stroke prevention in atrial fibrillation
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Stroke Prevention inStroke Prevention inAtrial FibrillationAtrial Fibrillation
A Review of New Study Results
and
An Exploration of their Clinical Implications
• 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 FibrillationStroke Prevention in Atrial Fibrillation -Question #1 -Question #1
• 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 FibrillationStroke Prevention in Atrial Fibrillation -Question #2 -Question #2
• 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 FibrillationStroke Prevention in Atrial Fibrillation -Question #3 -Question #3
• 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 FibrillationStroke Prevention in Atrial Fibrillation -Question #4 -Question #4
Stroke Prevention inStroke Prevention inAtrial FibrillationAtrial Fibrillation
A Review of New Study Results
and
An Exploration of their Clinical Implications
• Astra Zeneca Canada Inc.
• Boehringer Ingelheim Inc.
• Bristol Myers Squibb Canada
• Sanofi Aventis Pharma Inc.
• Servier Canada Inc.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Disclosures -Disclosures
Years after randomization
CumulativeMortality
(%)
00
1 2 3 4 5
5
10
15
20
25
30
All-cause mortality
Rhythm control
Rate control
P=0.08
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Mortality in Rate vs. Rhythm Control Patients -Mortality in Rate vs. Rhythm Control Patients
-The AFFIRM Study-The AFFIRM Study
• N Engl J Med 2002; 347: 1825-33.
Sinus Rhythm
Antiarrhythmic Use
Warfarin Use
Digoxin Use
0.5 1.0 1.5
Risk Ratio0
pValue
<0.0001
0.0005
<0.0001
0.0005
• N Engl J Med 2002; 347: 1825-33.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Mortality in Rate vs. Rhythm Control Patients -Mortality in Rate vs. Rhythm Control Patients
-The AFFIRM Study-The AFFIRM Study
2.0
Study Year
AFASAK I 1989; 1990
SPAF I 1991
BAATAF 1990
CAFA 1991
SPINAF 1992
EAFT 1993
All trials (n=6)
N=2,900
Relative Risk Reduction(95% CI)
Relative Risk Reduction(95% CI)
Favors Warfarin Favors Warfarin Favors Placeboor Control
Favors Placeboor Control
100%100% 50%50% 00 -50%-50% -100%-100%
Adjusted-dose warfarin comparedwith placebo or controlAdjusted-dose warfarin comparedwith placebo or control
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Efficacy of Warfarin -Efficacy of Warfarin
-Meta-Analysis of Antithrombotic Therapy in A Fib-Meta-Analysis of Antithrombotic Therapy in A Fib
• Ann Intern Med 2007; 146: 857-67.
Study Year
AFASAK I 1989; 1990
SPAF I 1991
EAFT 1993
ESPS II 1997
LASAF 1997
DailyAlternate day
UK-TIA300 mg daily1200 mg daily
1999
JAST 2006
Aspirin trials (n=7)
SAFT 2003
ESPS IIDipyridamoleCombination
1997
All antiplatelet trials (n=8)
Antiplatelet agents compared with placebo or controlAntiplatelet agents compared with placebo or control
Relative Risk Reduction(95% CI)
Relative Risk Reduction(95% CI)
Favors Antiplatelet Favors Antiplatelet Favors Placeboor Control
Favors Placeboor Control
100%100% 50%50% 00 -50%-50% -100%-100%N=4,876N=4,876
• Ann Intern Med 2007; 146: 857-67.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Efficacy of Anti-Platelet Therapy -Efficacy of Anti-Platelet Therapy
-Meta-Analysis of Antithrombotic Therapy in A Fib-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
Warfarin Antiplatelets
• Ann Intern Med 2007; 146: 857-67.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Efficacy and Safety of Current A Fib Treatments -Efficacy and Safety of Current A Fib Treatments
-Meta-Analysis of Antithrombotic Therapy in A Fib-Meta-Analysis of Antithrombotic Therapy in A Fib
05
10152025303540
Safety Outcomes
(n)
ICH Major ECH
WW
AA
WW
AA
-64
-22
-70
-60
-50
-40
-30
-20
-10
0
Risk Reduction in Stroke
(%)
% %
% %
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Anti-Thrombotic Therapy in Atrial Fibrillation-Anti-Thrombotic Therapy in Atrial Fibrillation
-ACC/AHA/ESC Guidelines 2006-ACC/AHA/ESC Guidelines 2006
• Europace 2006; 8: 651-745.
