Arrhythmia Pharmacotherapy
Michael Ujhelyi, Pharm.D, FCCP
Senior Principal Scientist
Clinical Associate Professor
Medtronic and University of Minnesota
Office 514-3674
Fax 514-2701
Email: Michael.Ujhelyi@Medtronic.com
Suggested Reading
1.
FUSTER ET AL., ACC/AHA/ESC GUIDELINES FOR THE
MANAGEMENT OF PATIENTS WITH ATRIAL FIBRILLATION
J Am Coll Cardiol 2001;38:1266-xx
www.acc.org/clinical/guidelines/atrial_fib/af_index.htm
2.
Falk RH. Atrial Fibrillation. NEJM 2001;344;1067-1078
3.
Peters NS, Schilling RJ, Kanagaratnam P. Atrial
fibrillation:strategies to control, combat and cure.
Lancet 2002;359:593-603.
Mechanisms of Atrial Fibrillation
1. Know signs, symptoms and
electrocardiographic features of AF and VT/VF
2. Understand the clinical consequences of AF
and VT/VF if not prevented or treated.
3. Know how to achieve the most efficacious
outcome using pharmacologic therapy for the
prevention and/or treatment of AF and VT/VF.
Atrial Fibrillation
• Irregular beat to beat rate
• No Visible P Waves
• Narrow QRS complex
Atrial Flutter
• Regular beat to beat rate
• Narrow QRS complex
• Evident P waves (flutter waves)
SA
AV
Objective
Rate = 50 180 BPM
Irregular Ventricular Rate
1
Mechanisms of Atrial Flutter
Classification of Atrial Fibrillation
80
SA
•
300
3 P’s of AF:
– Paroxysmal: terminates spontaneously
– Persistent: can only be converted with drugs
or DC energy
– Permanent: will not terminate
Rate = 140
-160 BPM
AV
Regular Ventricular Rate
Gallagher & Camm, Am J Cardiol 1998;82:18N-28N
Prevalence & Incidence of
Atrial Fibrillation
Pathology: What Causes AF
Disease
Incidence
with AF
Incidence
No AF
Valve
16.7%
6.7%
↑Thyroid
20-30%
<2%
MI
22.5%
13%
HTN with LVH
10.7%
4.4%
Diabetes
16.3
10.2
CHF
20.6%
3.2%
None
20%
Benjamin etal. Atrial fibrillation: Mechanisms and Management, 2nd ed. Lippincott-Raven
• Over 2 million people in U.S.
currently have atrial fibrillation
• Over 5.5 million cases worldwide
• 720,000 new cases per year
worldwide
Falk RH NEJM 2001;344:1067
Why Treat AF
AF Symptoms
Symptoms & Risks
Cardiac
• Decrease symptoms
• Prevent CHF?
• Improve quality of life
(Dofetilide)
• Increase survival?
Thromboembolic
• Decrease stroke
• Improve survival
60
% Reported Symptoms
AF
50
40
30
20
10
0
S
N
An
Sy
Fa
Ch
Pa
tig
nc
lpi
xie OB aus
es
op
ue
tat
ea
tP
ty
e
ion
ain
s
Gerstenfeld PACE (abstract) 1999
2
Quality of Life
Mortality Risk (SOLVD data)
Healthy General Population
Patients with Recent MI
Patients with CHF
Patients with AF
90
80
70
Score
Sinus Rhythm
.8
Event-free Survival
100
1
.9
60
50
40
.7
Atrial Fibrillation
.5
.4
.3
.2
30
.1
20
0
10
P < 0.001
.6
0
0
Physical
Function
General Health
Jung W, et al. JACC 1999; 33(2):104A.
Vitality
Social Function
Emotional
Function
Quality of Life Subscale Category
365
770
1095
1460
Follow-up time (days)
6,098
419
4,576
288
5,611
357
2,777
159
1,088
50
Sinus Rhythm
Atrial Fibrillation
Dries D, et al. JACC 1998; 32:695-703.
Heart Failure Risk (SOLVD
data)
Assumption for Therapy
1
Event-free Survival
.9
Sinus Rhythm
.8
Atrial Fibrillation
.7
• Patients are better off in NSR
P < 0.001
.6
• Reasonable efforts should be used before
declaring chronic AF.
