.

,
;
. , MD, FESC, FAHA

- .

-

-

-

-



, ab,


AstraZeneca, Bayer, Sanofi, Pfizer,
Vianex, MSD, Unilever, Boehringer,
Novartis, Abbott, Galenica, Amgen,
Specifar, Menarini, Merck,
Pharmaswiss, Winmedica

Unstable Plaque
Bhatt D. N Engl J Med 2007;357:2078-2081
Role of Platelet Activation and Aggregation in Ischemic Syndromes
The formula of aspirin is C
9
H
8
O
4


Aspirin: a modern medicine with ancient roots
ASA, acetylsalicylic acid; FDA, Food and Drug Administration; MI, myocardial infarction.
~1500 B Salicylates used by the ancient Egyptians for pain relief
~400 BC Salicylates recognised as having antipyretic and analgesic properties
1897 Friedrich Hoffmann synthesised a stable form of ASA
1899 ASA marketed as Aspirin

1915 Aspirin available for analgesia without a prescription
1948 Aspirin found to prevent recurrent MI
1971 Sir John Vane discovered mechanism of action of aspirin

1988 FDA approved aspirin for preventing recurrent MI
2010 Aspirin approved in 54 countries for prevention of a first stroke or MI

Section 1 6
Aspirins mechanism of action
COX, cyclooxygenase.
Patrono C et al. N Engl J Med 2005;353:237383.
Section 2 7
Improvements in Primary Prevention
Physicians Health Study: 44% RRR in MI
HOT trial: 36% RRR in MI
PPP: 56% RRR in CV death
Metanalysis of 55.580 patients: 32% RRR
for 1
st
MI
Aspirin Evidence: Primary Prevention in Men
Physicians Health Study (PHS)
22,071 men randomized to aspirin (325mg every other day) followed for an
average of 5 years









Aspirin significantly reduces the risk of MI in men
End point Relative Risk (95% CI) P value
Myocardial infarction
Fatal 0.34 (0.15-0.75) 0.007
Nonfatal 0.59 (0.47-0.74) <0.00001
Total 0.56 (0.45-0.70) <0.00001

Stroke
Fatal 1.51 (0.54-4.28) 0.43
Nonfatal 1.20 (0.91-1.59) 0.20
Total 1.22 (0.93-1.60) 0.15

Physicians Health Study Research Group. NEJM
1989;321:129-35
CI=Confidence interval, MI=Myocardial infarction
Aspirin Evidence: Primary Prevention
BDT, 1988
Combined
PPP, 2001
HOT, 1998
TPT, 1998
PHS, 1989
RR of MI
in Men
1.0 2.0 5.0 0.5 0.2
RR = 0.68 (0.54-0.86)
P=0.001
1.0 2.0 5.0 0.5 0.2
RR = 1.13 (0.96-1.33)
P=0.15
HOT, 1998
Combined
WHS, 2005
PPP, 2001
1.0 2.0 5.0 0.5 0.2
Aspirin Better Placebo Better
RR = 0.99 (0.83-1.19)
P=0.95
1.0 2.0 5.0 0.5 0.2
Aspirin Better Placebo Better
RR = 0.81 (0.69-0.96)
P=0.01
RR of CVA
in Men
RR of MI
in Women
RR of CVA
in Women
Ridker P et al. NEJM 2005;352:1293-304
CVA=Cerebrovascular accident, MI=Myocardial
infarction, RR=Relative risk
Aspirin is recommended in a range of US
guidelines
Guidelines Recommendations
USPSTF, 2009
1
Aspirin therapy is recommended for prevention of first MI in men aged 4579 years
and for stroke prevention in women aged 5579 years
ACCF/AHA,
2009
2
These recommendations confirm the use of aspirin as primary prevention
ACCP, 2008
3
Aspirin 75100 mg/day is recommended in patients at moderate risk of a coronary
event
AHA (women),
2007
4

Aspirin 75325 mg/day is recommended in high-risk women unless contraindicated
AHA/ASA,
2007
5
Oral aspirin 325 mg is recommended within 2448 hours after the onset of a stroke
AHA, 2002
6
Aspirin 75160 mg/day is recommended for persons at higher risk (especially with
10-year risk of CHD of 10%)
ACCF, American College of Cardiology Foundation; ACCP, American College of Chest Physicians; AHA, American
Heart Association; ASA, American Stroke Association; CHD, coronary heart disease; MI, myocardial infarction.
1. USPSTF. Ann Intern Med 2009;150:396404; 2. Redberg RF, et al. Circulation 2009;120:1296336;
3. ACCP. Chest 2008;133:776S814S; 4. Mosca L, et al. Circulation 2007;115:14811501;
5. AHA/ASA. Stroke 2007;38:16551711; 6. AHA. Circulation 2002;106:388391.
Section 7 12
Aspirin is consistently recommended in
patients with diabetes
Guidelines Recommendations
ACC/ADA/AHA
2010
1
Consider aspirin therapy (75162 mg/day) for adults with diabetes and no previous
history of CVD, at increased CV risk (10-year risk >10%) with no risk for bleeding
Aspirin (75162 mg/day) might be used for those with diabetes at intermediate CVD
ADA, 2010
2
Consider aspirin therapy (75162 mg/day) as a primary prevention strategy in those
with type 1 or type 2 diabetes at increased CV risk (10-year risk >10%)
Diabetes UK,
2009
3
Aspirin should be offered to patients with diabetes and a history of CV disease;
patients with no known CV history should consult their physician
NICE, 2008
4
Aspirin 75 mg should be offered to people with type 2 diabetes aged 50 years if
blood pressure is <145/90 mmHg or to people with type 2 diabetes aged 50 years
with other significant CV risk factors
ESC and
EASD, 2007
5
Aspirin should be given for the same indications and in similar dosages to diabetic
and non-diabetic patients for CV risk management
AHA/ADA,
2007
6

