Understanding Stroke
Prevention in Atrial
Fibrillation
Michel D’Astous
Cardiologist
Centre hospitalier universitaire
Dr Georges-L Dumont
University Hospital Center
Atrial Fibrillation
• Atrial fibrillation (AF) is the most common heart rhythm disturbance
• It is estimated that 1 in 4 individuals aged 40 will develop AF
Normal rhythm
AF=atrial fibrillation
AF
Lloyd-Jones DM, et al. Circulation 2004;110:1042-1046
ECG Showing Atrial Fibrillation
Key findings:
•Absence of P waves
•Irregularly irregular R-R intervals
•Irregular fluctuations in the baseline (most noticeable in leads III
and V1)
www.thrombosisadviser.com
Classification of Atrial Fibrillation
Terminology
Clinical features
Pattern
Initial event (first
detected episode)
Symptomatic or Asymptomatic
Onset unknown
May or may not
re-occur
Paroxysmal
Spontaneous termination <7 days
and most often <48 hours
Recurrent
Persistent
Not self-terminating: Lasting >7
days or prior cardioversion
Recurrent
Permanent (‘accepted’)
Not terminated, terminated but
relapsed, no cardioversion attempt
Established
Fuster V, et al. ACC/AHA/ESC 2006 guidelines. J Am Coll Cardiol 2006;48:854-906.
AF is a Progressive Disease
Relative
Importance
AF Duration
Trigger
dependent
Substrate
dependent
(Initiation)
(Maintenance)
Paroxysmal
Persistent
Permanent
Khan I.A. Int J Card 2003;87:301-302.
8
Treatment of AF
• 1: Find a cause
• 2:Heart rate control
• 3:Rhythm vs Rate control
• 4:ASA vs Anticoagulation
Treatment of AF
• 1:
• 2:Heart rate control
• 3:Rhythm vs Rate control
• 4:ASA vs Anticoagulation
Etiologies of AF
• Numerous causes:
• Think of:
– Hypertension
– Coronary heart disease
– Valvular heart disease
– Cardiomyopathies
– Any trauma, infection of lungs or heart
– R/o Hyperthyroidism
– Lone AF
Investigation of AF
• CBC, renal analysis, liver function tests
• ECG (LVH, Q waves, QT)
• Do not forget:
• TSH
• Echocardiogram
• Sometimes:
– Stress test, holter, Chest Xray, TEE
Treatment of AF
• 1: Find a cause
• 2:
• 3:Rhythm vs Rate control
• 4:ASA vs Anticoagulation
Treatment of AF
• 1: Find a cause
• 2:Heart rate control
• 3:
• 4:ASA vs Anticoagulation
Stroke Prevention in Atrial Fibrillation
-Mortality in Rate vs. Rhythm Control Patients
-The AFFIRM Study
All-cause mortality
30
25
Cumulative
Mortality
(%)
Rhythm control
20
Rate control
15
P=0.08
10
5
0
0
1
2
3
4
5
Years after randomization
• Randomized patients with atrial fibrillation and a high risk of stroke to
•
•
either cardioversion and treatment with antiarrhythmic drugs to maintain
sinus rhythm or the use of rate-controlling drugs
The use of anticoagulant drugs was recommended but not mandated
N Engl J Med 2002; 347: 1825-33.
Stroke Prevention in Atrial Fibrillation
-Mortality in Rate vs. Rhythm Control Patients
-The AFFIRM Study
p
Value
Sinus Rhythm
<0.0001
Antiarrhythmic Use
0.0005
Warfarin Use
<0.0001
Digoxin Use
0.0005
0
0.5
1.0
Risk Ratio
• N Engl J Med 2002; 347: 1825-33.
