Stroke Prevention in
Atrial Fibrillation
A Review of New Study Results
and
An Exploration of their Clinical Implications
Stroke Prevention in Atrial Fibrillation
-Question #1
•
Which of the following items are factors that determine
the effectiveness of a therapy?
A) Efficacy
B) Penetration
C) Adherence
D) All of the above
Stroke Prevention in Atrial Fibrillation
-Question #2
•
What percentage of patients with atrial fibrillation are
optimally treated with Warfarin (i.e. INR is at target) in
the Primary Care setting are?
A) 15%
B) 25%
C) 50%
D) 75%
Stroke Prevention in Atrial Fibrillation
-Question #3
•
What percentage of patients who have a documented
history of stroke secondary to atrial fibrillation, and
who now present to the hospital with a second stroke,
are optimally treated with Warfarin (i.e. INR is at
target)?
A) 10%
B) 20%
C) 40%
D) 80%
Stroke Prevention in Atrial Fibrillation
-Question #4
•
True or False: Treating patients with antiarrhythmic
medications to prevent recurrences of Atrial Fibrillation
help to prevent subsequent strokes.
A) True
B) False
Stroke Prevention in
Atrial Fibrillation
A Review of New Study Results
and
An Exploration of their Clinical Implications
Stroke Prevention in Atrial Fibrillation
-Disclosures
•
•
•
•
•
Astra Zeneca Canada Inc.
Boehringer Ingelheim Inc.
Bristol Myers Squibb Canada
Sanofi Aventis Pharma Inc.
Servier Canada Inc.
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
Years after randomization
•
N Engl J Med 2002; 347: 1825-33.
4
5
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
Stroke Prevention in Atrial Fibrillation
-Efficacy of Warfarin
-Meta-Analysis of Antithrombotic Therapy in A Fib
Relative Risk Reduction
(95% CI)
Adjusted-dose warfarin compared
with placebo or control
Study
Year
AFASAK I
1989; 1990
SPAF I
1991
BAATAF
1990
CAFA
1991
SPINAF
1992
EAFT
1993
All trials (n=6)
N=2,900
100%
50%
Favors Warfarin
•
Ann Intern Med 2007; 146: 857-67.
0
-50%
Favors Placebo
or Control
-100%
Stroke Prevention in Atrial Fibrillation
-Efficacy of Anti-Platelet Therapy
-Meta-Analysis of Antithrombotic Therapy in A Fib
Antiplatelet agents compared
with placebo or control
Study
Year
AFASAK I
1989; 1990
SPAF I
EAFT
ESPS II
LASAF
Daily
Alternate day
1991
1993
1997
1997
UK-TIA
300 mg daily
1200 mg daily
1999
JAST
2006
Relative Risk Reduction
(95% CI)
Aspirin trials (n=7)
SAFT
2003
ESPS II
Dipyridamole
Combination
1997
All antiplatelet trials (n=8)
N=4,876
•
100%
50%
0
Favors Antiplatelet
Ann Intern Med 2007; 146: 857-67.
-50%
-100%
Favors Placebo
or Control
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
0
-10
Risk
Reduction
in Stroke
(%)
-40
-50
-60
-70
•
-22 %
-20
-30
-64 %
Warfarin Antiplatelets
Ann Intern Med 2007; 146: 857-67.
40
35
30
Safety
25
Outcom es 20
15
(n)
10
5
0
W
A
W
A
ICH
Major ECH
Stroke Prevention in Atrial Fibrillation
-Anti-Thrombotic Therapy in Atrial Fibrillation
-ACC/AHA/ESC Guidelines 2006
High Risk
Moderate Risk
Rheumatic Valve
Prior Stroke/TIA
Or
>2 Risk Factors:
•Age >75
•Hypertension
•Diabetes
•Congestive Heart Failure
1 Risk Factor:
•Age >75
•Hypertension
•Diabetes
•Congestive Heart Failure
Warfarin
INR Range 2.0 – 3.0
Warfarin
INR Range 2.0 – 3.0
Or
Aspirin 75-325mg/day
•
Europace 2006; 8: 651-745.
