Transcript AF slide deck

1
Learning Objectives
After taking part in this activity, participants should
be better able to:
– Assess the significant clinical consequences and
burden of AF
– Apply new practice guidelines/best practices and
performance measures for the management of AF
– Interpret the latest clinical data on rate-control and
rhythm-control strategies for the management of
patients with AF
– Demonstrate an evidence-based approach for
reducing thromboembolic risk in patients with AF
2
Faculty Disclosure
The Network for Continuing Medical Education
requires that CME faculty disclose, during the
planning of an activity, the existence of any
personal financial or other relationships they or
their spouses/partners have with the commercial
supporter of the activity or with the manufacturer of
any commercial product or service discussed in the
activity.
Faculty and planner disclosure information is
included in the handout materials.
Epidemiology and
Burden of Disease
4
Case:
65-Year-Old Man With Recent Episodes of Palpitations,
Weakness, and Lightheadedness
Presentation
● A 65-year-old man presents with episodes of
palpitations, weakness, and significant
lightheadedness
● He describes his symptoms, which have been
occurring as often as 3 times each day for about 1
week, as severe and debilitating
5
Case:
65-Year-Old Man With Recent Episodes of Palpitations,
Weakness, and Lightheadedness
Medical History/Current Medications
The patient has been diagnosed with diabetes,
hypertension, and sleep apnea syndrome, and is taking
the following medications:
– Lisinopril 10 mg/d
– Metoprolol 50 mg/d
– Insulin (0.6 U/kg nightly)
6
Case:
65-Year-Old Man With Recent Episodes of Palpitations,
Weakness, and Lightheadedness
Physical Findings
● BP: 145/90 mm Hg; HR: 85 bpm
● Weight: 180 lb (82 kg); height: 5’10”; BMI: 25.9 m2/kg
● Chest auscultation and heart sounds
– Normal S1 and S2, no murmurs
– Irregularly irregular rhythm
● Abdominal examination findings: soft and nontender
7
Epidemiology of AF
● Most common sustained cardiac arrhythmia1
● Currently affects 5.1 million Americans2
● Prevalence expected to increase to 12.1 million by 2050
(15.9 million if increase in incidence continues)2
● Preferentially affects men and the elderly1,2
● Lifetime risk of developing AF: ~1 in 4 for adults 40
years of age3
1. Lloyd-Jones D, et al. [published online ahead of print December 17, 2009].
Circulation. doi:10.1161/CIRCULATIONAHA.109.192667.
2. Miyasaka Y, et al. Circulation. 2006;114(2):119-125.
3. Lloyd-Jones DM, et al. Circulation. 2004;110(9):1042-1046.
8
AF Is the Leading Cause of
Hospitalizations for Arrhythmia
Hospital Admissions in US
AF
AFL
Cardiac arrest
Conduction disease
Junctional
Premature beats
Sick sinus
Unspecified
VF
VT
0
200
400
600
800
1000
Hospital Days (thousands)
N=517,699 (representing 10% of CV admissions).
VF, ventricular fibrillation; VT, ventricular tachycardia.
Adapted from Waktare JE, et al. J Am Coll Cardiol. 1998;81(suppl 5A):3C-15C.
9
Mortality After Diagnosis of AF
100
4-month
HR, 9.62
Survival, %
80
Post-4 months
HR, 1.66
60
40
MN-white expected
Observed
20
P<.0001
P<.0001
0
0
2
4
6
8
Years From AF Dx
10 0
2
4
6
8
10
Years After 4 Mo
From AF Dx
Reproduced with permission from Miyasaka Y, et al. J Am Coll Cardiol. 2007;49(9):986-992.
10
Cumulative Incidence of AF
One Fifth of Heart Failure Patients
Develop AF Within 4 Years
Unadjusted cumulative incidence of first AF
after heart failure – Framingham Study
0.4
0.3
0.2
0.1
0
0
No. at risk 708
2
4
323
230
Years
6
8
10
146
92
62
Development of AF was associated with increased mortality:
HR, 1.6 (95% CI, 1.2-2.1) in men; 2.7 (95% CI, 2.0-3.6) in women
Reproduced with permission from Wang TJ, et al. Circulation. 2003;107(23):2920-2925.
11
AF Is a Marker for Worse Outcomes
in Heart Failure: CHARM Program
Cumulative
Distribution Function
Time to cardiovascular death or heart failure hospitalization
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0
Number at risk
No AF & Low EF
No AF & PEF
AF & Low EF
AF & PEF
Low EF:
Hazard ratio 1.29
(95% CI 1.14 – 1.46)
P<.001
AF at baseline (Low EF) <0.40
No AF at baseline (Low EF)
AF at baseline (Preserved)
LVEF >0.40
No AF at baseline (Preserved)
Preserved EF (PEF):
Hazard ratio 1.72
(95% CI 1.45 – 2.06)
P<.001
0
1
2
3
3906
2545
670
478
3207
2294
509
399
2755
2096
417
353
1963
1276
289
203
3.5
AF predicted mortality for both
preserved EF and depressed EF
groups, and CV death or heart
failure hospitalizations for
preserved EF group
Reproduced with permission from Olsson LG, et al. J Am Coll Cardiol. 2006;47(10):1997-2004.
12
Impact on QoL: AF vs Other CV Illness
100
SF-36 scalea
90
General population1
Recent MI1
AF2
HF1
80
70
60
50
40
Physical
Vitality
functioning
General
health
Mental
health
index
Emotional
Social
role
functioning
Baseline score
aHigher
numbers indicate higher QoL.
SF-36 = Medical Outcomes Study Short Form 36.
