Stroke Prevention With NOACsV - Final

Stroke Prevention with the
Newer Agents:
What is the Evidence?
L.PH.GM.02.2015.0211
Michelle Marie Q.Pipo, MD, FPCP, FPCC
Roadmap
Introduction
New anti-coagulants
Dabigatran RELY
Apixaban AVERROES, ARISTOTLE
Rivaroxaban ROCKET-AF
Comparison of trials
Conclusions
L.PH.GM.02.2015.0211
Guidelines
Introduction
Stroke a major cause of death and disability
Effects of 1st stroke compounded by recurrence
Cardioembolic mechanism in 15-20% of strokes
largely atrial fibrillation
Warfarin traditionally used and preferred
Anti-platelets also used
L.PH.GM.02.2015.0211
Challenges with current treatments
Stroke prevention in AF: VKAs vs placebo or no

treatment Reduction of risk of thromboembolism in AF
Study, year
Relative risk reduction (95% CI)
AFASAK I, 1989; 1990

SPAF I, 1991
BAATAF, 1991
CAFA, 1991
SPINAF, 1992
EAFT, 1993
100%
50%
Favours VKA
Hart RG et al. Ann Intern Med 2007;146:857867
50%
Favours placebo
100%
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All trials (n=6)
Stroke prevention in AF: VKAs vs antiplatelet

therapy Reduction of risk of thromboembolism in AF
Study, year
Relative risk reduction (95% CI)
AFASAK I, 1989; 1990

AFASAK II, 1998
BAFTA study, 2007
Chinese ATAFS, 2006
EAFT, 1993
PATAF, 1999
SPAF II, 1994
Age 75 years
Age >75 years
ASA trials (n=9)
SIFA, 1997
ACTIVE-W, 2006
All antiplatelet trials (n=12)

100%
Hart RG et al. Ann Intern Med 2007;146:857867
50%
Favours VKA
50%
100%
Favours antiplatelet
L.PH.GM.02.2015.0211
NASPEAF, 2004
Stroke in patients with AF is common,

despite the availability of VKAs
Registry of Canadian Stroke

Network data
Patients (n=537) with AF and
a high stroke risk who were
admitted for stroke were
identified
Although over 70% of patients
were prescribed antithrombotic
therapy:
Only 40% received warfarin
Only 10% were within the
therapeutic range of warfarin
Gladstone D et al. Stroke 2009;40:235240
Pre-admission medications for patients

with known AF admitted with stroke
Dual antiplatelet therapy
No antithrombotic
therapy
Single
antiplatelet
therapy
Warfarin/
sub-therapeutic
Warfarin/
therapeutic
L.PH.GM.02.2015.0211
Pharmacological
class
Anticoagulants
Platelet inhibitors
Agents
VKAs: warfarin,
phenprocoumon,
acenocoumarol
Benefits and limitations

Effective but challenging to
use due to many limitations1,2
ASA
Only modestly effective

(significantly less so than
warfarin)2
Clopidogrel
Addition to ASA increases

efficacy but also bleeding risk3
1. Finsterer J and Stllberger C. Neth J Med 2008;66:327333; 2. Hart RG et al. Ann Intern Med 2007;146:857
867; 3. ACTIVE Investigators. N Engl J Med 2009;360:20662078
L.PH.GM.02.2015.0211
Conventional pharmacological options for

stroke prevention in AF
Oral administration
Convenient use both in and out of hospital
Wide therapeutic window
Broad safety margin at a wide range of

effective doses
Low risk of food and drug

interactions
Ease of use regardless of concomitant

medications and diet
Predictability
Safe and effective regulation of coagulation

from the first dose and throughout therapy
No monitoring
No need for routine laboratory monitoring: saves

healthcare costs through fewer hospital/physician
visits and has less impact on patients time
Fixed dose
Fixed doses for the majority of patients: no

need for dose adjustment
Fast onset and offset of action
No need for bridging with heparins in case of

interventions
L.PH.GM.02.2015.0211
Properties of an ideal anticoagulant
The promise of novel oral anticoagulants

Simplified dosing regimen, no dietary
restrictions, predictable
anticoagulation and no need for
routine coagulation monitoring.
Can be given at fixed doses
Reduced
administrative
costs
Improved
QoL
Improved
compliance
Improved
benefit-risk
profile
Ansell J et al. Chest 2004;126:204S33S; Mueck W et al. Int J Clin Pharmacol Ther 2007;45:335344;
Mueck W et al. Clin Pharmacokinet 2008;47:203216; Mueck W et al. Thromb Haemost 2008;100:453461;
Raghavan N et al. Drug Metab Dispos 2009;37:7481; Shantsila E and Lip GY. Curr Opin Investig Drugs 2008;9:10201033
L.PH.GM.02.2015.0211
Less labourintensive
Less impact on
patients daily
life
Reduced potential
for food and drug
interactions
Roadmap
Introduction
New anti-coagulants
Dabigatran RELY
Conclusions
L.PH.GM.02.2015.0211
Guidelines
Properties of an ideal oral anticoagulant
IDEAL
Warfarin
Rivaroxaban
Dabigatran
Apixaban
L.PH.GM.02.2015.0211
Once
daily
No
significant
No routine
Wide
food
Predictable coagulation Fixed therapeutic
interactions response
monitoring dosing
window
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Mode of Action
Parameter
Target
Oral bioavailability
Plasma protein binding
Dosing (for
SPAF indication)
Prodrug
Half-life (h)
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
Thrombin
Factor Xa
Factor Xa
Factor Xa
6.5%
80100%*
~66%
50%
3435%
9295%
87%
4059%
Fixed, twice daily
Fixed, once daily
Fixed, twice daily
Fixed, once daily
Yes
No
No
No
813
911
1214
59 (young)
1113 (elderly)
Tmax (h)
2-6#
24
13
12
Routine coagulation
monitoring
No
No
No
No
*1520 mg to be taken with food; #postoperative period
L.PH.GM.02.2015.0211
Comparison of the pharmacological

characteristics of newer oral anticoagulants
Eriksson BI et al. Annu Rev Med 2011;62:4157; Frost C et al. J Thromb Haemost 2007;5(Suppl 2):P-M-664; Kubitza D et al. Clin
Pharm Ther 2005;78:412421; Lopes RD et al. Am Heart J 2010;159:331339; Ogata K et al. J Clin Pharmacol 2010; 50:743753;
ROCKET AF Study Investigators. Am Heart J 2010;159:340347.e1; Ruff CT et al. Am Heart J 2010;160:
635641.e2; Stangier J et al. J Clin Pharmacol 2005;45:555563; Dabigatran SmPC; Eliquis SmPC; Pradaxa SmPC; Xarelto SmPC
Parameter
Renal clearance
Potential drug
interactions
Dabigatran
Rivaroxaban
Apixaban
Edoxaban
80%
33%; additional
33% cleared
after metabolic
degradation to
inactive drug
~25%
35%
Potent P-gp
inhibitors and
inducers#
Potent
inhibitors of
both CYP3A4
and P-gp,*
strong inducers
of CYP3A4
Potent
CYP3A4
inhibitors*
Potent
inhibitors of
both CYP3A4
and P-gp
*CYP, cytochrome P-450 isoenzymes; P-gp, P-glycoprotein. Strong inhibitors of both CYP3A4 and Pgp
include azole antifungals (e.g. ketoconazole, itraconazole, voriconazole, posaconazole) and protease
inhibitors, such as ritonavir
#
P-gp transporter inhibitors (amiodarone, verapamil, clarithromycin, quinidine and ketoconazole) and
inducers (rifampicin, St. John`s wort (Hypericum perforatum), carbamazepine, or phenytoin)
Eriksson BI et al. Annu Rev Med 2011;62:4157, Xarelto SmPC May 2012
L.PH.GM.02.2015.0211
Comparison of the pharmacological

characteristics of newer oral anticoagulants
New oral anticoagulants for stroke prevention

in AF: clinical trial overview
Oral anticoagulant
Phase II studies
Phase III studies
PETRO1
RE-LY2,3
RELY-ABLE4
Direct thrombin inhibitors