Aspirin 75162 mg/day is recommended in patients with diabetes at increased CV
risk, including those >40 years or with additional risk factors
IDF, 2005
7
Aspirin 75100 mg/day is recommended for people with evidence of CV disease or
at high risk (unless aspirin-intolerant or with uncontrolled blood pressure)
ADA, American Diabetes Association; AHA, American Heart Association; CV, cardiovascular; EASD, European Association for the Study of
Diabetes; ESC, European Society of Cardiology; IDF, International Diabetes Federation; NICE, National Institute for Clinical Excellence.
1. Join Statement ACC/ADA/AHA: http://content.onlinejacc.org/; 2. ADA. Diabetes Care 2010;33(suppl 1):S11S61;
3. Diabetes UK. https://www.diabetes.org.uk/; 4. NICE. http://www.nice.org.uk/; 5. ESC/EASD Task Force. Eur Heart J 2007;28:88136;
6. Bluse JB, et al. Diabetes Care 2007;30:16272; 7. IDF. www.idf.org/.
Section 7 13
USPSTF recommendations for aspirin
USPSTF
1
advocates an individualised patient- and sex-based
approach to treatment
Men aged 4579 years to use aspirin when the potential benefit of
a reduction in MI outweighs the potential harm of an increase in GI
haemorrhage
Women aged 5579 years to use aspirin when the potential benefit of
a reduction in ischaemic strokes outweighs the potential harm of an
increase in GI haemorrhage
Aspirin recommended in patients aged 80 years who are without
additional risk factors for GI bleeding/able to tolerate a GI bleeding
episode
The ACCF/AHA (2009) also acknowledges the USPSTF
algorithm
2
ACCF, American College of Cardiology Foundation; AHA, American Heart Association; GI, gastrointestinal; MI, myocardial
infarction; USPSTF, US Preventive Services Task Force.
1. USPSTF. Ann Intern Med 2009;150:396404;
2. Redberg RF, et al. Circulation 2009;120:12961336.
Section 6 14
The USPSTF (2009) guidelines recommend
aspirin in primary prevention
The USPSTF found good evidence
that aspirin decreases the incidence
of MI in men and ischaemic strokes
in women
1

Clinicians should inform patients
about GI bleeding because they
might be mitigated by a patients
early recognition of the signs and
symptoms
1

The incidence of MI and stroke is
high in persons 80 years or older,
and thus the potential benefit of
aspirin is large
1

CHD, coronary heart disease; CVD, cardiovascular disease; GI, gastrointestinal; MI, myocardial infarction;
USPSTF, US Preventive Services Task Force.
1. USPSTF. Ann Intern Med 2009;150:396404.
Section 7 16
The ADA (2010) reconfirm the role of aspirin
in diabetes
The ADA (2010) guidelines
1
recommend aspirin
75162 mg/day as primary prevention in those with type 1 or 2
diabetes at increased CV risk >10%
The guidelines
1
add that although two recent randomised
controlled trials (JPAD, POPADAD) failed to show significant
reductions in CV endpoints in diabetes, the ATTC (2009) meta-
analysis found that aspirin reduced the risk of vascular events by
12% in primary prevention these findings were based on six key
trials involving 95 000 patients with 4000 diabetic patients
ADA, American Diabetes Association; ATTC, Antithrombotic Trialists Collaboration; CV, cardiovascular; JPAD,
Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes; POPADAD, Prevention Of Progression
of Arterial Disease And Diabetes .
1. ADA. Diabetes Care 2010;33(suppl 1):S11S61.
Section 7 17
Benefit of low-dose ASA therapy increases with
increased risk for CHD events
3 (24) 3 (24) 3 (24)
Major gastrointestinal bleeding
events caused
1 (02) 1 (02) 1 (02) Haemorrhagic stroke caused
14 (620) 8 (412) 3 (14) CHD events avoided
5% 3% 1%
Estimated 5-year risk for CHD
events at baseline
Outcome
US Preventive Services Task Force. Ann Intern Med 2002;136:15760 CHD = coronary heart disease
Patrono, C. et al. Chest 2004;126:234S-264S
The absolute risk of vascular complications is the
major determinant of the absolute benefit of
antiplatelet prophylaxis
JPAD study: design
IHD, ischaemic heart disease; JPAD, Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes; PAD, peripheral artery disease.
1. Ogawa H, et al. JAMA 2008;300:213441.
JPAD trial (2008)
Design Multicentre, prospective, randomised, blinded, endpoint trial
Objective To examine the efficacy of aspirin for the primary prevention of
atherosclerotic events in patients with type 2 diabetes
Patients 2539 patients (mean age 65 years; 55% males) with type 2
diabetes without a history of atherosclerotic disease
Regimen 1262 patients randomised to receive aspirin 81100 mg/day and
1277 patients randomised to receive placebo
Primary endpoint Atherosclerotic events, including fatal or nonfatal IHD, fatal or
nonfatal stroke, and PAD
Mean follow-up 4.4 years
Section 4 20
ASA was not
effective in the
primary of CV
events in pts with
asymptomatic PAD
Antioxidants
showed no benefit
as well
BMJ 2008, 337: 1840
ASA was not effective
in the primary of CV
events in pts with
asymptomatic PAD
Antioxidants showed
no benefit as well
BMJ 2008, 337: 1840
Did they have PAD? (ABI < 0,99)
Asymptomatic diabetics, aged > 40
No benefit of aspirin in this population
among participants
without clinical CV
disease, identified
with a low ABI based
on screening a
general population,
the administration of
ASA did not reduce
vascular events
AAA trial
Aspirin for Asymptomatic Atherosclerosis
among participants
without clinical CV
disease, identified
with a low ABI based
on screening a
general population,
the administration of
ASA did not reduce
vascular events
AAA trial
Aspirin for Asymptomatic Atherosclerosis
most pts with borderline ABI
70% of participants women
the rate of events lower than expected
- limited power of the study
enteric coated acetylsalicylic acid
The benefits of aspirin in primary prevention
were shown in the recent ATTC meta-analysis
Meta-
analysis
Trials
(n)
Patients
(n)
Outcomes with aspirin
ATTC
(2009)
1
6 95 000 First events
12% reduction in serious vascular events (p=0.0001)
18% reduction in major coronary events
23% reduction on nonfatal MIs
14% reduction in ischaemic stroke
ATTC
(2009)
1
16 17 000 Recurrent events
20% reduction in major coronary events
31% reduction in nonfatal MIs
13% reduction in coronary mortality
22% reduction in ischaemic stroke
9% reduction in vascular death
19% reduction in serious vascular events*
ATTC, Antithrombotic Trialists Collaboration; MI, myocardial infarction.
1. ATTC. Lancet 2009;373:184960.
Section 4 25

