Transcript For Rate Control

Rate Control in
Atrial Fibrillation:
Critically Important, Underappreciated
Renee M. Sullivan, MD
Brian Olshansky, MD
Division of Cardiology
University of Iowa
Treatment of AF is Not New
“Of all the stomachic remedies, the one whose
effects have appeared most constant and the
most prompt in many cases, is quinine mixed
with a little rhubarb. Long and rebellious
palpitations have ceded to this febrifuge
seconded with a light purgative.”
Jean-Baptiste de Senac Paris, 1749
75-yo Female in Clinic
Recent-Onset Atrial Fibrillation (AF)
History - fatigue, dyspnea for 2 weeks
Past history - hypertension
Physical: pulse -110, BP-115/70
Lungs – clear
 Heart – irregular rate, no murmur or gallop
 Extremities - no edema

EKG – AF rate 130 new since one month ago
Plan – control rate, anticoagulate, cardiovert
How do you control the rate?
AF - Uncontrolled Rate
A Common Problem
Rate Control in AF
What are the issues?
Does rate control matter? Why? When?
What is the goal for rate control?
What is the endpoint for rate control?
How is it best to control the rate?
How is rate control monitored?
Optimal management approach is unclear
Best rate is undefined
Consequences of Rapid Rate
Symptoms – dyspnea, fatigue, palpitations
Impaired quality-of-life
Poor exercise tolerance
Hemodynamic compromise and heart failure
Cardiomyopathy
Ischemia
Risk of death
Goals of Rate Control
What goal is most important?
Control rate (rest and/or exercise)
Alleviate symptoms
Improve functionality and quality-of-life
Optimize hemodynamics
Reduce risk of cardiomyopathy
Decrease hospitalizations, frequent care
Prevent complications
Reduce drug switches
Improve survival
Therapies may help one but not another
Rate Control Approach
Varies by AF Classification
First
Detected
Paroxysmal
(Self-terminating)
Persistent
(Not self-terminating)
Permanent
ACC/AHA/ESC Guidelines
Fuster V. Circulation 2006;114:700-752
Heart Rate and Mortality
25
All-Cause Mortality (%)
20
Men
Also true in AF??
Age: 40-80 years
Follow-up: 12 years
N=4756
15
Women
10
5
0
<60
60-70
70-80
80-90
>90
Resting Heart Rate (bpm)
Mensink GB. Eur Heart J 1997;18:1404-1410
Heart Rate and Mortality
Is Faster Rate in AF also Associated with Increased Mortality?
Healthy Men
Coronary Artery Disease
All-cause
Non-sudden death from MI
5,713 patients
Followed 23 years
Hazard Ratio
Relative Risk
Sudden death from MI
24,913 patients
Followed 14.7 years
Heart rate (bpm)
Jouven X. N Engl J Med 2005;352:1951– 8
Diaz A. Eur Heart J 2005;26:967–74
Fox K. J Am Coll Cardiol 2007;50:823-30
Heart rate (bpm)
Heart Rate - Adverse Outcomes
Results from BEAUTIFUL – Patients with CAD
CV Death
Admission for heart failure
Admission for MI
Coronary revascularization
Also true for patients with AF??
Fox K. Lancet 2008;372:817-821
Rapid Rate in AF–
A Risk for Death?
Many parameters of importance but does
rapid heart rate in AF increase mortality?
Kowey P. J Am Coll Cardiol 2004;43:1209-10
Heart Rate in AF and
Outcomes
Time to CV Hospitalization or Death
Time to Death
No difference between those achieving
or not achieving the AFFIRM heart rate goals
Cooper HA. Am J Cardiol 2004;93:1247-53
Heart Rate in AF and Survival
Patients with chronic heart failure
77 patients with AF at
baseline in PRIME II

Rate “low” (<80) or “high”(>80)
NYHA Class III or IV

Includes only patients in
neurohormonal substudy
Rienstra M. Int J Cardiol 2006;109:95-100
Why Control Rate?
To reduce symptoms
Symptoms vary by patient age and AF type
Levy S. Circulation 1999;99:3028
Rapid Rates in AF
Physiologic Consequences
Diastolic and systolic dysfunction-> pulmonary
congestion, heart failure
 Hypotension, poor cardiac output -> reduced endorgan perfusion -> ischemia, renal dysfunction
 Autonomic adjustments -> increased afterload and
contractility