Dabigatran
Direct Factor Xa inhibitors
Rivaroxaban
ROCKET AF5
J-ROCKET AF6
Apixaban
Phase II safety (Japan)7
ARISTOTLE8
AVERROES9
AVERROES-LTOLE10
Edoxaban
Phase II dose-finding11
Phase II safety (Asia)12
ENGAGE AF-TIMI 4813
L.PH.GM.02.2015.0211
Studies in yellow are complete, the others are ongoing

1. Ezekowitz MD et al. Am J Cardiol 2007;100:14191426; 2. Connolly SJ et al. N Engl J Med 2009;361:11391151;
3. Connolly SJ et al. N Engl J Med 2010;363:18751876; 4. NCT00808067; 5. Patel MR et al. N Engl J Med 2011;365:883891;
6. Hori M et al. Presented at the Congress of the ISTH 2011; 7. Ogawa S et al. Circ J 2011;75:18521859; 8. Granger CB et al.
N Engl J Med 2011;365:981992; 9. Connolly SJ et al. N Engl J Med 2011;364:806817; 10. NCT00496769; 11. Weitz J et al.
Thromb Haemost 2010;104:633641; 12. Chung N et al. Thromb Haemost 2011;105:535544; 13. Ruff CT et al. Am Heart J
2010;160:635641
Targets for anticoagulants

VII
TF VIIa
VKA
VKA
Initiation
IX
Inactive Factor
Active Factor
Transformation
VKA
Xa
IXa
Direct Factor Xa inhibition
II
Rivaroxaban
Apixaban
Edoxaban
Betrixaban
Catalysis
Direct Factor IIa inhibition

Dabigatran
Clot formation
Fibrinogen
Prothrombin
IIa
Thrombin
Fibrin
Piccini JP et al. Curr Opin Cardiol 2010;25:312320; Spyropoulos AC et al. Expert Opin Investig Drugs 2007;16:431440
L.PH.GM.02.2015.0211
Propagation
The rationale for Factor Xa inhibition

Effective anticoagulation strategy
Factor Xa is the pivotal point for amplification in the
coagulation cascade
Each molecule of Factor Xa generates ~1,000 molecules of thrombin
Observed improvement of anticoagulant efficacy with higher

selectivity for Factor Xa
Inhibits thrombin generation

Shallower doseresponse curve of Factor Xa compared
with thrombin suggests wider therapeutic window
Turpie AGG. Arterioscler Thromb Vasc Biol 2007;27:12381247
L.PH.GM.02.2015.0211
Leaves existing thrombin to maintain primary haemostasis
Advantages of direct Factor Xa inhibition

Direct Factor Xa inhibitors:
Interact with the active site of the Factor Xa molecule
Require no cofactors for activity
Can inhibit free Factor Xa in plasma and Factor Xa within the
prothrombinase complex, as well as fibrin-bound Factor Xa
Kubitza D and Haas S. Expert Opin Investig Drugs 2006;15:843855; Samama MM. Thromb Res 2011;127:497504
L.PH.GM.02.2015.0211
May be able to penetrate the clot; AT-bound indirect inhibitors

(e.g. heparins) are unable to do so
Roadmap
Introduction
New anti-coagulants
Dabigatran RELY
Conclusions
L.PH.GM.02.2015.0211
Guidelines
RE-LY: dabigatran vs warfarin - Rationale

To evaluate the safety and efficacy of dabigatran in
comparison with warfarin in patients with non-valvular AF
L.PH.GM.02.2015.0211
The primary outcome was stroke (including hemorrhagic)

or systemic embolism
RE-LY: dabigatran vs warfarin
Dabigatran 110 mg bid

Open-label warfarin
(target INR range 23)
Primary efficacy: composite of all-cause stroke or

systemic embolism
Major safety: major bleeding
Excludes: patients with severe renal impairment
(CrCl 30 ml/min)
*Previous stroke or TIA , NYHA Class II HF, LVEF <40%, age 75 years, age 65 with either a
history of coronary artery disease, hypertension or diabetes mellitus
Connolly SJ et al. N Engl J Med 2009;361:11391151
L.PH.GM.02.2015.0211
N=18,113
Follow-up
Nonvalvular
AF plus
at least 1
additional
risk factor*
End of
treatment
Randomized, phase III, open label, non-inferiority study
RE-LY: primary efficacy endpoint

Stroke or systemic embolism1
0.04
Dabigatran 110 mg bid2

HR=0.90 (0.74, 1.10)
p<0.001 (non-inferiority)
p=0.30 (superiority)
0.03
Warfarin
Dabigatran 150 mg bid2

HR=0.65 (0.52, 0.81)
p<0.001 (superiority)
0.02
0.01
0.00
Number of subjects at risk1

Dabigatran 110 mg
6015
Dabigatran 150 mg 6076
Warfarin
6022
12
18
6
24
Months since randomization
5862
5939
5862
5710
5779
5718
1. Connolly SJ et al. N Engl J Med 2009;361:11391151;

2. Connolly SJ et al. N Engl J Med 2010;363:18751876
4593
4682
4593
2945
3044
2890
30
1385
1429
1322
L.PH.GM.02.2015.0211
Cumulative Hazard Rate
0.05
Dabigatran
110 mg bid
%/year
(n=6,015)
Dabigatran
150 mg bid
%/year
(n=6,076)
Stroke/systemic
embolism#
1.54
1.11
All-cause stroke#
1.44
Ischaemic or
unspecified
stroke#
1.34
Haemorrhagic
stroke#
0.12
1.01
0.92
0.10
Warfarin
%/year
(n=6,022)
Dabigatran
110 mg bid
vs warfarin
RR, p-value*
Dabigatran
150 mg bid
vs warfarin
RR, p-value*
1.71
0.90
0.65
(0.741.10)
p=0.30
(0.520.81)
p=<0.001
0.91
0.64
(0.741.12)
p=0.38
(0.510.81)
p<0.001
1.58
1.21
0.38
1.11
0.76
(0.881.39)
p=0.35
(0.590.97)
p=0.03
0.31
0.26
(0.170.56)
p<0.001
(0.140.49)
p<0.001
*P-values are for superiority