1.5
2.0
Treatment of AF
• 1: Find a cause
• 2:Heart rate control
• 3:Rhythm vs Rate control
• 4:
Atrial Fibrillation
Major Risk Factor for Stroke
• Independent risk factor for stroke - increases the
risk of stroke by 5-fold1,2,3
• Accounts for approximately 15-20% of all strokes
nationally1,4
• Risk of stroke in AF patients increases with age
– 1.5% in 50–59 year olds
– 23.5% in 80–89 year olds
• Risk of stroke is the same in AF patients
regardless of whether they have paroxysmal or
sustained AF
AF=atrial fibrillation
1. Atrial Fibrillation Investigation Group. Arch Intern Med. 1994
2. Wolf PA, et al. Stroke 1991
3. Savelieva I, et al. Ann Med 2007
4. Singer DE, et al. Chest 2008
Stroke Risk is Independent of Type of
Atrial Fibrillation
Neuwfaat R, et al. Eur Heart J 2008
Incidence of Atrial Fibrillation Expected
to Increase as Population Ages
Projected Number of Persons With AF in the
United States Between 2000 and 2050
Millions
Age- and Sex-Adjusted
Incidence of AF in 1995-2000
Year
AF=atrial fibrillation
Miyasaka Y et al. Circulation. 2006;114:119-125
Diabetes and Atrial Fibrillation
Incidence of new onset AF
• AF is 44% more prevalent in
DM
• AF is 38% more likely to
develop in DM
• DM is a highly significant
independent predictor of AF
in women
AF = Atrial fibrillation
DM = Diabetes mellitus
Diabetes Care 2009;32:1851-1856
Blood Pressure in AF Patients
Risk of CVA/Systemic Embolus
Event rate (%/year)
4.0
SBP
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
100
110
120
130
140
150
160
Mean SBP (mmHg)
SBP = Systolic blood pressure
Lip GY et al; for the SPORTIF Investigators. Eur Heart J 2007;28:752-9.
27
•
Dec, 2003 issue
AF EPIDEMIC!
Pathophysiology of AF-Associated
Ischemic Stroke
About 16% of ischemic
strokes are associated
with AF, and 10% are
likely due to embolism of
left atrial appendage
thrombus
AF=atrial fibrillation
Hart RG & Halperin JL. Stroke 2001;32:803-808
Left Atrial Appendage (LAA)
Left atrial appendage
(LAA) is the most
common site for
thrombus formation in
patients with AF
AF=atrial fibrillation
Image courtesy of www.strokecenter.org
Albers G, Stanford Stroke Center, Stanford School of Medicine
Stroke Prevention in Atrial Fibrillation
-Efficacy and Safety of Current A Fib Treatments
-Meta-Analysis of Antithrombotic Therapy in A Fib
• Adjusted dose warfarin and antiplatelet agents have been shown to reduce the
risk of stroke compared with control by 64% and 22%, respectively, with an
increase in bleeding
• Warfarin has been shown to be more effective than aspirin, in reducing stroke
by 45%, but increasing the risk of bleeding
• Based on these results, warfarin and other oral anticoagulants (OAC) are
recommended for patients at increased risk of stroke; and aspirin is
recommended for patients at lower risk
W
%
A
W
%
A
Warfarin Antiplatelets
• Ann Intern Med 2007; 146: 857-67.
Warfarin Challenges:
Narrow Therapeutic Window
Relationship between clinical events and INR intensity
ICH=intracranial hemorrhage
INR=international normalized ratio
1. Hylek EM et al. Ann Intern Med. 1994;120:897-902;