.5
.4
.3
• Rhythm vs Rate control studies have questioned
this assumption.
.2
.1
0
0
365
770
1095
1460
Follow-up time (days)
4,576
288
5,611
357
6,098
419
2,777
159
1,088
50
Sinus Rhythm
Atrial Fibrillation
Dries D, et al. JACC 1998; 32:695-703.
Rhythm Vs. Rate Control Strategy
Rhythm Vs. Rate Control
AFFIRM: Mortality
N
F/u
(yrs)
AF (days)
AAD
%NSR
Rhythm
Group
%NSR
Rate
Group
PIAF
252
STAF
200
1
7-360
Amio
56%
10%
3
30-180
NA
23%
AFFIRM
0%
3657
5
0.25-180
Amio/Sot
60%
40%
RACE
522
3
1-360
Sot
40%
10%
•Hohnloser etal Lancet 2000;356:1789
•Carlsson etal PACE 2001;24:561
•JACC 2002
3
Rhythm Vs. Rate Control
Summary
• Rate control may be considered primary therapy strategy.
• Rhythm control is difficult to maintain with antiarrhythmic
agents.
• Antiarrhythmic agents may increase arrhythmic CV events
(AFFIRM).
• AF, regardless of strategy, may predict major CV events
(STAF).
Approach to Therapy –AF
Chronic AF
Paroxysmal/Persistent
Rate Control
Rate Control
Anticoagulation
Anticoagulation
(>24-48hr)
Termination
-Spontaneous
- Pacing (flutter)
- Pharmacologic
- DC cardioversion
Conclusion
Less toxic and more effective rhythm control therapies are
needed to test NSR benefits.
• Device Therapies
• Ablation/surgical therapy
Treatment Pathways for AF/AFL
AF
• DC Cardioversion
• RX Cardioversion
AFL
• Pacing Cardioversion
• DC Cardioversion
• RX Cardioversion
o
o
o
o
o
o
o
o
o
o
RX Prevention
Rate Control
Stroke Prevention
Pacing Prevention
Surgical/Ablation Cure
Ablation Cure
RX Prevention
Rate Control
Stroke Prevention
Pacing Prevention
Antiarrhythmic Pharmacology
Drug
Quinidine
Procainamide
Disopyrimide
Flecainide
Propafenone
Amiodarone
Sotalol
Ibutilide
Dofetilide
Azimilide
Prevalence of use
Moderate/low
low
very low
moderate
moderate
high
high
low
New
Investigational
Prevention
- Watchful waiting
- Pharmacologic
- Pacing therapies
- Catheter ablation
- Surgical ablation
Pharmacology Tool Box
Cardioversion
Maintenance
Rate Control
Anticoagulation
Quinidine
Procainamide
Flecainide
Propafenone
Amiodarone
Ibutilide
Dofetilide
Quinidine
Procainamide
Disopyramide
Flecainide
Propafenone
Amiodarone
Ibutilide
Sotalol
Dofetilide
blockers
Verapamil
Diltiazem
Digoxin
ASA
Warfarin
Antiarrhythmic Efficacy : Acute
Termination
Drug
Class
IA
IA
IA
IC
IC
III
III
III
III
III
Anticoagulation
Acute onset Persistent AF
IV or oral delivery
(< 7 days)
(> 7 days)
Flecainide
70-90%
?
Propafenone
50-90%
30%
Procainamide
Amiodarone
Sotalol
Ibutilide
Dofetilide
60-70%
50-90%
= placebo
46%?
67%
5%
40-70%
Placebo = 20-50% for lone AF
= <20% for OHD
15%
30%
Golzari etal Ann Int Med 1996;125:311
4
Doefetilide: Conversion to SR
Relative Efficacy: Maintain NSR
100
0.8
Placebo
% NSR (6-12 Month)
Probability of Remaining in AF
1.0
0.6
0.4
Dofetilide
0.2
Log-rank p=0.002
0.0
0
Number at risk
Dofetilde
Placebo
12
59
56
24
Time Months
4
17
36
1
12
48
40
20
0
P l Q u F le P r S o D o A m
op t
in
f
c
io
Li and Hohnloser. J Cardiovasc Pharmacol Therapeut 1998;3:185-94
Relative Efficacy: Maintain
NSR
Conversion & Prevention:
Drug Selection
100
80
Patients without
Recurrence (%)
60
0
2
Kober L, et al. Lancet 2000; 356:2052-58.