High Risk Moderate Risk Low 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
Age <75
No Additional Risk Factors
Warfarin
INR Range 2.0 – 3.0
Warfarin
INR Range 2.0 – 3.0
Or
Aspirin 75-325mg/day
Aspirin 75-325mg/day
• Efficacy is a necessary but not sufficient condition for the effective prevention of cardiovascular disease and is ideally established through randomized, controlled experimental studies
Effectiveness
Efficacy
Adherence
Penetration
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Effective vs. Efficacious Drug Therapy-Effective vs. Efficacious Drug Therapy
Unpredictable response
Routine coagulation monitoring
Slow onset/offset of action
Risk of BleedingComplications
Warfarin therapy has
several limitations
that make it difficult to
use in practice
Numerous drug-drug interactions
Numerous food-drug interactions
Frequent dose adjustments
Narrow therapeutic window
(INR range 2-3)
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Limitations of Warfarin Therapy in Atrial Fibrillation-Limitations of Warfarin Therapy in Atrial Fibrillation
• 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.
International Normalised Ratio (INR)
Target INR
(2.0-3.0)
<1.5 1.5–1.9 2.0–2.5 2.6–3.0 3.1–3.5 3.6-4.0 4.1-4.5 >4.50
20
40
60
80
Eve
nts
/ 10
00 p
atie
nt
year
s
Intracranial haemorrhageIschaemic stroke
The anticoagulant effect of vitamin K antagonists are optimized when therapeutic doses are maintained within a very narrow range
• N Engl J Med 2003; 349: 1019-26.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Limitations of Warfarin Therapy in Atrial Fibrillation-Limitations of Warfarin Therapy in Atrial Fibrillation
-Narrow Therapeutic Window-Narrow Therapeutic Window
INR Above TargetINR Above Target6%6%
Subtherapeutic INR Subtherapeutic INR 13%13%
INR at TargetINR at Target15%15%
No No warfarinwarfarin
65%65%
• Arch Intern Med 2000; 160: 967.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Limitations of Warfarin Therapy in Atrial Fibrillation-Limitations of Warfarin Therapy in Atrial Fibrillation
-Adequacy of Anticoagulation in Primary Care-Adequacy of Anticoagulation in Primary Care
• 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 FibrillationStroke Prevention in Atrial Fibrillation -Limitations of Warfarin Therapy in Atrial Fibrillation-Limitations of Warfarin Therapy in Atrial Fibrillation
-Preventable Strokes in Patients with Atrial Fib-Preventable Strokes in Patients with Atrial Fib
Subtherapeutic INR Subtherapeutic INR 29%29%
INR at TargetINR at Target10%10%
No No warfarinwarfarin
61%61%
• 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 FibrillationStroke Prevention in Atrial Fibrillation -Limitations of Warfarin Therapy in Atrial Fibrillation-Limitations of Warfarin Therapy in Atrial Fibrillation
-2-2oo Prevention of Strokes in Patients with A Fib Prevention of Strokes in Patients with A Fib
Subtherapeutic INR Subtherapeutic INR 39%39%
INR at TargetINR at Target18%18%
No No warfarinwarfarin
43%43%
PhysicianJudgement
(50.4%)
BleedingRisk
(23.5%)
PatientPreference
(26.1%)
• N Engl J Med 2009; 360: 2066-78.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Reasons for Coumadin Non-Adherence-Reasons for Coumadin Non-Adherence
-The ACTIVE-A Study-The ACTIVE-A Study
PhysicianJudgement
(50.4%)
BleedingRisk
(23.5%)
PatientPreference
(26.1%)
Fall Risk (9.8%)
Hypertension (3.2%)
Previous Bleedingon OAC (5.8%)
EtOHUse
(1.1%)
PUD(0.7%)
Low Plt(2.2%)
NSAIDUse
(1.6%)
• N Engl J Med 2009; 360: 2066-78.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Reasons for Coumadin Non-Adherence-Reasons for Coumadin Non-Adherence
