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
History - fatigue, dyspnea for 2 weeksPast history - hypertensionPhysical: pulse -110, BP-115/70Lungs – clearHeart – irregular rate, no murmur or gallop Extremities - no edema
EKG – AF rate 130 new since one month agoPlan – control rate, anticoagulate, cardiovert
Recent-Onset Atrial Fibrillation (AF)
How do you control the rate?
Rate Control in AF
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?
What are the issues?
Optimal management approach is unclearBest 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
Control rate (rest and/or exercise)Alleviate symptomsImprove functionality and quality-of-lifeOptimize hemodynamicsReduce risk of cardiomyopathyDecrease hospitalizations, frequent care Prevent complicationsReduce drug switches Improve survivalTherapies may help one but not another
What goal is most important?
PersistentPersistent(Not self-terminating)(Not self-terminating)
PersistentPersistent(Not self-terminating)(Not self-terminating)
ParoxysmalParoxysmal(Self-terminating)(Self-terminating)
ParoxysmalParoxysmal(Self-terminating)(Self-terminating)
First First DetectedDetected
First First DetectedDetected
PermanentPermanentPermanentPermanent
Rate Control ApproachVaries by AF
Classification
Fuster V. Circulation 2006;114:700-752ACC/AHA/ESC Guidelines
Mensink GB. Eur Heart J 1997;18:1404-1410
25
20
15
10
5
0<60 60-70 70-80 80-90 >90
Resting Heart Rate (bpm)
All
-Cau
se M
ort
alit
y (%
)
Women
Men
Age: 40-80 yearsFollow-up: 12 years
N=4756
Heart Rate and Mortality
Also true in AF??
Heart Rate and Mortality
Healthy Men Coronary Artery Disease
Jouven X. N Engl J Med 2005;352:1951– 8Diaz A. Eur Heart J 2005;26:967–74Fox K. J Am Coll Cardiol 2007;50:823-30
Heart rate (bpm)
Haz
ard
Rat
io
All-cause
Non-sudden death from MI
Sudden death from MI
Heart rate (bpm)
Rel
ati
ve
Ris
k
5,713 patientsFollowed 23 years
24,913 patientsFollowed 14.7 years
Is Faster Rate in AF also Associated with Increased Mortality?
Heart Rate - Adverse Outcomes
Fox K. Lancet 2008;372:817-821
CV Death Admission for heart failure
Admission for MI Coronary revascularization
Results from BEAUTIFUL – Patients with CAD
Also true for patients with AF??
Rapid Rate in AF–A Risk for Death?
Kowey P. J Am Coll Cardiol 2004;43:1209-10
Many parameters of importance but does rapid heart rate in AF increase mortality?
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
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
Patients with chronic heart failure
Rienstra M. Int J Cardiol 2006;109:95-100
Why Control Rate?
To reduce symptoms
Levy S. Circulation 1999;99:3028
Symptoms vary by patient age and AF type
Rapid Rates in AF
Diastolic and systolic dysfunction-> pulmonary congestion, heart failure
Hypotension, poor cardiac output -> reduced end-organ perfusion -> ischemia, renal dysfunction
Autonomic adjustments -> increased afterload and contractility
Physiologic Consequences
Autonomic Response to AF
MSNA – muscle sympathetic nerve activity Grassi G. Acta Physiol Scand 2003;177:399-404
* p<0.05
Tachycardia-Mediated Cardiomyopathy
AF is most common causeDue to fast and/or irregular rates24 patients with NYHA Class III or IV heart failure, LVEF = 0.26 0.09With rate or rhythm control, LVEF improved to 0.51 0.05Despite 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 worsenSymptomsHemodynamicsEjection fraction
AV nodal ablation with pacemaker implantation can regularize rhythm and control rate
Narasimhan C. Cardiovasc Electrophysiol 1998;9:S146-50
Pharmacologic Options
Beta-adrenergic blockersCa2+ channel antagonistsDigoxinAmiodaroneDronedarone Drug combinationsAntiarrhythmics (sotalol, propafenone)Sinus rhythm may be best way to control rate
For Rate Control
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)
Longstanding Rate Control
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 dosingSome drugs have circadian absorption
Upward titration and addition of drugs yields the best rate control results
A patient-centered approach
Rate Control of AF
Mean VR 82 9 p<0.0001
Mean VR 102 29 p<0.03
Ve
ntr
icu
lar
Ra
te, b
pm
180
160
140
120
100
80
602
Time, min
4 10 12
Digoxin 0.25 mgDiltiazem 240 mgAtenolol 50 mgDig 0.25 mg + diltiazem 240 mgDig 0.25 mg + atenolol 50 mg
6 8
Mean VR 125 28
Mean VR 93 26 p<0.005
Mean VR 105 15 p<0.02
P vsdigoxin
Farshi R. J Am Coll Cardiol 1999;33:304-310
N= 12
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 activityHolter monitorEvent monitor6-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, bradycardiaConsider β-blocker with ISA if tachy-brady syndrome
Rate Control with -Blockers
Hilliard AA. Am J Cardiol 2008;102:704-708
Alone or in combination
D - DigoxinCCB - Ca2+ Channel BlockerBB - -Blocker
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 Ca2+ Channel Antagonists
Ventricular rate at rest, 50 and 80% of maximum, and maximal workloads
Mean ventricular rate on 24 hour Holter monitor
Lundstrom T. J Am Coll Cardiol 1990;16:86-90
Digoxin
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
Vagotonic inhibition of AV nodal conduction
Digoxin for Rate Control
Digoxin
Placebo
Co
nve
rsio
n R
ate,
%
0
40
60
80
100
20
0 2 4 6 168 10 12 14
Hours
P=0.003H
eart
Rat
e (b
pm
)0
40
60
80
160
20
140
120
100
Hours
0 2 4 6 168 10 12 14
ns P=0.0001P<0.0001 P<0.0001
P<0.0001
Digoxin
Placebo
P=NS
The DAAF Trial Group. Eur Heart J. 1997;18:649-654
AFFIRM Is Digoxin a Risk?