C
80
Amiodarone (n=201)
60
Propafenone (n=101)
40
20
Sotalol (n=101)
•
•
•
•
•
Efficacy
Structural heart disease
QRS or QT interval
Systolic function
Comorbidities / life expectancy
0
0
100
300
200
400
500
600
Days of Follow-up
Roy et al. N Engl J Med 2000;342:913-20.
Conversion & Prevention:
Drug Selection
Mortality: Quinidine prophylaxis
Meta Analysis
Class I Agents
Avoid - Increased proarrhythmia if:
• Structural heart disease
– Ischemic heart disease
– Systolic and diastolic
dysfunction
• QRS > 120 ms
• QTc > 480 ms
Cast Trial: NEJM 1991;324:781-88.
3
6
9
12
Odds Ratio
Coplan etal. Circulation 1990;82:1106-16
5
Conversion & Prevention:
Mortality with Class I Agents
Conversion & Prevention:
Drug Selection
Class III Agents: Sotolol and Ibutilide
Avoid - Increased proarrhythmia if:
• HR < 50 bpm
• QTc interval > 480 ms
• K+ < 3.6 mmol
• Mg < 1.0 mmol
• LV dysfunction: EF < 30%:
Flaker. J Am Coll Cardiol 1992;20:527-32
Conversion & Prevention:
Drug Selection
Class III Proarrhythmia
Class III Agents: Amiodarone
Avoid if:
• HR < 50 bpm
• Life expectancy > 10 years
• Liver disease
• Pulmonary disease
Pharmacologic Conversion
Structural heart disease
No
Propafenone
or
ibutilide
Structural heart disease
Yes
No
Proarrhythmia Risks
No
Ibutilide
Pharmacologic Prevention:
Sotalol or
Dofetilide
EF < 40%
Yes
Yes
Correct
DC CV
Yes
No
flecainide
No
flecainide
Yes
Propafenone
life expectancy
<10 yr
Sotalol or
dofetilide
amiodarone
Proarrhythmia Risks
No
amiodarone
amiodarone
amiodarone
>10 yr
Sotalol or
dofetilide
Yes
amiodarone
6
Pharmacologic Considerations
Pharmacologic Considerations
Sotalol
Quinidine
Propafenone
• TDP risk (not
dose related)
• Discontinue if
QTc > 500 ms
• Dig interaction
• Beta blocker
• Poorly
metabolized
(7%) pts.
• CNS adverse
effects
Flecainide
• TDP risk (dose
related)
• CNS adverse
effects
• TDP risk > in females
• Inexpensive
• Most effective agent
• Discontinue if QTc >
500 ms
Flecainide
100-200 mg BID
Propafenone
150-300 mg bid
to TID
Amiodarone
200 mg
Sotalol
80 – 160 mg BID
Ibutilide
Dofetilide
1 mg in 10 min
500 ug bid
• Cumulative dose end
organ damage
• Very long half-life and
many Rx interactions
Pharmacologic Therapy:
In hospital initiation ?
Pharmacologic Dosing
324Tid up to 684
TID
Procainamide 500-1500mg TID
to QID
• Improve CHF
symptoms
• Renal elimination
must adjust dose
• Dig interaction
Drug
Quinidine
• Very low
proarrhythmia
• Discontinue if
QRS > 120 ms
• Very
proarrhythmic
Dosing
Amiodarone
• Beta blocker
Monitoring
Blood level: 2.5-5 ug/mL
QTc >500 decrease dose
Blood level: 4-8 ug/mL,
NAPA + PA < 25 ug/mL
QT >500 decrease dose
Adjust for renal failure
• Dofetilide – Required by labeling
• Sotalol therapy (Prystowsky EN. Clin Cardiol 1994;117:7-10)
QRS > 140 decrease dose
Adjust for renal failure
– Structural heart disease
– Sinus node dysfunction
– AV conduction delay
– Long QT
– Electrolyte imbalance
– IV therapy
QRS > 140 decrease dose
No dosing modifications
QTc > 500ms decrease dose
Adjust for renal failure
Stop infusion if QTs>550 ms
QTc > 500ms decrease dose
Adjust for renal failur
Rate Control Efficacy
Rapid AF : Rate Control
180
Digoxin
• Beta Blockers
• Diltiazem or verapamil
• Digoxin
Ventricular Rate, bpm
Diltiazem
160
Atenolol
140
Dig+dilt
Dig+atn
120
100
80
60
1
2
3
Farshi R, et al. JACC 1999; 33:304-10.
