Transcript Atrial Fibrillation: Is is time for a change of pace?

Atrial Fibrillation:
Is is time for a change of pace?
Resident Grand Rounds
Dr. Lee Graham
Emergency Medicine R2
November 19, 2009
Disclosure
• I just got
KEYNOTE.
• Be prepared to be Dazzled!
Scenario #1
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76 year old Female
Chronic paroxysmal A Fib X 6 years
Meds: include Diltiazem / Coumadin
CAD / Stroke / COPD / DM / OA
Presents to ED with recurrent palpitations /
presyncope
Been to Emerg 3 times in the last 3 months
HR ~135 / BP 115/76
Question
•“Is there a role for longterm anti-arrhythmic
medications in this
patient?”
Scenario #2
• 52 yr old Male
• Sudden onset palpitations - 6 hrs ago
• Feels weak / No CP / NO dyspnea
• PMed Hx - Nil
• Meds - Nil
• HR~140
Question
•“What is the evidence
for chemical
cardioversion for acute
Atrial Fibrillation?”
So why should we
talk about this?
Objectives.
• What is the role of rhythm control in
Atrial Fibrillation? Dronedarone?
• Should we attempt to be getting
patients back into sinus rhythm in
Emerg?
• If time...at the end A Fib Potpourri
Atrial Fibrillation is
Bad.
What is Atrial
Fibrillation?
•Risk Factor
• (causative)
•Risk Marker
•
(bystander)
Terminology
• Acute - <48hrs after onset
• Paroxysmal - intermittent / recurrent /
self-terminating
• Persistent - will not self-terminate / can
cardiovert to sinus rhythm
• Permanent - cannot be terminated by
cardioversion or only terminates for
brief intervals
• Lone - <60yrs and no heart or lung
disease
Secondary
First
Detected
Paroxsymal
(Self-terminating)
Persistent
(Non self-terminating)
Permanen
t
The great debate...
• “Rate” vs “Rhythm”
“Rate” vs “Rhythm”
• 5 RCTS
AFFIRM
RACE
PIAF
STAF
HOT CAFE
• Meta-analysis
Closer look at
AFFIRM
• Foundation of our management of A Fib
• Randomized / Multi-center
• 4060 patients
Inclusion
• Age > 65 years old
• Other risk factors for death
• “likely to be recurrent”
• “likely to cause illness or death”
• “treatment warranted”
Groups
• RHYTHM
• Use what you want
• Could use Cardioversion
• RATE
• Use what you want
• Goal HR 80 at rest. 110 during activity.
Anti-coagulation
•RATE
•Continuous
•RHYTHM
•“Encouraged” = could be stopped
• > 4 weeks
• >12 weeks (preferably)
Rhythm Control
Drugs
“almost significant trend
in mortality”
RATE RHYTHM
CNS EVENT
NO WARF
Bad INR
w/ Afib
25
27
42
44
17
25
• AFFIRM
• NEJM 2002
• Circulation 2006
analysis
= Intention to treat
= “In treatment”
Covariate Analysis
Sinus rhythm 0.53
Rhythm-control 1.49
AFFIRM
•Rate
• =
•Rhythm
ACTUAL
POSITIVE “side effects”
+
NEGATIVE “side effects”
control
ACTUAL
control
POSITIVE “side effects”
+
NEGATIVE “side effects”
AFFIRM
•Rate
• =
•Rhythm
ACTUAL
POSITIVE “side effects”
+
NEGATIVE “side effects”
control
ACTUAL
control
POSITIVE “side effects”
+
NEGATIVE“side effects”
Why is everyone
getting so excited?
• First “A Fib” Drug approved in last 10
years
• First drug to show effect on hard
outcomes (other than atrial fibrillation
recurrence)
Dronedarone
• SR33589 / Multaq
• Noniodinated benzofuran
• Electrophysiologic effects similar to
AMIODARONE
• Na, K, Ca currents, acteylcholineactivated potassium currents, antiadrenergic
Amiodarone
• IodineSide Effects
X
• Pulmonary
• Hepatitis
• Thyroid
• Eye
•
effects
MAY have fewer side
Long lost
brothers????