0
5
10
15
0 30 60 90 180 270 360 450
HR 0.81
(0.73-0.90)
P=0.0004
Prasugrel
Clopidogrel
HR 0.80
P=0.0003
HR 0.77
P=0.0001
Days

P
r
i
m
a
r
y

E
n
d
p
o
i
n
t

(
%
)

12.1
(781)
9.9
(643)
Primary Endpoint
CV Death,MI,Stroke
NNT= 46
ITT= 13,608
LTFU = 14 (0.1%)
Diabetic Subgroup

0
2
4
6
8
10
12
14
16
18
0 30 60 90 180 270 360 450
HR 0.70
P<0.001
Days
E
n
d
p
o
i
n
t

(
%
)

CV Death / MI / Stroke
TIMI Major
NonCABG Bleeds
NNT = 46
N=3146
17.0
12.2
Prasugrel
Clopidogrel
Prasugrel
Clopidogrel
2.6
2.5
PLATO study design
Primary endpoint: CV death + MI + Stroke
Primary safety endpint: Total major bleeding
612-month exposure
Clopidogrel
If pre-treated, no additional loading dose;
if naive, standard 300 mg loading dose,
then 75 mg qd maintenance;
(additional 300 mg allowed pre PCI)
Ticagrelor
180 mg loading dose, then
90 mg bid maintenance;
(additional 90 mg pre-PCI)
NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)
Clopidogrel-treated or -naive;
randomised within 24 hours of index event
(N=18,624)
PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid;
CV = cardiovascular; TIA = transient ischaemic attack
8,688
8,763
0 10 20 30
8
6
4
2
0
C
u
m
u
l
a
t
i
v
e

i
n
c
i
d
e
n
c
e

(
%
)

Clopidogrel
Ticagrelor
4.77
5.43
HR 0.88 (95% CI 0.771.00), p=0.045
No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
8,875
8,942
8,763
8,827
Days after randomisation
31 90 150 210 270 330
8
6
4
2
0
Clopidogrel
Ticagrelor
5.28
6.60
8,688
8,673
8,286
8,397
6,379
6,480
Days after randomisation
*

HR 0.80 (95% CI 0.700.91), p<0.001
8,437
8,543
6,945
7,028
4,751
4,822
C
u
m
u
l
a
t
i
v
e

i
n
c
i
d
e
n
c
e

(
%
)

Primary efficacy endpoint over time
(composite of CV death, MI or stroke)
*Excludes patients with any primary event during the first 30 days
Prevalence of AF increases with
age
33 Data from Heeringa J et al. Eur Heart J 2006;27:94953
Women (n=4053)
Age (yrs)

P
r
e
v
a
l
e
n
c
e

(
%
)

0
5
10
15
20
5559 6064 6569 7074 7579 8084 >85
Men (n=2590)
Prevalence at baseline assessed in 6808 participants in a European population-based study


Frost L et al. Neuroepidemiology 2007;28:10915
22-year follow-up of 75 126 men in the Danish National Registry of Patients
()

1
0
0
0

()
45
40
35
30
25
20
15
10
5
0

: CHADS
2
National Registry of Atrial
Fibrillation (NRAF)