Autonomic Response to AF
* p<0.05
MSNA – muscle sympathetic nerve activity
Grassi G. Acta Physiol Scand 2003;177:399-404
CVP and Sympathetic
Activity in AF and Sinus
* p<0.05
Grassi G. Acta Physiol Scand 2003;177:399-404
Tachycardia-Mediated
Cardiomyopathy
AF is most common cause
Due to fast and/or irregular rates
24 patients with NYHA Class III or IV heart
failure, LVEF = 0.26 ± 0.09
With rate or rhythm control, LVEF improved to
0.51 ± 0.05
Despite improvement - 5 had rapid decline in EF
with recurrent tachycardia, 3 had sudden death
Nerheim P. Circulation 2004;110:247-252
Irregularity of Rate
Irregular ventricular rhythm may worsen
Symptoms
 Hemodynamics
 Ejection fraction

AV nodal ablation with pacemaker implantation
can regularize rhythm and control rate
Narasimhan C. Cardiovasc Electrophysiol 1998;9:S146-50
AF – Heart Rate Variation
Irregular Rhythm Impairs
Cardiac Output
Daoud E. Am J Cardiol 1996;78:1433-1436
Pharmacologic Options
For Rate Control
Beta-adrenergic blockers
Ca2+ channel antagonists
Digoxin
Amiodarone
Dronedarone
Drug combinations
Antiarrhythmics (sotalol, propafenone)
Sinus rhythm may be best way to control rate
Acute Rate Control
Goal - control rate within minutes to hours
If unstable, electrical cardioversion
Approach depends on AF duration, LV function,
clinical presentation
Medications - diltiazem, verapamil, metoprolol,
esmolol, amiodarone, digoxin (IV or oral)
AV junctional ablation (rare)
Acute Rate Control
Diltiazem IV may have the edge
Siu C-W. Crit Care Med 2009; 37:2174 –2179
Longstanding Rate Control
A patient-centered approach
Begin with rate control at rest, in AF and in sinus
Consider drug T1/2 and metabolism and
comorbidities, when choosing a drug
Long-acting drugs will minimize dosing
 Some drugs have circadian absorption

Upward titration and addition of drugs yields the
best rate control results
Rate Control of AF
Digoxin 0.25 mg
Diltiazem 240 mg
Atenolol 50 mg
Dig 0.25 mg + diltiazem 240 mg
Dig 0.25 mg + atenolol 50 mg
Ventricular Rate, bpm
180
160
P vs
digoxin
Mean VR 125  28
140
Mean VR 105  15
Mean VR 102  29
p<0.02
p<0.03
Mean VR 93  26
Mean VR 82  9
p<0.005
p<0.0001
120
100
80
60
N= 12
2
4
6
8
10
12
Time, min
Farshi R. J Am Coll Cardiol 1999;33:304-310
Titration of Medications
Medication dosage – review at every visit
If rate is slow, medication may need reduction
If rate is too fast, medication may need to be
increased or added
Evaluate rate with rest and activity
Holter monitor
 Event monitor
 6-minute walk

β-Blockers
Can convert recent onset AF and decrease
recurrence (especially postoperatively)
Decreases resting rate but blunts rate with
exercise (may not be better than other options)
Can control rate but increase symptoms
May treat comorbidities
May cause hypotension, bradycardia