-The ACTIVE-A Study-The ACTIVE-A Study
PhysicianJudgement
(50.4%)
BleedingRisk
(23.5%)
PatientPreference
(26.1%)
• N Engl J Med 2009; 360: 2066-78.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Reasons for Coumadin Non-Adherence-Reasons for Coumadin Non-Adherence
-The ACTIVE-A Study-The ACTIVE-A Study
PhysicianJudgement
(50.4%)
BleedingRisk
(23.5%)
PatientPreference
(26.1%)
Concerns re: Adherence(0.7%)
Both(22.8%)
CoumadinNot Indicated
(28.6%)
• N Engl J Med 2009; 360: 2066-78.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Reasons for Coumadin Non-Adherence-Reasons for Coumadin Non-Adherence
-The ACTIVE-A Study-The ACTIVE-A Study
PhysicianJudgement
(50.4%)
BleedingRisk
(23.5%)
PatientPreference
(26.1%)
• N Engl J Med 2009; 360: 2066-78.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Reasons for Coumadin Non-Adherence-Reasons for Coumadin Non-Adherence
-The ACTIVE-A Study-The ACTIVE-A Study
PhysicianJudgement
(50.4%)
BleedingRisk
(23.5%)
PatientPreference
(26.1%)Another 22.8% of
Patients “Not WillingTo Take Coumadin”“Not Willing To Take Coumadin”
is the sole reason in 26.1% of Patients • N Engl J Med 2009; 360: 2066-78.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Reasons for Coumadin Non-Adherence-Reasons for Coumadin Non-Adherence
-The ACTIVE-A Study-The ACTIVE-A Study
Documented AF + 1 risk factor:
Age 75, Hypertension, Prior stroke/TIA, LVEF<45, PAD, Age 55-74 + CAD or diabetes
ACTIVE WClopidogrel+ASA vs. Warfarin
Contra-indications to Warfarin or Unwilling
ACTIVE AClopidogrel+ASA vs. ASA
No Exclusion criteria for ACTIVE I
ACTIVE IIrbesartan vs placebo
6500 patients 7500 patients
~9000 patients
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -The ACTIVE Program -The ACTIVE Program
0.0
0.02
0.04
0.06
0.08
0.10
0.0 0.5 1.0 1.5
OAC
Clopidogrel+ASA
Cu
mul
ativ
e H
azar
d R
ates
Years
3.93 %/year
5.64 %/yearRR = 1.45
P = 0.0002
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Stroke, Embolism, MI and Vascular Death-Stroke, Embolism, MI and Vascular Death
-The ACTIVE-W Study-The ACTIVE-W Study
• Lancet 2006; 367: 1903-12.
0.0
0.01
0.02
0.03
0.04
0.0 0.5 1.0 1.5
OAC
Clopidogrel+ASACu
mul
ativ
e H
azar
d R
ates
Years
2.4 %/year
2.2 %/year
RR = 1.06
P = 0.67
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Major Bleeding-Major Bleeding
-The ACTIVE-W Study-The ACTIVE-W Study
• Lancet 2006; 367: 1903-12.
INR RangePercent 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 FibrillationStroke Prevention in Atrial Fibrillation -INR Control in the ACTIVE-W Study-INR Control in the ACTIVE-W Study
-The ACTIVE-W Study-The ACTIVE-W Study
0.0
0.02
0.04
0.06
0.08
0.10
0.0 0.5 1.0 1.5
OAC
C+A
0.0
0.02
0.04
0.06
0.08
0.10
0.0 0.5 1.0 1.5
OAC
C+A
65% INR in Range <65% INR in Range
Cu
mu
lati
ve H
azar
d R
ates
Years
RR = 1.83
P < 0.0001
RR = 1.11
P = 0.47
• Lancet 2006; 367: 1903-12.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Stroke, Embolism, MI and Vascular Death by INR-Stroke, Embolism, MI and Vascular Death by INR
-The ACTIVE-W Study-The ACTIVE-W Study
Documented AF + 1 risk factor:
Age 75, Hypertension, Prior stroke/TIA, LVEF<45, PAD, Age 55-74 + CAD or diabetes
ACTIVE WClopidogrel+ASA vs. Warfarin
Contra-indications to Warfarin or Unwilling
ACTIVE AClopidogrel+ASA vs. ASA
No Exclusion criteria for ACTIVE I
ACTIVE IIrbesartan vs placebo
6500 patients 7500 patients
~9000 patients
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -The ACTIVE Program -The ACTIVE Program
832 (6.8%/year)
00 11 22 33 44
0.00.0
0.10.1
0.20.2
0.30.3
0.40.4
Cu
mu
lati
ve I
nci
de
nce
Cu
mu
lati
ve I
nci
de
nce
YearsYears
Cum
ulat
ive
Haz
ard
Rat
es0.