Low Risk
Age <75
No Additional Risk
Factors
Aspirin 75-325mg/day
Stroke Prevention in Atrial Fibrillation
-Effective vs. Efficacious Drug Therapy
Efficacy
Penetration
Adherence
Effectiveness
•
Efficacy is a necessary but not sufficient condition for the effective
prevention of cardiovascular disease and is ideally established through
randomized, controlled experimental studies
Stroke Prevention in Atrial Fibrillation
-Limitations of Warfarin Therapy in Atrial Fibrillation
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
Numerous food-drug
interactions
Numerous drug-drug
interactions
Risk of Bleeding
Complications
Warfarin was #1 in 2003 and 2004 in the number of mentions of “deaths
for drugs causing adverse effects in therapeutic use”
Warfarin caused 6% of the 702,000 ADEs treated in the ED/year; 17%
required hospitalization
J Thromb Thrombolysis 2008; 25: 52-60.
Stroke Prevention in Atrial Fibrillation
-Limitations of Warfarin Therapy in Atrial Fibrillation
-Narrow Therapeutic Window
Target
INR
(2.0-3.0)
80
Events / 1000 patient years
Ischaemic stroke
Intracranial haemorrhage
The anticoagulant
effect of vitamin K
antagonists are
optimized when
therapeutic doses are
maintained within a
very narrow range
60
40
20
0
•
<1.5
1.5–1.9
2.0–2.5
2.6–3.0
N Engl J Med 2003; 349: 1019-26.
3.1–3.5
3.6-4.0
4.1-4.5
>4.5
International Normalised Ratio (INR)
Stroke Prevention in Atrial Fibrillation
-Limitations of Warfarin Therapy in Atrial Fibrillation
-Adequacy of Anticoagulation in Primary Care
No warfarin
65%
INR Above Target
6%
INR at Target
15%
Subtherapeutic INR
13%
•
Arch Intern Med 2000; 160: 967.
Stroke Prevention in Atrial Fibrillation
-Limitations of Warfarin Therapy in Atrial Fibrillation
-Preventable Strokes in Patients with Atrial Fib
No warfarin
61%
INR at Target
10%
Subtherapeutic INR
29%
•
•
Analyzed 597 patients with a first ischemic stroke who had known atrial
fibrillation, were classified as high risk for stroke, and who had no known
contraindications to anticoagulation
Stroke 2009; 40: 235-40.
Stroke Prevention in Atrial Fibrillation
-Limitations of Warfarin Therapy in Atrial Fibrillation
-2o Prevention of Strokes in Patients with A Fib
No warfarin
43%
INR at Target
18%
Subtherapeutic INR
39%
•
•
Analyzed 323 patients with a second ischemic stroke who had known
atrial fibrillation at the time of their first stroke, and who had no known
contraindications to anticoagulation
Stroke 2009; 40: 235-40.
Stroke Prevention in Atrial Fibrillation
-Reasons for Coumadin Non-Adherence
-The ACTIVE-A Study
Bleeding
Risk
(23.5%)
Physician
Judgement
(50.4%)
Patient
Preference
(26.1%)
•
N Engl J Med 2009; 360: 2066-78.
Stroke Prevention in Atrial Fibrillation
-Reasons for Coumadin Non-Adherence
-The ACTIVE-A Study Low Plt
NSAID
Bleeding
Risk
(23.5%)
EtOH
Use
(1.1%)
PUD
(0.7%) (2.2%)
Use
(1.6%)
Previous Bleeding
on OAC (5.8%)
Hypertension (3.2%)
Fall Risk (9.8%)
Patient
Preference
(26.1%)
•
N Engl J Med 2009; 360: 2066-78.
Physician
Judgement
(50.4%)
Stroke Prevention in Atrial Fibrillation
-Reasons for Coumadin Non-Adherence
-The ACTIVE-A Study
Bleeding
Risk
(23.5%)
Physician
Judgement
(50.4%)
Patient
Preference
(26.1%)
•
N Engl J Med 2009; 360: 2066-78.