A
T
H
E
N
A
• A T rial with dronedarone to prevent
d ath in patie
H ospitalization or E
N ts with
A trial fibrillation
• 4628 patients with ATRIAL
FIBRILLATION and ADDITIONAL RF
for death
• Dronedarone 400mg BID vs PLACEBO
Outcomes
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Primary Outcome
COMPOSITE of:
•cardiovascular hospitalization
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+
•
death
Secondary Outcome
i)
death any cause
ii) death from CV cause
iii) hosptilalization due to CV
Inclusion
• Paroxysmal or persistent A Fib or A Flutter
• + one of
• >70 years old
• Hypertension (> 2 meds)
• DM
• previous stroke / TIA / embolism
• Left atrial diameter > 50mm
• LVEF <40%
• EKGs within 6 months (one in sinus / one in afib)
Inclusion
Inclusion Criteria
Changed During
Study
• Paroxysmal or persistent A Fib or A Flutter
• + one of
• >70 years old
>75
• Hypertension (> 2 meds)
• DM
<70
excluded
• previous stroke / TIA / embolism
• Left atrial diameter > 50mm
• LVEF <40%
• EKGs within 6 months (one in sinus / one in afib)
Exclusion
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Permanent atrial fibrillation
Decompensated heart failure within 4 weeks
NYHA class IV CHF
Acute MI
Planned major surgery
HR <50
PR 0.28
Previous sinus-node disease not with a pacemaker
NON CARDIAC
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GFR <10ml/min
K < 3.5 mmol if currently not being corrected
going to die / pregnant / breast feeding
Exclusion
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Permanent atrial fibrillation
Decompensated heart failure within 4 weeks
NYHA class IV CHF
Acute MI
Planned major surgery
HR <50
PR 0.28
Previous sinus-node disease not with a pacemaker
NON CARDIAC
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GFR <10ml/min
K < 3.5 mmol if currently not being corrected
going to die / pregnant / breast feeding
Patient
•MeanCharacteristics
age 71.6
•46.9% female
•Hypertension 59.6%
•LVEF < 35% (3.9%), LVEF <45%
(11.9%)
•Hx of NYHA II - 17.1%
•
III - 4.4%
ATHENA
•Follow-up - mean 21 +- 5 months
•Study drug discontinued prematurely in:
•Dronedarone
- 30.2%
•Placebo
- 30.8%
Intolerance
Anti-arrhythmic drug
Side Effects
• Bradycardia
• QT - prolongation
• Gastrointestinal (26.2% vs 22.0%)
P<0.001
• Nausea
• Rash
• Increase in serum creatinine
Outcomes
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Primary Outcome
COMPOSITE of:
•cardiovascular hospitalization
•
+
•
death
Secondary Outcome
i)
death any cause
ii) death from CV cause
iii) hosptilalization due to CV
Primary Outcome
•Dronedarone
31.9%
Hospitalization
Death 2.6%
29.3%
Placebo
•
Death 2.5%
36.9%
39.4%
Hospitalization
Hazard ratio 0.76 (0.69 - 0.84)
Secondary Outcomes
i) death any cause
•Dronedarone 5.0%
•
Placebo
HR 0.84 (0.66 - 1.08)
6.0%
ii) death from CV cause
•Dronedarone 2.7%
•
Placebo
HR 0.71 (0.51 - 0.98)
3.9%
iii) first hosptilalization due to CV
HR 0.74 (0.67 - 0.82)
•
Dronedarone
29.3%
•
Placebo
36.9%
First Hospitalization
A Fib
CHF
Dronedaron
e
Placebo
P - value
335 (14.6)
510 (21.9)
<0.001
132 (5.7)
0.22
112 (4.9)
ACS
62 (2.7)
89 (3.8)
0.03
Syncope
27 (1.2)
32 (1.4)
0.54
Ventricular
arrhythmia
13 (0.6)
12 (0.3)
0.83
Contribution of
A Fib Hospitalization
A Fib
Dronedarone
Placebo
335 (14.6)
510 (21.9)
= 7.3
• CV Hospitalization = 7.6
• Primary Outcome = 7.5
Limitations
• High rate of discontinuing study drug
• No comparison to other anti-arrhythmic
• Importance of primary outcome?