2. Hylek EM et al. N Engl J Med. 1996;335:540-546
Limitations of Warfarin Therapy
Unpredictable
response
Narrow therapeutic
window
(INR range 2-3)
Routine coagulation
monitoring
Frequent dose
adjustments
Warfarin therapy
has several
limitations that
make it difficult to
use in practice
Slow onset/offset
of action
Ansell J, et al. Chest 2008;133:160S-198S; Umer Ushman MH, et al. J Interv Card
Electrophysiol 2008; 22:129-137; Nutescu EA, et al. Cardiol Clin 2008; 26:169-187
Numerous food-drug
interactions
Numerous drug-drug
interactions
Warfarin resistance
INR Control
Clinical Trials Versus Clinical Practice
INR* control in clinical trial versus clinical practice (TTR**)
66%
% of eligible patients
receiving warfarin
Clinical trial1
44%
Clinical practice2
38%
25%
18%
9%
<2.0
*INR = International normalized ratio;
** TTR = Time in Therapeutic Range (INR2.0-3.0
* Pooled data: up to 83% to 71% in individualized trials
2.0 – 3.0
1. Kalra L, et al. BMJ 2000;320:1236-1239;
2. Matchar DB, et al. Am J Med 2002; 113:42-51
>3.0 INR
Stroke Prevention in Atrial Fibrillation
-The ACTIVE Program
Documented AF + 1 risk factor:
Age 75, Hypertension, Prior stroke/TIA,
LVEF<45, PAD, Age 55-74 + CAD or diabetes
Contra-indications to Warfarin or Unwilling
ACTIVE W
6500 patients
Clopidogrel+ASA
vs. Warfarin
ACTIVE A
7500 patients
Clopidogrel+ASA
vs. ASA
No Exclusion criteria for ACTIVE I
ACTIVE I
~9000vspatients
Irbesartan
placebo
Stroke Prevention in Atrial Fibrillation
0.10
-Stroke, Embolism, MI and Vascular Death
-The ACTIVE-W Study
0.08
RR = 1.45
P = 0.0002
0.06
Clopidogrel+ASA
0.04
3.93 %/year
0.02
OAC
0.0
Cumulative Hazard Rates
5.64 %/year
0.0
0.5
1.0
Years
• Lancet 2006; 367: 1903-12.
1.5
Stroke Prevention in Atrial Fibrillation
-Major Bleeding
-The ACTIVE-W Study
RR = 1.06
0.03
P = 0.67
0.01
0.02
2.2 %/year
OAC
Clopidogrel+ASA
0.0
Cumulative Hazard Rates
0.04
2.4 %/year
0.0
0.5
1.0
Years
• Lancet 2006; 367: 1903-12.
1.5
Stroke Prevention in Atrial Fibrillation
-The ACTIVE Program
Documented AF + 1 risk factor:
Age 75, Hypertension, Prior stroke/TIA,
LVEF<45, PAD, Age 55-74 + CAD or diabetes
Contra-indications to Warfarin or Unwilling
ACTIVE W
6500 patients
Clopidogrel+ASA
vs. Warfarin
ACTIVE A
7500 patients
Clopidogrel+ASA
vs. ASA
No Exclusion criteria for ACTIVE I
ACTIVE I
~9000vspatients
Irbesartan
placebo
Stroke Prevention in Atrial Fibrillation
0.4
-Stroke, Embolism, MI and Vascular Death
-The ACTIVE-A Study
11% RRR
924 (7.6%/year)
HR=0.89 (0.81-0.98)
p=0.014
0.3
RR=0.89 (95% CI,
0.81–0.98; P=0.01)
0.3
832 (6.8%/year)
0.2
Aspirin
ASA
0.2
0.1
Clopidogrel+Aspirin
Clopidogrel + ASA
0.1
0.0
Incidence
Cumulative
Cumulative
Hazard
Rates
0.4
0.0
00
11
22
No. at Risk
C+A 3772
ASA 3782
3456
3427
3180
3103
Years
• N Engl J Med 2009; 360: 2066-78.
33
44
2523
2459
1180
1153
Years
Stroke Prevention in Atrial Fibrillation
-Stroke (All Types)
-The ACTIVE-A Study
Cumulative Incidence
0.15
408 (3.3%/year)
28% RRR
RR=0.72 (95% CI,
0.62–0.83; P=<0.001)
ASA
0.10
296 (2.4%/year)
0.05
Clopidogrel + ASA
0.0
0
1
2
Years
• N Engl J Med 2009; 360: 2066-78.