Stroke Prevention in Atrial Fibrillation
-Reasons for Coumadin Non-Adherence
-The ACTIVE-A Study
Bleeding
Risk
(23.5%)
Concerns re: Adherence
(0.7%)
Coumadin
Not Indicated
(28.6%)
Physician
Judgement
(50.4%)
Patient
Preference
(26.1%)
•
N Engl J Med 2009; 360: 2066-78.
Both
(22.8%)
Stroke Prevention in Atrial Fibrillation
-Reasons for Coumadin Non-Adherence
-The ACTIVE-A Study
Bleeding
Risk
(23.5%)
Physician
Judgement
(50.4%)
Patient
Preference
(26.1%)
•
N Engl J Med 2009; 360: 2066-78.
Stroke Prevention in Atrial Fibrillation
-Reasons for Coumadin Non-Adherence
-The ACTIVE-A Study
Bleeding
Risk
(23.5%)
Physician
Judgement
(50.4%)
Patient
Preference
(26.1%)
“Not Willing To Take Coumadin”
is the sole reason in 26.1% of Patients
•
N Engl J Med 2009; 360: 2066-78.
Another 22.8% of
Patients “Not Willing
To Take Coumadin”
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
ACTIVE A
6500 patients
Clopidogrel+ASA vs. Warfarin
7500 patients
Clopidogrel+ASA vs. ASA
No Exclusion criteria for ACTIVE I
ACTIVE I
~9000 patients
Irbesartan vs 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
0.02
2.2 %/year
0.01
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
-INR Control in the ACTIVE-W Study
-The ACTIVE-W Study
•
INR Range
Percent patient months
in range
<2.0
20.8
2.0-3.0
63.9
>3.0
15.4
Lancet 2006; 367: 1903-12.
Stroke Prevention in Atrial Fibrillation
0.10
C+A
0.06
0.06
RR = 1.83
RR = 1.11
C+A
P = 0.47
0.04
0.04
P < 0.0001
0.02
0.02
OAC
0.0
OAC
0.0
•
<65% INR in Range
0.08
0.08
 65% INR in Range
0.0
Cumulative Hazard Rates
0.10
-Stroke, Embolism, MI and Vascular Death by INR
-The ACTIVE-W Study
0.5
1.0
1.5
0.0
Years
Lancet 2006; 367: 1903-12.
0.5
1.0
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
ACTIVE A
6500 patients
Clopidogrel+ASA vs. Warfarin
7500 patients
Clopidogrel+ASA vs. ASA
No Exclusion criteria for ACTIVE I
ACTIVE I
~9000 patients
Irbesartan vs 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
28% RRR
408 (3.3%/year)
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
Stroke Prevention in Atrial Fibrillation
-Risk vs. Benefit of ASA+Clopidogrel vs. Warfarin
-The ACTIVE-A Study
Meta-analysis
ACTIVE A
OAC vs ASA2
Clopidogrel + ASA vs ASA3
38%
28%
Relative increase in major
extracranial bleeding
70%
51%
Relative increase in
intracranial bleeding
128%
87%
Benefit
Relative reduction in
stroke
Risk
•
If 1000 patients were treated with clopidogrel plus ASA over the course of 3 years,
this would prevent 28 strokes, 17 of which would be fatal or disabling as well as 6
MIs1
•
This would occur at a cost of 20 major (non-stroke) bleeds, including 3 fatal bleeds
•
•
Ann Intern Med 2007; 146: 857-67.
N Engl J Med 2009; 360: 2066-78.
Stroke Prevention in Atrial Fibrillation
-Pradax (dabigatran): An Oral Direct Thrombin
Inhibitor
• Dabigatran is a reversible oral direct thrombin inhibitor (DTI)
• It blocks the activity of thrombin (both free and clot-bound), the
•
•
•
•
•
•
•
central enzyme in the process responsible for clot (thrombus)
formation
6.5% bioavailability
Rapid onset of action (Peak Plasma concentration at 2 h post-dose)
~ 80% renally excreted
T½ of 12-17 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 RE-LY Study
-Study Design
Atrial fibrillation with ≥ 1 risk factor
Absence of contraindications
R
Warfarin
1 mg, 3 mg, 5 mg
(INR 2.0-3.0)
N=6000
•
•
•
Dabigatran etexilate
110 mg bid
N=6000
Dabigatran etexilate
150 mg bid
N=6000
Primary objective: To establish the non-inferiority of dabigatran etexilate to warfarin
Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up
N Engl J Med 2009; 361 : 1139-51.
