED DOSING FOR
SPAF

150 mg BID Recommended dose of Dabigatran

110 mg BID Recommended for patients 80 years

The presence high bleeding risk, at least one or

more than following factors :
150 mg BID Patients 75 years
Patients with moderate renal impairment
OR Concomitant with strong P-gp Inhibitors
110 mg BID Concomitant with antiplatelets
Previous gastrointestinal bleed
Other patients at increased risk of bleeding

Pradaxa Local Product Information, 2017

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WHICH DOSE OF DABIGATRAN ETEXILATE
WHAT DO THE GUIDELINE SAY ?

WHEN DABIGATRAN IS PRESCRIBED,

a dose of 150 mg BID SHOULD BE CONSIDERED
FOR MOST PATIENT in preference to 110 mg
BID, with the latter dose recommended in:

Elderly patients, age 80 years

Concomitant use of interacting drugs
(e.g. verapamil)
High bleeding risk (HAS-BLED score 3)
Moderate renal impairment
(CrCl 3049 mL/min)

Camm AJ et al. Eur Heart J 2012;33:2719-2747

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IS DABIGATRAN TRIAL SUPPORTED WITH DAILY
PRACTICE DATA (REAL WORLD DATA) ?

Randomized Controlled Trial vs Real World Data

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INDEPENDENT FDA STUDY OF MEDICARE PATIENTS MIRRORS
THE FAVOURABLE BENEFIT-RISK PROFILE OF DABIGATRAN
FROM RELY

RR: 0.76 RR: 0.41 RR: 0.93 RR: 1.48 RR: 1.27 RR: 0.88

Event rate (% per year)

P=0.03 P<0.001 P=0.32 P=0.001 P=0.12 P=0.05

RE-LY1-4

Warfarin
D150 BID ISCHAEMIC ICH MAJOR GI MI MORTALITY
STROKE BLEEDING BLEEDING
Incidence rate per
100 person-years

MEDICARE*5

Warfarin HR: 0.80 HR: 0.34 HR: 0.97 HR: 1.28 HR: 0.92 HR: 0.86
D150 & D75 BID combined P=0.02 P<0.001 P=0.50 P<0.001 P=0.29 P=0.006

In the USA, the licensed doses for Pradaxa are: 150 mg BID and 75 mg BID for the prevention of stroke and systemic embolism in adult patients with
NVAF. In the EU, dabigatran 110 mg BID is indicated for certain patients, and was shown to be as effective vs VKA for prevention of stroke/SE. RE-LY was
a PROBE (prospective, randomized, open-label with blinded endpoint evaluation) study
*Primary findings for dabigatran are based on analysis of both 75 mg & 150 mg together without stratification by dose NVAF, nonvalvular atrial
fibrillation; 1. Connolly SJ et al. N Engl J Med 2009;361:113951; 2. Connolly SJ et al. N Engl J Med 2010;363:18756; 3. Pradaxa: Local Product
Information, 2016; 4. Connolly et al. N Engl J Med 2014 ;371:1464-1465; 5. Graham DJ et al. Circulation 2015;131:15764
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 DABIGATRAN COMPARED TO WARFARIN AND ASPIRIN
LOWER INCIDENCE OF ISCHEMIC STROKE

Ischemic Stroke
% 10.
/
ye
ar 8.
7.95 HONGKONG AF REGISTRY
7.34
6.
5.95
Total Patients : 8754
4. 4.39
Dabigatran Pts : 393
Mean follow up : 3 years
3.1
2.
2.24

0.
Aspirin Q1 Q2
Warfarin Q3 Q4 Dabigatran Overall

TTR quartiles: Q1: <17.9%; Q2: 17.9%38.8%; Q3: 38.8%56.2% ; Q4: >56.2%)

Adapted from Ho CW et al. Stroke 2015;46:23-30

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 DABIGATRAN COMPARED TO WARFARIN AND ASPIRIN
LOWER INCIDENCE OF INTRACRANIAL HEMORRHAGE
Intracranial Hemorrhage
1.75
% / year

1.4
1.37
% / year

1.05 HONGKONG AF REGISTRY

0.86 0.82
0.7 0.8
0.74 0.75 Total Patients : 8754
Dabigatran Pts : 393
0.35 Mean follow up : 3 years
0.32
0.
Aspirin Q2 Q4 Overall

Warfarin

TTR quartiles: Q1: <17.9%; Q2: 17.9%38.8%; Q3: 38.8%56.2% ; Q4: >56.2%)

Adapted from Ho CW et al. Stroke 2015;46:23-30

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 AN INDEPENDENT FDA STUDY OF >118 000 MEDICARE
PATIENTS COMPARED
DABIGATRAN 150 MG BID WITH RIVAROXABAN 20 MG OD