00.
10.
20.
30.
4
0 1 2 3 4
Aspirin
Clopidogrel+Aspirin
HR=0.89 (0.81-0.98) p=0.014
3772 3456 3180 2523 11803782 3427 3103 2459 1153
No. at Risk
ASAC+A
Years
ASA
924 (7.6%/year) 11% RRR RR=0.89 (95% CI, 0.81–0.98; P=0.01)
11% RRR RR=0.89 (95% CI, 0.81–0.98; P=0.01)
Clopidogrel + ASA
• N Engl J Med 2009; 360: 2066-78.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Stroke, Embolism, MI and Vascular Death-Stroke, Embolism, MI and Vascular Death
-The ACTIVE-A Study-The ACTIVE-A Study
296 (2.4%/year)
408 (3.3%/year)
Cu
mu
lati
ve In
cid
ence
Cu
mu
lati
ve In
cid
ence
28% RRR RR=0.72 (95% CI,
0.62–0.83; P=<0.001)
28% RRR RR=0.72 (95% CI,
0.62–0.83; P=<0.001)
0.0
0.05
0.10
0.15
0 1 2 3 4
ASA
Clopidogrel + ASA
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Stroke (All Types)-Stroke (All Types)
-The ACTIVE-A Study-The ACTIVE-A Study
• N Engl J Med 2009; 360: 2066-78.
YearsYears
• 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
Meta-analysis ACTIVE A
OAC vs ASA2 Clopidogrel + ASA vs ASA3
BenefitRelative reduction in
stroke38% 28%
RiskRelative increase in major extracranial bleeding
Relative increase in intracranial bleeding
70%
128%
51%
87%
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Risk vs. Benefit of ASA+Clopidogrel vs. Warfarin-Risk vs. Benefit of ASA+Clopidogrel vs. Warfarin
-The ACTIVE-A Study-The ACTIVE-A Study
• Ann Intern Med 2007; 146: 857-67.
• N Engl J Med 2009; 360: 2066-78.
• 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 FibrillationStroke Prevention in Atrial Fibrillation -Pradax (dabigatran): An Oral Direct Thrombin -Pradax (dabigatran): An Oral Direct Thrombin
InhibitorInhibitor
Atrial fibrillation with ≥ 1 risk factorAbsence of contraindications
R
Warfarin1 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 FibrillationStroke Prevention in Atrial Fibrillation -The RE-LY Study-The RE-LY Study
-Study Design-Study Design
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
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -The RE-LY Study-The RE-LY Study
-Inclusion Criteria-Inclusion Criteria
• N Engl J Med 2009; 361 : 1139-51.
0.50 0.75 1.00 1.25 1.50
Dabigatran 110 mg vs. warfarin
Dabigatran 150 mg vs. warfarin
Noninferiorityp-value
<0.001
<0.001
Superiorityp-value
0.34
<0.001
Ma
rgin
= 1
.46
HR (95% CI)
• N Engl J Med 2009; 361: 1139-51.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -The RE-LY Study-The RE-LY Study
-Primary Outcome: Stroke or Systemic Embolism-Primary Outcome: Stroke or Systemic Embolism
0.01
0.02
0.03
0.05
0.04
Cu
mu
lati
ve h
azar
d r
ates
RR 0.91(95% CI: 0.74–1.11)p<0.001 (NI)p=0.34 (Sup)
RR 0.66(95% CI: 0.53–0.82)p<0.001 (NI)p<0.001 (Sup)
Years0 0.5 1.0 1.5 2.0 2.5
0.0
WarfarinDabigatran etexilate 110 mgDabigatran etexilate 150 mg
RRR34%
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -The RE-LY Study-The RE-LY Study
-Primary Outcome: Stroke or Systemic Embolism-Primary Outcome: Stroke or Systemic Embolism
• N Engl J Med 2009; 361: 1139-51.