A
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D
A
•A N tiarrhythmic trial withDRO nedarone in
Moderate-to-severe Congestive Heart
A se
EFailure valuating Morbidity
D ecre
• Multi-center / Double-blind design
• 1000 patients hospitalized for
symptomatic heart failure and severe
left ventricular systolic failure
• After 627 patients (310 dronedarone)
• Prematurely stopped
Mortality
• Dronedarone 8.1%
• Placebo
3.8%
“related to worsening heart failure”
So where does
Dronedarone fit in?
•First trial of an anti-arrhythmic to show a
reduction in an endpoint other than
RECURRENCE of A Fib
•Effect of trial or drug?
✓Dronedarone compared to other AAR
✓Dronedarone in context of Rate vs
Rhythm
✓Dronedarone compared to other
AAR
Text
• Not published, or presented
• 504 patients randomized
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Documented AF (not continuous)
“need for cardioversion and antiarrhythmic treatment”
On anticoagulants
Not in “clinically overt” NYHA 3-4
Primary Endpoint
COMPOSITE:
• 1) AF recurrence
• or
• II) premature drug discontinuation for
intolerance of lack of efficacy
Primary Outcome
P < 0.001
•
Dronedarone
73.9%
A Fib 36.5%
Stopped Drug
10.4%
•
Amiodarone
55.3%
A Fib 24.3%
Stopped Drug
13.3%
• Systematic overview of RCTs
• INDIRECT META-ANALYSIS
• Drugs have not been compared Head
to Head
“Dronedarone is LESS effective for maintaining
SINUS RHYTHM, but has FEWER adverse
effects”
Weakness of analysis
• All Dronedarone studies have
EXCLUDED PERMANENT A Fib
• Amiodarone pts more likely to have
persistent/permanent A Fib and
STRUCTURAL Heart Disease
Odds Ratios
Dronedarone
Amiodarone
A Fib
Adverse
Death
Dronedarone
Amiodarone
Study Conclusions
• For every 1000 patients treated with
Dronedarone instead of Amiodarone
• 228
• 9.6
X
• 62
MORE recurrences of A Fib
FEWER deaths
FEWER adverse events requiring
stoppage
So where does
Dronedarone fit in?
•First trial of an anti-arrhythmic to show a
reduction in an endpoint other than
RECURRENCE of A Fib
•Effect of trial or drug?
✓Dronedarone compared to other AAR
✓Dronedarone in context of Rate vs
Rhythm
✓Dronedarone in context of Rate vs
Rhythm
• Multicenter / Randomized
• 1376 pts
• Rhythm vs Rate
• LVEF < 35%
• Symptoms of CHF
• Atrial Fibrillation
Survival
% in A Fib
Canadian Trial of
Atrial Fibrillation
Dronedarone
Amiodarone
Mortality
?
✓
Dronedarone
“POTENTIAL”
Benefit
ANDROMEDA
ATHENA
No Heart Failure
1
Dronedarone
INCREASED
Mortality
2
NYHA
3
4
Thoughts...
•STILL no studies showing RHYTHM
superior to RATE
•If sinus rhythm is important for mortality
• ...Amiodarone would be superior to
Dronedarone
My take...
• Dronedarone not ready for prime time
• Rate and Rhythm are STILL equivalent
• Anti-coagulation! ANTICOAGULATION!
Indications for
Rhythm
• Symptomatic
• Secondary cause
• Failed Rate control
• Patient preference
Chance at sinus...