3
4
CHADS2 Score
• 1 point for Congestive Heart Failure
• 1 point for Hypertension
• 1 point for Age ≥ 75 years
• 1 point for Diabetes Mellitus
• 2 points for Prior Stroke or TIA
Patient Case - Alice
Condition
Points
Congestive heart failure
0
Hypertension
1
Age, 74 yr
0
Diabetes mellitus
0
Prior stroke/TIA
2
Total Points
3
Gage BF, et al. JAMA. 2001;285:2864-2870
CHADS2
Score*
Stroke rate
0
1.9 (1.2 -3.0)
1
2.8 (2.0-3.8)
2
4.0 (3.1-5.1)
3
5.9 (4.6-7.3)
4
8.5 (6.3 -11.1)
5
12.5 (8.2-17.5)
6
18.2 (10.5-17.4)
*Score 0: Patients can be administered aspirin
*Score 1: Patients can be on aspirin and anticoagulant therapy
*Score ≥2: Patients should be on anticoagulant therapy
CHA DS VASc
Risk Factors
Points
• C CHF
• 1
• H Hypertension
• 1
• A Age > 75
• 2
• D Diabetes
• 1
• S Stroke/TIA/TE
• 2
• V Vascular disease (MI, PVD, Aortic)
• 1
• A Age 65-75
• 1
• Sc Sex category ( female gender)
• 1
CHA DS -VASc
CHA2DS2-VASc score
TE Rate during 1 year %
• 0
• 0
• 1
• 0,7
• 2
• 1,9
• 3
• 4,7
• 4
• 2,3
• 5
• 3,9
• 6
• 4,5
• 7
• 10,1
• 8
• 14,2
Risk Factors for Bleeding
•
Age ≥ 65
• Previous Stroke
• Previous peptic ulcer disease
• Previous gastrointestinal bleeding
Higher rate of bleeding for patients ≥
65 yr versus younger patients
(hazard ratio 2.6, 95% confidence
interval 1.0-6.9).
• Renal impairment
• Anemia
• Thrombocytopenia
• Liver disease
• Diabetes mellitus
• Use of antiplatelet drugs
Kearon C, et al. N Engl J Med 2003;349:631-639
Bleeding rates increased with the
number of risk factors present,
hazard ratio associated with each
additional risk factor, 1.7 (95%
confidence interval, 1.1-2.6).
Anticoagulation Contraindications
• Pregnancy
• Unsupervised patients with
– Associated with developmental abnormalities
• Threatened abortion, eclampsia
and pre-eclampsia
– CNS; eye; traumatic surgery, resulting
in large open surfaces
• Bleeding tendencies associated with
active ulceration or overt bleeding
– GI, GU or RT
– Cerebrovascular haemorrhage aneurysms–
cerebral, dissecting aorta
– Bacterial endocarditis
CNS = central nervous system; GI = gastrointestinal;
GU = genitourinary; RT = reproductive tract
– Psychosis
– Other lack of patient co-operation
• Spinal puncture
• Recent surgery
– Pericarditis and pericardial effusions
– Alcoholism
• Any diagnostic or therapeutic
procedures with potential for
uncontrollable bleeding
• Miscellaneous
– Major regional
– Lumbar block anaesthesia
– Malignant hypertension
– Known warfarin hypersensitivity
www.rxlist.com/cgi/generic/warfarin_ad.htm
Warfarin and Stroke Prevention
in Patients with Atrial Fibrillation
Adjusted dose warfarin compared
with placebo or control
AFSAK I
SPAF I
BAATAF
CAFA
SPINAF
EAFT
All trials (n = 6)
AFSAK I = Copenhagen Atrial Fibrillation, Aspirin and Anticoagualtion Study
SPAF I = Stroke Prevention in Atrial Fibrillation Study
BAATAF = Boston Area Anticoagulation Trial doe Atrial Fibrillation
CAFA = Canadian Atrial Fibrillation Anticoagulation
SPINAF = Stroke Prevention in Nonrheumatic Atrial Fibrillation
Hart RG et al. Ann Intern Med 2007;146:857-867
EAFT = European Atrial Fibrillation Trial
Underutilization of Warfarin in
Atrial Fibrillation*
Approximately half of high-risk patients with atrial fibrillation receive warfarin
therapy
13 community hospitals
21 academic hospitals
Warfarin therapy
No warfarin therapy
*US population January–December 2002
Waldo AL, et al. J Am Coll Cardiol 2005
Stroke: Under Treatment
Sub-optimal Primary Prevention of Stroke in Patients