#
Post-hoc analysis including additional events that were not reported at the time of the original analysis
L.PH.GM.02.2015.0211
RE-LY: primary efficacy endpoint
Dabigatran
110 mg bid
%/year
(n=6,015)
Dabigatran
150 mg bid
%/year
(n=6,076)
Major bleeding
(principal safety
outcome)*
2.87
3.32
Major
gastrointestinal
bleeding*
1.15
Intracranial
haemorrhage*
0.23
1.56
0.32
Warfarin
%/year
(n=6,022)
Dabigatran
110 mg bid
vs warfarin
RR, p-value
Dabigatran
150 mg bid
vs warfarin
RR, p-value
3.57
0.80
0.93
(0.700.93)
p=0.003
(0.811.07)
p=0.32
1.08
1.48
(0.851.38)
p=0.52
(1.181.85)
p<0.001
0.30
0.41
(0.190.45)
p<0.001
(0.280.60)
p<0.001
1.07
0.76
*Post-hoc analysis including additional events that were not reported at the time of the original analysis
L.PH.GM.02.2015.0211
RE-LY: safety outcomes
RE-LY: conclusions
Among patients with AF:
Dabigatran 110 mg bid was associated with:
Stroke/systemic embolism rate similar to warfarin

A lower rate of major bleeding
Dabigatran 150 mg bid was associated with:
A lower stroke/systemic embolism rate

versus warfarin
L.PH.GM.02.2015.0211
A similar rate of major bleeding
Roadmap
Introduction
New anti-coagulants
Dabigatran RELY
Conclusions
L.PH.GM.02.2015.0211
Guidelines
AVERROES: apixaban vs ASA - Rationale

To evaluate the efficacy and safety of Apixaban versus
ASA in patients with AF who were not able or willing to
take a VKA.
Eikelboom JW et al. Am Heart J 2010;159:348-353.e1
L.PH.GM.02.2015.0211
The primary outcome was stroke or systemic embolism
AVERROES: apixaban vs ASA

Randomized, phase III, double-blind, double dummy, superiority trial
Apixaban 5 mg bid (94%)

Apixaban 2.5 mg bid* (6%)
AND have been

shown to be or
are expected to
be unsuitable
for VKA therapy
Follow-up
N=5,599
End of
treatment
Non-valvular
AF plus
at least one
additional risk
factor for stroke
ASA 81324 mg od
*Patients with at least 2 of the following criteria: age 80 years, body weight 60 kg,
serum creatinine 1.5 mg/dl
L.PH.GM.02.2015.0211
Primary efficacy: composite of stroke (ischaemic or

haemorrhagic) or systemic embolism
Apixaban
ASA
n (%/y)
n (%/y)
51 (1.6%) 113 (3.7%)
HR
0.45
95% CI
0.320.62
p-value
<0.001
49 (1.6%) 105 (3.4%)
0.46
0.330.65
<0.001
Ischaemic stroke
35 (1.1%)
93 (3.0%)
0.37
0.250.55
<0.001
Haemorrhagic stroke
6 (0.2%)
9 (0.3%)
0.67
0.241.88
0.45
Unspecified
9 (0.3%)
4 (0.1%)
2.24
0.697.27
0.18
2 (0.1%)
13 (0.4%)
0.15
0.030.68
0.01
Primary efficacy:
stroke or systemic
embolism
Stroke
Systemic embolism
L.PH.GM.02.2015.0211
AVERROES: primary efficacy outcomes
Outcome
Apixaban
n (%/y)
ASA
n (%/y)
HR
95% CI
p-value
Major bleeding*
44 (1.4%)
39 (1.2%)
1.13
0.74 1.75
0.57
Intracranial
11 (0.4%)
13 (0.4%)
0.85
0.381.90
0.69
Subdural#
4 (0.1%)
2 (0.1%)
Other intracranial#,
1 (<0.1%)
2 (0.1%)
33 (1.1%)
27 (0.9%)
1.23
0.74 2.05
0.42
Gastrointestinal
12 (0.4%)
14 (0.4%)
0.86
0.40 1.86
0.71
Non-gastrointestinal
20 (0.6%)
13 (0.4%)
1.55
0.77 3.12
0.22
Fatal
4 (0.1%)
6 (0.2%)
0.67
0.19 2.37
0.53
Non-major clinically
relevant bleeding
96 (3.1%)
84 (2.7%)
1.15
0.861.54
0.35
Minor
188 (6.3%)
153 (5.0%)
1.24
1.001.53
0.05
Extracranial or
unclassfied
*Principal safety outcome in ITT population, defined as clinically overt bleeding accompanied by one or
more of the following: a decrease in the haemoglobin level of 2 g/dl over a 24-hour period, a transfusion
of 2 units of packed red cells, bleeding at a critical site or fatal bleeding. #HRs and p-values were not
calculated because there were so few events. Excluding haemorrhagic stroke and subdural bleeding
L.PH.GM.02.2015.0211
AVERROES: safety outcomes
AVERROES - conclusion
Among patients with AF for whom VKA therapy was
unsuitable, apixaban:
Reduced the risk of stroke or systemic embolism versus ASA
L.PH.GM.02.2015.0211
Did not increase the risk of major bleeding or

intracranial haemorrhage
AVERROES subgroup analysis secondary

prevention - Rationale
Diener H-C et al. Lancet Neurol 2012; 11: 22531
L.PH.GM.02.2015.0211
subgroup analysis from AVERROES to investigate

whether the subgroup of patients with previous stroke or
TIA would show a greater benefit from apixaban
compared with aspirin than would patients without
previous cerebrovascular events

prevention Results: efficacy endpoint
A
Aspirin
Apixaban
HR 0.51 (95% CI 0.35-0.74)
0.10
0.08
ratio
Cumulative hazard
0.12
No previous stroke or TIA
Previous stroke or TIA

HR 0.29 (95% CI 0.15-0.60)
0.06
0.04
0.02
0
Number at risk
Aspirin
Apixaban
2415
2417
2354
2379
6
9
12
Time (months)
2190
2200
1830
1840
1356
1335
15
18
925
938
554
548
374
390
360
378
6
9
12
Time (months)
331
345
281
284
186
186
15
18
126
117
73
67
Cumulative HR for the primary efficacy outcome according to

treatment group, in patients with and without history of stroke or TIA
L.PH.GM.02.2015.0211

prevention Results: safety endpoint
C
Aspirin
Apixaban
HR 1.08 (95% CI 0.64-1.80)
0.05
0.04
ratio
Cumulative hazard
0.06
No previous stroke or TIA
Previous stroke or TIA

HR 1.28 (95% CI 0.58-2.82)
0.03
0.02
0.01
0
Number at risk
Aspirin
Apixaban
2415
2417
2367
2381
6
9
12
Time (months)
2207
2221
1851
1838
1379
1336
15
18
940
935
567
550
374
390
369
377
6
9
12
Time (months)
341
344
288
281
191
184
15
18
130
116
74
69
Cumulative HR for the primary safety outcome (major bleeding) according

to treatment group, in patients with and without history of stroke or TIA
L.PH.GM.02.2015.0211

prevention - Conclusion
L.PH.GM.02.2015.0211
Apixaban was similarly effective whether or not patients

with AF have had a previous stroke or TIA.
Roadmap
Introduction
New anti-coagulants
Dabigatran RELY
Conclusions
L.PH.GM.02.2015.0211
Guidelines
ARISTOTLE: apixaban vs warfarin Rationale