Stroke Prevention in Atrial Fibrillation
-The RE-LY Study
-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
N Engl J Med 2009; 361 : 1139-51.
Stroke Prevention in Atrial Fibrillation
-The RE-LY Study
-Primary Outcome: Stroke or Systemic Embolism
Noninferiority
p-value
Margin = 1.46
Dabigatran 110 mg
vs. warfarin
Dabigatran 150 mg
vs. warfarin
0.50
0.75
1.00
1.25
HR (95% CI)
•
N Engl J Med 2009; 361: 1139-51.
1.50
Superiority
p-value
<0.001
0.34
<0.001
<0.001
Stroke Prevention in Atrial Fibrillation
-The RE-LY Study
-Primary Outcome: Stroke or Systemic Embolism
RR 0.91
(95% CI: 0.74–1.11)
p<0.001 (NI)
p=0.34 (Sup)
Cumulative hazard rates
0.05
0.04
RRR
34%
Warfarin
Dabigatran etexilate 110 mg
Dabigatran etexilate 150 mg
0.03
RR 0.66
(95% CI: 0.53–0.82)
p<0.001 (NI)
p<0.001 (Sup)
0.02
0.01
0.0
0
0.5
1.0
1.5
Years
•
N Engl J Med 2009; 361: 1139-51.
2.0
2.5
Stroke Prevention in Atrial Fibrillation
-The RE-LY Study
-Intracranial Bleeding
Warfarin
Dabigatran etexilate 110 mg
Dabigatran etexilate 150 mg
Cumulative hazard rates
0.02
RRR
60%
0.01
RR 0.40
(95% CI: 0.27–0.60)
p<0.001 (Sup)
RR 0.31
(95% CI: 0.20–0.47)
p<0.001 (Sup)
0.0
0
0.5
1.0
1.5
Years
•
N Engl J Med 2009; 361: 1139-51.
2.0
2.5
RRR
69%
Stroke Prevention in Atrial Fibrillation
-The RE-LY Study
-Major Bleeding in the RE-LY Study
Dabigatran
110 mg
Dabigatran
150 mg
Warfarin
Number of patients (n)
6015
6076
6022
Major bleeding
2.71
3.11
- Life threatening
- Non-life threatening
- Gastrointestinal
1.22
1.66
1.12
1.45
1.88
1.51
Data represents %/year
•
N Engl J Med 2009; 361: 1139-51.
P-value
110 vs. W
P-value
150 vs. W
3.36
0.003
0.31
1.80
1.76
1.02
<0.001
0.56
0.43
0.037
0.47
<0.001
Stroke Prevention in Atrial Fibrillation
-The RE-LY Study
-Major Bleeding in the RE-LY Study
Dabigatran
110 mg
Dabigatran
150 mg
Warfarin
Number of patients (n)
6015
6076
6022
Major bleeding
2.71
3.11
- Life threatening
- Non-life threatening
- Gastrointestinal
1.22
1.66
1.12
1.45
1.88
1.51
Data represents %/year
•
N Engl J Med 2009; 361: 1139-51.
P-value
110 vs. W
P-value
150 vs. W
3.36
0.003
0.31
1.80
1.76
1.02
<0.001
0.56
0.43
0.037
0.47
<0.001
Stroke Prevention in Atrial Fibrillation
-The RE-LY Study
-Most Common Side Effects
Dyspepsia*
Dabigatran 110 mg Dabigatran 150 mg
%
%
11.8
11.3
Warfarin
%
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
•
N Engl J Med 2009; 361: 1139-51.
Stroke Prevention in Atrial Fibrillation
-The RE-LY Study
-Most Common Side Effects
Dabigatran 110 mg
%
11.8
Dabigatran 150 mg
%
11.3
Warfarin
%
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
Dyspepsia*
*Occurred more commonly on dabigatran p<0.001
•
N Engl J Med 2009; 361: 1139-51.