CHADS
2

Cardiac failure ( ) 1
Hypertension () 1
Age 75 yrs ( 75 ) 1
Diabetes mellitus ( ) 1
Stroke or TIA (
)
2
Gage BF et al. JAMA 2001;285:286470
TIA =
CHADS2

Gage BF, JAMA 285 (2001), pp. 28642870.
Real Life Observations of
Clinical Outcomes With Rhythm-
and Rate-Control Therapies for
Atrial Fibrillation in the
RECORDAF Registry
A. John Camm, Gnter Breithardt,
Harry Crijns, Paul Dorian, Peter Kowey,
Jean-Yves Le Heuzey, Ihsen Merioua,
Laurence Pedrazzini, Eric N. Prystowsky,
Peter J. Schwartz, Christian Torp-
Pedersen, William Weintraub
REgistry on Cardiac rhythm disORDers: an international, observational,
prospective survey assessing the control of Atrial Fibrillation
Antithrombotic Treatment at 1 year
According to CHADS2 Score
Total
N=4925
CHADS2 Score
Antithrombotic treatment (%)
0
N=920
1
N=1752
2
N=2253
Aspirin 42.9 43.2 43.0 42.8
Other antiplatelet agent 5.9 4.1 6.1 6.7
Vitamin K antagonist 52.1 39.4 49.7 59.2
None 10.7 21.5 12.0 5.1
J Am Coll Cardiol 2011;58:493-501
A

AFASAK 35 807
SPAF 65 1457
EAFT 130 838

*
230 3102

-

100 50 0 -50 -100
Aspirin Aspirin
(%)
* 3 21%
Warfarin
, 5
AFASAK 27 811
BAATAF 15 922
CAFA 14 478
SPAF 23 508
SPINAF 29 972
* 108 3691

-

100 50 0 -50 -100
Warfarin
Warfarin
, %
*
5
68%
Hart RG et al. Ann Intern Med 1999;131(7)192

- 36%
Hart RG et al. Ann Intern Med 1999;131(7)192


43 v2 December 2010
NARROW THERAPEUTIC RANGE WITH VKAs

INR = International normalized ratio; VKA = vitamin K antagonist.
Hylek EM, et al. N Eng J Med 2003;349:1019-1026.
<1.5 1.51.9 2.02.5 2.63.0 3.13.5 3.64.0 4.14.5 >4.5
0
20
40
60
80
E
v
e
n
t
s

/

1
0
0
0

p
a
t
i
e
n
t

y
e
a
r
s

Ischaemic stroke Intracranial hemorrhage
The anticoagulant effect
of VKAs is optimized
when therapeutic doses
are maintained within a
very narrow range
Target
INR
(2.03.0)
44 v2 December 2010
INR CONTROL: CLINICAL TRIALS VS.
CLINICAL PRACTICE (TTR)
INR = international normalized ratio ; TTR = time-in-therapeutic-range (INR 2.03.0).
1. Kalra L, et al. BMJ 2000;320:1236-1239; *Pooled data: up to 8371% in individualized trials.
2. Samsa GP, et al. Arch Intern Med 2000;160:967-973. 3. Matchar DB, et al. Am J Med 2002;113:42-51.
Clinical trial
1
Clinical practice
2,3
<2.0 2.03.0 >3.0
E
l
i
g
i
b
l
e

p
a
t
i
e
n
t
s

r
e
c
e
i
v
i
n
g

W
a
r
f
a
r
i
n

(
%
)

38%
44%
18%
66%
9%
25%
INR
The RE-LY Study:
Randomized Evaluation of Long-
term anticoagulant therapY

Dabigatran Compared to Warfarin in 18,113 Patients
with Atrial Fibrillation at Risk of Stroke


0.50 0.75 1.00 1.25 1.50
Dabigatran 110 vs. Warfarin
Dabigatran 150 vs. Warfarin
-
p-value
<0.001
<0.001

p-value
0.30
<0.001
Margin = 1.46
HR (95% CI)

D 110mg D 150mg warfarin
D 110 mg vs.
Warfarin
D 150 mg vs.
Warfarin
Number
rate/yr
Number
rate/yr
Number
rate/yr
RR
95% CI
p
RR
95% CI
p
I
152
1.29 %/yr
103
0.9 %/yr
133
1.1 %/yr
1.14
0.90-1.43
0.28
0.76
0.59-0.98
0.03

14
0.1 %/yr
12
0.1 %/yr
45
0.4 %/yr
0.31
0.17-0.56
<0.001
0.26
0.14-0.49
<0.001
I/


159
1.3 %/yr
111
0.9 %/yr
142
1.2 %/yr
1.11
0.89-1.40
0.32
0.76
0.60-0.98
0.03

Dabigatran
110mg
Dabigatran
150mg
warfarin
D 110mg vs.
Warfarin
D 150mg vs.
Warfarin






RR
95% CI
p
RR
95% CI
p

()
1.1 % 1.5 % 1.0 %
1.10
0.86-1.41
0.43
1.50
1.19-1.89
<0.001
0.2 % 0.3 % 0.7 %
0.31
0.20-0.47
<0.001
0.40
0.27-0.60
<0.001
M

( ,
-
)
1.5 % 1.5 % 1.8 %
0.85
0.70-1.04
0.11
0.87
0.71-1.06
0.16
Dabigatran 150 mg vs. 110 mg
Dabigatran
110mg
Dabigatran
150mg
D 150mg vs. D 110 mg