To evaluate the safety and efficacy of apixaban compared
to warfarin in patients with AF
Lopes RD et al Am Heart J 2010; 159 (3): 331339
L.PH.GM.02.2015.0211
The primary outcome was stroke and systemic embolism
ARISTOTLE: apixaban vs warfarin

Randomized, phase III, double-blind, non-inferiority, event-driven trial
AF or atrial flutter
Apixaban 2.5 mg bid*

Warfarin target INR range 23
*Lower dose for patient with any two of the following:

Age 80 years
Body weight 60 kg
Serum creatinine 1.5 mg/dl (133 mol/l)
Granger CB et al. N Engl J Med 2011;365:981992
L.PH.GM.02.2015.0211
N=18,201
Follow-up
Apixaban 5 mg bid
End of
treatment
And at least
1 additional
risk factor:
Prior stroke/
TIA or SE
Age 75 years
Symptomatic HF
or LVEF 40%
Diabetes mellitus
Hypertension
ARISTOTLE: primary efficacy endpoint

Stroke or systemic embolism
Warfarin
HR=0.79 (0.66, 0.95)

Apixaban
2
Number of subjects at risk

Apixaban
9120
Warfarin
9081
12
18
24
Months since randomization
8726
8620
8440
8301
6051
5972
3464
3405
30
1754
1768
ITT-population
39
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Cumulative event rate (%)
Apixaban
n (%/year)
212 (1.27)
Warfarin
n (%/year)
265 (1.60)
HR
0.79
95% CI
0.660.95
p-value
<0.001 (noninferiority)
0.01 (sup)
199 (1.19)
250 (1.51)
0.79
0.65 0.95
0.01
Ischaemic stroke
(including uncertain
type of stroke)
162 (0.97)
175 (1.05)
0.92
0.741.13
0.42
Haemorrhagic
stroke
40 (0.24)
78 (0.47)
0.51
0.350.75
<0.001
Systemic embolism
15 (0.09)
17 (0.10)
0.87
0.44 1.75
0.70
Primary efficacy:
composite of stroke
and systemic
embolism
Stroke
ITT population
L.PH.GM.02.2015.0211
ARISTOTLE: primary efficacy outcomes
ARISTOTLE: bleeding outcomes

Apixaban
n (%/year)
Warfarin
n (%/year)
HR
95% CI
p-value
Major bleeding
327 (2.13)
462 (3.09)
0.69
0.600.80
<0.001
Intracranial
haemorrhage
52 (0.33)
122 (0.80)
0.42
0.300.58
<0.001
Other location
275 (1.79)
349 (2.27)
0.79
0.68-0.93
0.004
Gastrointestinal
105 (0.76)
119 (0.86)
0.89
0.70-1.15
0.37
613 (4.07)
877 (6.01)
0.68
0.61 0.75
<0.001
2,356 (18.1)
3,060 (25.8)
0.71
0.680.75
<0.001
Major or nonmajor clinically

relevant bleeding
Any bleeding
Safety population. Major bleeding is defined as clinically overt bleeding accompanied by 1 of the
following: a fall in haemoglobin of 2 g/dl; a transfusion of 2 units of packed red blood cells; and/or
bleeding that is fatal or occurs in at least one critical site
L.PH.GM.02.2015.0211
Other bleeding outcomes
ARISTOTLE: study conclusions

In patients with AF, compared with warfarin, apixaban:
Was superior in preventing stroke or systemic embolism
Caused less bleeding
L.PH.GM.02.2015.0211
Resulted in lower mortality compared with warfarin
Roadmap
Introduction
New anti-coagulants
Dabigatran RELY
Conclusions
L.PH.GM.02.2015.0211
Guidelines
Comprehensive Late-stage Development

Programme
Acute
Indications
Chronic
Indications
Study
Facts
Indication
Status
12,729 patients vs.

standard therapy
VTE prevention after orthopedic surgery
(enoxaparin)
Launched in
>85 countries
8,101 patients vs.

standard therapy
(enoxaparin)
VTE prevention in medically ill patients
Completed
4,832 patients vs.

standard therapy
(enoxaparin &
warfarin)
VTE treatment and secondary prevention
Completed
14,264 patients vs.

standard therapy
Stroke prevention in atrial fibrillation
(warfarin)
15,526 patients in
addition to
Secondary prevention ACS
standard therapy
Completed
Completed
L.PH.GM.02.2015.0211
Area
ROCKET AF - Rationale
To evaluate the efficacy and safety of rivaroxaban
compared with warfarin in a moderate to high-risk set of
patients with non-valvular AF
L.PH.GM.02.2015.0211
The primary endpoint was stroke and systemic embolism
*After 10% enrolment with 2 risk factors, subsequent patients required > 3 risk factors or prior
stroke/TIA or non-CNS SE
#Duration of therapy varies for each patient as this study is event driven. The trial was expected
to last about 42 months
Patel et al, 2010
L.PH.GM.02.2015.0211
ROCKET AF: Study Design
L.PH.GM.02.2015.0211
ROCKET AF: Recruitment
Rationale for the rivaroxaban dose

in ROCKET AF
20 mg od was chosen as the rivaroxaban dose for the phase III

ROCKET AF trial based on the phase II dose-finding programme for
DVT treatment
EINSTEIN DVT1 and ODIXa DVT2 both demonstrated that:

Efficacy of rivaroxaban did not increase with increasing total daily dose
(20, 40, 60 mg in ODIXa DVT; 20, 30, 40 mg in EINSTEIN DVT)
Major bleeding was similar irrespective of total daily dose and
comparable to the standard of care
Early clinical pharmacology studies showed that rivaroxaban inhibited
thrombin generation (and thereby continued to prevent coagulation)
beyond 24 hours after administration3
Supports once-daily dosing
1. Agnelli G et al. Circulation 2007;116:180187; 2. Bller HR et al. Blood 2008;112:22422247; 3. Harder S et al. ICT 2004
L.PH.GM.02.2015.0211
Supports 20 mg total daily dose (as lowest effective dose evaluated)
ROCKET AF: patient flow

Rivaroxaban
Randomized
(n=14,264)
7,131
Warfarin
7,133
50
43
7,081
ITT population:
all patients randomized (n=14,171)
7,090
20
8
all ITT patients who received 1 dose of
study drug (n=14,143)
7,082
103
78
6,958
Per-protocol population:
all ITT patients without major predefined
protocol violations (n=13,962)
Patel MR et al. N Engl J Med 2011;365:883891
7,004
L.PH.GM.02.2015.0211
7,061
Safety population:
ITT population
Patel et al, 2010
L.PH.GM.02.2015.0211
ROCKET AF: Baseline Demographics
Moderate to high risk patient enrolled in the