*Antiarrhythmic drug*Antiarrhythmic drug
Time-Dependent Covariates Associated With SurvivalTime-Dependent Covariates Associated With Survival
Sinus rhythmSinus rhythm <0.0001<0.0001 0.530.53 0.39-0.720.39-0.72
Warfarin useWarfarin use <0.0001<0.0001 0.500.50 0.37-0.690.37-0.69
Digoxin useDigoxin use 0.00070.0007 1.421.42 1.09-1.861.09-1.86
AAD* useAAD* use 0.00050.0005 1.491.49 1.11-2.011.11-2.01
CovariateCovariate PP-Value-Value Hazard RatioHazard Ratio 99% CI99% CI
HR <1.00: decreased risk of death.HR <1.00: decreased risk of death.
HR >1.00: increased risk of death.HR >1.00: increased risk of death.
The AFFIRM Investigators. Circulation 2004;109:1509-1513
Amiodarone
Used IV acutely as second-line drug
Less hypotension than other drugs
Used in combination long term
Long half-life
Multiple toxicities
Can help control rate as well as rhythm
Dronedarone
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;360:668-782 Kober L. N Engl J Med 2008;358:2678-87
Can help control rate as well as rhythm
ERATO TrialDronedarone Controls Rate in AF
Rate control at rest
Rate control with maximal exercise
Rate control over time
Rate control with drug combinations
Davy J-M. Am Heart J 2008;156:527
Drug Combinations
Potentially beneficialBeta-blocker – digoxinBeta-blocker – amiodarone
Potentially adverseDofetilide – verapamilVerapamil – digoxinDigoxin – amiodaroneBeta-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 controlOlshansky B. J Am Coll Cardiol 2004;43:1201-8
Drug Selection in AFFIRM
Gender History of coronary diseaseCongestive heart failureHypertension Pulmonary diseaseFirst episode of AF Baseline heart rate
Significant Variables
Olshansky B. J Am Coll Cardiol 2004;43:1201-8
AFFIRM - Rate Control
p = 0.08
Overall rate control with first drug therapy70% 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
RACE Rate Control
Randomized 256 patients (persistent AF)
Rate control - resting rate < 100 bpm
Issues: Rate control was lenientNo measure of heart rate with exerciseNo mention of drug switches
Rienstra M. Eur Heart J 2007;28:741-751
Heart Rates AFFIRM vs RACE
Van Gelder I. Europace 2006;8:935-42
Not necessarily the same population or the same way to measure
Does Rate Predict Outcome?
Van Gelder I. Europace 2006;8:935-42
What endpoint matters?
AFFIRM vs RACE - “event-free survival”
Heart Rate Considerations
More attention paid to rate in trials than practice
Rate control in AF may lead to issues in sinusTachy-brady syndromeProfound 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 AFEndpoints: cardiovascular morbidity and mortality, neurohormonal activation, NYHA class, LV function, LA size, quality-of-life, costStudy is underway
Van Gelder I. Am Heart J 2006;152:420-6
Non-pharmacologic Options
Electrical cardioversion
AV nodal (junctional) ablation
Atrial fibrillation ablation
Novel pacing options
Vagal nerve stimulation
When medications alone don’t control rate
AF in Heart Failure
Khan M. N Engl J Med 2008;359:1778-1785
Pulmonary Vein Isolation vs AVN Ablation with Bi-Ventricular Pacing
Rate Control During AF
0
20
40
60
80
100
P=0.04P=0.62
Mental Health General HealthPhysical Function
US Norm Preablation 1 MonthPostablation
6 MonthsPostablation
N=22P=0.50
SF
-36
Sc
ore
Benefits: Symptoms by SF-36 Post-ablation
Bubien R. Circulation 1996;94:1585-1591
AV Node Ablation and QOL
107 patients with paroxysmal or persistent AFAV node ablation improved: vigorous exercise, moderate exercise, carrying
groceries, climbing stairs, walking on flat ground, bathing, dressingFitzpatrick AP. Am Heart J 1996;131:499-507
AIRCRAFT Trial
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).
Weerasooriya R. J Am Coll Cardiol 2003;41:1703-6
Conclusions
Ablate/pace in symptomatic permanent AF patients did not worsen cardiac function in long-term follow-up. QOL improved.*AVJAP=AV junctional ablation
and pacemaker
*
Is Ablate and Pace the Way to Go?
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
From Boston Scientificbut, there is more RV pacing
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