/

/
Relative Risk
95% CI
p


1.53 % 1.11 %
0.73
0.58-0.91
0.005
I/

1.34 % 0.92 %
0.69
0.54-0.88
0.002
0.12 % 0.10 %
0.85
0.39-1.83
0.67
M 2.67 % 3.11 %
1.17
1.01-1.36
0.05



1.12 % 1.51 %
1.36
1.09-1.70
0.007
7.09 % 6.91 %
0.98
0.89-1.08
0.66
Dabigatran
110 mg
%
Dabigatran
150 mg
%
Warfarin
%
* 11.8 11.3 5.8
9.3 9.5 9.7
8.1 8.3 9.4
7.9 7.9 7.8
6.6 6.6 6.2
5.7 5.7 6.0
5.2 6.2 5.9
A 4.5 5.5 5.7
5.3 5.2 5.6
5.6 5.4 5.6
6.3 6.5 5.7
5.5 5.9 5.8
4.5 4.8 5.6


4.8 4.7 5.2

* dabigatran p<0.001
Rivaroxaban Once-daily oral direct factor Xa inhibition
Compared with vitamin K antagonism for prevention of
stroke and Embolism Trial in Atrial Fibrillation
Primary Efficacy Outcome
Stroke and non-CNS Embolism
Event Rates are per 100 patient-years
Based on Protocol Compliant on Treatment Population
0
1
2
3
4
5
6
0 120 240 360 480 600 720 840 960
No. at risk:
Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634
Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655
Warfarin
HR (95% CI): 0.79 (0.66, 0.96)
P-value Non-Inferiority: <0.001
Days from Randomization
C
u
m
u
l
a
t
i
v
e

e
v
e
n
t

r
a
t
e

(
%
)

Rivaroxaban
Rivaroxaban Warfarin
Event
Rate
1.71 2.16
Rivaroxaban Warfarin
Event Rate Event Rate HR (95% CI) P-value
Vascular Death,
Stroke, Embolism
4.51 4.81 0.94 (0.84, 1.05) 0.265
Stroke Type
Hemorrhagic
Ischemic
Unknown Type

0.26
1.62
0.15

0.44
1.64
0.14

0.58 (0.38, 0.89)
0.99 (0.82, 1.20
1.05 (0.55, 2.01)

0.012
0.916
0.871
Non-CNS Embolism 0.16 0.21 0.74 (0.42, 1.32 0.308
Myocardial Infarction 1.02 1.11 0.91 (0.72, 1.16) 0.464
All Cause Mortality
Vascular
Non-vascular
Unknown Cause
4.52
2.91
1.15
0.46
4.91
3.11
1.22
0.57
0.92 (0.82, 1.03)
0.94 (0.81, 1.08)
0.94 (0.75, 1.18)
0.80 (0.57, 1.12)
0.152
0.350
0.611
0.195
Key Secondary Efficacy Outcomes
Event Rates are per 100 patient-years
Based on Intention-to-Treat Population
Rivaroxaban Warfarin
Event Rate
or N (Rate)
Event Rate
or N (Rate)
HR
(95% CI)
P-
value
Major
>2 g/dL Hgb drop
Transfusion (> 2 units)
Critical organ bleeding
Bleeding causing death
3.60
2.77
1.65
0.82
0.24
3.45
2.26
1.32
1.18
0.48
1.04 (0.90, 1.20)
1.22 (1.03, 1.44)
1.25 (1.01, 1.55)
0.69 (0.53, 0.91)
0.50 (0.31, 0.79)
0.576
0.019
0.044
0.007
0.003
Intracranial Hemorrhage 55 (0.49) 84 (0.74) 0.67 (0.47, 0.94) 0.019
Intraparenchymal 37 (0.33) 56 (0.49) 0.67 (0.44, 1.02) 0.060
Intraventricular 2 (0.02) 4 (0.04)
Subdural 14 (0.13) 27 (0.27) 0.53 (0.28, 1.00) 0.051
Subarachnoid 4 (0.04) 1 (0.01)
Event Rates are per 100 patient-years
Based on Safety on Treatment Population
Primary Safety Outcomes
Presented on behalf of the ARISTOTLE Investigators
and Committees
Apixaban versus Warfarin in
Patients with Atrial Fibrillation
Results of the ARISTOTLE Trial
Sponsored by Bristol-Myers Squibb and Pfizer
Primary Outcome
Stroke (ischemic or hemorrhagic) or systemic embolism
Apixaban 212 patients, 1.27% per year
Warfarin 265 patients, 1.60% per year
HR 0.79 (95% CI, 0.660.95); P (superiority)=0.011
No. at Risk
Apixaban 9120 8726 8440 6051 3464 1754
Warfarin 9081 8620 8301 5972 3405 1768
P (non-inferiority)<0.001
21% RRR
Efficacy Outcomes
Outcome
Apixaban
(N=9120)
Warfarin
(N=9081)
HR (95% CI)
P
Value Event Rate
(%/yr)
Event Rate
(%/yr)
Stroke or systemic embolism* 1.27 1.60 0.79 (0.66, 0.95) 0.011
Stroke 1.19 1.51 0.79 (0.65, 0.95) 0.012
Ischemic or uncertain 0.97 1.05 0.92 (0.74, 1.13) 0.42
Hemorrhagic 0.24 0.47 0.51 (0.35, 0.75) <0.001
Systemic embolism (SE) 0.09 0.10 0.87 (0.44, 1.75) 0.70
All-cause death* 3.52 3.94 0.89 (0.80, 0.998) 0.047
Stroke, SE, or all-cause death 4.49 5.04 0.89 (0.81, 0.98) 0.019
Myocardial infarction 0.53 0.61 0.88 (0.66, 1.17) 0.37
* Part of sequential testing sequence preserving the overall type I error
Major Bleeding
ISTH definition
Apixaban 327 patients, 2.13% per year
Warfarin 462 patients, 3.09% per year
HR 0.69 (95% CI, 0.600.80); P<0.001
No. at Risk
Apixaban 9088 8103 7564 5365 3048 1515
Warfarin 9052 7910 7335 5196 2956 1491
31% RRR
Adverse Events and Liver Function
Tests
N (%)
Apixaban
(N=9088)
Warfarin
(N=9052)
Total patients with an adverse event 7406 (81.5) 7521 (83.1)
Total patients with a serious adverse event 3182 (35.0) 3302 (36.5)
Serious adverse events reported in 1% of
patients in either treatment group

