Thomas D. Callahan, IV, MD, FACC, FHRS.
Associate Program Director, Cardiology Fellowship, Robert and Suzanne Tomsich, Dept of Cardiovascular
Medicine, Sydell and Arnold Miller Family Heart and Vascular Institute, Cleveland Clinic.
Corresponding Author: Thomas D. Callahan, IV, MD, FACC, FHRS, Associate Program Director, Cardiology Fellowship,
Robert and Suzanne Tomsich, Dept of Cardiovascular Medicine, Sydell and Arnold Miller Family Heart and Vascular Institute, Cleveland Clinic, 9500 Euclid Avenue / J2-2, Cleveland, Ohio 44195.
Despite great strides in our understanding and
treatment of atrial fibrillation over the past decade
or so, much remains to be learned. Debate continues
over the relative merits of rate versus rhythm
control strategies. More recently, even the optimal
targets for rate control have come into question.
Specifically, the results of the RACE II trial support
a more lenient rate control target compared to more
traditional targets. This paper will review the role
elevated heart rates play in the morbidity associated
with atrial fibrillation, tools available for rate
control and their relative merits as well as the targets
for rate control.
There is no doubt that atrial fibrillation is associated
with profound morbidity. Atrial fibrillation
can be associated with astounding morbidity. The
cost associated with atrial fibrillation and its sequelae
is estimated at over 6.5 billion dollars.1
European study of hospitalized patients with atrial
fibrillation by ECG or holter found close to 70%
of patients experienced symptoms.2
myocardial infarction occurred in 6% of all patients
While the exact incidence is difficult
to determine, atrial fibrillation is the most common
cause of tachycardia-mediated cardiomyopathy.5-7
Finally, in patients with atrial fibrillation and left
ventricular dysfunction, some element of tachycardia
mediated cardiomyopathy is seen in 25-50%.8-10
What is more difficult to discern is the contribution
of elevated heart rates in atrial fibrillation to
the morbidity relative to the atrial fibrillation itself.
Multiple trials including RACE, AFFIRM, PIAF
and STAF have compared a rate control strategy to
maintenance of sinus rhythm with anti-arrhythmics
and found that patients managed with rate
control have similar symptom reduction, mortality
rates and rates of stroke and heart failure
progression as those managed with anti-arrhythmics.11
However, this does not mean that the risk
associated with atrial fibrillation is soley the result
of elevated heart rates. Other data implicates atrial
not simply elevated heart rates. Analyses of AF-
FIRM and DIAMOND support a mortality benefit
from the maintenance of sinus rhythm and it
has been postulated that this benefit is completely
offset by the risks of currently available antiarrhythmics.
Pulmonary vein isolation offers a
potential cure for atrial fibrillation, however, it too
carries potential morbidity and less-than-perfect
success rates. Studies to tell us how it stacks up
to anti-arrhythmics and rate control are still underway,
but should provide additional insight
into the contributions of arrhythmia and elevated
heart rate in the development morbidity in atrial
With limited data regarding the contributions of
rate and rhythm to the morbidity of atrial fibrillation,
the decision to choose a rate control or a
rhythm control strategy may be challenging.
Currently, symptoms are the most helpful factor
in choosing a strategy. When symptoms persist
strategy is clearly indicated. Conversely,
in patients who are completely asymptomatic in
atrial fibrillation, rate control may be sufficient.
Challenges arise when patients report mild symptoms
or nebulous symptoms such as fatigue or
shortness of breath which could be the result of
other processes such as pulmonary disease, obe-sity or deconditioning. In these cases we often
pursue a rhythm control strategy and fall back to
rate control if symptoms do not improve when sinus
rhythm is restored. Other challenges include
patients with prior CVA and young patients with
atrial fibrillation. In these cases, data supporting
the mortality benefit of maintenance of sinus
rhythm, while limited, may seem to have more
sway. Finally, patients refractory to heart rate control,
with very elevated ventricular rates despite
medical therapy, would likely benefit from maintenance
of sinus rhythm.
The goals of therapy with rate control in atrial fibrillation
are quite simple: To minimize or eliminate
symptoms and to prevent morbidity associated
with elevated heart rates. That said, the
target heart rate that best achieves those goals are
less certain. Until recently, an average heart rate
of less than 80 beats per minute was recommended.
Since many patients with satisfactory resting
heart rates in atrial fibrillation will develop
marked tachycardia with exertion, heart rates of
90 to 115 with submaximal exercise or a maximum
heart rate of less than 110 beats per minute during
hospitalization or death from any
In RACE II, patients with atrial fibrillation
were randomized to strict heart rate control (<80
bpm at rest and <110 bpm with moderate exercise)
or lenient heart rate control (<110 bpm at rest). No
difference was seen between the groups with regard
to the composite endpoint which included
death from cardiovascular causes, hospitalization
for CHF, CVA, systemic embolization, major
bleed or life-threatening arrhythmias.3
it should be noted that mean resting heart rates
did not differ greatly with a mean resting heart
rate of 85 in the lenient group and 76 in the strict
control group. These findings are also tempered
by follow-up of only a few years, and it is possible
that certain subgroups may benefit from tighter
control. New or increasing symptoms should
prompt an investigation with either ambulatory
cardiac monitoring and/or exercise testing to en-
sure satisfactory rate control.
While goals of therapy may be changing, our tools for heart rate control have changed little recently.
Pharmacologic strategies are typically used. AV
node ablation, while effective, necessitates implantation
of a pacing device with the attendant
risks. The mainstays of pharmacologic rate control
are beta-blockers, calcium channel blockers and
digoxin. Less frequently used medications include
amiodarone, dronedarone and sotalol.