Stroke Prevention in Atrial Fibrillation
-Major Bleeding in the RE-LY Study
-The Dabigatran Capsule
Dabigatran
Capsule
Dabigatran
Pellet
Tartaric
Acid Core
Dabigatran
Coat
Seal Coating
Stroke Prevention in Atrial Fibrillation
-The Antithrombotic Therapy In Perspective
Warfarin vs. Placebo
Warfarin vs. ASA
Warfarin vs. ASA + clopidogrel
Warfarin vs. dabigatran 150
0
0.3
0.6
0.9
Favours warfarin
1.2
1.5 1.8 2.0
Favours other treatment
Stroke Prevention in Atrial Fibrillation
-The Antithrombotic Therapy In Perspective
More
Bleeding
Warfarin
Less
Strokes
1.5 ASA+Clopidogrel
0.75
1.5
2.0
2.5
3.0
0.75
Dabigatran
Aspirin
0.5
Less
Bleeding
Placebo
More
Strokes
Stroke Prevention in Atrial Fibrillation
-The Antithrombotic Therapy In Perspective
Treatment
Stroke Risk
(/year)
No Therapy
4.5
ASA
3.7
ASA + Clopidogrel
2.8
Warfarin
1.7
Dabigatran 110
1.5
Dabigatran 150
1.1
Stroke Prevention in Atrial Fibrillation
-The Antithrombotic Therapy In Perspective
Treatment
Stroke Risk
(/year)
No Therapy
4.5
ASA
3.7
ASA + Clopidogrel
2.8
Warfarin
1.7
Dabigatran 110
1.5
Dabigatran 150
1.1
64%
Stroke Prevention in Atrial Fibrillation
-The Antithrombotic Therapy In Perspective
Treatment
Stroke Risk
(/year)
No Therapy
4.5
ASA
3.7
ASA + Clopidogrel
2.8
Warfarin
1.7
Dabigatran 110
1.5
Dabigatran 150
1.1
34%
Stroke Prevention in Atrial Fibrillation
-The Antithrombotic Therapy In Perspective
Treatment
Stroke Risk
(/year)
No Therapy
4.5
ASA
3.7
ASA + Clopidogrel
2.8
Warfarin
1.7
Dabigatran 110
1.5
Dabigatran 150
1.1
76%
Stroke Prevention in Atrial Fibrillation
-The Natural History of Atrial Fibrillation
Paroxysmal
A Fib
Persistent
A Fib
Permanent
A Fib
Sinus Rhythm
Asymptomatic A Fib
Symptomatic A Fib
Cardiovascular Outcomes
(Stroke, Death, Hospitalization)
Stroke Prevention in Atrial Fibrillation
-A “New” Way to Look at Atrial Fibrillation
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
ACTIVE A
6500 patients
Clopidogrel+ASA vs. Warfarin
7500 patients
Clopidogrel+ASA vs. ASA
SBP>110mmHg
Not on an ATII Blocker
No Proven Indication for an ATII Blocker
No Contraindication for an ATII Blocker
ACTIVE I
~9000 patients
Irbesartan vs placebo
Stroke Prevention in Atrial Fibrillation
-Time to First Stroke, MI or Vascular Death
-The ACTIVE-I Study
Cumulative Incidence
0.4
0.3
0.2
0.1
0.0
0
•
1
2
Years
3
4
4.5
Presented at the European Society of Cardiology, Barcelona, 2009.
Stroke Prevention in Atrial Fibrillation
-Stroke and Other Thromboembolic Events
-The ACTIVE-I Study
Stroke
TIA
Non-CNS Embolism
Stroke/TIA/Non-CNS Emb
•
Irbesartan
(n=4,518)
n
%/year
380
2.1
130
0.7
49
0.3
518
2.9
Placebo
(n=4,498)
n
%/year
411
2.3
150
0.8
65
0.4
585
3.4
Hazard
Ratio
95% CI
p
Value
0.92
0.86
0.74
0.87
0.80-1.05
0.68-1.09
0.51-1.07
0.78-0.98
0.213
0.208
0.114
0.024
Presented at the European Society of Cardiology, Barcelona, 2009.