Atrial fibrillation 301 (3.3) 287 (3.2)
Pneumonia 202 (2.2) 231 (2.6)
Discontinuations due to an adverse event 688 (7.6) 758 (8.4)
ALT or AST > 3X ULN and total bilirubin > 2X ULN 30/ 8788 (0.3) 31/ 8756 (0.4)
ALT elevation
> 3X ULN 100/ 8790 (1.1) 89/ 8759 (1.0)
> 5X ULN 45/ 8790 (0.5) 47/ 8759 (0.5)
> 10X ULN 16/ 8790 (0.2) 20/ 8759 (0.2)
> 20X ULN 8/ 8790 (<0.1) 12/ 8759 (0.1)
N=5.599
522
81324 mg OD

Apixaban 5 mg BD
(2,5 mg )


AF



VKA (

VKA)

,


,
, ,

AVERROES: Apixaban ,
VKA

AVERROES=Apixaban VERsus Acetylsalicylic Acid (ASA) to PRevent StrOkES/Apixaban
(ASA) .

Connolly SJ et al. N Engl J Med. 2011;364:806817
Eikelboom JW et al. Am Heart J 2010;159:348353.e1.
AVERROES
23

. .
2791 2716 2530 2112 1543 628
Apixaban 2808 2758 2566 2125 1522 615
apixaban, 0,45
(95% CI, 0,320,62)
0 3 6 9 12 18
0.00
0.01
0.02
0.03
0.04
0.05

Apixaban
p<0,001
Connolly SJ et al. N Engl J Med 2011;364:806817

()
AVERROES



Apixaban
(n=2808)

(n=2791) Apixaban
.


%/
.


%/

95% CI p

SE
51 1.6 113 3.7 0.45 0.320.62 <0.001


49 1.6 105 3.4 0.46 0.330.65 <0.001
35 1.1 93 3.0 0.37 0.250.55 <0.001
6 0.2 9 0.3 0.67 0.241.88 0.45


9 0.3 4 0.1 2.24 0.697.27 0.18
SE 2 0.1 13 0.4 0.15 0.030.68 0.01
Connolly SJ et al. N Engl J Med 2011;364:806817
CI, , RR, , SE,
AVERROES
. .

2791 2738 2557 2140 1571 642
Apixaban 2808 2759 2566 2120 1521 622

apixaban, 1,13
(95% CI, 0,74-1,75)

Apixaban
p=0,57
0 3 6 9 12 18
0.00
0.005
0.010
0.015
0.020
Connolly SJ et al. N Engl J Med 2011;364:806817
CI,
()

AVERROES



Apixaban
(n=2808)

(n=2791) Apixaban

-








95% CI p
44 1.4 39 1.2 1.13 0,74 1,75 0.57
11 0.4 13 0.4 0.85 0,38 1,90 0.69
4 0.1 2 0.1 - - -

,




1 <0.1 2 0.1 - - -


33 1.1 27 0.9 1.23 0,74 2,05 0.42
12 0.4 14 0.4 0.86 0,40 1,86 0.71
20 0.6 13 0.4 1.55 0,77 3,12 0.22
4 0.1 6 0.2 0.67 0,19 2,37 0.53
96 3.1 84 2.7 1.15 0,86 1,54 0.35
188 6.3 153 5 1.24 1,00 1,53 0.05
Connolly SJ et al. N Engl J Med 2011;364:806817
AVERROES
RELY
Dabigatran 110
mg
Dabigatran 150
mg
Warfarin
CHADS
2
Mean
0-1 (%)
2 (%)
3+ (%)
2.1
32.6
34.7
32.7
2.2
32.2
35.2
32.6
2.1
30.9
37.0
32.1
C. Michael Gibson, M.S., M.D.
ROCKET AF
Rivaroxaban Warfarin
CHADS
2
Mean
2 (%)
3 (%)
4 (%)
5 (%)
6 (%)
3.5
13
43
29
13
2
3.5
13
44
28
12
2
ARISTOTLE
Rivaroxaban Warfarin
CHADS
2
Mean
0-1 (%)
2 (%)
3+ (%)
2.1
34
35.8
30.2
2.1
34
35.8
30.2
Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011
3+
87%
RE-LY
Dabigatran 110 mg 1.53% per year
Dabigatran 150 mg 1.11% per year
Warfarin 1.69% per year