4
5
6
7
Time, min
8
9
10
11
12
7
Acute Rate Control
Chronic Rate Control
Systolic Dysfunction (EF <40%)
Hypotension (SBP < 95 mmHg)
No
Hyperactive
airway disease
Beta Blocker
Diltiazem or
verapamil
IV Diltiazem
Yes
IV Digoxin
Yes
Hyperactive
airway disease
Pulmonary congestion
No
Yes
No
No
Yes
Yes
No
Beta Blocker
Diltiazem or
verapamil
Yes
No
Oral therapy
IV therapy
Anticoagulation
When to Consider
• AF > 48 hrs
• Chronic AF
• Multiple sustained AF events > 2 hours
When to Stop
• 3 Weeks following cardioversion & NSR?
Effective rate control
Yes
No
Effective rate control
Moderate to severe symptoms
Beta Blocker
or oral Digoxin
Yes
No
Add oral
digoxin
Continue
therapy
Increase
dose or Add
oral beta
blocker
Continue
therapy
Anticoagulation Guideline
• No Structural Heart Disease
<65 y/o ⇒ ASA
>65 y/o ⇒ Warfarin
• Structural Heart Disease
⇒ Warfarin
• Previous Thromboembolic Event
⇒ Warfarin
• No episodes for > 6 months?
Anticoagulation Guideline
Pharmacologic Summary
• Acute Conversion: Class I & ibutilide
Hylek EM etal.. Ann Intern Med 1994;120:897-902.
• Conversion of refractory patients:
oral amiodarone
• Maintenance of NSR:
• Class 1C agents only in healthy hearts
• Sotalol for healthy hearts or > 10 yr
life expectancy
• Amiodarone for <10 yr life expectancy
or refractory patients.
• Rate control:
• Beta and Ca+ blockers equally
effective
• Avoid Ca+ when EF < 40%
• Anticoagulation: Risk factor dependent and
AF frequency
8
Non Pharmacologic Therapies
AF Mechanisms: Triggers
• Catheter Ablation
• Surgical Ablation
Case Studies: Patient Assessment
• Symptom history
¾ Frequency consider cardioversion
¾ Assess for prophylaxis
¾ Anticoagulation
• ECG
¾ Ventricular response
¾ QRS and QT interval
• Hemodynamic stability
• Echocardiogram
¾ Structural heart disease
¾ LV ejection fraction
• Thyroid Function
• Drug history
Case I
ECG: Atrial fibrillation, rate 95-145 beats/min, all intervals
within normal limits.
Medications
furosemide 40 mg Bid
captopril 25 mg BID
Patient Assessment
Design a therapeutic plan.
Case I
AL is a 61 year old female with valvular heart disease
(secondary to rheumatic fever) who presents to the clinic
with chief complaints of shortness of breath on exertion
and palpitations.
She states that these symptoms
presented when walking her dog last evening. Upon rest
she notes that she is no longer short of breath but still feels
heart palpitations. AL was noted to be in no apparent
distress during the physical exam.
Vitals: BP 113/76 mmHg, Pulse 133 beats/min irregular,
Resp 16/min and afebrile
PMH: Mild/moderate mitral valve regurgitation
Dilated cardiomyopathy
Congestive heart failure (NYHA class II)
Case I
AL is asymptomatic and resting comfortably. AL, however
remains in AF.
• Explain the pros and cons of rate control management versus
cardioversion and maintaining normal sinus rhythm.
• It was decided to try pharmacologic CV. What
would be the most appropriate therapy?
• Explain any additional information needed prior to
designing a therapeutic plan.
• What should be done to maintain NSR
• What should be done to treat the patient’s symptoms.
• Should anticoagulation be prescribed?
9
Case I: Follow up
AL is successfully treated and is discharged home. Over the
next year AL has had seven hospital admission for symptomatic
atrial fibrillation.