FAVORS RATE
FAVOR RHYTHM
Persistent - Recurrent
History Afib > 1yr
>65 years of age
HTN
AAD failure
LA > 60cm
No previous CHF
Patient Preference
Paroxysmal AF
First Episode of AF
<65 yrs of age
NO HTN
No AAD failure
LA < 60cm
History of CHF
So what about in the
ED?
• Retrospective chart-review (5 yrs)
all patients who received IV
Procainamide
• “Routine Care”
• 169 pts
Sinus
• Chemical ElectricalA Fib
DC w/ no meds
+- Cardiology FU
Rate
Anticoagulaion
Exclusion
• >48 hrs (unless anticoagulated)
• Permanent or Long standing A Fib
• Another dx requiring admission (CHF
etc..)
• Unknown duration
Patient
Characteristics
• Age, median
68
• Previous A Fib
• HTN
• CAD
• CHF
• Thromboembolic
65.4%
32.8%
24.9%
5.3%
5.0%
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Outcomes
(within 6hrs)
SBP < 100mg
Bradycardia
Syncope
Heart Block
VT
Torsades
CVA
Death
Recurrence of A Fib
(within 7 days)
Results
• Chemical cardioversion
• Electrical cardioversion
• Discharge home
• Discharge in sinus
50.4%
91.0%
94.4%
88.9%
Median conversions time = 55 minutes (2 - 390)
Adverse events
• Hypotension
• Bradycardia
• Ventricular arrhythmia
• Death / Badness
• Relapse within seven days
28 (8.5%)
2 (0.6%)
1 (0.3)
0 (0.0%)
10 (2.9%)
Limitations
• Retrospective
• Short term follow-up
• Generalizability
• No telephone or death registry review
How effective is Procainamide?
Is converting these patients doing anything?
How effective is Procainamide
• Retrospective
50%
24hrs
Procainamide50.4%
chart review of
patient
presenting with
Atrial Fibrillation
to the ED as the
primary
diagnosis
x
x
NO IV available
Black Box
x
x
PO
Slow / Ineffective
Vernelakant
Limitations
• Retrospective
• Short term follow-up
• Generalizability
• No telephone or death registry review
How effective is Procainamide?
Is converting these patients doing anything?
Is converting these patients doing anything?
• Prospective / randomized / OPEN
• 2 X 2 design
• 144 pt randomized - trans-telephonic monitoring BID
• DIGOXIN
• ACUTE
(<24hrs)
vs
vs
VERAPAMIL
ROUTINE electrical cardioversion
• “Acute cardioversion did not
improve long term rhythm
control”
• Retrospective review of:
• 1950 pts receiving 2630 DC
Cardioversions
• 4 week post chart follow + contacted
treating physician
•258 pts Afib < 2 days
Coumadin PRE / POST - 60
NO Coumadin PRE / POST - 198
# Stroke
0
1
0.3%
•“New-onset AF is associated with a
significantly higher risk for death compared
with no AF or persistent AF”
•Mortality
9.62 (8.93 - 10.32)
•>4 months HR 1.66 (1.59 - 1.73)
•<4 months
HR
• “Through safe in these studies, it may
be prudent to perform TEE (or delay
cardioversion for 1 month) Even without
use of TEE, anticoagulation with
heparin immediately prior to
cardioversion may be appropriate.”
Grade 2C
• NO RCT’s <48hrs
Patient
Characteristics
C
H A D S
• Age, median
68
• Previous A Fib
• HTN
• CAD
• CHF
• Thromboembolic
65.4%
32.8%
24.9%
5.3%
5.0%
A
H
C
S
Patient
Characteristics
• Age, median
68
• Previous A Fib
• HTNParoxysmal
• CAD
• CHF
• Thromboembolic
65.4%
32.8%
24.9%
5.3%
5.0%
Conclusions
• Procainamide - moderately efficacious
• Cardioversion “helping” pts with
secondary atrial fibrillation
• Decision to start ANTI-COAGULATION
and RATE/RHYTHM needs to be
patient SPECIFIC
Questions?