ROCKET AF: Median CHADS2 is 3.48
Rivaroxaban
(N=7,131)
Warfarin
(N=7,133)
3.48 0.94
3.46 0.95
2, n (%)
925 (13.0)
934 (13.1)
3, n (%)
3,058 (42.9)
3,158 (44.3)
4, n (%)
2,092 (29.3)
1,999 (28.0)
5, n (%)
932 (13.1)
881 (12.4)
6, n (%)
123 (1.7)
159 (2.2)
Previous stroke/TIA or SE
3,916 (54.9)
3,895 (54.6)
Congestive heart failure
4,467 (62.6)
4,441 (62.3)
Hypertension
6,436 (90.3)
6,474 (90.8)
Diabetes mellitus
2,878 (40.4)
2,817 (39.5)
Previous MI
1,182 (16.6)
1,286 (18.0)
Peripheral vascular disease
401 (5.6)
438 (6.1)
Chronic obstructive pulmonary disease
754 (10.6)
743 (10.4)
67 (52, 88)
67 (52, 86)
Characteristic
CHADS2 score, mean SD
CrCl, median (25th, 75th), ml/min
ITT population
L.PH.GM.02.2015.0211
Co-existing conditions, n (%)
ITT population
L.PH.GM.02.2015.0211
ROCKET AF: Baseline Demographics
Patel et al, 2010
ROCKET AF: primary efficacy endpoint- PPP

Warfarin
5
4
3
Rivaroxaban
HR 0.79 (0.66, 0.96)
1
0
0

Rivaroxaban
6,958
Warfarin
7,004
120
240
480
600
360
Days since randomization
720
840
6,211
6,327
5,786
5,911
2,472
2,539
1,496
1,538
5,468
5,542
4,406
4,461
3,407
3,478
PPP=Per-protocol population as treated = all ITT patients without major predefined protocol violations
L.PH.GM.02.2015.0211
ROCKET AF: primary efficacy endpoint - ITT

Warfarin
HR=0.88 (0.75, 1.03)
Rivaroxaban
3
2
1
0

Rivaroxaban
7,081
Warfarin
7,090
120
240
360
480
600
Days since randomization
720
840
6,879
6,871
6,683
6,656
2,951
2,944
1,785
1,783
6,470
6,440
5,264
5,225
4,105
4,087
ITT population=intention to treat population=all patients randomized

L.PH.GM.02.2015.0211
ROCKET AF: primary efficacy endpoint

p-value
Rivaroxaban
(% per year)
Warfarin
(% per year)
Non-inf.
Per-protocol,
on treatment
1.7
2.2
<0.001
Safety,
on treatment
1.7
2.2
ITT
2.1
2.4
On
treatment
1.7
2.2
0.02
Off
treatment
4.7
4.3
0.58
0.02
<0.001
0.12
0.5
Favours
rivaroxaban
2
Favours
warfarin
L.PH.GM.02.2015.0211
Sup.
HR and
95% CIs
ROCKET AF: primary efficacy endpoint components

Rivaroxaban
Endpoints
Primary efficacy endpoint
n
n
(% per year) (% per year)
HR
(95% CI)
189 (1.7)
243 (2.2)
0.79 (0.65, 0.95)*
184 (1.7)
221 (2.0)
0.85 (0.70,1.03)
Haemorrhagic stroke
29 (0.3)
50 (0.4)
0.59 (0.37,0.93)*
Ischaemic stroke
149 (1.3)
161 (1.4)
0.94 (0.75,1.17)
Unknown stroke type
7 (0.1)
11 (0.1)
0.65 (0.25,1.67)
Non-CNS systemic embolism
5 (0.04)
22 (0.2)
0.23 (0.09, 0.61)*
All-cause stroke
Safety population on-treatment analysis

*Statistically significant
HR and
95% CIs
0.2
0.5
Favours
rivaroxaban
2
Favours
warfarin
L.PH.GM.02.2015.0211
(N=7,061)
Warfarin
(N=7,082)
ROCKET AF primary efficacy endpoint

subgroup analysis# - ITT
Rivaroxaban
n/N
(%)
n/N
269/7,081
3.8
306/7,090
Hazard ratio
and 95% CIs
(%) p-value*
4.3
Sex
Male
Female
0.93
143/4,279
126/2,802
3.3
4.5
164/4,287
142/2,803
3.8
5.1
Age (years)
<75
75
144/3,999
125/3,082
3.6
4.1
152/4,008
154/3,082
3.8
5.0
Weight (kg)
70
7090
>90
93/2,013
126/3,031
50/2,035
4.6
4.2
2.5
109/2,012
151/3,135
46/1,942
5.4
4.8
2.4
CrCl (ml/min)
<50
5080
>80
77/1,490
126/3,298
65/2,285
5.2
3.8
2.8
86/1,459
151/3,400
68/2,222
5.9
4.4
3.1
0.31
0.71
0.90
ITT population
*p-value for interaction
#
0.1 0.2
0.5
Favours
rivaroxaban
Favours
warfarin
10
L.PH.GM.02.2015.0211
Overall
Warfarin
ROCKET AF Primary Efficacy Endpoint Center-Based

INR Control*
cTTR, centre-based time in therapeutic range

Based on Rosendaal method with all INR values included
*p-value for interaction = 0.74
Safety population (N=7061 [rivaroxaban], N=7082 [warfarin])
Patel et al, 2010
2
1
0.5
Favors rivaroxaban Favors warfarin
L.PH.GM.02.2015.0211
Better INR control
Hazard ratio and 95% CIs
Safety population on-treatment analysis

*Statistically significant
Patel et al, 2010
L.PH.GM.02.2015.0211
ROCKET AF Secondary Endpoints
ROCKET AF: bleeding analysis

Warfarin
(N=7,125)
n (% per year)
n (% per year)
HR
(95% CI)
1,475 (14.9)
1,449 (14.5)
1.03 (0.96,1.11)
395 (3.6)
386 (3.4)
1.04 (0.90,1.20)
Haemoglobin drop
(2 g/dl)
305 (2.8)
254 (2.3)
1.22 (1.03,1.44)*
Transfusion
183 (1.6)
149 (1.3)
1.25 (1.01,1.55)*
Critical organ bleeding
91 (0.8)
133 (1.2)
0.69 (0.53,0.91)*
Intracranial
haemorrhage
55 (0.5)
84 (0.7)
0.67 (0.47,0.93)*
Fatal bleeding
27 (0.2)
55 (0.5)
0.50 (0.31,0.79)*
1,185 (11.8)
1,151 (11.4)
1.04 (0.96,1.13)
Parameter
Principal safety endpoint
Major bleeding
Non-major clinically
relevant bleeding
Major bleeding from gastrointestinal site (upper, lower and rectal):

rivaroxaban = 224 events (3.2%); warfarin = 154 events (2.2%); p<0.001*
Safety population on-treatment analysis. *Statistically significant
HR and
95% CIs
0.2
0.5 1
2
5
Favours
Favours
rivaroxaban
warfarin
L.PH.GM.02.2015.0211
Rivaroxaban
(N=7,111)
Adverse event, n (%)