1. Ware JE, et al. New England Medical Center Health Survey; 1993.
2. Dorian P, et al. J Am Coll Cardiol. 2000;36(3):1303-1309.
13
AF Is Associated With
Increased Thromboembolic Risk
● Major cause of stroke in elderly1
● 5-fold ↑ in risk of stroke1,2
● 15% of strokes in US are attributable to AF3
● Stroke severity (and mortality) is worse with AF
than without AF4
● Incidence of all-cause stroke in patients
with AF: 5%1
● Stroke risk persists even in asymptomatic AF5
1.
2.
3.
4.
5.
Fuster V, et al. J Am Coll Cardiol. 2001;38(4):1231-1266.
Benjamin EJ, et al. Circulation. 1998;98(10):946-952.
Atrial Fibrillation Investigators. Arch Intern Med. 1994;154(13):1449-1457.
Dulli DA, et al. Neuroepidemiology. 2003;22(2):118-123.
Page RL, et al. Circulation. 2003;107(8):1141-1145.
14
Pathophysiology
15
Pathophysiology of AF
• HTN and/or
vascular
disease
?Inflammation
Compliance
• Mitral
regurgitation
Atrial dilatation/stretch
• Left ventricular hypertrophy
• Diastolic dysfunction
?Inflammation
Stretch-activated channels
Dispersion of refractoriness
Pulmonary vein focal/discharges?
Increased vulnerability to AF?
Adapted with permission from Gersh BJ, et al. Eur Heart J Suppl. 2005;7(suppl C):C5-C11.
16
What Happens When AF Persists?
Structural
Remodeling
 LA and LAA dilatation
 Fibrosis
Electrophysiologic
Remodeling
 Decrease in Ca++ currents
 Shortening of atrial action
potential
 Increased importance of
early activating K+
channels: IKur, IKto
Remodeling explains why “AF begets AF”
17
Classification of AF
Recurrent AFa
(≥2 episodes)
Paroxysmal
• Arrhythmia
terminates
spontaneously
• AF is sustained
≤7 days
Persistent
Permanent
• Arrhythmia does
not terminate
spontaneously
• AF is sustained
>7 days
• Both paroxysmal and
persistent AF can
become permanent
aTermination
with pharmacologic therapy or direct-current cardioversion does not change the designation.
Fuster V, et al. Circulation. 2006;114(7):e257-e354.
18
Clinical Evaluation
19
Case:
65-Year-Old Man With Recent Episodes of Palpitations,
Weakness, and Lightheadedness
ECG Findings
20
Case:
65-Year-Old Man With Recent Episodes of Palpitations,
Weakness, and Lightheadedness
Echocardiogram Findings
● Mild LVH and nl LV function
– LV wall thickness 1.3 cm
– LA size 4.2
21
Case:
65-Year-Old Man With Recent Episodes of Palpitations,
Weakness, and Lightheadedness
What other tests would you perform for
this patient at this time?
A.
B.
C.
D.
E.
F.
6-Minute walk or exercise test
Holter monitoring/event recording
Electrophysiology study
Cardiac catheterization
Cardiac MRI
None
22
Clinical Evaluation for AF Patients:
Etiology, AAD Risk, Embolic Risk
● Treatment of AF is dependent on etiologic (cause, severity,
reversible/modifiable) as well a patient factors (embolic risk, concomitant
disorders)
● Some anatomic or functional disorders pose risks from AAD treatment (eg,
organ toxicity and ventricular proarrhythmia)
● At a minimum, an evaluation requires
– History
– Echocardiogram
– Physical
– Blood chemistries
– ECG
– Stress test (if CAD is suspected)
– Chest x-ray (and possibly PFTs) if pulmonary disease is suspect
and/or HF is a consideration
● Current guidelines emphasize the prospectively determined CHADS2
risk-scoring system for embolic risk
Fuster V, et al. Circulation. 2006;114(7):e257-e354.
23
Conditions Frequently Associated
With Nonvalvular AF1-4
●
●
●
●
●
●
●
●
●
●
1.
2.
3.
4.
Hypertension
Aging
Male sex
Obesity/metabolic syndrome/diabetes
Ischemic heart disease
Heart failure/diastolic dysfunction
Obstructive sleep apnea
Physical inactivity
Thyroid disease
Inflammation?
Wattigney WA, et al. Circulation. 2003;108(6):711-716.
Gersh BJ, et al. Eur Heart J Suppl. 2005;7(suppl C):C5-C11.
Fuster V, et al. J Am Coll Cardiol. 2006;48(4):854-906.
Mozaffarian D, et al. Circulation. 2008;118(8):800-807.
24
Case:
65-Year-Old Man With Recent Episodes of Palpitations,
Weakness, and Lightheadedness
What is the patient’s diagnosis?
A.
B.
C.
D.
Paroxysmal AF
Persistent AF
Permanent AF
Other
25
Case:
65-Year-Old Man With Recent Episodes of Palpitations,
Weakness, and Lightheadedness
Would you recommend antithrombotic
therapy for this patient at this time?
A. Yes
B. No
26
Case:
65-Year-Old Man With Recent Episodes of Palpitations,
Weakness, and Lightheadedness
If so, which risk stratification model
would you use to decide on the strategy?
A.
B.
C.
D.
E.
ACCP
AFI (Atrial Fibrillation Investigators)
CHADS2
Framingham study
SPAF (Stroke Prevention and Atrial Fibrillation)
Investigators
F. Other
27
CHADS2 Risk Criteria for Stroke
in Nonvalvular AF
Risk Factors
Score
C
Recent congestive heart failure
1
H
Hypertension
1
A
Age ≥75 y
1
D
Diabetes mellitus
1
History of stroke or transient ischemic
S2 attack
Gage BF, et al. JAMA. 2001;285(22):2864-2870.