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)
Cu
mu
lati
ve h
azar
d r
ates
WarfarinDabigatran etexilate 110 mgDabigatran etexilate 150 mg
Years
0.0
0.01
0.02
0 0.5 1.0 1.5 2.0 2.5
RRR60%
RRR69%
• N Engl J Med 2009; 361: 1139-51.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -The RE-LY Study-The RE-LY Study
-Intracranial Bleeding-Intracranial Bleeding
Dabigatran110 mg
Dabigatran150 mg
WarfarinP-value
110 vs. WP-value
150 vs. W
Number of patients (n) 6015 6076 6022
Major bleeding 2.71 3.11 3.36 0.003 0.31
- Life threatening- Non-life threatening - Gastrointestinal
1.221.661.12
1.451.881.51
1.801.761.02
<0.0010.560.43
0.0370.47
<0.001
Data represents %/year
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -The RE-LY Study-The RE-LY Study
-Major Bleeding in the RE-LY Study-Major Bleeding in the RE-LY Study
• N Engl J Med 2009; 361: 1139-51.
Dabigatran110 mg
Dabigatran150 mg
WarfarinP-value
110 vs. WP-value
150 vs. W
Number of patients (n) 6015 6076 6022
Major bleeding 2.71 3.11 3.36 0.003 0.31
- Life threatening- Non-life threatening - Gastrointestinal
1.221.661.12
1.451.881.51
1.801.761.02
<0.0010.560.43
0.0370.47
<0.001
Data represents %/year
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -The RE-LY Study-The RE-LY Study
-Major Bleeding in the RE-LY Study-Major Bleeding in the RE-LY Study
• N Engl J Med 2009; 361: 1139-51.
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
• N Engl J Med 2009; 361: 1139-51.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -The RE-LY Study-The RE-LY Study
-Most Common Side Effects-Most Common Side Effects
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
• N Engl J Med 2009; 361: 1139-51.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -The RE-LY Study-The RE-LY Study
-Most Common Side Effects-Most Common Side Effects
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Major Bleeding in the RE-LY Study-Major Bleeding in the RE-LY Study
-The Dabigatran Capsule-The Dabigatran Capsule
DabigatranCapsule
DabigatranPellet
TartaricAcid Core
Seal CoatingDabigatran
Coat
Warfarin vs. Placebo
Warfarin vs. ASA
Warfarin vs. ASA + clopidogrel
Warfarin vs. dabigatran 150
0 0.3 0.6 0.9 1.2 1.5 1.8 2.0
Favours warfarin Favours other treatment
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -The Antithrombotic Therapy In Perspective-The Antithrombotic Therapy In Perspective
LessBleeding
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -The Antithrombotic Therapy In Perspective-The Antithrombotic Therapy In Perspective
Warfarin
1.5 2.0 2.5 3.00.75
0.5
1.5
0.75Dabigatran
ASA+Clopidogrel
PlaceboAspirin
MoreBleeding
LessStrokes
MoreStrokes
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -The Antithrombotic Therapy In Perspective-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 FibrillationStroke Prevention in Atrial Fibrillation -The Antithrombotic Therapy In Perspective-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 FibrillationStroke Prevention in Atrial Fibrillation -The Antithrombotic Therapy In Perspective-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 FibrillationStroke Prevention in Atrial Fibrillation -The Antithrombotic Therapy In Perspective-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 FibrillationStroke Prevention in Atrial Fibrillation -The Natural History of Atrial Fibrillation-The Natural History of Atrial Fibrillation
Cardiovascular Outcomes(Stroke, Death, Hospitalization)
Sinus Rhythm
Asymptomatic A Fib
Symptomatic A Fib
ParoxysmalA Fib
PersistentA Fib
PermanentA Fib
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -A “New” Way to Look at Atrial Fibrillation-A “New” Way to Look at Atrial Fibrillation
Documented AF + 1 risk factor:
Age 75, Hypertension, Prior stroke/TIA, LVEF<45, PAD, Age 55-74 + CAD or diabetes
ACTIVE WClopidogrel+ASA vs. Warfarin
Contra-indications to Warfarin or Unwilling
ACTIVE AClopidogrel+ASA vs. ASA
SBP>110mmHgNot on an ATII BlockerNo Proven Indication for an ATII BlockerNo Contraindication for an ATII Blocker
ACTIVE IIrbesartan vs placebo
6500 patients 7500 patients
~9000 patients
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -The ACTIVE Program -The ACTIVE Program
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Time to First Stroke, MI or Vascular Death-Time to First Stroke, MI or Vascular Death
-The ACTIVE-I Study-The ACTIVE-I Study
• Presented at the European Society of Cardiology, Barcelona, 2009.