ROCKET AF
Rivaroxaban 20mg 1.7% per year
Warfarin 2.2% per year

ARISTOTLE
Apixaban 5 mg 1.27% per year
Warfarin 1.60% per year
Primary Endpoint of Stroke or Systemic
Embolism: Non-inferiority Analysis
p<0.001
p<0.001
p<0.001
Non Inferiorirty
p vs warfarin
ITT Analysis
Modified ITT
No ITT analysis is available for non-inferiority in Rocket AF. An on treatment or per-protocol analysis is generally
performed in the assessment of non-inferiority. If numerous patients come off of study drug, this biases the trial
towards a non-inferior result in an ITT analysis. This is the basis for performing a per-protocol analysis in a non-
inferiority assessment.
C. Michael Gibson, M.S., M.D.
p<0.001
ITT Analysis
Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011
HR = 0.79
HR = 0.79
HR = 0.91
HR = 0.66
Hemorrhagic Stroke
Dabigatran 110 mg 0.12% / yr 0.31 <0.001
Dabigatran 150 mg 0.10% / yr 0.26 <0.001

Warfarin 0.38% / yr
HR
ITT
P-value
Rivaroxaban 20 mg 0.26% / yr 0.59 0.012*

Warfarin 0.44% / yr
ROCKET
RELY
C. Michael Gibson, M.S., M.D.
*In an on treatment analysis in Rocket AF Hemorrhagic Stoke rates were 0.26% / yr for rivaroxaban
and 0.44% / yr for warfarin, p=0.024. No on treatment analysis is available from RE-LY.
Apixaban 5 mg 0.24% / yr 0.51 <0.001

Warfarin 0.47% / yr
ARISTOTLE
Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011
Ischemic Stroke
Dabigatran 110 mg 1.34% / yr 1.20 0.35
Dabigatran 150 mg 0.92% / yr 0.76 0.03

Warfarin 1.20% / yr
HR
ITT
P-value
Rivaroxaban 20 mg 1.62% / yr 0.99 0.92*

Warfarin 1.64% / yr
ROCKET
RELY
C. Michael Gibson, M.S., M.D.
*In an on treatment analysis in Rocket AF Ischemic Stoke rates were 1.34% / yr for rivaroxaban and
1.42% / yr for warfarin, p=0.58. No on treatment analysis is available from RE-LY.
Apixaban 5 mg 0.97% / yr 0.92 0.42

Warfarin 1.05% / yr
ARISTOTLE
Patel MR et al, NEJM 2011; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151; Granger C et al, N Eng J Med; 2011
ESC 2012
Adapted from Camm et al. Eur Heart J 2012;e-published August 2012, doi:10.1093/eurheartj/ehs253.


*

<65 & ( )

(CHA
2
DS
2
-VASc score)
0 1 2
(HAS-BLED score)




NOAC**

VKA


**NOAC VKA (INR 23) .





VKA

OAC

EHRA practical guide on the use of
new oral anticoagulants in patients with
non-valvular atrial fibrillation
Hein Heidbuchel
1
, M.D., Ph.D., Peter Verhamme
1
, M.D., Ph.D., Marco Alings
2
, M.D., Ph.D.,
Matthias Antz
3
, M.D., Werner Hacke
4
, M.D., Jonas Oldgren
5
, M.D., Ph.D.,
Peter Sinnaeve
1
, M.D., Ph.D., A. John Camm
6
, M.D., Paulus Kirchhof
7
, M.D., Ph.D.
1. Department of Cardiovascular Medicine, University Hospital Gasthuisberg, University of Leuven,
Leuven, Belgium; 2. Department of Cardiology, Amphia Ziekenhuis, Breda, Netherlands; 3. Department of Cardiology, Klinikum Ol denburg,
Oldenburg, Germany; 4. Department of Neurology, Ruprecht Karls Universitt, Heidelberg, Germany; 5. Uppsala Clinical Research Center and
Dept of Medical Sciences, Uppsala University, Uppsala, Sweden; 6. Clinical Cardiology, St Georges University, London, United Kingdom;
7. University of Birmingham Centre for Cardiovascular Sciences, Birmingham, UK, and Department of Cardiology and Angiology,
University of Mnster, Germany
Measuring the anticoagulant effect of NOACs
Dabigatran Apixaban Edoxaban Rivaroxaban
Plasma peak 2h after ingestion 1-4h post ingestion 1-2h after ingestion 2-4h after ingestion
Plasma trough 12-24h after ingestion 12-24h after
ingestion
12-24h after ingestion 16-24h after
ingestion
PT cannot be used cannot be used prolonged but no known
relation with bleeding risk
prolonged: may
indicate excess
bleeding risk but
local calibration
required
INR cannot be used cannot be used cannot be used cannot be used
aPTT at trough >2x ULN
suggests excess
bleeding risk
cannot be used prolonged but no known
relation with bleeding risk
cannot be used
dTT At trough >200ng/ml
65s: excess bleeding
risk
cannot be used cannot be used cannot be used
Anti-FXa assays n/a no data yet quantitative; no data on
threshold values for
bleeding or thrombosis
quantitative; no
data on threshold
values for bleeding
or thrombosis
Ecarin clotting time at trough >2x ULN:
excess bleeding risk
not affected;
cannot be used
not affected; cannot be
used
not affected; cannot
be used
12
www.escardio.org/EHRA
Possible drug-drug interactions
Effect on NOAC plasma levels part 1
Dabigatran Apixaban Edoxaban Rivaroxaban
Atorvastatin P-gp/ CYP3A4 +18% no data yet no effect no effect
Digoxin P-gp no effect no data yet no effect no effect
Verapamil P-gp/ wk CYP3A4
+12180%