2
28
Stroke Risk in Patients With Nonvalvular AF Not
Treated With Anticoagulation Based on the CHADS2
Index
Patients
(N=1733)
120
(95% CI)
CHADS2 Score
0
463
1
523
2
337
3
220
4
65
5
5
6
0
5
10
15
20
25
Adjusted Stroke Rate (% per y)
Warfarin
30
CHADS2, Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or
transient ischemic attack.
Gage BF, et al. JAMA. 2001;285(22):2864-2870.
29
Case:
65-Year-Old Man With Recent Episodes of Palpitations,
Weakness, and Lightheadedness
If you were stratifying this patient’s risk
based on CHADS2, what score would he
receive?
A.
B.
C.
D.
0
1
2
≥3
30
Clinical Evaluation for Selecting
Antithrombotic Therapy
●
Consider the following before selecting an anticoagulation strategy:
– Bleeding or thrombotic risk, history of/tendency for injuries
– Concomitant requirement for warfarin or antiplatelet therapy
– Drug compliance history and willingness for dietary compliance
– Concomitant therapies (including prescription drugs,
OTCs, herbals)
– Patient activities that risk injury or are contraindications
to warfarin
● Perform a clinical evaluation is prior to initiating anticoagulation strategy
● Testing the genetic pattern of warfarin metabolism may be helpful in
facilitating the initiation phase of warfarin therapy
Fuster V, et al. Circulation. 2006;114(7):e257-e354.
31
Case:
65-Year-Old Man With Recent Episodes of Palpitations,
Weakness, and Lightheadedness
What antithrombotic strategy would
you suggest?
A.
B.
C.
D.
E.
F.
Aspirin 80 mg/d
Aspirin 325 mg/d
Warfarin INR 2-3.5
Warfarin INR 1.5-2.5
Clopidogrel 75 mg/d + aspirin 80 mg/d
Dabigatran 110 mg/bid
32
Treatment
33
Treatment Goals and Strategies
Rate control
Pharmacologic
•
•
•
•
•
Maintenance of SR
Stroke prevention
Pharmacologic Nonpharmacologic
Ca2+
blockers
-blockers
Digitalis
Amiodarone
Dronedaronea
Nonpharmacologic
• Ablate and pace
Prevent Remodeling
Pharmacologic
Class IAb
Class IC
Class III
-blocker
CCB
ACE-I, ARB
Statins
Fish oil
Catheter ablation
Pacing
Surgery
Implantable devices
• Warfarin
• Aspirin
• Thrombin Inhibitor
Nonpharmacologic
• Removal/isolation
LA appendage
a Only
in patients with nonpermanent AF; b the
antiarrhythmic drug classes are based on the
Vaughan Williams classification.
34
ACC/AHA/ESC 2006 Atrial Fibrillation Guidelines
Rhythm Control Therapies to Maintain Sinus Rhythm
Maintenance of SR
No (or minimal)
heart disease
Hypertension
CAD
HF
Flecainide
Propafenone
Sotalol
Substantial LVH
Dofetilide
Sotalol
Amiodarone
Dofetilide
No
Amiodarone
Dofetilide
Yes
Catheter
ablation
Flecainide
Propafenone
Sotalol
Amiodarone
Dofetilide
Catheter
ablation
Amiodarone
Amiodarone
Catheter
ablation
Catheter
ablation
Catheter
ablation
Note: In 2009, the FDA approved
dronedarone to reduce the risk of CV
hospitalization in patients with paroxysmal or
persistent AF or AFL, with a recent episode of
AF/AFL and associated CV risk factors, who
are in sinus rhythm or who will be
cardioverted. Consensus regarding its place in
the treatment paradigm is not yet available.
Reproduced with permission from Fuster V, et al. Circulation. 2006;114(7):e257-e354.
35
Individualized Patient Management
AF chronicity
Paroxysmal
Persistent
Chronic
Pharmacologic
Maintain sinus
rhythm
Catheter ablation
Surgical maze
+/- valve/CAD surgery
AF symptoms
Aggravation of HF
Anticoagulation
Risk/benefit
Pharmacologic
Therapy tolerance
Risk/benefit
Rate control
AVJ ablation
ICD or pacer
Courtesy of KA Ellenbogen, MD.
36
Rate Control
● End point
– Resting and ambulatory ventricular rates similar
to those expected in sinus rhythm
– Best assessed with Holter monitoring
– Determining pulse on exam and heart rate on
ECG are not sufficient
● Methods
– Digitalis: in sedentary patients or CHF
– β-blockers and/or CCBs (verapamil, diltiazem): needed in
most active individuals
– AVN ablation plus pacemaker: in resistant patients
● Special considerations
– Brady-tachy syndrome (pindolol, or pacer plus drugs)
– Preexcitation (focus on the BT as well as the AVN)
37
Cardioversion
Direct Current
– Biphasic is best
(can do internal CV if needed)
Intravenous AAD
– Ibutilide is best of the available drugs
(2 mg/30 min; have MgSO4 available)
– Amiodarone (≥1 g over 24 h)
– Procainamide, quinidine
– Emerging drugs (eg, vernakalant)
Conversion With Class IC Rx
Conversion Rates From AF to
Sinus Rhythm at 3 and 8 Hours
100%
3 hours
8 hours
80%
72%
(44/61)
60%
51%
Oral AAD
– Oral IC is best (70%-80% by 6-8 h;
mean, <4 h)
– Dofetilide (30%-50% by 48 h)
(500 μg bid)
– Amiodarone (30 mg/kg), IA are
other alternatives
– Emerging drugs
39%
(31/61)
(24/62)
40%
18%
20%
(11/62)
0%
Placebo
Propafenone
600 mg
Adapted from Capucci A, et al.
Am J Cardiol. 1994;74(5):503-505.