Total patients with treatment-emergent adverse events #
Epistaxis*
Peripheral oedema
Dizziness
Nasopharyngitis
Cardiac failure
Bronchitis
Dyspnoea
Diarrhoea
Cough
Back pain
Upper respiratory tract infection
Headache
Arthralgia
Haematuria*
Urinary tract infection
ALT >3 ULN and bilirubin >2 ULN
either on same day or within following 30 days
Rivaroxaban
(N=7,111)
5,791 (81.4)
721 (10.1)
435 (6.1)
433 (6.1)
421 (5.9)
397 (5.6)
396 (5.6)
380 (5.3)
379 (5.3)
343 (4.8)
338 (4.8)
336 (4.7)
324 (4.6)
301 (4.2)
296 (4.2)
293 (4.1)
33 (0.5)
Warfarin
(N=7,125)
5,810 (81.5)
609 (8.6)
444 (6.2)
449 (6.3)
455 (6.4)
420 (5.9)
417 (5.9)
394 (5.5)
397 (5.6)
353 (5.0)
347 (4.9)
325 (4.6)
363 (5.1)
331 (4.7)
242 (3.4)
321 (4.5)
35 (0.5)
Safety population; *p<0.05. 15 most frequent based on rivaroxaban treatment arm

#
Events that started on or after the first dose and up to 2 days after the last dose of study medication
Patel MR et al. N Engl J Med 2011;365:883891;
1.
2. Xarelto Product monograph: http://www.bayer.ca/files/XARELTO-PM-ENG-18JUL2012-154961.pdf?#
L.PH.GM.02.2015.0211
ROCKET AF: most frequent treatmentemergent adverse events1,2
ROCKET AF: conclusions
Based on the prespecified primary efficacy outcome:

A once-daily fixed-dose regimen of rivaroxaban was non-inferior to warfarin for prevention
of stroke or non-CNS systemic embolism
Rivaroxaban was superior to warfarin while patients were taking study drug
Safety:
Similar overall incidence of bleeding and adverse events
Increase in gastrointestinal bleeds but fewer intracranial haemorrhages and less fatal
bleeding with rivaroxaban
Associated with numerically lower rate of MI vs Warfarin
Implication:
Rivaroxaban, administered once daily, has demonstrated non-inferiority to warfarin in the
prevention of stroke or systemic embolism, with similar overall bleeding and fewer
intracranial haemorrhages and fatal bleeds
L.PH.GM.02.2015.0211
L.PH.GM.02.2015.0211
ROCKET AF: Subanalysis of patients

with previous stroke or transient
ischaemic attack (TIA)
ROCKET AF subanalysis: secondary

prevention - Rationale
The aim of this prespecified subanalysis was to investigate whether the

efficacy and safety of rivaroxaban compared with warfarin is consistent
among the subgroups of patients with and without previous stroke or TIA and
the entire ROCKET AF study population
Because treatment effects might differ between patients with prior stroke/TIA
patients because there may be a higher risk of recurrence of stroke and
higher risk of bleeding events
Cohorts:
History of stroke/TIA (stroke cohort) versus
7468 (52%) patients had a previous stroke (n=4907; 65%) or TIA (n=2561;
34%)
Hankey G et al. Lancet Neurol 2012; 11: 31522
L.PH.GM.02.2015.0211
No history of stroke/TIA (non-stroke cohort)
ROCKET AF subanalysis: secondary prevention Results: Primary efficacy endpoint

(ITT)
7
Prior stroke/TIA,
warfarin
Prior stroke/TIA,
rivaroxaban
No prior stroke/TIA,
warfarin
No prior stroke/TIA,
rivaroxaban
3
2
1
0
0
Intention-to-treat population
12
18
24
Months from randomisation
30
L.PH.GM.02.2015.0211
Cumulative event rate stroke or

systemic embolism (%)
KaplanMeier survival curve showing time to the primary outcome (stroke or systemic embolism)

prevention - Results
Compared to patients without prior stroke/TIA
patients with a prior stroke/TIA had
Fewer concomitant risk factors but higher CHADS2
scores (4 vs 3)
Higher rates of stroke and systemic embolism
L.PH.GM.02.2015.0211
Lower rates of major and non-major clinically relevant

bleeding events

prevention - Conclusion
Efficacy and safety results in patients with prior stroke/TIA were
consistent
With patients without prior stroke/TIA and
With the entire ROCKET AF study population
Overall bleeding rates were similar

in both treatment arms and
in patients with and without prior stroke/TIA
These results support the use of rivaroxaban as an alternative

to warfarin for both primary and secondary stroke prevention in
AF
L.PH.GM.02.2015.0211
Fatal bleedings as well as ICH were less frequent in the

rivaroxaban arm, but this difference did not reach statistical
significance
Roadmap
Introduction
New anti-coagulants
Dabigatran RELY
Conclusions
L.PH.GM.02.2015.0211
Guidelines
Recent VKA-Controlled Phase III SPAF Trials

ROCKET AF
ARISTOTLE
ENGAGE-AF
NEJM Aug 09
NEJM Nov 10a
NEJM Aug 11
NEJM Aug 11
Nov 13
Patient number
18,113
14,264
18,201
21,105
Median follow
up
2.0 years
1.9 years
1.8 years
2.8 years
Study arms
1:1:1
Dabigatran 150 mg
BD:
Dabigatran 110 mg
BD:
Warfarin
1:1
Rivaroxaban 20 mg
OD:
Warfarin
1:1
Apixaban 5 mg BD:
Warfarin
1:1:1
Edoxaban 60 mg OD:
Edoxaban 30 mg OD:
Warfarin
Trial design
Prospective
Randomized Openlabel Blinded
Endpoint
Double-blind
double-dummy
Double-blind
double-dummy
Double-blind
double-dummy
Publication
a Newly identified events in the RE-LY trial. N Engl J Med. 2010;363:1875-6.

b Count all outcome events - including events that occurred after permanent discontinuation of
study drug - till common date when all studies sites were notified of end-of-study.
c Only count outcome events that occurred before permanent discontinuation of study drug
L.PH.GM.02.2015.0211
RE-LY
Phase III SPAF Trials Baseline Characteristics

RE-LY
ROCKET AF
ARISTOTLE
ENGAGE AF
Da150
Da110
Warf
Riva
Warf
Apix
Warf
Edo60
Edo30
Warf
Number
6015
6076
6022
7131
7133
9120
9081
7035
7034
7036
Female, %
36.8
35.7
36.7
39.7
39.7
35.5
35.0
37.9
38.8
37.5
13.0
13.0
16.0
16.1
16.0*
16.0
16.0
Asian-Pacific, %
15.4 for whole studya