Consider β-blocker with ISA if tachy-brady syndrome
Rate Control with b-Blockers
Alone or in combination
D - Digoxin
CCB - Ca2+ Channel Blocker
BB - b-Blocker
Hilliard AA. Am J Cardiol 2008;102:704-708
Ca2+ Channel Antagonists
Rate control with rest and exercise
First-line for acute management and patients
with no heart disease
Negative inotrope and may cause hypotension
and bradycardia
Can increase risk of death in select populations
Caution - heart failure, hypotension, 10 AV
block, bradycardia, WPW syndrome
Rate Control with
2+
Ca Channel Antagonists
Mean ventricular rate on
24 hour Holter monitor
Ventricular rate at rest, 50 and 80% of
maximum, and maximal workloads
Lundstrom T. J Am Coll Cardiol 1990;16:86-90
Digoxin
Vagotonic inhibition of AV nodal conduction
More effective in the elderly
Good combined with other AV nodal blockers
Improves contractility
Does not convert AF (may do the opposite)
Less effective during exercise (maybe)
Narrow therapeutic range
Caution with renal dysfunction, hypokalemia
Digoxin for Rate Control
160
Digoxin
Placebo
140
80
Heart Rate (bpm)
Conversion Rate, %
100
60
P=NS
40
20
0
ns P=0.0001
P<0.0001
P<0.0001
P<0.0001
120
100
80
60
40
Placebo
20
Digoxin
P=0.003
0
0
2
4
6
8
10 12 14 16
Hours
0
2
4
6
8
10 12 14 16
Hours
The DAAF Trial Group. Eur Heart J. 1997;18:649-654
AFFIRM Is Digoxin a Risk?
Time-Dependent Covariates Associated With Survival
Covariate
P-Value
Hazard Ratio
99% CI
Sinus rhythm
<0.0001
0.53
0.39-0.72
Warfarin use
<0.0001
0.50
0.37-0.69
Digoxin use
0.0007
1.42
1.09-1.86
AAD* use
0.0005
1.49
1.11-2.01
HR <1.00: decreased risk of death.
HR >1.00: increased risk of death.
*Antiarrhythmic drug
The AFFIRM Investigators. Circulation 2004;109:1509-1513
Amiodarone
Can help control rate as well as rhythm
Used IV acutely as second-line drug
Less hypotension than other drugs
Used in combination long term
Long half-life
Multiple toxicities
Rate Control with Amiodarone
Clemo HF. Am J Cardiol 1998; 81:594-598
Dronedarone
Can help control rate as well as rhythm
Slows rate effectively in AF
Shorter T1/2 than amiodarone and less toxicity
Reduces cardiovascular death and
hospitalization1
Higher risk of death with acute heart failure2
1 Hohnloser SH. N Engl J Med 2009;360:668-78
2 Kober L. N Engl J Med 2008;358:2678-87
ERATO Trial
Dronedarone Controls Rate in AF
Rate control at rest
Rate control with
drug combinations
Rate control with
maximal exercise
Rate control
over time
Davy J-M. Am Heart J 2008;156:527
Drug Combinations
Potentially beneficial
Beta-blocker – digoxin
 Beta-blocker – amiodarone

Potentially adverse
Dofetilide – verapamil
 Verapamil – digoxin
 Digoxin – amiodarone
 Beta-blocker- amiodarone

AFFIRM Rate Control
Randomized 2027 patients (paroxysmal/persistent)
Rate control defined as
Rate < 80 bpm at rest or < 110 bpm on 6-min walk
 Mean rate < 100 bpm on 24-hour Holter with no rate
>100% max predicted age-adjusted exercise rate

Any rate control drug could be used
AV junctional ablation in only a small minority
Drug switches helped rate control
Olshansky B. J Am Coll Cardiol 2004;43:1201-8
Drug Selection in AFFIRM
Significant Variables
Gender
 History of coronary disease
 Congestive heart failure
 Hypertension
 Pulmonary disease
 First episode of AF
 Baseline heart rate

Olshansky B. J Am Coll Cardiol 2004;43:1201-8
AFFIRM - Rate Control
Overall rate control with first drug therapy
p = 0.08
70% with beta blockers
(± digoxin)
 54% with calcium channel blockers (± digoxin)
 58% with digoxin alone

