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?

AF - Uncontrolled RateA Common Problem

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

CVP and Sympathetic Activity in AF and Sinus

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

AF – Heart Rate Variation

Irregular Rhythm Impairs Cardiac Output

Daoud E. Am J Cardiol 1996;78:1433-1436

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)

Acute Rate Control

Siu C-W. Crit Care Med 2009; 37:2174 –2179

Diltiazem IV may have the edge

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

Rate Control with Amiodarone

Clemo HF. Am J Cardiol 1998; 81:594-598

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

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 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 Ablation in Heart Failure

Hsu L. N Engl J Med 2004;351:2373-2283

AF in Heart Failure

Khan M. N Engl J Med 2008;359:1778-1785

Pulmonary Vein Isolation vs AVN Ablation with Bi-Ventricular Pacing

AV Junctional Ablation

block

paced

HRA

I

III

II

aVF

VI

V6

Output

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

Ablate and Pace - Survival

Ozcan C. N Engl J Med 344:1043, 2001

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