Stroke Prevention in Atrial Fibrillation
-Etiology of Stroke in Atrial Fibrillation
-The ACTIVE-I Study
Lacunar
20%
SAH
10%
Hemorrhagic
20%
Thromboembolic
10%
Cardioembolic
20%
Ischemic
80%
ICH
10%
Other 5%
•
Stroke 2006; 37: 2493-8.
Unknown
25%
Stroke Prevention in Atrial Fibrillation
-Etiology of Stroke in Atrial Fibrillation
-The ACTIVE-I Study
Stroke Prevention in Atrial Fibrillation
-Prevention of A Fib with ACE-I and ATII Blockers
-A Meta-Analysis
ACE-I
VanDenBerg
SOLVD
TRACE
Ueng
CAPP
STOPH2
GISSI
Subtotal
ARB
Madrid
ValHeFT
Charm
LIFE
Subtotal
Total
Relative Risk Reduction
(95% CI)
Control
711
45/188
42/787
32/75
135/5493
357/4409
721/8846
1339/19809
9/79
116/2209
179/2769
179/4417
483/9474
22/75
173/2200
216/2749
252/4387
663/9411
0.39 (0.19-0.79)
0.67 (0.53-0.84)
0.82 (0.68-1.00)
0.71 (0.59-0.85)
0.71 (0.60-0.84)
1517/27089
2002/29220
0.72 (0.60-0.85)
0.1
•
RR (95% CI)
0.45 (0.13-1.57)
0.22 (0.12-0.43)
0.52 (0.31-0.87)
0.60 (0.37-0.97)
0.87 (0.68-1.11)
1.12 (0.95-1.32)
0.92 (0.83-1.02)
0.72 (0.56-0.93)
Treatment
2/7
10/186
22/790
18/70
117/5492
200/2205
665/8865
1034/17615
0.2
Favors Treatment
J Am Coll Cardiol 2005; 45: 1832-9.
1.0
5.0
Favors Control
10.0
Stroke Prevention in Atrial Fibrillation
-Arrhythmia Outcomes
-The ACTIVE-I Study
•
There was no difference in the Number of Patients who
converted to Normal Sinus Rhythm from Atrial
Fibrillation
There was no difference in the Number of Patients who
progressed from Normal Sinus Rhythm to Atrial
Fibrillation
There was no difference in Hospital Admissions for
Atrial Fibrillation
There was no difference in Cardioversions
•
•
•
•
Presented at the European Society of Cardiology, Barcelona, 2009.
Stroke Prevention in Atrial Fibrillation
-Baseline Characteristics
-The ACTIVE-I Study
Age (mean)
% Female
Atrial Fibrillation
-Permanent (%)
-Paroxysmal (%)
-Persistent (%)
Sinus Rhythm (%)
Heart Failure (%)
CHADS Risk Score
SBP/DBP (mmHg)
Heart Rate
•
Irbesartan
(n=4,518)
69.5
39.2
Placebo
(n=4,498)
69.6
39.3
66.0
19.6
14.3
18.7
32.3
1.99
138/83
75.3
64.4
20.5
14.9
19.6
31.6
1.97
138/82
74.9
Presented at the European Society of Cardiology, Barcelona, 2009.
Stroke Prevention in Atrial Fibrillation
-Baseline Characteristics
-The ACTIVE-I Study
Age (mean)
% Female
Atrial Fibrillation
-Permanent (%)
-Paroxysmal (%)
-Persistent (%)
Sinus Rhythm (%)
Heart Failure (%)
CHADS Risk Score
SBP/DBP (mmHg)
Heart Rate
•
Irbesartan
(n=4,518)
69.5
39.2
Placebo
(n=4,498)
69.6
39.3
66.0
19.6
14.3
18.7
32.3
1.99
138/83
75.3
64.4
20.5
14.9
19.6
31.6
1.97
138/82
74.9
Presented at the European Society of Cardiology, Barcelona, 2009.