Over time, patients on Ca2+ channel blockers or
digoxin were switched to other drug (p< 0.0001)
Olshansky B. J Am Coll Cardiol 2004;43:1201-8
AFFIRM - Rate Control
Olshansky B. J Am Coll Cardiol 2004;43:1201-8
AFFIRM - Drug Crossovers
Olshansky B. J Am Coll Cardiol 2004;43:1201-8
AFFIRM – Reason to Stop
Rate Controlling Drugs
Olshansky B. J Am Coll Cardiol 2004;43:1201-8
RACE Rate Control
Randomized 256 patients (persistent AF)
Rate control - resting rate < 100 bpm
Issues:
Rate control was lenient
 No measure of heart rate with exercise
 No mention of drug switches

Rienstra M. Eur Heart J 2007;28:741-751
Heart Rates AFFIRM vs RACE
Not necessarily the same population
or the same way to measure
Van Gelder I. Europace 2006;8:935-42
Does Rate Predict Outcome?
AFFIRM vs RACE - “event-free survival”
What endpoint matters?
Van Gelder I. Europace 2006;8:935-42
Heart Rate Considerations
More attention paid to rate in trials than practice
Rate control in AF may lead to issues in sinus
Tachy-brady syndrome
 Profound bradycardia leading to pacemaker

What is the appropriate endpoint?

Heart rate? Symptoms? Hemodynamics?
Hospitalizations? Death?
RACE II
Prospective randomized trial of stringent vs
lenient control of heart rate in AF
Endpoints: cardiovascular morbidity and
mortality, neurohormonal activation, NYHA
class, LV function, LA size, quality-of-life, cost
Study is underway
Van Gelder I. Am Heart J 2006;152:420-6
Non-pharmacologic Options
When medications alone don’t control rate
Electrical cardioversion
AV nodal (junctional) ablation
Atrial fibrillation ablation
Novel pacing options
Vagal nerve stimulation
AF Ablation in Heart Failure
Hsu L. N Engl J Med 2004;351:2373-2283
AF in Heart Failure
Pulmonary Vein Isolation vs AVN Ablation with
Bi-Ventricular Pacing
Khan M. N Engl J Med 2008;359:1778-1785
I
II
III
paced
aVF
VI
block
V6
HRA
AV Junctional Ablation
Output
Rate Control During AF
Benefits: Symptoms by SF-36 Post-ablation
US Norm
100
P=0.50
Preablation
1 Month
Postablation
N=22
80
SF-36 Score
6 Months
Postablation
P=0.04
P=0.62
60
40
20
0
Mental Health
Physical Function
General Health
Bubien R. Circulation 1996;94:1585-1591
AV Node Ablation and QOL
107 patients with paroxysmal or persistent AF
AV node ablation improved: vigorous exercise, moderate exercise, carrying
groceries, climbing stairs, walking on flat ground, bathing, dressing
Fitzpatrick AP. Am Heart J 1996;131:499-507
Ablate and Pace - Survival
Ozcan C. N Engl J Med 344:1043, 2001
AIRCRAFT Trial
Is Ablate and Pace the Way to Go?
Results
•LVEF, exercise time same both groups.
•Peak rate lower in the AVJAP group with
exercise and daily activities (p<0.05).
•AVJAP group less symptoms (p = 0.004)
•Global subjective QOL using the "ladder of
life" 6% better in AVJAP group (p = 0.011).
*
Conclusions
*AVJAP=AV junctional ablation
and pacemaker
Ablate/pace in symptomatic permanent AF
patients did not worsen cardiac function in
long-term follow-up. QOL improved.
Weerasooriya R. J Am Coll Cardiol 2003;41:1703-6
CRT Works in AF
. . .but AV Junctional Ablation May Be Needed
Gasparini M. J Am Coll Cardiol 2006;48:734-743
Pacing with Ventricular Rate
Regulation – Controls Rate
but, there is more RV pacing
From Boston Scientific
Recommendations
Assess rate with rest and activity
Determine need and intensity of rate control

If unstable, rhythm control should be emergently
considered
Consider beta-blockers, alone or in combination,
as first-line AF therapy for rate
If rate control is refractory to drugs, consider
other options
Conclusion
Rate control in AF is critical but often ignored
A stepwise approach to effective rate control
has as its purpose several important endpoints
Any reasonable and comprehensive strategy to
treat AF requires a plan for rate control
Critical issues regarding rate control in AF
remain unexplored