with AF in Canada
Secondary Stroke Prevention Patients only Marginally Better
Primary prevention in Canadian
Stroke Registry (n=597*)
Warfarin,
subtherapeutic
Secondary prevention in Canadian
Stroke Registry (n=323*†)
No antithrombotic
tx
No antithrombotic
tx
29%
29%
Warfarin,
subtherapeutic
15%
39%
25%
10%
29%
Warfarin,
therapeutic
18%
2%
Dual
antiplatelet
tx
Single
antiplatelet
tx
Warfarin,
therapeutic
Single
antiplatelet
tx
3%
Dual
antiplatelet
tx
AF: atrial fibrillation; TIA: transient ischemic attack. *history of AF, classified high risk for systemic emboli according to
published guidelines, no contraindications to anticoagulation. †Patients with acute ischemic stroke/TIA
Gladstone et al. Stroke 2009;40:235-40
Update in Antiplatelets and Anticoagulants
-Newer Antithrombotic Agents
Intrinsic
pathway
Extrinsic
pathway
Xll
Xl
lX
Coumadin
TF
Fondaparinux
VII
VIII
X
LMWH
V
II
XIII
Fibrin Clot
Heparin
Stroke Prevention in Atrial Fibrillation
-New Agents for the Prevention of Stroke
Intrinsic
pathway
Extrinsic
pathway
Xll
Xl
lX
TF
VII
VIII
X
Direct Factor Xa Inhibitors
-apixaban
-rivaroxaban
II
Direct Thrombin Inhibitors
-dabigatran
V
XIII
Fibrin Clot
Dabigatran Etexilate (Direct Thrombin
Inhibitor) in Atrial Fibrillation
• Reversible direct thrombin inhibitor (DTI)
• Oral prodrug that is converted to
dabigatran,
• Rapid onset of action
• Half life of 12-17 h
• Renal excretion ~ 80%
• Low potential for drug-drug interactions,
no drug-food interactions
• No requirement for routine coagulation
monitoring
Stangier J. Clin Pharmacokinet 2008;47:285-295
®
RE-LY :
Randomised Evaluation of
Long Term Anticoagulant Therapy
• 18,113 patients who had atrial
fibrillation and at least one risk factor
for stroke
• 50% of enrolled patients were naïve to
previous oral AC
• Median treatment duration: 2 years
• Primary outcome: stroke or systemic
embolism
Dabigatran etexilate is in clinical development and not licensed for clinical
use in stroke prevention for patients with atrial fibrillation
Connolly SJ, et al. N Engl J Med 2009;361:1139-1151
®
RE-LY :
Inclusion Criteria
1. Documented atrial fibrillation, and
2. One additional risk factor for stroke:
a) History of previous stroke, TIA, or systemic embolism
b) LVEF less than 40%
c) Symptomatic Heart Failure, NYHA Class II or greater
d) Age of 75 years or more
e) Age of 65 years or more and one of the following
additional risk factors: Diabetes mellitus, CAD
or Hypertension
Dabigatran etexilate is in clinical development and not licensed for clinical
use in stroke prevention for patients with atrial fibrillation
Connolly SJ, et al. N Engl J Med 2009;361:1139-1151
Baseline characteristics
Characteristic
Dabigatran 110 mg
Dabigatran 150 mg
Warfarin
Randomized
6015
6076
6022
Mean age (years)
71.4
71.5
71.6
Male (%)
64.3
63.2
63.3
CHADS2 score
(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
Prior stroke/TIA
(%)
19.9
20.3
19.8
Prior MI (%)
16.8
16.9
16.1
CHF (%)
32.2
31.8
31.9
Baseline ASA (%)
40.0
38.7
40.6
VKA naïve (%)
50.1
50.2
48.6
Connolly SJ., et al. N Engl J Med 2009; 361:1139-1151.
Dabigatran etexilate is in clinical development and not licensed for
clinical use in stroke prevention for patients with atrial fibrillation
Stroke or systemic embolism (SSE)
Noninferiority Superiority
p-value
p-value
<0.001
0.30
Dabigatran 150 mg
vs. warfarin
<0.001
<0.001
Margin = 1.46
Dabigatran 110 mg
vs. warfarin
0.50
Connolly SJ., et al. N Engl J Med 2009; 361:1139-1151.