38
“Pill in the Pocket”
Candidates
• Recognized acute and recent onset
• No AAD risk markers
• Adequate tolerance (no pulmonary edema, syncope, etc)
Step 2
Step 1
• Rate control (~100 bpm)
to prevent 1:1 flutter
• Propafenone 600 mg
(single dose)
• Short-acting CCB or
β-blocker
• Flecainide 300 mg
(single dose)
Step 3
• Observe for effect
and tolerance
(first episode)
Subsequent events
• Treat at home (convenient and inexpensive)
• Improves QoL, reduces ER visits/hospitalization, costs
Acute load on chronic therapy
• 2 extra “pill in the pocket” dosing regimens have been used to treat breakthrough
episodes (max. daily dose vs substitute bolus dose)a
Alboni P, et al. N Engl J Med. 2004;351(23):2384-2391.
aReiffel
JA. Pacing Clin Electrophysiol. 2009;32(8):1073-1084.
39
Case:
65-Year-Old Man With Recent Episodes of Palpitations,
Weakness, and Lightheadedness
Which of the following management
goals may not be necessary in every
patient with AF?
A. Control of the ventricular rate
B. Reduction of thromboembolism risk (particularly
stroke)
C. Restoration and maintenance of sinus rhythm
40
AAD Treatment Goals
● Remember to keep goals realistic!
● AF is rarely life-threatening and is usually recurrent
● Thus, goals should be to:
– Reduce the frequency of recurrences
– Reduce the duration of recurrences
– Reduce the severity of recurrences
– Minimize intolerance and risk of therapy
41
Antiarrhythmic Drugs for AF
● Class I:
– Class IC: propafenone (also very weak β-blocker), flecainide
(no β-blockade effects)
• Sustained-release propafenone (Rythmol SR) and
flecainide are bid;
• Propafenone appears to be less proarrhythmic
– Class IA: disopyramide, quinidine, procainamide
• No longer included in the ACC/AHA/ESC algorithm
• Disopyramide may be useful in vagally induced AF
● Class III:
–
–
–
–
Sotalol (class III plus β-blocker)
Dofetilide (pure class III)
Amiodarone (class III plus class I, II, IV)
Dronedarone (similar to amiodarone with different pharmacokinetics
and markedly reduced organ toxic potential)
42
Ventricular Proarrhythmia With AAD
● Torsade de pointes:
– A consequence of class III and
IA AAD
– Incidence varies within drug class,
and with LVH
– Can be as low as 0.1%-0.4%
● Monomorphic VT:
– A consequence of class I AAD
(esp. IC) in SHD (ischemic,
impaired cell connections)
– Thus, class I AAD are contraindicated
as first-line therapy in SHD patients
● Ventricular fibrillation:
– May degenerate from TdP or VT
– May be idiopathic
43
Mortality Associated With Flecainide and
Encainide for Supraventricular Arrhythmias
Estimated 1-Year Mortality (Point Estimate, 95% CI)
14
12
Mortality, %
10
8
6
4
2
0
Total N =
1 Year N =
CAST
Enc + Flec
720
272
CAST
Placebo
725
286
Comparison
SVA
165
144
Comparison
Expected*
-
Flecainide
SVA
238
93
Flecainide
Expecteda
-
Exponential Model
aBased
on age, race, and sex-specific mortality rates in the United States in 1980.
Adapted from Pritchett EL, Wilkinson WE. Am J Cardiol. 1991;67(11):976-980.
44
Case:
65-Year-Old Man With Recent Episodes of Palpitations,
Weakness, and Lightheadedness
What treatment to manage the AF
would you suggest at this time?
A.
B.
C.
D.
E.
Catheter ablation
Flecainide
Dronedarone
Amiodarone
AV node ablation and PPM
45
Case:
65-Year-Old Man With Recent Episodes of Palpitations,
Weakness, and Lightheadedness
If dronedarone is chosen, where
should treatment be initiated?
A. Inpatient administration is mandatory
B. Outpatient administration is feasible
46
Site of AAD Initiation
● Inpatient is mandated for dofetilide
● The recommendations are mixed for sotalol (PI says
inpatient, ACC/AHA/ESC guidelines allow outpatient
initiation in patients without TdP risk markers who
are in NSR)
● The only class IA agent approved for AF is quinidine,
with initiation as an inpatient
● Outpatient is allowed for class IC and dronedarone, and
is customary for amiodarone (which is not FDA approved
for AF), assuming normal SN and normal conduction
47
Judging Antiarrhythmic Efficacy
● In patients with symptomatic AF:
– Reduction or abolishment of symptoms
● In symptomatic and asymptomatic AF patients:
– Normalization of pulse on self-examination twice a day
– Assessment with autotriggered loop recorder
(devices that can be patient triggered and can
automatically record for programmed criteria,
including AF)
– Assessment with pacemaker interrogation
48
Dronedarone vs Amiodarone: Structural and
Functional Characteristics
Blocks Multiple K Channels
= Shared
= Dronedarone
Overall Effects

Na+
Channel
Blockade




Sympatholytic
Blockade




Ca++ Channel
Blockade
a1
Slows heart rate
Slows ventricular rate in AF
Prolongs APD and QT/QTc
Similar EP and antifibrillatory effects in
ventricles and atria
Reduces effect of EDA in M-cells and PF
Reduces intrinsic and drug-induced
heterogeneity of myocardial refractoriness
Negligible proarrhythmia and no antitorsadogenic potential
No negative inotropy
Elimination half-life 1-2 days
Reduces Likelihood of Thyroid
Hormone Effects
to 2 days for dronedarone vs 30 to 50 days for amiodarone.
Zimetbaum PJ. N Engl J Med. 2009;360(18):1811-1813..