A echocardiogram two months ago
documented an ejection fraction of 32%. She presents today
with palpitations, severe shortness of breath and dizziness which
is unrelieved by rest. On ECG she is noted to be in atrial
fibrillation with a systolic pressure of 85 mmHg. It was decided
to electively use DCC, which placed AL into sinus rhythm. On
exam after cardioversion, AL was noted to be in less distress and
more comfortable.
Medications on Admission:
digoxin 0.125 mg QD
metoprolol 50 mg QD
Warfarin 5 mg QD
captopril 25 mg TID
sotalol 120 mg BID, also failed quinidine
Types of Ventricular Arrhythmias
•
origin of arrhythmia is within
the ventricle
Ventricular Tachycardia
• Primarily regular beat
• Wide QRS complex
• No P waves
Case I: Follow up
What is your assessment of this patient's problems compared to
last visit.
What will be your therapeutic goal and which therapy will be
used to achieve this goal
State expected outcomes from therapy.
Premature Ventricular Contractions
• An early Irregular beat
• Wide QRS complex
• No P waves
Mechanisms PVC & VT
Atrium
One Cycle = PVC
Rate = 100
-250 BPM
Two or more = VT
Regular Ventricular Rate
10
Ventricular Fibrillation
Mechanisms of Ventricular Fibrillation
• Irregular chaotic beat
• non distingusible QRS
• No P waves
Chaotic Ventricular Rate
Symptoms & Risks
VT
Palpitations,
Skipped Beats
Symptoms & Risks
VF
Ventricular
Rate
BP & CO
No Ventricular Rate
O2 Demand and
Supply
Dizziness,
SOB
No BP & CO
Ischemia - Chest
Pain
Causes of Ventricular Arrhythmias
Cardiac causes
Acute and chronic ischemic heart disease
Cardiomyopathy – Heart Failure
Cardiac Hypertrophy
Valvular heart disease
Ion Channel Gene Defect
Congenital heart disease
Noncardiac causes
Stimulants: caffeine, cocaine, alcohol
Metabolic abnormalities: acidosis, hypoxemia, hyperkalemia,
hypokalemia, hypomagnesemia
Drugs: digoxin (Lanoxin), theophylline, antipsychotics, tricyclic
antidepressants, antiarrhythmics with proarrhythmic potential (e.g.,
flecainide [Tambocor], dofetilide [Tikosyn], sotalol [Betapace],
quinidine)
Death
Treatment of Acute Ventricular
Tachycardia and VF
Hemodynamically Stable
No
DC Cardioversion
and ACLS protocol
Yes
Patient
resuscitated
Amiodarone
Lidocaine
Procainamide
Are there reversible Causes
No
Assess for ICD and/or
chronic antiarrhythmic
drug therapy
Yes
No
Correct cause
Yes
Monitor and assess in 2-3 days
11
Chronic Management and Prevention of
Sudden Cardiac Death (SCD)
Patient Stratification
SCD Risk Stratification:
At Risk:
•
•
•
•
•
•
Post MI
EF <40%
NSVT
Inducible VT
VT/VF event
Genetic ion channel defect with SCD
family history
• Primary prevention
– Patients at risk for life threatening ventricular
arrhythmias
• Secondary prevention
– Resuscitated arrhythmic sudden death
– Sustained ventricular tachycardia
– Hemodynamically unstable non sustained VT
Primary Prevention Clinical Trials:
Sudden Death Prevention
AA drugs vs. placebo
Post-MI
Heart Failure
BHAT
CAST, EMIAT,
CAMIAT,
SWORD
ALIVE*
GESICA,
CHF-STAT,
SCD-HeFT* DIAMOND
SCD Primary Prevention:
Drug Therapy?