50.2
50.1
48.6
62.3
62.5
57.1
57.2
58.8
59.2
58.8
Median age,
year
71.5b
71.4b
71.6b
73
73
70
70
72
72
72
22.4
23.2
15.0
15.2
19.6c
19.0c
19.3c
CrCl<50ml/min,
%
19.4 for whole study
Heart failured, %
31.8
32.3
31.9
62.6
62.3
35.5
35.4
58.2
56.6
57.5
Hypertension, %
78.9
78.8
78.9
90.3
90.8
87.3
87.6
93.7
93.5
93.6
Diabetes, %
23.1
23.4
23.4
40.4
39.5
25.0
24.9
36.4
36.2
35.8
Prior stroke or
TIAe, %
20.3
19.9
19.8
54.9
54.6
19.2
19.7
28.1
28.5
28.3
Prior MI, %
16.9
16.8
16.1
16.6
18.0
14.5
13.9
CHADS2 mean
2.2
2.1
2.1
3.5
3.5
2.1
2.1
2.8
2.8
2.8
L.PH.GM.02.2015.0211
VKA use, %
a East and South Asians; b Mean in RE-LY; c 50 ml/min for ENGAGE AF; d Ejection fraction 35% in ROCKET AF; 40% for RE-LY and ARISTOTLE; e Includes
ROCKET AF1
RE-LY2
ARISTOTLE3,6
AVERROES4
ENGAGE AFTIMI 485
14,264
18,113
18,201
5,599
20,500
Non-inferiority
Non-inferiority
Non-inferiority
Superiority
Non-inferiority
Study drug
Double-blind
rivaroxaban
Two doses of
double-blind
dabigatran
Double-blind
apixaban
Double-blind
apixaban
Two doses of
double-blind
edoxaban
Control
Double-blind
warfarin
(INR 23)
Open-label
warfarin
(INR 23)
Double-blind
warfarin
(INR 23)
Double-blind
ASA
Double-blind
warfarin
(INR 23)
AF type of pts
included
Non-valvular
Non-valvular
All except
mechanical
valves
Non-valvular
Non-valvular
No. of patients
Statistical
objective
No. study arms
1. Patel MR et al, 2011; 2. Connolly SJ et al, 2009; 3. Lopes RD et al, 2010;

4. Connolly SJ et al, 2011; 5. Ruff CT et al, 2010; 6.Granger CB et al, 2011.
L.PH.GM.02.2015.0211
Study design and inclusion
Dosing and dose evaluation for

special populations
RE-LY
ARISTOTLE3,6
& AVERROES4
ENGAGE AF-TIMI 485
Rivaroxaban
Dabigatran
Apixaban
Edoxaban
20 mg od (15 mg od)
110 mg bid
or
150 mg bid
5 mg bid (2.5 mg bid)
30 mg od (15 mg od)
or
60 mg od (30 mg od)
(randomized to two
separate arms)
Dose adjustment for
patients with:
Moderate renal
impairment CrCl 30-49
ml/min
No dose adjustment
(randomized to two
separate arms)
Dose adjustment for
patients fulfilling 2 of
the following criteria
at baseline:
Dose adjustment for

patients fulfilling 1 of
the following criteria at
baseline:
Age 80 years
Concomitant verapamil
or quinidine
Body weight 60 kg
Serum creatinine
1.5 mg/dl (133 mol/l)
1. Patel MR et al, 2011; 2. Connolly SJ et al, 2009; 3. Lopes RD et al, 2010;

4. Connolly SJ et al, 2011; 5. Ruff CT et al, 2010.
Body weight 60 kg
CrCl 30-50 ml/min
L.PH.GM.02.2015.0211
ROCKET AF
Patient Characteristics Across Trials
*
#
Notably higher rates of diabetes, CHF, and prior stroke in

ROCKET population
L.PH.GM.02.2015.0211
*CHF or LVEF 40%;

#CHF or LVEF 35%
Connolly N Engl J Med 2009;361:1139; Patel N Engl J Med 2011365:883;Granger N Engl J Med 2011;365:981; Ruff Am Heart J 2010;160:635
CHADS2 Distribution Across Trials
Dabigatran and apixaban: evaluated across a spectrum of stroke risk

categories
Rivaroxaban: evaluated in patients at high risk of stroke
Connolly N Engl J Med 2009;361:1139; Patel N Engl J Med 2011365:883; Granger N Engl J Med 2011;365:981; Ruff
L.PH.GM.02.2015.0211
CHADS2 Score
NOAC SPAF Trials: Can They Be Compared?

Cross trial comparisons are
hazardous
These trials involve
different drug class
different trial methods
Best method to compare is headto-head, randomized trials in

large populations
L.PH.GM.02.2015.0211
different patient risks
Roadmap
Introduction
New anti-coagulants
Dabigatran RELY
Conclusions
L.PH.GM.02.2015.0211
Guidelines
ESC 2012 guidelines: selection of patients

for OACs
Non-valvular atrial fibrillation
Yes
Valvular atrial fibrillation
< 65 years and lone AF including women
Stroke risk assessment using CHA2DS2-VASc

0
2
Oral anticoagulant
Assess bleeding risk (HAS-BLED score);

consider patient values/preferences
No antithrombotic therapy
Camm AJ et al. Eur Heart J 2012
New oral anticoagulant;

rivaroxaban, dabigatran
apixaban
Vitamin K antagonist
Slide line preferred; dotted line alternative
ESC 2012 guidelines: ASA/DAPT
Antiplatelet therapy for SPAF should be limited to patients who

refuse/cannot take VKAs/NOACs
Consider in patients who refuse OAC and at low bleeding risk
DAPT (ASA/clopidogrel) or
less effectively ASA
No evidence for the decrease in total or CV mortality with ASA (or

antiplatelet drugs) in SPAF
Antiplatelet therapy (including ASA monotherapy) carries a similar

risk of major bleeding and ICH as OAC, particularly in the elderly
Camm AJ et al. Eur Heart J 2012; DAPT=dual antiplatet therapy; ICH=intracranial haemorrhage
UK: NICE guidance 2012

Risk category
Low
Moderate
High
Aged <65 years with no

moderate or high risk
factors
Age 65 years with no

high risk factors
or
Age <75 years with
hypertension, diabetes
mellitus or vascular
disease
Previous ischaemic
stroke/TIA
or
Previous
thromboembolic event
or
Age 75 years with
hypertension, diabetes
mellitus or vascular
disease
or
Clinical evidence of
valve disease or heart
failure or impaired LVF
on echocardiography
ASA*
VKA** or
Rivaroxaban or
(Dabigatran) or
ASA*
VKA** or
Rivaroxaban# or
Dabigatran#
Scheme
NICE
Therapy
NICE dabigatran: http://guidance.nice.org.uk/TA249; rivaroxaban: http://www.nice.org.uk/nicemedia/live/13746/59294/59294.pdf; Accessed June 2012

*75-300 mg/d; **INR 2.5 [range 2-3]; #only indicated in non-valvular AF; 65 years and one of: diabetes, CAD, hypertension
Canadian Cardiovascular Society

2012 guidelines
Risk category
Low
Intermediate
High
CHADS2=0
CHADS2=1
CHADS22
No
antithrombotic
OR
ASA
(75325 mg/d)
OR
OAC
OAC
OAC
dabigatran,
rivaroxaban or
apixaban in
preference to warfarin
dabigatran,
rivaroxaban or
apixaban in
preference to warfarin
Scheme
Canadian
Cardiovascular
Society 2012
guidelines
Therapy
Skanes AC et al. Can J Cardiol 2012; 28: 125136
ESC 2012 guidelines: recommendations for

new OACS
All NOACs are recommended for SPAF in patients at risk of stroke (CHA2DS2VASc2) in preference over a VKA
Rivaroxaban 20 mg od
Apixaban
Rivaroxaban 15 mg od
with:
HAS-BLED 3
CrCl 30-49 mL/min
Dabigatran 110 mg bid in:

80 years
Concomitant use of
interacting drugs
HAS-BLED 3
CrCl 30-49 mL/min
No recommendation in
severe renal impairment
CrCl <30 mL/min
No recommendation for
cardioversion *
Peri-cardioversion
No specific
recommendations due to
regulatory approval
status
CrCl < 30 mL/min
No recommendation for
cardioversion*
CrCl < 30 mL/min
Camm AJ et al. Eur Heart J 2012; od=once daily; bid=twice daily*based on lack of published data
Roadmap
Introduction
New anti-coagulants
Dabigatran RELY
Guidelines
Conclusions
Conclusions
Stroke is a major cause of deaths and disability
Cardioembolism a major mechanism
Warfarin effective primary/secondary prevention, aspirin weak
NOACs have many benefits over warfarin
Non-inferior/superior to warfarin in efficacy, safety
Efficacious in primary and secondary prevention
Rivaroxaban convenient once-a-day dosing
ROCKET-AF - double-blind RCT, higher risk patients
Use supported by guidelines
THANK YOU
ESC 2012 guidelines: specific recommendations for

new OACs
Recommendations
Class*
Level#
IIa
IIa
None of the new OACs recommended in severe renal

impairment CrCl <30 mL/min
III
Annual assessments of renal function (by CrCl) for all patients

on a NOACs; more frequently for moderate renal impairment
II
Rivaroxaban 20 mg od is preferred
Rivaroxaban 15 mg od with:
HAS-BLED 3
Moderate renal impairment: CrCl 30-49 mL/min
Dabigatran 150 mg bid is preferred
Dabigatran 110 mg bid with:
Elderly patients 80 years
Concomitant use of interacting drugs such as verapamil
HAS-BLED 3
Moderate renal impairment: CrCl 30-49 mL/min
Camm AJ et al. Eur Heart J 2012 *Class of recommendation; #Level of evidence
ESC 2012 guidelines: CHA2DS2-VASc to

assess stroke risk
Recommendation to identify AF patients at truly low risk of
stroke:
CHA2DS2-VASc to assess stroke risk in AF (recommendation IA)
CHA2DS2-VASc=0: no antithrombotic recommended(e.g. age <65
years and lone AF; recommendation IA)
CHA2DS2-VASc=1: OAC based on risk assessment (except women
<65 year with lone AF; recommendation IA)
CHA2DS2-VASc2: NOAC in preference to VKA (recommendation
IA)
ESC 2012 guidelines: eligibility criteria for use of

antithrombotic therapy includes CHA2DS2-VASc
Recommendations
Class*
Level#
Antithrombotic therapy for all patients with AF, except in those at

low risk (lone AF, age <65 years or with contraindications)
Decision should be based on the absolute risks of

stroke/thromboembolism (using CHA2DS2-VASc) and bleeding
CHA2DS2VASc to assess stroke risk in non-valvular AF
No antithrombotic therapy for patients with a CHA 2DS2VASc= 0

(age <65 and lone AF)
No antithrombotic therapy for women <65 years with lone AF;

CHA2DS2VASc=1
IIa
Only consider dual antiplatelet therapy (ASA/clopidogrel) in those

refusing OAC and low bleeding risk; or, less effective ASA alone
IIa
Camm AJ et al. Eur Heart J 2012 *Class of recommendation; #Level of evidence
ESC 2012 guidelines: management of

bleeding with NOACs
Patient on a NOAC presenting
with bleeding
Check haemodynamic status, basic coagulation tests
to assess anticoagulation effect
Minor
Moderate
Very severe
Camm AJ et al. Eur Heart J 2012
Delay next dose or discontinue treatment
Symptomatic/supportive treatment
Mechanical compression
Fluid replacement
Blood transfusion
Oral charcoal if recently ingested
Consider rFVIIa or PCC

Charcoal filtration
Dabigatran only: haemodialysis
CHADS2 risk stratification for stroke

prevention in patients with AF
Congestive heart failure +1
Hypertension
+1
Age 75 years
+1
Risk category
Low
Diabetes mellitus
Prior Stroke or TIA
+1
Intermediate
+2
High
Score
1 or 2 points are assigned as shown for each of the risk

factors above
Stroke risk low, intermediate, high is determined by
the cumulative score
Gage BF et al. Circulation 2004;110:22872292; Fuster V et al. Circulation 2006;114:e257354;
You JJ et al. Chest 2012;141(2)Suppl:e531S575S
CHA2DS2-VASc scheme
Risk factor
Points
Congestive heart failure/left ventricular dysfunction*
+1
Hypertension
+1
Age 75 years
+2
Diabetes mellitus
+1
Previous stroke/TIA/thromboembolism
+2
Vascular disease (MI, aortic plaque, peripheral

artery disease)#
+1
Age 6574 years
+1
Sex category (female)
+1
Maximum score
*Left ventricular ejection fraction <40%; #Including prior revascularization, amputation due to
peripheral artery disease, or angiographic evidence of peripheral artery disease
Lip GY et al. Chest 2010;137:263272; Camm AJ et al. Eur Heart J 2010;31:23692429

Stroke Prevention With NOACsV - Final

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Stroke Prevention with the

Michelle Marie Q.Pipo, MD, FPCP, FPCC

Challenges with current treatments

Stroke prevention in AF: VKAs vs placebo or no

Relative risk reduction (95% CI)

AFASAK I, 1989; 1990

Hart RG et al. Ann Intern Med 2007;146:857867

All trials (n=6)

Stroke prevention in AF: VKAs vs antiplatelet

Relative risk reduction (95% CI)

AFASAK I, 1989; 1990

All antiplatelet trials (n=12)

Stroke in patients with AF is common,

Registry of Canadian Stroke

Gladstone D et al. Stroke 2009;40:235240

Pre-admission medications for patients

Benefits and limitations

Only modestly effective

Addition to ASA increases

Conventional pharmacological options for

Convenient use both in and out of hospital

Wide therapeutic window

Broad safety margin at a wide range of

Low risk of food and drug

Ease of use regardless of concomitant

Safe and effective regulation of coagulation

No need for routine laboratory monitoring: saves

Fixed doses for the majority of patients: no

Fast onset and offset of action

No need for bridging with heparins in case of

Properties of an ideal anticoagulant

The promise of novel oral anticoagulants

Properties of an ideal oral anticoagulant

Fixed, twice daily

Fixed, once daily

Fixed, twice daily

Fixed, once daily

*1520 mg to be taken with food; #postoperative period

Comparison of the pharmacological

Comparison of the pharmacological

New oral anticoagulants for stroke prevention

Phase III studies

Direct thrombin inhibitors

Phase II safety (Japan)7

ENGAGE AF-TIMI 4813

Studies in yellow are complete, the others are ongoing

Targets for anticoagulants

Direct Factor Xa inhibition

Direct Factor IIa inhibition

The rationale for Factor Xa inhibition

Observed improvement of anticoagulant efficacy with higher

Inhibits thrombin generation

Turpie AGG. Arterioscler Thromb Vasc Biol 2007;27:12381247

Leaves existing thrombin to maintain primary haemostasis

Advantages of direct Factor Xa inhibition

May be able to penetrate the clot; AT-bound indirect inhibitors

RE-LY: dabigatran vs warfarin - Rationale

The primary outcome was stroke (including hemorrhagic)

RE-LY: dabigatran vs warfarin

Dabigatran 110 mg bid

Primary efficacy: composite of all-cause stroke or

Randomized, phase III, open label, non-inferiority study

RE-LY: primary efficacy endpoint