Transcript atrial fibrillation and stroke

ATRIAL FIBRILLATION AND STROKE
Vijay Ramu. M.D.
Associate Professor
Director for Electrophysiology
Cardiology Division
East Tennessee State University
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DISCLOSURES
None
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VIJAY K RAMU
EP
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EVERTHING’S POSSIBLE
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DESIGN OF THE PRESENTATION
• EPIDEMIOLOGY OF AFIB AND
STROKE
• MANAGEMENT OF ACUTE STROKE
AND AFIB
• MAJOR TRIALS REVIEW
• PREVENTION OF STROKE
• ANTICOAGULATION ISSUES
• NEW HORIZONS
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INTRODUCTION
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APPLIED ANATOMY
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Future of Atrial Fibrillation
National Projections based on Olmstead
County
Miyasaka et al 2006
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Stroke and atrial fibrillationfeatures
• Strokes tend to be more severe
• TIA tend to last longer
• Retinal events compared to
hemispheric events- AF versus Carotid
disease
• 25:1 versus 2:1
• Anticoagulated patients tend to have
smaller infarcts
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Atrial Fibrillation
Outcomes: Stroke
• Leading cause of stroke
from embolism
% of strokes attributable to
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AF
• AF increases stroke risk
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~17X w/ Rheumatic Heart Dz
~ 5X in non-valvular AF
– Risk of stroke ~5%/yr
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• Proportion of strokes
attributable to AF increases
with  Age
5
0
50-59
60-69
70-79
80-89
[Kannel 1998]
AF Serious Events & Different Vascular Territories
Event
No. of patients (%)
(n=3,298)
Stroke*
Vascular death
Transient ischemic attack
Peripheral thromboembolism
Myocardial infarction
151 (4.6%)
177 (5.4%)
30 (0.9%)
26 (0.8%)
46 (1.4%)
Data from meta-analysis of randomized controlled trials in patients with AF1
*Fatal or at least moderately disabling.
1. Taylor FC et al. BMJ 2001; 322: 321–326.
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Management
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Very similar to any patient with stroke
TEE is needed in some situations
Role of Fibrinolytics in management
NINDS trial
The therapeutic effects and the risks of
fibrinolytics are exaggerated when afib
is present
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Antithrombotic therapy
• Heparin and LMWH is not beneficial in
acute stroke in general
• Clinical scenarios when they may be
considered ?
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• Patients with a submaximal stroke in a
major arterial territory, in whom imaging
and Doppler studies have shown that
the embolus has not migrated or lysed,
may be subject to progressive
neurologic injury.
• High risk for recurrent emboli and
residual LAA thrombus
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Role of Aspirin in acute stroke
• IST and CAST trials
• Aspirin is recommended in acute stroke
patients until the anticoagulation goal is
achieved
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Coumadin
• Can be started as soon as patient is
medically and neurologically stable and
when normotensive
• Consider 2 week delay if there is
evidence of a large stroke or poorly
controlled hypertension.
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Prophylaxis for stroke
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CHADS2 SCORE
POINTS
Congestive heart failure
C
1
Hypertension
H
1
Age greater than 75
A
1
Diabetes
D
1
Stroke
S
2
CHADS SCORE
ANNUAL RISK%
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
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8.5
6.3–11.1
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12.5
8.2–17.5
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18.2
10.5–27.4
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Table 2. Risk of Stroke in National Registry of Atrial Fibrillation (NRAF) Participants, Stratified
by CHADS2 Score*.
Gage, B. F. et al. JAMA 2001;285:2864-2870
Copyright restrictions may apply.
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Anticoagulation and CHADS 2
score
0- ASA
1- ASA or Coumadin
2 and above Coumadin
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Coumadin History
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Warfarin and Coumarin Derivatives
Historical Insights
1924
1941
1947
1950’s
1983
1994
2004
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Relative Risk Reduction of Stroke in Atrial
Fibrillation – Warfarin Compared with Placebo
Adjusted-dose warfarin compared with placebo
1. Lip GYH et al. BMJ 2002; 325: 1022–1025.
Relative Risk Reduction of Stroke in Atrial
Fibrillation – ASA Compared with Placebo
1. Lip GYH et al. BMJ 2002; 325: 1022–1025.
Relative Risk Reduction of Stroke in Atrial
Fibrillation – Warfarin Compared with ASA
1. Lip GYH et al. BMJ 2002; 325: 1022–1025.
Proper Therapeutic Range for INR:
INR Values with Stroke or Intracranial Bleed
Odds Ratio
15.0
STROKE
10.0
INTRACRANIAL BLEED
5.0
1.0
0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
INR
EFFICACY AND SAFETY OF WARFARIN
Hylek et al. 1994
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RATE VERSUS RHYTHM CONTROL
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AFFIRM TRIAL
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CRITICS ON AFFIRM TRIAL
• During a mean follow-up of 3.5 years, there were 356 deaths in
the rhythm-control patients and 310 deaths in the rate-control
patients (P=0.07). In the rhythm-control group, 129 patients (9%)
died of a cardiac cause, and in the rate-control group, 130
patients (10%) died (P=0.95). Both groups had similar rates of
arrhythmic and nonarrhythmic cardiac deaths. The numbers of
vascular deaths were similar in the 2 groups: 35 (3%) in the
rhythm-control group and 37 (3%) in the rate-control group
(P=0.82). There were no differences in the rates of ischemic
stroke and central nervous system hemorrhage. In the rhythmcontrol group, there were 169 noncardiovascular deaths (47.5%
of the total number of deaths), whereas in the rate-control arm,
there were 113 noncardiovascular deaths (36.5% of the total
number of deaths) (P=0.0008). Differences in noncardiovascular
death rates were due to pulmonary and cancer-related deaths.