5.
Dabigatran
HR 1.48 (1.321.67) Rivaroxaban
per 100 person-years*

3.75 HR 1.40 (1.231.59)

Incidence rate

HR 1.15 (1.001.32)
2.5

1.25 HR 0.81 (0.651.01)

HR 1.65 (1.202.26)

0.
Major extracranial bleeding Major GI bleeding ICH Thromboembolic stroke Death

Rivaroxaban was associated with a STATISTICALLY SIGNIFICANT INCREASED RISK OF

MAJOR EXTRACRANIAL BLEEDING, MAJOR GI BLEEDING and ICH compared with Dabigatran

*Incidence rates are unadjusted; hazard ratios (HR) are adjusted HR (95% CI) comparing inverse probability of treatment-
weighted new-user cohorts; bold values indicate statistical significance; average follow-up duration <4 months;
ICH, intracranial haemorrhage; GI, gastrointestinal; Graham, et al. JAMA Intern Med 2016;
doi:10.1001/jamainternmed.2016.5954
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 DABIGATRAN COMPARED TO RIVAROXABAN
LOWER RISK OF MAJOR GI HEMORRHAGE

KaplanMeier analysis An independent FDA study of > 118.000 Medicare patients compared
Weighted failure curves Dabigatran 150 mg BID vs. Rivaroxaban 20 mg OD

2.5 Major GI bleeding 2.0 Death

2.0 Rivaroxaban Rivaroxaban
1.5
Cumulative adjusted

Dabigatran Dabigatran
incidence rate, %

1.5
1.0
1.0

0.5
0.5

0 0
0 60 120 180 240 300 0 60 120 180 240 300
Follow-up time, days Follow-up time, days

Patients initiating treatment with Dabigatran experienced a STATISTICALLY

SIGNIFICANTLY LOWER RISK OF MAJOR GI BLEEDING than those initiating
treatment with Rivaroxaban

Average follow-up duration <4 months; Graham, et al. JAMA Intern Med 2016; doi:10.1001/jamainternmed.2016.5954
GPM-PXS-0006-ID
 DABIGATRAN COMPARED TO RIVAROXABAN
LOWER RISK OF INTRACRANIAL HEMORRHAGE

KaplanMeier analysis An independent FDA study of > 118.000 Medicare patients compared
Weighted failure curves Dabigatran 150 mg BID vs. Rivaroxaban 20 mg OD

Thromboembolic stroke ICH

0.6 0.6
Rivaroxaban Rivaroxaban
Cumulative adjusted

Dabigatran Dabigatran
incidence rate, %

0.4 0.4

0.2 0.2

0 0
0 60 120 180 240 300 0 60 120 180 240 300
Follow-up time, days Follow-up time, days

The INCREASED RATE OF ICH with Rivaroxaban

EXCEEDED ITS (NON SIGNIFICANTLY) DECREASED RATE
OF THROMBOEMBOLIC STROKE
Average follow-up duration <4 months; ICH, intracranial haemorrhage. Graham, et al. JAMA Intern Med 2016;
doi:10.1001/jamainternmed.2016.5954
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Safety in Nonvalvular Atrial Fibrillation

CONCLUSIONS: Dabigatran, rivaroxaban, and

apixaban appear to have similar effectiveness,
although apixaban may be associated with a
lower bleeding risk and rivaroxaban may be
associated with an elevated bleeding risk.

CHEST 2016; 150(6):1302-1312

Peter A. Noseworthy, MD, Xiaoxi Yao, PhD, Neena S. Abraham, MD, Lindsey R. Sangaralingham,
MPH, Robert D. McBane, MD, Nilay D. Shah, PhD.
 CONCLUSION

1. Aim of anticoagulation: Prevention of Ischemic and

Haemorrhagic stroke, with no compromise on safety1

2. Dabigatran gives Superior Protection both on Ischemic

Haemorrhagic stroke with no compromise on safety. Two available Dabigatran dose
RCT enable tailored treatment based on patient condition2
3. Independent analysis of MEDICARE data & HONGKONG AF Registry
shows the consistent benefit of Dabigatran vs Warfarin (FDA)3 and Dabigatran vs
Aspirin in Asian patient setting4
4. The new independent FDA analysis of MEDICARE data showed that
Dabigatran is associated with lower risk of ICH, major extracranial (including GI)
bleeding compared with Rivaroxaban5

1. Circulation. 2008; 118 : 2029-2037. 2. Connolly SJ et al. N Engl J Med 2014; 371:14645. 3. Graham DJ et al. Circulation
2015;131:15764; 4. Ho CW et al. Stroke 2015;46:23-30; 5. Graham, et al. JAMA Intern Med 2016;
doi:10.1001/jamainternmed.2016.5954
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