Beta-blockers are generally effective for rate control
in patients with atrial fibrillation, but not all
beta-blockers are equivalent in this regard. Blockade
of the beta-1 receptor is primarily responsible
for the heart rate effects of beta blockers. The
beta-2 receptor blockade effects predominantly
the blood vessels and bronchi with little, effect
on heart rate. As a result, beta-1 selective agents
such as atenolol, esmolol, metoprolol and biso-
prolol, are generally more effective for heart rate
control in patients with atrial fibrillation. Patients
with a history of congestive heart failure may
be prescribed non-selective beta-blocker such as
carvedilol preferentially. This can be titrated to
suppress the ventricular rate, but in patients on
non-selective beta-blockers in whom rate control
is not achieved, we will typically change to a Beta1
hypotension, worsening reactive airway
disease, depression, and increased risk of hypoglycemia
in insulin-dependent patients may be
seen patients on beta-blockers and may limit the
maximum tolerated dose.
Calcium channel blockers are also effective in
heart rate control in atrial fibrillation. As with
beta-blockers, the calcium channel blockers are
not all equally effective. Calcium channel blockers
block the L-type calcium channels found in
vascular smooth muscle, cardiac myocytes and
cardiac nodal tissue. The dihydropyridine calcium
channel blockers exert their effect primarily on the
L-type calcium channels of the vascular smooth
muscle.Non-dihydropyridine calcium channel
blockers, verapamil and diltiazem, are relatively
selective toward cardiac L-type calcium channels.
As a result, the non-dihydropyridine calcium
channel blockers may provide control of the heart
rate in atrial fibrillation by slowing conduction
down the AV node while the dihydropyridines are
largely ineffective in that regard. Compared to be-ta-blockers, non-dihydropiridine calcium channel
blockers alone do not appear quite as efficacious as
beta-blockers alone for heart rate control.16
decrease the excretion of digoxin by 30%.
Digoxin has long been used for heart rate control
in patients with atrial fibrillation. It acts by enhancing
prolonging AV node refractoriness.17,18
of the AV node. Thus, digoxin may be
effective in bed-bound patients or hospitalized
patients but may be much less effective when the
patient leaves the hospital and is active.19
used in combination with beta-blockers or calci-
um channel blockers, however, digoxin improves
heart rate control even in active patients.20,21
combination of beta-blockers with digoxin may be
somewhat more efficacious than calcium channel
blockers with digoxin.16
While classified as anti-arrhythmics, sotalol, amiodarone
been shown to decrease
the average heart rate for patients in atrial
Guidelines support the use of amiodarone
for rate control in patients with CHF.27
In our practice amiodarone and dronedarone are
used for rate control only in special circumstances
given the less-favorable side-effect profile of these
medications compared to other available rate control
may limit their use as rate control agents.
Invasive strategies for rate control are usually re-
served for those who cannot tolerate a pharmacologic
strategy or those in whom medications
have failed. AV node ablation is highly effective
at reducing ventricular rates in atrial fibrillation. Recurrence of conduction is seen about 5% of patients
undergoing complete AV node ablation.
However, this commits the patient to an implantable
attendant risks including infection and RV pacing-
mediated cardiomyopathy. Furthermore, PABACHF
depressed EF to either PVI or AV node ablation28
and biventricular pacemaker implantation and
found patient randomized to PVI peformed better
on a 6 minute walk, and reported a higher quality
When the strategy of AV node ablation is
employed for rate control in AF, implantation of a
permanent pacemaker or defibrillator is often performed
several days to weeks in advance as lead
dislodgement is more common early after implant.
Sudden cardiac death may be seen after AV node
ablation for atrial fibrillation and is thought to be
secondary to changes in cardiac repolarization
from long-standing, elevated ventricular rates.
Programming the lower rate limit to 80 beats per
minute for the first 6 weeks after AV node ablation
greatly reduces the risk of sudden cardiac death
after this procedure.30-32
When patients fail a rate
control strategy our practice has been to pursue
rhythm control with either medications or abla-
tion. AV node ablation and pacemaker or defibril-
lator implantation is typically reserved for patients
who have failed pharmacologic rate and rhythm
control and are deemed too frail to tolerate invasive
attempts at rhythm control.
AV node modification may be performed by targeting
rates of 60 to 80 beats per minute at rest and
rates of less than 120 beats per minute with isoproterenol
successful in controlling the heart rate in 25 to
85% of patients.33-40
AV node modification is used
rarely compared to AV node ablation as it still often
The ventricular rate is often elevated in patients
with atrial fibrillation and these elevated rates do
contribute to morbidity. The mainstays of rate control,
beta-blockers, calcium channel blockers and
digoxin, either alone or in combination, are effective
these fail, ablation of the AV node and implantation
the heart rate.However, much remains to be
learned about how best to use these tools. Aggres-
sive use of rate control agents to achieve "normal"
resting heart rates may, in some cases, be counterproductive.
AV node ablation leaves the patients
forever dependent on a pacemaker, and in some cases, patients remain symptomatic from the atrial
arrhythmia. More data is required to determine if
certain cohorts benefit from tighter heart rate control.
Finally, heart rate control may be inferior to
maintenance of sinus rhythm in many patients if
not for the toxicities and potential complications
of our tools for rhythm control. While we await
the results of trials to help answer these questions,
patient symptoms continue to serve as one of the
most important guides in treatment of challenging
and prevalent disorder.
Dr. Thomas has received Speaker's honoraria: Boston
Scientific, St. Jude, Biotronik. >$5000.
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