Stroke Prevention in Atrial Fibrillation
-Population Attributable Fraction for Hypertension
-The ARIC Study
Lacunar
Thromboembolic
Cardioembolic
40
35
30
% Of
Patients
25
20
15
10
5
0
•
•
•
Hypertension
Diabetes
Smoking
Followed 14,448 people who were free of clinical stroke for 13.4 years
Hypertension is the most powerful predictor for all stroke subtypes
Stroke 2006; 37: 2493-8.
Stroke Prevention in Atrial Fibrillation
-Effect of BP on Stroke in Patients with A Fib
-The SPORTIF Trials
4.0
Event Rate (%/Year)
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
100
110
120
130
Mean SBP (mmHg)
•
European Heart Journal 2007; 28: 752-9.
140
150
160
Stroke Prevention in Atrial Fibrillation
-Baseline Characteristics
-The ACTIVE-I Study
Age (mean)
% Female
Atrial Fibrillation
-Permanent (%)
-Paroxysmal (%)
-Persistent (%)
Sinus Rhythm (%)
Heart Failure (%)
CHADS Risk Score
SBP/DBP (mmHg)
Heart Rate
•
Irbesartan
(n=4,518)
69.5
39.2
Placebo
(n=4,498)
69.6
39.3
66.0
19.6
14.3
18.7
32.3
1.99
138/83
75.3
64.4
20.5
14.9
19.6
31.6
1.97
138/82
74.9
Presented at the European Society of Cardiology, Barcelona, 2009.
Stroke Prevention in Atrial Fibrillation
-Baseline Characteristics
-The ACTIVE-I Study
Age (mean)
% Female
Atrial Fibrillation
-Permanent (%)
-Paroxysmal (%)
-Persistent (%)
Sinus Rhythm (%)
Heart Failure (%)
CHADS Risk Score
SBP/DBP (mmHg)
Heart Rate
•
Irbesartan
(n=4,518)
69.5
39.2
Placebo
(n=4,498)
69.6
39.3
66.0
19.6
14.3
18.7
32.3
1.99
138/83
75.3
64.4
20.5
14.9
19.6
31.6
1.97
138/82
74.9
Presented at the European Society of Cardiology, Barcelona, 2009.
Stroke Prevention in Atrial Fibrillation
-Baseline Medications
-The ACTIVE-I Study
Irbesartan
(n=4,518)
60.2
54.4
54.3
27.0
11.9
Placebo
(n=4,498)
60.6
54.6
54.1
27.2
11.1
Aspirin
58.7
59.3
Warfarin
38.1
37.6
Antiarrhythmics
22.7
23.1
Digoxin
35.1
34.7
ACE-I (%)
Beta-Blockers (%)
Diuretic (%)
Ca2+ Channel Blocker (%)
Alpha-Blocker/Vasodilator (%)
•
Presented at the European Society of Cardiology, Barcelona, 2009.
Stroke Prevention in Atrial Fibrillation
-Baseline Medications
-The ACTIVE-I Study
Irbesartan
(n=4,518)
60.2
54.4
54.3
27.0
11.9
Placebo
(n=4,498)
60.6
54.6
54.1
27.2
11.1
Aspirin
58.7
59.3
Warfarin
38.1
37.6
Antiarrhythmics
22.7
23.1
Digoxin
35.1
34.7
ACE-I (%)
Beta-Blockers (%)
Diuretic (%)
Ca2+ Channel Blocker (%)
Alpha-Blocker/Vasodilator (%)
•
Presented at the European Society of Cardiology, Barcelona, 2009.
Stroke Prevention in Atrial Fibrillation
-Wading into the Deep End
Stroke Prevention in Atrial Fibrillation
-Dronedarone: A New Antiarrhythmic Medication
Dronedarone
O
(CH2)3CH3
CH3SO2HN
O(CH2)3N
(CH2)3CH3
(CH2)3CH3
O
O
(CH2)3CH3
I
O(CH2)2N
Amiodarone
O
I
CH2CH3
CH2CH3
Stroke Prevention in Atrial Fibrillation
-Study Design
-The ATHENA Study
4,628 patients >75 years with atrial fibrillation or 70-75 years with atrial fibrillation
and at least one additional cardiovascular Risk Factor* prior to randomization.