0.75
1.00
1.25
HR (95% CI)
1.50
Dabigatran etexilate is in clinical development and not licensed for
clinical use in stroke prevention for patients with atrial fibrillation
Time to first stroke / SSE
RR 0.90
(95% CI: 0.74–1.10)
p<0.001 (NI)
p=0.30 (Sup)
Cumulative hazard rates
0.05
0.04
RRR
35%
Warfarin
Dabigatran etexilate 110 mg
Dabigatran etexilate 150 mg
0.03
RR 0.65
(95% CI: 0.52–0.81)
p<0.001 (NI)
p<0.001 (Sup)
0.02
0.01
0.0
0
0.5
1.0
1.5
2.0
2.5
Years
RR, relative risk; CI, confidence interval; NI, non-inferior; Sup, superior
Connolly SJ., et al. N Engl J Med 2009; 361:1139-1151.
Dabigatran etexilate is in clinical development and not licensed for
clinical use in stroke prevention for patients with atrial fibrillation
All cause mortality
RR 0.91 (95% CI: 0.80–1.03)
p=0.13 (sup)
RR 0.88 (95% CI: 0.77–1.00)
p=0.051 (sup)
4.00
4.13
3.75
3.64
D110 mg BID
D150 mg BID
Warfarin
446 / 6,015
438 / 6,076
487 / 6,022
% per year
3.00
2.00
1.00
0.00
Connolly SJ., et al. N Engl J Med 2009; 361:1139-1151.
Dabigatran etexilate is in clinical development and not licensed for
clinical use in stroke prevention for patients with atrial fibrillation
Major bleeding rates
RR 0.80 (95% CI: 0.70–0.93)
4.00
p=0.003 (sup)
RR 0.93 (95% CI: 0.81–1.07)
p=0.32 (sup)
RRR
20%
3.50
3.00
% per year
2.50
3.57
3.32
2.87
2.00
1.50
1.00
0.50
0.00
D110 mg BID
342 / 6,015
Connolly SJ., et al. N Engl J Med 2009; 361:1139-1151.
D150 mg BID
399 / 6,076
Warfarin
421 / 6,022
Dabigatran etexilate is in clinical development and not licensed for
clinical use in stroke prevention for patients with atrial fibrillation
Hemorrhagic stroke
RR 0.31 (95% CI: 0.17–0.56)
p<0.001 (sup)
RR 0.26 (95% CI: 0.14–0.49)
50
p<0.001 (sup)
45
Number of events
40
RRR
74%
RRR
69%
0.38%
30
20
10
14
0.12%
12
0.10%
0
D110 mg BID
D150 mg BID
Warfarin
6,015
6,076
6,022
Connolly SJ., et al. N Engl J Med 2009; 361:1139-1151.
Dabigatran etexilate is in clinical development and not licensed for
clinical use in stroke prevention for patients with atrial fibrillation
®
RE-LY :
Rates of MI
Characteristic
Dabigatran
110 mg
(N=6015)
Dabigatran
150 mg
(N=6076)
Warfarin
(N=6022)
P-value
Dabigatran 110 mg
vs. Warfarin
P-value
Dabigatran 150 mg
vs. Warfarin
Myocardial Infarction
(%/year)
0.82
0.81
0.64
0.09
0.12
Connolly SJ, et al. N Engl J Med
2009;361:1139-1151
Time to first intra-cranial bleed
Warfarin
Dabigatran etexilate 110 mg
Dabigatran etexilate 150 mg
Cumulative hazard rates
0.02
RRR
59%
0.01
RRR
70%
RR 0.41
(95% CI: 0.28–0.60)
p<0.001 (Sup)
RR 0.30
(95% CI: 0.19–0.45)
p<0.001 (Sup)
0.0
0
0.5
1.0
1.5
2.0
2.5
Years
RR, Relative risk; CI, confidence interval; Sup, superior
Connolly SJ., et al. N Engl J Med 2009; 361:1139-1151.