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Rhythm or rate control in AF
Cerebrovascular events
1.28 (0.95 – 1.72)
AFFIRM
(n = 4,060)
2.25 (1.88 – 5.75)
RACE
(n =
522)
3.01 (0.35 – 25.30)
STAF
(n =
200)
4.92 (0.58 – 41.50)
PIAF
(n =
252)
1.36 (1.03 – 1.78)
TOTAL
(n = 5,034)
p = 0.04
0.4
0.6
0.8
1.0
rhythm control better
1.2
1.4
1.6
1.8
2.0
2.2
2.4
rhythm control worse
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Warfarin Drug Interactions
• 46% of patients on warfarin for prevention of
stroke in AF take concomitant agent(s) that
increases bleeding risk.
• Average of 1.4 potentiating drugs per patient
• Most common classes of interacting drugs
– Antibiotics (67%)
– Aspirin and other antiplatelets (15%)
– NSAIDs not including aspirin (4%)
Howard. J Am Coll Cardiol. 2001;37(suppl A):516A.
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Contraindications for coumadin in afib?
% of AF patients in whom oral anticoagulant
contraindicated
50
%
43%
38%
40
37%
30
17.5%
20
10
0
Sudlow
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Standard
contraindications to
warfarin use in AF
patients >65 years
Brass
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Kalra
Standard
contraindication to
OAC (including
ASA and NSAID)
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Contraindications
to OAC in
randomly selected
AF patients aged
>75 years
Go
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Conventional
contraindication to
warfarin (ASA and
NSAID not
included)
1. Sudlow et al. Lancet 1998; 352: 1167–1171.
2. Brass LM et al. Stroke 1997; 28: 2382–2389.
3. Kalra et al. Stroke 1999; 30: 1218–22/ Heart 1999; 82: 570–574.
4. Go et al. Ann Intern Med 1999; 131: 927–934.
Atrial Fibrillation Clopidogrel Trial with Irbesartan
for Prevention of Vascular Events (ACTIVE)
 ACTIVE W
 Non-inferiority trial : Clopidogrel 75 mg + aspirin 75150 mg vs. adjusted dose (INR 2.0-3.0) oral anticoagulation (OAC)
 ACTIVE A
 Superiority trial: clopidogrel 75 mg vs. Placebo on a
background of standard aspirin 75-150 mg per day
 ACTIVE I
 Partial factorial design: irbesartan 150 mg with
automatic titration to 300 mg vs. Placebo
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Challenges in Treating AF
Warfarin is not always well-tolerated
• Narrow therapeutic range (INR between 2.0 – 3.0)
• Effectiveness is impacted by interactions with
some foods and medications
• Requires frequent monitoring and dose adjustments
• White, et al report less than 50% of patients eligible are
being treated with warfarin due to tolerance or noncompliance issues
• SPORTIF trials suggest only 60% of patients treated are
within a therapeutic INR range, while 29% have INR levels
below 2.0 and 15% have levels above 3.0
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New Horizons
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Re LY Study and Dabigatran
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DABIGATRAN
• Primary indication- Non Valvular atrial
fibrillation
• Dose 150 mg twice daily
• If creat clearance less than 30ml/min 75mg twice daily
• If creat clearance less than 15 ml/minno clear evidence
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Re LY STUDY
• 18000 PATIENTS
• 3 arms –
DABIGATRAN
110MG BID
• Non inferiority trial for 2 yr duration
• Primary outcoume- stroke or systemic
embolism
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Criteria
• Any of the following risk factor for
stroke
• Stroke or TIA
• Lvef less than 40%
• NYHA class II or higher CHF
• Age 75
• Age 64-75 with diabetes
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CONCLUSIONS
• 150mg dosing of Dabigatran was
superior to warfarin for primary
outcome stroke or systemic embolism
• 110 mg dosing of Dabigatran was non
inferior to warfarin for primary outcome
of stroke and systemic embolism
• Major bleeding -Coumadin v/s150mg of
Dabigatran – non significant
• Major bleeding -Coumadin v/s110mg of
Dabigatran – Dabigatran was superior 54
Adverse effects
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Gastrointestinal: Dyspepsia (11%; includes abdominal
discomfort/pain, epigastric discomfort)
Hematologic: Bleeding (8% to 33%; major: ≤6%)
Gastrointestinal: GI hemorrhage (≤6%), gastritis-like symptoms (eg,
GERD, esophagitis, erosive gastritis, GI ulcer)
Hematologic: Anemia (1% to 4%), hematoma (1% to 2%), hemoglobin
decreased (1% to 2%), hemorrhage (postprocedural or wound: 1% to
2%)
Hepatic: ALT increased (≥3 x ULN: 2% to 3%)
Renal: Hematuria (1%)
Miscellaneous: Wound secretion (5%), postprocedural discharge (1%)
<1% (Limited to important or life-threatening): Allergic edema,
anaphylactic shock, anaphylaxis, AST increased, bloody discharge,
ecchymosis, epistaxis, hemarthrosis, hematocrit decreased,
hemorrhage (catheter site, hemorrhoidal, incision site, rectal), hepatic
function abnormal, occult blood positive, pruritus, rash,
thrombocytopenia, urticaria
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• Invasive or surgical procedures:
• DC Dabigatran 1-2 days (Clcr ≥50
mL/minute) or 3-5 days (Clcr <50 mL/minute)
before invasive procedures
• If surgery cannot be delayed, the risk of
bleeding is elevated; weigh risk of bleeding
with urgency of procedure. Bleeding risk can
be assessed by the ecarin clotting time
(ECT) if available; if ECT is not available, use
of aPTT may provide an approximation of
dabigatran’s anticoagulant activity.