Ineffective
SCD Total
Class I
• CAST I & II
Sotalol
ICD vs. AA drugs
MADIT
MUSTT
MADITT II
AMIOVERT
SCD-HeFT*
*Ongoing
ICD vs. placebo
• Julian Study
• SWORD
Dofetilide
CABG Patch
Non-Pharmacologic Therapies:
Implantable Cardioverter Defibrillator
(ICD)
Effective
SCD Total
Amiodarone
• GESICA
• CHF-STAT
• EMIAT
• CAMIAT
Beta Blockers
• Alive Study
Class I antiarrhythmic drugs for primary prevention
(CAST Trial)
NEJM 1989;321:406
12
β Blockers for primary prevention
Amiodarone for primary prevention - Mortality Trials
Importance of heart rate
*
Hjalmarson Clin Cardiol 1998;21:II3
Lancet 1997;349:675 & Lancet 1997;349:667-74
Amiodarone + Beta Blocker
Rate/yr
*
No Β Blocker
ICD vs Drugs MUSTT and MADITT
Non-cardiac death
CAD, NSVT, EF < 0.40
Non arrhythmic death
Resus Cardiac arrest
Evaluate and Treat Ischemia
Arrhythmic Death
EPS
N=2202
Β Blocker
No Sustained VT Induced
N=1435 (65%)
Registry
Pl
AM
Inducible Sustained VT
N=767 (35%)
Randomized
N=704 (92%)
Refused
Randomization
N=63 (8%)
PL AM
Boutitie etal Circ 1999;99:2268
Buxton AE. N Engl J Med 1999;341:1882-90.
MADITT and MUSTT Summary
MADIT II – Primary Prevention
Patient Inclusion
• Documented prior MI
• EF <30%
• >3 months from
cardiac event or
surgery.
• No previous VT/VF
events.
Prystowsky etal AJC 2000;86:1214
Moss etal NEJM 2002;346:877-883
13
1998 ACC/AHA Class I Indication:
RCT Evidence (MADIT)
What to do with the non MUSTT and
MADIT patients?
Primary Prevention
– A history of previous MI and EF <30% or all of the
following:
• Ischemic heart disease
• NSVT on Holter monitoring
• LVEF <35% and NYHA Class I-III
• Inducible VT on EP testing
Await outcome of SCD-HEFT
Secondary prevention: Drugs vs Devices (AVID
Study)
Antiarrhythmic drugs for secondary
prevention:
100
Proportion Surviving
• Β Blocker therapy
• Amiodarone therapy
• Combination of both
75.4
80
60
ICD
64.1
First line therapy:
• Only to used if an implantable defibrillator is refused by patient
• If ICD can not be used
Second line therapy:
• Used with ICD to reduce number of shocks
AAT
40
p<0.02
20
Indicated drugs:
•Amiodarone
• no placebo controlled trials
0
0
NEJM 1997;337:1576-83
1 yr
2 yr
3 yr
Years after Randomization
1998 ACC/AHA Class I Indication:
RCT Evidence (AVID)
Secondary Prevention
1. Cardiac arrest due to VF or VT not due to
transient or
reversible cause.
2. Spontaneous sustained VT.
3. Syncope of undetermined origin with clinically
relevant, hemodynamically significant sustained
VT or VF induced
at EP study when drug therapy is ineffective, not
tolerated, or not preferred.
• Beta blockers
• no placebo controlled trials
On Going Trials
SCD-HeFT : EF <35%
Placebo vs Amiodarone vs ICD
Gregoratos G. J Am Coll Cardiol. 1998;31:1175-1209.
14
Drug vs Device Tradeoff
• ICDs trade one problem for another
9 SCD versus ICD complications
• ICDs are not preventative
9 ICD therapy is noxious and unwanted
9 Therapy storms are detrimental and can cause
PTSD ( Int J Emerg Ment Health 2000 Fall;2 (4): 259 –63).
9 Requires support groups and psychosocial
therapy
• 20% of patients do not accept ICD therapy
9 Worsen quality of life
9 Preexisting psychiatric illness predict poor
acceptance (Pacing Clin Electrophysiol 2000 Jun;23(6):939)
Drug vs Device Tradeoff
• ICDs are costly
9 $40-50K for dual chamber ICD
• ICD use requires highly specialized MD
9 Extremely complicated technology
9 Electrophysiologist in low supply
• Beta blockers and/amiodarone.
9 Relatively inexpensive
9 Cardiologist can easily prescribe
Conclusions
Secondary Prevention:
•ICD are Superior
Primary Prevention:
•ICDs are Superior in high risk post MI patients
with inducible VT/VF.
•Beta blockers ± amiodarone in all patients
with EF <40%
Beta blockers should be aggressively employed in
ALL ICD patients: Drug plus Device Paradigm.
Patients should be carefully selected for ICD
therapy to assure psychological acceptance.
15