Adapted from Camm J.: Oral presentation at ESC on Aug. 30, 2009.
http://www.escardio.org/congresses/esc2009/webcasts/pages/sunday.aspx
Dabigatran etexilate is in clinical development and not licensed for
clinical use in stroke prevention for patients with atrial fibrillation
Vascular mortality
RR 0.90 (95% CI: 0.77–1.06)
3.00
p=0.21 (sup)
RR 0.85 (95% CI: 0.72–0.99)
p=0.04 (sup)
2.43
2.28
D110 mg BID
D150 mg BID
289/ 6,015
274 / 6,076
% per year
2.00
RRR
15%
2.69
1.00
0.00
Connolly SJ., et al. N Engl J Med 2009; 361:1139-1151.
Warfarin
317 / 6,022
Dabigatran etexilate is in clinical development and not licensed for
clinical use in stroke prevention for patients with atrial fibrillation
®
RE-LY :
Most Common
Adverse Events
Dabigatran 110 mg (%)
Dabigatran 150 mg (%)
Warfarin (%)
Dyspepsia*
11.8
11.3
5.8
Dyspnea
9.3
9.5
9.7
Dizziness
8.1
8.3
9.4
Peripheral edema
7.9
7.9
7.8
Fatigue
6.6
6.6
6.2
Cough
5.7
5.7
6.0
Chest pain
5.2
6.2
5.9
Arthralgia
4.5
5.5
5.7
Back pain
5.3
5.2
5.6
Nasopharyngitis
5.6
5.4
5.6
Diarrhea
6.3
6.5
5.7
Urinary tract infection
4.5
4.8
5.6
Upper respiratory tract infection
4.8
4.7
5.2
*Occurred more commonly on dabigatran p<0.001
Dabigatran etexilate is in clinical development and not licensed for clinical
use in stroke prevention for patients with atrial fibrillation
Connolly SJ, et al. N Engl J Med 2009;361:1139-1151
®
RE-LY :
Summary Results
• 110 mg dose versus warfarin
– Comparable rates of stroke/systemic embolism
– Statistically significant reduction in hemorrhagic stroke
– Statistically significant reduction in major bleeding rates
– Significant reduction in total bleeds, life threatening bleeds and intracranial bleeds
• 150 mg dose versus warfarin
– Statistically significant reduction in stroke/systemic embolism
– Statistically significant reduction in hemorrhagic stroke
– Statistically significant reduction in vascular mortality
– Comparable rates of major bleeding rates
– Significant reduction in total bleeds, life threatening bleeds and intracranial bleeds
Dabigatran etexilate is in clinical development and not
licensed for clinical use in stroke prevention for patients
with atrial fibrillation
Connolly SJ, et al. N Engl J Med 2009;361:1139-1151
Renal Impairment
• Exposure to dabigatran is increased by renal impairment and correlates with the
severity of renal dysfunction.
• Dabigatran can be partly (62-68%) removed from plasma by haemodialysis.
Dabigatran etexilate is in clinical development and not licensed for
clinical use in stroke prevention for patients with atrial fibrillation
Stangier Clin Pharmacokinet 2010; 49(4):259-268
Stroke Prevention in Atrial Fibrillation
-Apixaban: An Oral Direct Factor Xa Inhibitor
• Apixaban is a reversible oral direct Factor Xa Inhibitor
• Apixaban binds directly to the active site on Factor Xa, and does not
require Antithrombin in order exert its pharmacological effect
• 50% bioavailability
• Peak Plasma concentration achieved at 3-4 h post-dose
• Multiple excretion pathways, ~ 27% renally excreted
• T½ of 12 h
• No known drug-drug/food-drug interactions
• Predictable and consistent anticoagulant effects
• No requirement for routine coagulation monitoring
Stroke Prevention in Atrial Fibrillation
-The AVERROES Study
-Study Design
Apixaban 5 mg BID
AF and ≥1 risk factor, and
demonstrated or expected unsuitable
for VKA
2.5 mg BID in selected patients
R
5,600 patients
Double-Blind
ASA (81-324 mg/d)
•
•
Primary objective: To establish the non-inferiority of apixaban 5mg bid to ASA 81-324mg od
Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up
•
Presented at the European Society Cardiology, Stockholm September 2010.