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Device therapy for
prophylaxis
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WATCHMAN LAA Closure Device in situ
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PROTECT AF STUDY Criteria(ACC
2009)
• Key Inclusion Criteria
• Age 18 years or older
• Documented non-valvular AF
• Eligible for long-term warfarin therapy, and no other conditions
that would require long-term warfarin therapy
• Calculated CHADS2 score > 1
• Key Exclusion Criteria
• NYHA Class IV Congestive Heart Failure
• ASD and/or atrial septal repair or closure device
• Planned ablation procedure within 30 days of potential
WATCHMAN Device implant
• Symptomatic carotid disease
• LVEF < 30%
• TEE Criteria: Suspected or known intracardiac thrombus (dense
spontaneous echo contract)
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Patient Demographics
Baseline Demographics
Characteristic
WATCHMAN
N= 463
Control
N= 244
P-value
71.7 ± 8.8
72.7 ± 9.2
0.1800
463 (46.0, 95.0)
244 (41.0, 95.0)
68.2 ± 4.2
68.4 ± 4.2
462 (54.0, 82.0)
244 (59.0, 78.0)
195.3 ± 44.4
194.6 ± 43.1
463 (85.0, 376.0)
244 (105.0, 312.0)
Female
137/463 (29.6)
73/244 (29.9)
Male
326/463 (70.4)
171/244 (70.1)
Age (years)
Height (inches)
Weight (lbs)
0.6067
0.8339
Gender
0.9276
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Intent-to-Treat
Primary Safety Results
Randomization allocation (2 device : 1 control)
Device
Events
(no.)
Cohort
900 pt-yr
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Control
Total
pt-yr
Rate
(95% CI)
554.2
Events
(no.)
8.7
(6.4, 11.3)
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Total
pt-yr
312.0
Rate
(95% CI)
Rel. Risk
(95% CI)
4.2
(2.2, 6.7)
2.08
(1.18, 4.13)
Event-free
probability
1.0
ITT Cohort:
patients analyzed
based on their
randomly assigned
group (regardless of
treatment received)
Control
0.9
WATCHMAN
0.8
0
365
730
1,095
Days
244
463
143
261
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87
11
19
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Intent-to-Treat
Primary Efficacy Results
Randomization allocation (2 device : 1 control)
Device
Cohort
(no.)
900 pt-yr
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Posterior
Probabilities
Control
pt-yr
Events Total
Rate
Events Total
Rate
(95% CI)
(no.)
pt-yr
(95% CI)
(95% CI)
582.3
3.4
(2.1, 5.2)
16
318.0
5.0
(2.8, 7.6)
Rel. Risk
Noninferiority Superiority
0.68
0.998
(0.37, 1.41)
0.837
Event-free
probability
1.0
WATCHMAN
0.9
Control
ITT Cohort:
patients analyzed
based on their
randomly assigned
group (regardless of
treatment received)
0.8
0
365
730
1,095
Days
244
463
147
270
52
92
12
22
64
3001664-2
Summary of Primary Efficacy and
Safety Results by Analysis Cohort
Relative risk is ratio of WATCHMAN rate to control rate
Cohort
Intent-to-treat
Primary efficacy
RR (95% CI)
0.68 (0.37, 1.41)
Primary safety
RR (95% CI)
2.08 (1.18, 4.13)
Postprocedure
0.49 (0.24, 1.06)
0.93 (0.48, 1.97)
Per protocol
0.44 (0.20, 1.03)
0.40 (0.16, 0.96)
• ITT relative risk of 0.68 forms basis of noninferiority claim
• 86% of WATCHMAN patients successfully implanted
•
and discontinued warfarin therapy
These patients experience a greater than 50% reduction in
efficacy and safety events
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