Anti-ischemic &
Antifibrillatory
Improves LVEF
in CHF
Reduces
Likelihood of
Pulmonary
Fibrosis
A Much Shorter
Half-lifea
49
The ERATO Rate-Reduction Trial
ERATO: Secondary Study End Point
Dronedarone Significantly Decreased
Ventricular Rate (24-hour Holter)
Dronedarone Significantly Decreased
Maximal Exercise Ventricular Rate
(Mean ± SEM)
(Mean ± SEM)
Placebo
Dronedarone 400 mg bid
Ventricular Rate, bpm
95
90
90.2
90.6
86.5
11.7 bpma
(P<.0001)
85
80
75
70
76.2
Baseline
D14
Ventricular Rate (bpm) During
Maximal Exercise
ERATO: Primary Study End Point
Placebo
Dronedarone 400 mg bid
170
165
160
155
152.6
effect estimate by ANCOVA
24.5 bpma
(P<.0001)
150
145
140
135
130
129.7
125
120
Baseline
Time
aTreatment
159.6
162.4
D14
Time
aTreatment
effect estimate by ANCOVA
Adapted with permission from Davy JM, et al. Am Heart J. 2008;156(3):527:e1-527.e9.
50
EURIDIS
0.8
Cumulative Incidence
Cumulative Incidence
EURIDIS and ADONIS Primary End Point:
Patients With First Recurrence of AF/AFL
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Time
(days) 0
Log-rank test results: P=.01
60
120
180
240
300
Placebo
360
ADONIS
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Time
(days) 0
Log-rank test results: P=.002
60
120 180 240 300 360
Dronedarone 400 mg bid
Results: a significant and consistent reduction in first recurrence of AF/AFL
AF, atrial fibrillation; AFL, atrial flutter.
Adapted with permission from Singh BN, et al. N Engl J Med. 2007;357(10):987-999.
51
EURIDIS and ADONIS: Dronedarone Reduced
Ventricular Rate at First AF/AFL Recurrence
Mean Ventricular Rate (with TTM)
Placebo
120
116.6
P<.001
Dronedarone
117.5
P<.001
115
110
104.6
105
102.3
100
95
n=102
n=188
n=117
n=199
90
ADONIS
EURIDIS
TTM, transtelephonic monitoring.
Singh BN, et al. N Engl J Med. 2007;357(10):987-999.
52
ANDROMEDA Primary End Point: Time to
Death or Hospitalization for Worsening HF
No. of patients with end point
Placebo
n=317
Dronedarone 400 mg bid
n=310
40
53
RR
1.38
95% CI
Log-rank’s test result (P value)
(0.92-2.09)
.12
All-cause mortality: placebo, n=12; dronedarone, n=25; HR, 2.13; P=.03
Køber L, et al. N Engl J Med. 2008;358(25):2678-2687.
53
Athena: Primary Outcome Results
Cumulative Incidences for the Composite of First
Hospitalization Due to CV Events or Death From Any Cause
Cumulative Incidence, %
100
75
Placebo
50
P<.001
Dronedarone
25
0
0
6
12
18
24
30
Months
Reproduced with permission from Hohnloser SH, et al. N Engl J Med. 2009;360(7):668-678.
54
ATHENA Post Hoc Analysis:
Reduction in Stroke
Cumulative Incidence, %
5
HR=0.66 (95%Cl, 0.46-0.96)
P=.027
• Dronedarone reduced the
Placebo
risk of stroke from 1.8%
(n=70, annual rate=1.8%)
per year to 1.2% per year
(HR, 0.66; P=.027)
4
3
Dronedarone
(n=46, annual rate=1.2%)
2
1
0
0
6
12
18
24
30
• The effect of dronedarone
was similar whether or not
patients were receiving
oral anticoagulant therapy
• Dronedarone had a
greater effect in patients
with higher CHADS2
scores
Months
Reproduced with permission from Connolly SJ, et al; for the ATHENA Investigators
Circulation. 2009;120(13):1174-1180.
55
Emerging Antiarrhythmic Drugs for AF
● Agents under study for sinus rhythm maintenance
– “Atrial-selective” (“atrial-specific”) agents
• Vernakalant (Kynapid®) is pending FDA approval (in
October 2010, the FDA suspended enrollment of the
ACT 5 trial due to patient safety concerns)
• Others
● Agents under study for pharmacologic cardioversion
– “Atrial-selective” (“atrial-specific”) agents
– Others
● Agents currently marketed for a non-AF indication
– Ranolazine (Ranexa®)
● Agents with unconventional anti-arrhythmic mechanisms
– Stretch receptor antagonists, sodium-calcium exchanger
blockers, late sodium channel inhibitors, gap junction modifiers
Savelieva I, Camm J. Europace. 2008;10(6):647-665.
56
Preventing Thromboembolism
57
ACC/AHA/ESC 2006 Atrial Fibrillation Guidelines
Preventing Thromboembolism
I
IIa IIb III
A
A
A
A
Antithrombotic therapy to prevent thromboembolism is recommended
for all patients with AF, except those with lone AF or contraindications
The antithrombotic agent should be chosen based upon the absolute
risks of stroke and bleeding and the relative risk and benefit for a
given patient
For patients at high risk of stroke,a chronic oral anticoagulant therapy
with a vitamin K antagonist (INR 2.0 to 3.0) is recommended, unless
contraindicated
Anticoagulation with a vitamin K antagonist is recommended for
patients with >1 moderate risk factorb
aFactors
bAge
include prior stroke, TIA, or systemic embolism, rheumatic mitral stenosis, mechanical heart valve.
≥75 years, hypertension, diabetes mellitus, HF, or impaired LV systolic EF.
Fuster V, et al. Circulation. 2006;114(7):e257-e354.