76
Stroke Prevention in Atrial Fibrillation
0.0 0.01 0.02 0.03 0.04 0.05 0.06
ASA 81-324mg od
Apixaban 5 mg bid
0.03
Cumulative Risk
-The AVEROES Study
-Primary Outcome: Stroke or Systemic Embolism
RRR
54%
RR 0.46
(95% CI: 0.33–0.64)
p<0.001
0
3
6
12
15
18
21
626
617
329
353
Months
No. at Risk
ASA 2791
Apix 2809
9
2720
2761
2541
2567
2124
2127
1541
1523
• Presented at the European Society Cardiology, Stockholm September
Rivaroxaban (Factor Xa inhibitor)
in Atrial Fibrillation: ROCKET
Patients with atrial fibrillation + ≥2 risk factors: CHF,
hypertension, age ≥75, diabetes or stroke, TIA or
systemic embolus
n ~14,000
Rivaroxaban
Warfarin
20 mg daily
15 mg for CrCl 30–49
INR target 2.5
(2.0–3.0 inclusive)
Monthly monitoring and adherence to
standard of care guidelines
Primary endpoint: stroke or non-CNS systemic
embolism over 4 years (Estimated study
completion: May 2010)
TIA, transient ischaemic attack; CrCl, creatine clearance
www.clinicaltrials.gov/ct2/show/NCT00403767
ROCKET AF
• Presented AHA Nov 15th, 2010
• Rivaroxaban non-inferior but not superior in
intention-to-treat ( vs Warfarin)
• Comparable major and non-major bleeds
• Less fatal and intracerebral bleeds with
Rivaroxaban
• 90% CHADS2 score of 3 or higher
New Oral Anticoagulants
• 1- Who will pay?
• 2-Assessing compliance?
• 3-Treating bleeding complications?
New Oral Anticoagulants
• Compliance?
• With Apixaban:
– RNI
• With Dabigatran:
– Thrombin Clotting time
– aPTT
New Oral Anticoagulants
• Bleeding often controlled with supportive measures
• Dabigatran dialysable
• Specific agents for reversal of anticoagulant effects:
– Recombinant activated Factor VII
– PCCs ( Prothrombin complexe concentrates)
Atrial Fibrillation Guidelines Update
Introduction
Anne M Gillis MD, FRCPC, FHRS
Professor of Medicine
Department of Cardiac Sciences
University of Calgary
Libin Cardiovascular Institute of Alberta
Leadership. Knowledge. Community.
Recommendations - Antithrombotic

2. We recommend that patients at very low risk of
stroke (CHADS2 = 0) should receive aspirin (75325 mg/day). (Strong recommendation, High Quality
Evidence). We suggest that some young persons with
no standard risk factors for stroke may not require ay
antithrombotic therapy. (Conditional recommendation,
Moderate Quality Evidence).
Leadership. Knowledge. Community.
Recommendations - Antithrombotic

3. We recommend that patients at low risk of stroke
(CHADS2 = 1) should receive OAC therapy (either
warfarin [INR 2 – 3] or dabigatran). (Strong
recommendation, High Quality Evidence). We
suggest, based on individual risk/benefit
considerations, that aspirin is a reasonable
alternative for some. (Conditional recommendation,
Moderate Quality Evidence).

4. We recommend that patients at moderate risk of
stroke (CHADS2 ≥ 2) should receive OAC therapy
(either warfarin [INR 2 – 3] or dabigatran). (Strong
recommendation, High Quality Evidence)
Leadership. Knowledge. Community.
Recommendations - Antithrombotic

5. We suggest, that when OAC therapy is indicated,
most patients should receive dabigatran in
preference to warfarin. In general, the dose of
dabigatran 150 mg po bid is preferable to a dose
of 110 mg po (exceptions discussed in text).
(Conditional recommendation. High Quality Evidence).
Leadership. Knowledge. Community.
Recommendations – Stable CAD

10. We suggest that patients with AF or AFL who have
stable CAD should receive antithrombotic therapy
selected based upon their risk of stroke (aspirin for
CHADS2 = 0 and OAC for CHADS2 ≥ 1). Warfarin is
preferred over dabigatran for those at high risk of
coronary events.
(Conditional Recommendation, Moderate Quality
Evidence)
Leadership. Knowledge. Community.
THANK YOU!
QUESTIONS?