00 11 22 33 44
0.00.0
0.10.1
0.20.2
0.30.3
0.40.4
Cu
mu
lati
ve I
nci
de
nce
Cu
mu
lati
ve I
nci
de
nce
YearsYears4.54.5
• Presented at the European Society of Cardiology, Barcelona, 2009.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Stroke and Other Thromboembolic Events-Stroke and Other Thromboembolic Events
-The ACTIVE-I Study-The ACTIVE-I Study
Irbesartan(n=4,518)
Placebo(n=4,498) Hazard
Ratio 95% CIp
Valuen %/year n %/year
Stroke 380 2.1 411 2.3 0.92 0.80-1.05 0.213
TIA 130 0.7 150 0.8 0.86 0.68-1.09 0.208
Non-CNS Embolism 49 0.3 65 0.4 0.74 0.51-1.07 0.114
Stroke/TIA/Non-CNS Emb 518 2.9 585 3.4 0.87 0.78-0.98 0.024
ICH10%
SAH10%
Lacunar20%
Thromboembolic10%
Cardioembolic20%
Other 5%Other 5%
Unknown25%
Ischemic Ischemic 80%80%
Hemorrhagic Hemorrhagic 20%20%
• Stroke 2006; 37: 2493-8.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Etiology of Stroke in Atrial Fibrillation-Etiology of Stroke in Atrial Fibrillation
-The ACTIVE-I Study-The ACTIVE-I Study
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Etiology of Stroke in Atrial Fibrillation-Etiology of Stroke in Atrial Fibrillation
-The ACTIVE-I Study-The ACTIVE-I Study
• J Am Coll Cardiol 2005; 45: 1832-9.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Prevention of A Fib with ACE-I and ATII Blockers-Prevention of A Fib with ACE-I and ATII Blockers
-A Meta-Analysis-A Meta-Analysis
0.10.1 0.20.2 1.01.0 5.05.0 10.010.0 Favors Treatment Favors Treatment Favors Control Favors Control
ACE-I Treatment Control
VanDenBerg 2/7 711
SOLVD 10/186 45/188
TRACE 22/790 42/787
Ueng 18/70 32/75
CAPP 117/5492 135/5493
STOPH2 200/2205 357/4409
GISSI 665/8865 721/8846
Subtotal 1034/17615 1339/19809
Relative Risk Reduction(95% CI)
Relative Risk Reduction(95% CI)
ARB
Madrid 9/79 22/75
ValHeFT 116/2209 173/2200
Charm 179/2769 216/2749
LIFE 179/4417 252/4387
Subtotal 483/9474 663/9411
Total 1517/27089 2002/29220
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)
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)
0.72 (0.60-0.85)
• 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
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Arrhythmia Outcomes-Arrhythmia Outcomes
-The ACTIVE-I Study-The ACTIVE-I Study
• Presented at the European Society of Cardiology, Barcelona, 2009.