58
ACC/AHA/ESC 2006 Atrial Fibrillation Guidelines
Preventing Thromboembolism (cont)
I
IIa IIb III
A
INR should be determined at least weekly during initiation of therapy
and monthly when stable
A
Aspirin, 81-325 mg daily, is recommended in low-risk patients or in
those with contraindications to oral anticoagulation
B
For patients with mechanical heart valves, the target intensity of
anticoagulation should be based on the type of prosthesis,
maintaining an INR of at least 2.5
C
Antithrombotic therapy is recommended for patients with atrial flutter
as for AF
C
Long-term anticoagulation is not recommended for primary stroke
prevention in patients <60 years without heart disease (lone AF)
Fuster V, et al. Circulation. 2006;114(7):e257-e354.
59
ACC/AHA/ESC 2006 Atrial Fibrillation Guidelines
Risk Stratification for AF:
Antithrombotic Therapy
Risk Category
Recommendation
Low Risk
No moderate-risk factors
CHADS2 = 0
Aspirin, 81-325 mg a day
Moderate Risk
One moderate-risk factor
CHADS2 = 1
Aspirin, 81-325 mg a day
or warfarin (INR 2.0-3.0)
High Risk
Any high-risk factor or ≥2 moderate-risk factors
CHADS2 = ≥2
aINR
Warfarin (INR 2.0-3.0a)
2.5-3.5 for prosthetic valves. What to do about “weaker” risk factors?
Fuster V, et al. Circulation. 2006;114(7):e257-e354.
60
Currently Available
Antithrombotic Agents
 Warfarin
 Low–molecular-weight heparin
 Unfractionated heparin
 Aspirin
 Aspirin + clopidogrela
 Dabigatran
a Not
currently FDA approved.
61
Limitations of Warfarin
Limitations
Consequences
Slow onset of action
Overlap with parenteral anticoagulant
Genetic variation in metabolism
Variable dose requirements
Multiple food and drug interactions
Frequent coagulation monitoring
Narrow therapeutic window
Frequent coagulation monitoring
Hirsh J. N Engl J Med. 1991;324(26):1865-1875.
Bates SM, Weitz JI. Br J Haematol. 2006;134(1):3-19.
Courtesy of PR Kowey, MD.
62
The ACTIVE Studies
ACTIVE-W1
– Compared warfarin (INR, 2-3) vs clopidogrel 75 mg/d + ASA
–
–
–
–
(75-100 mg/d) in high-risk AF patients
6706 patients randomized
1.28 years of follow-up
Primary end point: stroke, systemic embolus, MI, vascular death
Study stopped early due to superiority of warfarin
ACTIVE-A2
– Compared clopidogrel 75 mg/d + ASA (75-100 mg/d) vs ASA alone in
–
–
–
–
high-risk AF patients who could not or would not take warfarin
7554 patients randomized
Same primary end point
3.6 years of follow-up
Stroke occurred in 296 (2.4%/y) patients on clopidogrel + ASA and in
408 patients (3.3%/y) on ASA alone (RR, 0.72; P<.001). However, major
bleeding occurred in 251 (2.0%/y) patients on clopidogrel + ASA and in
162 (1.3%/y) patients on ASA alone (RR, 1.57; P<.001)
1. ACTIVE Investigators. Lancet. 2006;367(9526):1903-1912.
2. ACTIVE Investigators. N Engl J Med. 2009;360(20):2066-2078.
63
AHA/ASA 2010 Guidelines for the Prevention of Stroke
in Patients With Stroke or TIA
Recommendations for Atrial Fibrillation
I
A
IIa IIb III
Aspirin alone is recommended for patients
unable to take oral anticoagulants
B The combination of clopidogrel plus aspirin
carries a risk of bleeding similar to that of
warfarin and therefore is not recommended for
patients with a hemorrhagic contraindication to
warfarin (new recommendation)
Furie KL, et al. Stroke. [published online October 21, 2010]. doi:
10.1161/STR.0b013e3181f7d043.
64
RE-LY: Study Design
Nonvalvular atrial fibrillation at moderate
to high risk of stroke or systemic embolism
(at least 1 additional risk factor)
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: noninferiority to warfarin
Minimum 1-year follow-up, maximum of 3 years and mean of
2 years of follow-up
Primary end point: stroke or systemic embolism
Connolly SJ, et al. N Engl J Med. 2009;361(12):1139-1151.
65
RE-LY: Primary Outcome
Reproduced with permission from Connolly SJ, et al; the RE-LY Steering Committee and
Investigators. N Engl J Med. 2009;361(12):1139-1151.
66
RE-LY: Bleeding Events
Dabigatran
110 mg
Dabigatran
Dabigatran 110 mg vs Dabigatran 150 mg
Warfarin
Warfarin
vs Warfarin
150 mg
Annual
Rate
Annual
Rate
Annual
Rate
RR
95% CI
P Value
RR
95% CI
P Value
Major
2.7%
3.1%
3.4%
0.80
0.69-0.93
.003
0.93
0.81-1.07
.31
Lifethreatening
(major)
1.2%
1.5%
1.8%
0.68
0.55-0.83
<.001
0.81
0.66-0.99
.04
Gastrointestinal
(major)
1.1%
1.5%
1.0%
1.10
0.86-1.41
.43
1.50
1.19-1.89
<.001
<.001
0.91
0.85-0.97
.005
<.001
0.91
0.86-0.97
.002
Minor
Major or
minor
13.2%
14.8%
16.4%
14.6
16.4%
18.2%
0.79
0.74-0.84
0.78
0.74-0.83
Connolly SJ, et al; the RE-LY Steering Committee and Investigators. N Engl J Med.
2009;361(12):1139-1151.
