AACN Advanced Critical Care

Volume 23, Number 2, pp.120–125

© 2012, AACN

ECG Challenges
Earnest Alexander, PharmD, and
Gregory M. Susla, PharmD
Department Editors

Efficacy and Safety of Pharmacological

Options for Rate Control in Atrial Fibrillation
Katie O’Brien, PharmD
Earnest Alexander, PharmD
Lindsay Patel, PharmD, BCPS

A trial fibrillation (AF) is the most common arrhythmia, and its prevalence
will continue to increase as people age. Approximately 3 million people
in the United States currently have AF, with an estimated 7.5 million people by
the year 2050.1 Atrial fibrillation is characterized by uncoordinated atrial fir-
ing, which disrupts the normal sinus rhythm of the heart. The arrhythmia can
be classified by the occurrence of its symptoms, such as first episode, recurrent,
paroxysmal, and persistent. When AF is not controlled, the symptoms may be
severe and interrupt a patient’s activities of daily life. Mortality rates of patients
with AF are double those of patients in normal sinus rhythm.2 Furthermore, AF
may require urgent treatment to prevent or correct events such as stroke, throm-
boembolism, and hemodynamic compromise. Although the underlying cause of
AF is unknown, several disorders contribute to its development. Hypertension,
diabetes, and congestive heart failure are just a few causes that can contribute to
the clinical risk factors for AF. On the basis of the potential negative clinical out-
comes, health care providers must understand the role of pharmacological man-
agement strategies that can improve quality of life and care in patients with AF.

Rhythm Control Versus Rate Control

When a patient is diagnosed with persistent or permanent AF, pharmacological
management of either heart rate or rhythm is the mainstay of treatment. Under nor-
mal conditions, cardiac output is directly related to heart rate and stroke volume.
Increases in heart rate and/or stroke volume generally result in a proportional in-
crease in cardiac output. During AF, the atria of the heart quiver, resulting in dimin-
ished atrial filling, decreased stroke volume, and decreased cardiac output. During
AF with rapid ventricular response (RVR), cardiac output is further decreased by
both quivering atria and fast ventricle contraction because of reduced atrial and
ventricular filling. Pharmacological management strategies are based on improving
atrial and ventricular filling and increasing cardiac output. Rate control therapy
aims to manage the ventricular rate, whereas rhythm control strives to restore or
maintain normal sinus rhythm. Both strategies result in increased cardiac output.
Over the last 10 years, a few trials have shed light on the ongoing controversy
concerning the rhythm versus rate control management strategies and which is

Katie O’Brien is Clinical Pharmacist, Tampa General Hospital, 1 Tampa General Circle, Tampa, FL 33606
(ko’brien@tgh.org).
Earnest Alexander is Clinical Manager, Department of Pharmacy Services, and Critical Care Pharmacy
Residency Program Director, Tampa General Hospital, Tampa, Florida.
Lindsay Patel is Clinical Pharmacist, Tampa General Hospital, Tampa, Florida.
The authors have no relevant financial or personal relationships to disclose.
DOI: 10.1097/NCI.0b013e318242fdd0

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 VOLUME 23 • NUMBER 2 • APRIL–JUNE 2012
the preferred option. The Atrial Fibrillation
Follow-up Investigation of Rhythm Manage-
ment (AFFIRM) trial sought to determine
whether the rate control strategy or the rhythm
control strategy was associated with a better
survival outcome.3 The AFFIRM study was a
large, randomized controlled trial evaluating a
population of more than 4000 patients with AF
with RVR. Inclusion criteria led to the enroll-
ment of patients who were at least 65 years old
or had 1 other risk factor for stroke or death.
Mean duration of patient follow-up for the
trial was 3.5 years. Patients in the rate control
arm of the study received digoxin, -blockers,
or calcium-channel blockers. Amiodarone and
sotalol were the agents used in the rhythm
control arm. The study defined rate control as
an average heart rate of less than 80 beats per
minute and a maximum heart rate of less than
100 beats per minute during a 6-minute walk or
an average heart rate of less than 100 beats per
minute over a 24-hour period. No statistically
significant differences in overall mortality were
reported between the 2 groups (25.9% and
26.7%, respectively; heart rate: 1.15 beats per
minute; 95% confidence interval: 0.99–1.34;
P  .08).3 The study was the first of its kind
to show that rate control is equally effective as
rhythm control in terms of overall mortality.
This study has changed the management of
patients with AF with RVR, shifting the focus
of treatment to rate control strategies rather
than rhythm control.
The AFFIRM study has helped to establish
the role of rate control in the management of
patients with AF with RVR. With trials such as
AFFIRM and other studies establishing a role
for rate control strategies, this topic deserves
further elaboration. Compared with antiar-
rhythmic medications (used in rhythm con-
trol), agents used for rate control are generally
considered safer and better tolerated. Agents
used for rate control include digoxin, -block-
ers, and nondihydropyridine calcium-channel
blockers. Refer to Table 1 for an overview of
dosing and other considerations. This column
discusses and evaluates specific nuances of
rate control, targeting efficacy and safety of
specific agents, management of rate control in
an emergent setting, and the intensity of rate
control.
Digoxin
Digoxin is a cardiac glycoside exhibiting its
mechanism of action by binding to the sodium
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NCI200194.indd 121
Drug Update
and potassium adenosine triphosphatase pump,
which eventually increases calcium ions, which
results in a prolonged cardiac action potential
decreasing heart rate. Once considered the first-
line agent in emergent settings for rate control,
digoxin has since fallen out of favor with the
publication of studies proving other agents to
be more appropriate in certain settings. Digoxin
acts relatively slowly when given intravenous-
ly, taking approximately 60 minutes to work,
with peak effects not being reached for at least
6 hours. Furthermore, digoxin has a narrow
therapeutic index, with a target dose range of
0.125 to 0.375 mg orally once daily. The drug
may have toxic or suboptimal effects when
levels fall outside the therapeutic range of 0.5
to 2.0 ng/mL. Appropriate dosing is critical,
especially in patients with renal dysfunction,
and close monitoring for therapeutic levels is a
key consideration with this agent.
Despite these considerations, digoxin may
benefit patients who do not respond to other
options alone. Previous studies have examined
the usefulness of digoxin and its efficacy in AF
therapy. Wattanasuwan and colleagues4 evalu-
ated the differences between intravenous diltia-
zem alone to control rate in patients with AF
with RVR and a combination of intravenous
digoxin and diltiazem. Successful rate control
was defined as a ventricular rate of less than
100 beats per minute persisting for 1 hour or
conversion to sinus rhythm. Loss of rate con-
trol was significantly less in the combination
group than in the diltiazem-alone group (14
vs 39 episodes; P  .05). The length of time
taken to achieve rate control (mean  SD) was
also shorter for the combination group (15 
16 minutes vs 22  22 minutes; P  .20), but
this difference was not statistically significant.4
Patients who are sedentary and do not
require exercise tolerance may benefit from
digoxin therapy because it is not effective when
sympathetic activity is increased. Digoxin is a
positive inotropic agent and can be advanta-
geous to patients with AF and heart failure with
systolic dysfunction, especially when used in
combination therapy with diltiazem in situa-
tions in which conversion to sinus rhythm is not
indicated. Digoxin is also an option for patients
who cannot tolerate further blood pressure
lowering as seen with other agents.
-Blockers
-Blockers work by blocking the effects of nor-
epinephrine and epinephrine. -Blockers are
09/04/12 6:00 PM
 Drug Update AACN