Double blind. Randomized. Placebo controlled. International multicenter. Mean
follow-up 21 months.
R
Dronedarone 400 mg BID
Placebo
12-30 mos. follow-up


•
•
Primary Endpoint: composite of all-cause mortality combined
with cardiovascular hospitalization
Secondary Endpoint: death from any cause, cardiovascular
death, hospitalization for cardiovascular reasons
*Risk Factor=Htn, diabetes, prior stroke/TIA, LA ≥50 mm, LVEF <40%
N Engl J Med 2009; 360: 668-78.
Stroke Prevention in Atrial Fibrillation
-Cardiovascular Hospitalization or Death
-The ATHENA Study
Cumulative Incidence (%)
50
Placebo on top of standard therapy*
Dronedarone 400mg bid on top of standard therapy*
24%
40
reduction
in relative
risk
30
20
HR=0.76
p<0.001
10
Months
0
0
•
•
6
12
18
24
30
*Standard therapy may have included anti-thrombotic therapy and/or rate
control agents and/or other cardiovascular agents such as ACE-I statins
N Engl J Med 2009; 360: 668-78.
Stroke Prevention in Atrial Fibrillation
-Cardiovascular Hospitalization
-The ATHENA Study
Reason for first CV
hospitalisation
Placebo
n=2327
Dronedarone
n=2301
HR
95% CI
p value
859
675
0.74
0.67; 0.82
<0.001
Atrial Fibrillation
510
335
0.63
0.55; 0.72
<0.001
CHF
132
112
0.86
0.67; 1.10
0.22
ACS
89
62
0.70
0.51; 0.97
0.03
Syncope
32
27
0.85
0.51; 1.42
0.54
Ventricular arrhythmia or
cardiac arrest
12
13
1.09
0.50; 2.39
0.83
Any reason
•
N Engl J Med 2009; 360: 668-78.
Stroke Prevention in Atrial Fibrillation
-Effect of Dronedarone on Stroke
-The ATHENA Study
Placebo on top of standard therapy*
Dronedarone (DR) 400mg bid on top of standard therapy*
Cumulative Incidence (%)
5
34%
reduction in
relative risk
HR=0.66
p=0.027
4
3
2
1
0
0
•
•
•
6
12
18
24
HR=0.48 if CHAD>1, but no benefit if CHADS<1
60% of patients were on Warfarin
Circulation 2009; 120: 1174-1180.
30
Months
Stroke Prevention in Atrial Fibrillation
-Conclusions
•
•
•
While Warfarin has been proven to be an efficacious
therapy for the prevention of stroke in atrial fibrillation,
its effectiveness is limited by poor adherence as a
result of both physician and patient related factors
Novel strategies have been developed to potentially
replace Warfarin, including combination antiplatelet
therapy and oral direct thrombin inhibitors, which are
both safe and effective
Antiarrhythmic medications may be making a
resurgence in the prevention of stroke in atrial
fibrillation
Stroke Prevention in Atrial Fibrillation
-Practical Aspects to Dabigatran Administration
• Dosing:




Currently Dabigatran is only available in the 110mg formulation and should be
dosed at 110mg po bid for Stroke Prevention in Atrial Fibrillation
Should not use if the CrCL<30mL/min (80% Renally Excreted)
When switching from Warfarin to Dabigatran, the Warfarin should be held, and
the Dabigatran should be started when the INR falls below 2
Aspirin, Plavix or Aggrenox may be used concomitantly with Dabigatran
• Surgical Considerations:


Dabigatran should be discontinued at least 24 hours prior to elective surgical
procedures
Dabigatran should be resumed as soon as it is clinically feasible post procedure
• Bleeding:




Dabigitran has a half-life of 12-17 hours
FFP may be used to help control bleeding
Can use aPTT or Thrombin Time to monitor effect
Dabigatran is dialyzable
Stroke Prevention in Atrial Fibrillation
-Etiology of Stroke in Atrial Fibrillation
-The ACTIVE-I Study