67
Emerging Anticoagulants for
Stroke Prevention in AF
Direct factor Xa inhibitors
–
–
–
–
Apixaban (AVERROES, ARISTOTLE)
Betrixaban (EXPLORE Xa)
Edoxaban (ENGAGE AF–TIMI 48)
Rivaroxaban (ROCKET AF)
Vitamin K antagonists
– Tecarfarin
Usman MH, et al. Curr Treat Cardiovasc Med. 2008;10(5):388-397.
68
Case:
65-Year-Old Man With Recent Episodes of Palpitations,
Weakness, and Lightheadedness
Scheduled Follow-up Visit at 4 Weeks
● The patient continues to take dronedarone as
prescribed
● His ECG shows sinus rhythm without other
abnormalities
● He reports no side effects from the medication;
however, he continues to experience episodes of AF
2 to 3 times per week that last several hours at a
time, and complains of severe palpitations and
fatigue during the AF episodes
69
Case:
65-Year-Old Man With Recent Episodes of Palpitations,
Weakness, and Lightheadedness
What treatment would you now
suggest?
A.
B.
C.
D.
E.
Catheter ablation
Flecainide
Dofetilide
Amiodarone
AV node ablation and PPM
70
Surgical and Catheter Ablation
71
HRS/EHRA/ECAS 2007 Expert Consensus Statement on Catheter
and Surgical Ablation of Atrial Fibrillation
Indications for Surgical Ablation
● Symptomatic AF patients undergoing other cardiac surgery
● Selected asymptomatic AF patients undergoing cardiac surgery
in whom the ablation can be performed with minimal risk
● Symptomatic AF patients who prefer a surgical approach, have
failed 1 or more attempts at catheter ablation, or are not
candidates for catheter ablation
Best results are obtained in patients with paroxysmal AF
who are young and otherwise healthy
Calkins H, et al; Heart Rhythm Society Task Force on catheter and surgical
ablation of atrial fibrillation. Heart Rhythm. 2007;4(6):816-861.
72
Patient Selection for Ablation
Variable
Symptoms
Highly symptomatic
Minimally symptomatic
1
0
Paroxysmal
Long-standing persistent
Younger (<70 years)
Older (70 years)
Smaller (<5.0 cm)
Larger (5.0 cm)
Normal
Reduced
Congestive heart failure
No
Yes
Other cardiac disease
No
Yes
Pulmonary disease
No
Yes
Sleep apnea
No
Yes
Obesity
No
Yes
Prior stroke/TIA
No
Yes
Class I and III drugs failed
AF type
Age
LA size
Ejection fraction
Courtesy of Hugh Calkins, MD.
73
Initiation of AF From
Pulmonary Vein Focus
Reprinted with permission from Haissaguerre M, et al. N Engl J Med. 1998;339(10):659-666.
74
AF Is a Complex Arrhythmia
SVC
RSPV
LSPV
LIPV
Vein and
ligament of Marshall
RIPV
IVC
Reprinted with permission from Calkins H, et al. Heart Rhythm. 2007;4(6):816-861.
75
Surgical and Minimally Invasive
Surgical Ablation
76
Cox-Maze Procedure
In a trial of 190 patients, 1987-1997:
92% had freedom from AF and were off AAD agents
Reprinted with permission from Sundt TM 3rd, et al. Cardiol Clin. 1997;15(4):739-748.
77
ACC/AHA/ESC 2006 Atrial Fibrillation Guidelines
Recommendations for Catheter Ablation
I
IIa IIb III
Heart rate control:
When pharmacologic therapy is insufficient or associated
with side effects
B
C
When rate cannot be controlled pharmacologically or
tachycardia-mediated cardiomyopathy is present
C
C
Should not be attempted without prior trial of medication
Rhythm control:
Reasonable alternative to pharmacologic therapy to
prevent recurrent AF in symptomatic patients with little or
no LA enlargement
Fuster V, et al. Circulation. 2006;114(7):e257-e354.
78
HRS/EHRA/ECAS 2007 Expert Consensus Statement on Catheter
and Surgical Ablation of Atrial Fibrillation
Indications for Catheter Ablation
● Symptomatic AF refractory or intolerant to at least 1 Class
1 or 3 antiarrhythmic medication
● In rare clinical situations, it may be appropriate
as first-line therapy
● Selected symptomatic patients with heart failure and/or
reduced ejection fraction
● Presence of a left atrial thrombus is contraindication to
catheter ablation of AF
Calkins H, et al; Heart Rhythm Society Task Force on catheter and surgical ablation of
atrial fibrillation. Heart Rhythm. 2007;4(6):816-861.
79
Meta-analyzed Proportion of Patients, %
Efficacy of Catheter Ablation in
Patients With AF
90
42 (3,562)
34 (3,481)
52 (4,786)
57%
71%
72%
77%
Singleprocedure
success
off AAD
Multipleprocedure
success
off AAD
Singleprocedure
success
on/off med
Multipleprocedure
success
on/off med
75
60
31 (2,800)
45
30
15
0
Adapted with permission from Calkins H, et al. Circ Arrhythmia Electrophysiol. 2009;2(4):349-361.
80
Catheter Ablation of the AV Junction
Advantages
–
–
–
–
Simple
Highly effective
Safe
Allows a reduction in
medication
– Reduces symptoms
But:
– Does not prevent AF
– Does not restore a normal
heart rhythm
– Requires placement of a
pacemaker
– Does not lower the risk
of stroke
81
Catheter Ablation of AF: Meta-analysis
of 4 Randomized Clinical Trials
Source
Risk Ratio
(95% CI)
% Weight
Pappone et al, 2006
3.86 (2.65-5.63)
37.5
Stabile et al, 2006
6.43 (2.91-14.21)
18.1
Wazni et al, 2005
4.22 (2.14-8.32)
22.0
Krittayaphong et al, 2003
2.00 (1.02-3.91)
22.4
Overall (95% CI)
3.73 (2.47-5.63)
0.04
0.20
1.00
ADT More Effective
5.00
25.00
CPVA More Effective
Risk Ratio
Reproduced with permission from Noheria A, et al. Arch Intern Med. 2008;168(16):581-586.