• Presented at the European Society of Cardiology, Barcelona, 2009.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Baseline Characteristics-Baseline Characteristics
-The ACTIVE-I Study-The ACTIVE-I Study
Irbesartan(n=4,518)
Placebo(n=4,498)
Age (mean) 69.5 69.6
% Female 39.2 39.3
Atrial Fibrillation -Permanent (%) -Paroxysmal (%) -Persistent (%)
66.019.614.3
64.420.514.9
Sinus Rhythm (%) 18.7 19.6
Heart Failure (%) 32.3 31.6
CHADS Risk Score 1.99 1.97
SBP/DBP (mmHg) 138/83 138/82
Heart Rate 75.3 74.9
• Presented at the European Society of Cardiology, Barcelona, 2009.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Baseline Characteristics-Baseline Characteristics
-The ACTIVE-I Study-The ACTIVE-I Study
Irbesartan(n=4,518)
Placebo(n=4,498)
Age (mean) 69.5 69.6
% Female 39.2 39.3
Atrial Fibrillation -Permanent (%) -Paroxysmal (%) -Persistent (%)
66.019.614.3
64.420.514.9
Sinus Rhythm (%) 18.7 19.6
Heart Failure (%) 32.3 31.6
CHADS Risk Score 1.99 1.97
SBP/DBP (mmHg) 138/83 138/82
Heart Rate 75.3 74.9
0
5
10
15
20
25
30
35
40
Hypertension Diabetes Smoking
Lacunar
Thromboembolic
Cardioembolic
% OfPatients
• 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 FibrillationStroke Prevention in Atrial Fibrillation -Population Attributable Fraction for Hypertension -Population Attributable Fraction for Hypertension
-The ARIC Study-The ARIC Study
• European Heart Journal 2007; 28: 752-9.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Effect of BP on Stroke in Patients with A Fib-Effect of BP on Stroke in Patients with A Fib
-The SPORTIF Trials-The SPORTIF Trials
110110100100 120120 130130 140140
Mean SBP (mmHg)Mean SBP (mmHg)
0.50.5
00
1.01.0
4.04.0
Eve
nt
Rat
e (%
/Yea
r)E
ven
t R
ate
(%/Y
ear)
150150 160160
1.51.5
2.02.0
2.52.5
3.03.0
3.53.5
• Presented at the European Society of Cardiology, Barcelona, 2009.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Baseline Characteristics-Baseline Characteristics
-The ACTIVE-I Study-The ACTIVE-I Study
Irbesartan(n=4,518)
Placebo(n=4,498)
Age (mean) 69.5 69.6
% Female 39.2 39.3
Atrial Fibrillation -Permanent (%) -Paroxysmal (%) -Persistent (%)
66.019.614.3
64.420.514.9
Sinus Rhythm (%) 18.7 19.6
Heart Failure (%) 32.3 31.6
CHADS Risk Score 1.99 1.97
SBP/DBP (mmHg) 138/83 138/82
Heart Rate 75.3 74.9
• Presented at the European Society of Cardiology, Barcelona, 2009.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Baseline Characteristics-Baseline Characteristics
-The ACTIVE-I Study-The ACTIVE-I Study
Irbesartan(n=4,518)
Placebo(n=4,498)
Age (mean) 69.5 69.6
% Female 39.2 39.3
Atrial Fibrillation -Permanent (%) -Paroxysmal (%) -Persistent (%)
66.019.614.3
64.420.514.9
Sinus Rhythm (%) 18.7 19.6
Heart Failure (%) 32.3 31.6
CHADS Risk Score 1.99 1.97
SBP/DBP (mmHg) 138/83 138/82
Heart Rate 75.3 74.9
• Presented at the European Society of Cardiology, Barcelona, 2009.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Baseline Medications-Baseline Medications
-The ACTIVE-I Study-The ACTIVE-I Study
Irbesartan(n=4,518)
Placebo(n=4,498)
ACE-I (%) 60.2 60.6
Beta-Blockers (%) 54.4 54.6
Diuretic (%) 54.3 54.1
Ca2+ Channel Blocker (%) 27.0 27.2
Alpha-Blocker/Vasodilator (%) 11.9 11.1
Aspirin 58.7 59.3
Warfarin 38.1 37.6
Antiarrhythmics 22.7 23.1
Digoxin 35.1 34.7
• Presented at the European Society of Cardiology, Barcelona, 2009.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Baseline Medications-Baseline Medications
-The ACTIVE-I Study-The ACTIVE-I Study
Irbesartan(n=4,518)
Placebo(n=4,498)
ACE-I (%) 60.2 60.6
Beta-Blockers (%) 54.4 54.6
Diuretic (%) 54.3 54.1