no data yet
+ 53% (slow release)

minor effect
Diltiazem P-gp/ wk CYP3A4 no effect +40% No data minor effect
Quinidine P-gp +50% no data yet +80% +50%
Amiodarone P-gp +1260% no data yet no effect minor effect
Dronedarone P-gp/CYP3A4 +70100% no data yet +85% no data yet
Ketoconazole;
itraconazole;
voriconazole;
posaconazole;
P-gp and BCRP/
CYP3A4
+140150% +100% no data yet up to +160%
19
www.escardio.org/EHRA
Red contraindicated; orange reduce dose; yellow consider dose reduction if another yellow factor present;
hatching no data available; recommendation made from pharmacokinetic considerations
Possible drug-drug interactions
Effect on NOAC plasma levels part 2
Interaction Dabigatran Apixaban Edoxaban Rivaroxaban
Fluconazole CYP3A4 no data no data no data +42%
Cyclosporin;
tacrolimus
P-gp no data no data no data +50%
Clarithromycin;
erythromycin
P-gp/ CYP3A4 +1520% no data no data +3054%
HIV protease
inhibitors
P-gp and BCRP/
CYP3A4
no data strong increase no data up to +153%
Rifampicin;
St Johns wort;
carbamezepine;
phenytoin;
phenobarbital
P-gp and BCRP/
CYP3A4/CYP2J2
-66% -54% -35% up to -50%
Antacids GI absorption -12-30% no data no effect no effect
20
www.escardio.org/EHRA
Red contraindicated; orange reduce dose; yellow consider dose reduction if another yellow factor present;
hatching no data available; recommendation made from pharmacokinetic considerations
When to stop NOACs before a planned
surgical intervention
Dabigatran Apixaban Edoxaban * Rivaroxaban
No important bleeding risk and/or local haemostasis possible: perform at trough level
(i.e. 12h or 24h after last intake)
Low risk High risk Low risk High risk
Low
risk
High risk Low risk High risk
CrCl 80 ml/min 24h 48h 24h 48h
no data
yet
no data
yet
24h 48h
CrCl 5080 ml/min 36h 72h 24h 48h
no data
yet
no data
yet
24h 48h
CrCl 3050 ml/min

48h 96h 24h 48h
no data
yet
no data
yet
24h 48h
CrCl 1530 ml/min

not
indicated
not
indicated
36h 48h
no data
yet
no data
yet
36h 48h
CrCl <15 ml/min no official indication for use
40
www.escardio.org/EHR
A
Last intake of drug before elective surgical intervention
*no EMA approval yet.; Low risk: surgery with low risk of bleeding. High risk: surgery with high risk of bleeding many of these patients may be
on the lower dose of dabigatran (i.e. 2x110 mg/d) or apixaban (i.e. 2x2.5 mg/d), or have to be on the lower dose of rivaroxaban (15 mg/d).
When to restart NOACs after a planned
surgical intervention
Procedures with immediate and complete
haemostasis:
Atraumatic spinal/epidural anethesia
Clean lumbar puncture
Resume 68 h after surgery
Procedures associated with immobilization:

Procedures with post-operative risk of
bleeding:
Initiate reduced venous or intermediate dose of
LMWH 68 h after surgery if haemostasis achieved.
Restart NOACs 4872h after surgery upon
complete haemostasis
Thromboprophylaxis (e.g. with LMWH) can be
initiated 6-8 h after surgery
41
www.escardio.org/EHR
A
11. Patients undergoing an urgent surgical
intervention
Discontinue NOAC.
Try to defer surgery at least 12 h and ideally 24 h after last dose.
Urgent surgery associated with much higher rates of bleeding than elective
procedures, but lower than VKA-treated patients.
1
Coagulation tests can be considered (classical test or specific tests) but
strategy based on these results has never been evaluated. Therefore such
strategy cannot be recommended and should not be used routinely.
43
www.escardio.org/EHRA
1. Healey et al, Circulation 2012:126;343-8
Scenario 3. Recommendations concerning
new onset AF in patients with a remote(>1
year ACS)
Anticoagulation without additional antiplatelet agents is sufficient
for most AF patients with stable CAD.
Advantages of NOACs over VKAs likely to be preserved: NOACs
may be safe and effective alternatives to VKAs.
1
No preference given to any of NOACs.
If using dabigatran, consider lower dose (110 mg BID) plus
low-dose aspirin (clopidogrel in case of allergy to aspirin).
2

52
www.escardio.org/EHRA
1. Hohnloser et al, Circulation 2012;125:669-675; 2. Dans et al Circulation 2013;127:634-40