82
NaviStar® ThermoCool®
Diagnostic/Ablation Catheter
●
●
●
●
●
Steerable, multi-electrode, deflectable
3.5-mm tip and 3 ring electrodes
6 saline ports in the tip for irrigation and cooling (open irrigation)
A location sensor and a temperature sensor incorporated into the tip
Approved by the FDA on February 6, 2009, for treatment of AF
83
Freedom From AF Recurrence
ThermoCool® Catheter vs AAD:
Time to Chronic Failures
1.0
0.8
64% Ablation
(n=103)
0.6
P<.001
0.4
16% AAD
(n=56)
0.2
0.0
0
30
60
Number of subjects at risk:
90
120 150 180 210
240 270 300
330
360
Days Into Effectiveness Follow-up
Ablation
103
69
69
66
63
62
61
54
52
37
15
3
2
AAD
56
39
29
19
16
13
11
10
7
2
0
0
0
Effectiveness cohort, N=159. Circles in the graph represent 14 censored catheter ablation subjects.
Wilber D. Presented at: American Heart Association 2008 Scientific Sessions;
November 11, 2008; New Orleans, LA.
84
Case:
65-Year-Old Man With Recent Episodes of Palpitations,
Weakness, and Lightheadedness
Catheter Ablation and Follow-up Visit at
3 Months
● The patient undergoes successful catheter ablation
● On follow-up 3 months post-catheter ablation, he is in
AF and reports that AF recurred about 3 weeks
following the ablation procedure and has been
present constantly since that time
● He complains of continued palpitations and fatigue
● An ECG confirms the presence of AF
85
Case:
65-Year-Old Man With Recent Episodes of Palpitations,
Weakness, and Lightheadedness
What treatment would you now
suggest?
A.
B.
C.
D.
E.
F.
Repeat catheter ablation
MiniMaze procedure
DCC
Pharmacologic cardioversion
Amiodarone
AV node ablation and PPM
86
Case:
65-Year-Old Man With Recent Episodes of Palpitations,
Weakness, and Lightheadedness
DCC and Follow-up Visit at 6 Months
Post-Catheter Ablation
● The DCC was successful in restoring sinus rhythm
● At a 6-month follow-up visit after the catheter ablation,
the patient reports 1 episode of AF each month lasting
approximately 20 minutes
87
Case:
65-Year-Old Man With Recent Episodes of Palpitations,
Weakness, and Lightheadedness
At this point, what treatment would you
suggest?
A.
B.
C.
D.
E.
F.
G.
Repeat catheter ablation
MiniMaze procedure
DCC
Pharmacologic cardioversion
Dronedarone
AV node ablation and PPM
Clinical follow-up
88
Possible “Upstream” Treatments and
Mechanisms for AF Prevention
ACEIs/ARBs Statins Glucocorticoids Physical activity Omega-3 fatty acids
Inflammation Oxidative stress RAAS activity Endothelial function
Autonomic nervous system activity
Plaque stability Atrial remodeling Stabilize left atrial endocardium
Atrial fibrillation
Courtesy of CJ Pepine, MD.
89
2010 ESC Guidelines
for the Management of
Atrial Fibrillation
90
2010 Guidelines for the Management of AF
The Task Force for the Management of AF of the
European Society of Cardiology (ESC)a
New recommendations
● Addition of “long-standing persistent AF” as a
patient category
● Introduction of the EHRA symptom score for arrhythmias
● Establishment of better risk profiles to assess who will benefit
most from new anticoagulants to prevent stroke
– CHA2DS2-VASc score (refinement of CHADS2 score)
– HAS-BLED (new score for assessing bleeding risk)
a
Developed together with the European Heart Rhythm Association (EHRA) and endorsed by the
European Association for Cardio-Thoracic Surgery (EACTS).
Camm AJ, et al. Eur Heart J. 2010;31:2369-2429.
91
2010 Guidelines for the Management of AF (cont)
The Task Force for the Management of AF of the
European Society of Cardiology (ESC)a
Changes from the previous ACC/AHA/ESC
2006recommendations
● New guidance in the area of rate control
● Advice on how to use the antiarrhythmic drug dronedarone
● Formal indications for the use of ablation therapy
● Recommendations on “upstream” therapies to prevent the
deterioration of AF
● Advice on certain “special situations”
a
Developed together with the European Heart Rhythm Association (EHRA) and endorsed by the
European Association for Cardio-Thoracic Surgery (EACTS).
Camm AJ, et al. Eur Heart J. 2010;31:2369-2429.
92
www.escardio.org/guidelines
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www.escardio.org/guidelines
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www.escardio.org/guidelines
www.escardio.org/guidelines
www.escardio.org/guidelines
www.escardio.org/guidelines
www.escardio.org/guidelines
www.escardio.org/guidelines
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www.escardio.org/guidelines
www.escardio.org/guidelines
Question-and-Answer
Session
111
AF Performance Improvement
Outcomes Study
● NCME has partnered with Harvard Clinical Research Institute (HCRI) to
evaluate the impact of this educational activity
● The goal of the study is to:
– help each participating hospital gain perspective on how their
institution manages AF
– directly assess improvements in patient outcomes
● Data will be collected via a secure online Web site
● Baseline data will be collected representing a period prior to the grand
rounds lecture, and then one year as a follow up
● Study closely aligns with QI programs your hospital is already involved
in (eg, reporting to Joint Commission and CMS)
● $500 honorarium will be provided to each participation institution
● To sign up for the study complete the enrollment form provided to
your CME coordinator or send an e-mail message to
[email protected]
112
Thank you
for participating!
113