Ca2+ Channel Blocker (%) 27.0 27.2
Alpha-Blocker/Vasodilator (%) 11.9 11.1
Aspirin 58.7 59.3
Warfarin 38.1 37.6
Antiarrhythmics 22.7 23.1
Digoxin 35.1 34.7
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Wading into the Deep End-Wading into the Deep End
Dronedarone
CH3SO2HN O(CH2)3
N
O
O
(CH2)3CH3
(CH2)3CH3
Amiodarone
O(CH2)2
N
O
O
CH2CH3
CH2CH3
(CH2)3CH3
(CH2)3CH3
I
I
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Dronedarone: A New Antiarrhythmic Medication-Dronedarone: A New Antiarrhythmic Medication
Primary Endpoint: composite of all-cause mortality combined Primary Endpoint: composite of all-cause mortality combined with cardiovascular hospitalizationwith cardiovascular hospitalization
Secondary Endpoint: death from any cause, cardiovascular Secondary Endpoint: death from any cause, cardiovascular death, hospitalization for cardiovascular reasonsdeath, hospitalization for cardiovascular reasons
DDronedarone 400 mg BIDronedarone 400 mg BID PlaceboPlacebo
4,628 patients 4,628 patients >>75 years with atrial fibrillation or 70-75 years with atrial fibrillation 75 years with atrial fibrillation or 70-75 years with atrial fibrillation and at least one additional cardiovascular Risk Factor* prior to randomization. and at least one additional cardiovascular Risk Factor* prior to randomization. Double blind. Randomized. Placebo controlled. International multicenter. Mean Double blind. Randomized. Placebo controlled. International multicenter. Mean
follow-up 21 months. follow-up 21 months.
RR
12-30 mos. follow-up12-30 mos. follow-up
• *Risk Factor=Htn, diabetes, prior stroke/TIA, LA ≥50 mm, LVEF <40%
• N Engl J Med 2009; 360: 668-78.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Study Design-Study Design
-The ATHENA Study-The ATHENA Study
Months0
10
20
40
50
30
Cum
ulat
ive
Inci
denc
e (%
)
6 12 18 24 300
Placebo on top of standard therapy*
Dronedarone 400mg bid on top of standard therapy*
HR=0.76
p<0.001
24% reductionin relativerisk
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Cardiovascular Hospitalization or Death-Cardiovascular Hospitalization or Death
-The ATHENA Study-The ATHENA Study
• *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.
Reason for first CV hospitalisation
Placebon=2327
Dronedarone n=2301 HR 95% CI p value
Any reason 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
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Cardiovascular Hospitalization-Cardiovascular Hospitalization
-The ATHENA Study-The ATHENA Study
• N Engl J Med 2009; 360: 668-78.
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Effect of Dronedarone on Stroke-Effect of Dronedarone on Stroke
-The ATHENA Study-The ATHENA Study
• HR=0.48 if CHAD>1, but no benefit if CHADS<1
• 60% of patients were on Warfarin
• Circulation 2009; 120: 1174-1180.
Months
5
3
2
1
00
Cum
ula
tive
Inc
iden
ce (
%)
Placebo on top of standard therapy*
Dronedarone (DR) 400mg bid on top of standard therapy*
34% reduction in relative risk
HR=0.66p=0.027
4
126 18 3024
• 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 FibrillationStroke Prevention in Atrial Fibrillation -Conclusions -Conclusions
• 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 FibrillationStroke Prevention in Atrial Fibrillation -Practical Aspects to Dabigatran Administration-Practical Aspects to Dabigatran Administration
Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation -Etiology of Stroke in Atrial Fibrillation-Etiology of Stroke in Atrial Fibrillation
-The ACTIVE-I Study-The ACTIVE-I Study
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