Table 1: Rate Control Medication Overview

Monitoring
Drug Purpose Dose Administration Parameters
Acebutolol Maintenance Maintenance: 200–1200 mg/d Oral Monitor blood
rate control orally in divided doses glucose, blood
(max: 1200 mg/d) pressure,
orthostatic
hypotension, heart
rate, CNS effects
Digoxin Emergent or Emergent: Oral or IV Monitor for low
maintenance blood pressure
Normal renal function:
rate control when given IV;
500 mcg IV x 1, then 250 mcg monitor digoxin
IV (6 h after the first dose) x 2 levels: therapeutic
Renal failure: 250 mcg IV x 1, range 0.5–2 ng/mL
then 125 mcg IV (6 h after
the first dose) x 2

Maintenance: 0.125–0.375 mg
orally daily
Diltiazem Emergent or Emergent: Oral or IV Monitor blood
maintenance pressure, LFTs,
Rate control: 0.25 mg/kg over
rate control heart rate
2 min, if no response, may
repeat with 0.35 mg/kg
after 15 min

Lenient rate control: 0.2 mg/kg

over 10 min

Maintenance:

Continuous infusion: Start at

5-10 mg/h, increase up to
15 mg/h

Oral maintenance: dosing

varies
Esmolol Emergent rate Emergent: 1000 mcg/kg IV bolus IV Monitor blood
control over 30 s, followed by a pressure, MAP,
50 mcg/kg per min heart rate,
continuous infusion; may respiratory rate
increase in 50 mcg/kg per min
increments as needed every
4 min to a max rate of
300 mcg/kg per min
Metoprolol Emergent or Emergent: 2.5–5 mg IV every Oral or IV Monitor blood
maintenance 2–5 min (max: 15 mg over a pressure, heart
rate control 10-min period) rate

Maintenance: 25–100 mg/d

orally immediate release
(max: 400 mg/d)
Pindolol Maintenance Maintenance: 15–20 mg orally Oral Monitor blood
rate control daily (max: 60 mg/d) pressure, heart
rate, respiratory
function
Abbreviations: CNS, central nervous system; IV, intravenous; LFTs, liver function tests; MAP, mean arterial pressure; max, maximum.

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 VOLUME 23 • NUMBER 2 • APRIL–JUNE 2012
sympatholytic drugs affecting both beta1 (1)
receptors and beta2 (2) receptors, depending
on the drug’s selectivity. The heart contains
both 1 and 2 receptors but mostly comprises
1 receptors. 2 Receptors are located in the
vascular smooth muscle. By blocking both these
effects, heart rate (chronotropy) and contractil-
ity (inotropy) are decreased by -blockers.5
The intravenous use of -blockers can be ben-
eficial in an acute setting in patients who are
candidates for -blocker therapy for whom rate
control is indicated. Esmolol, propranolol, and
metoprolol have been used intravenously in the
emergent setting to control rate. These agents
have a rapid onset of about 5 minutes.
Esmolol has a very short half-life of ap-
proximately 9 minutes and has the advantage
of its metabolism being independent of both
hepatic and renal function. This unique char-
acteristic provides value in patients who have
multisystem organ failure or who are critical-
ly ill and their organ function cannot be as-
sessed. However, esmolol must be given as a
continuous infusion, whereas metoprolol and
propranolol can be administered as intermit-
tent intravenous injections. Esmolol is dosed
as an initial 1000 mcg/kg loading dose over
30 seconds, followed by a 50 mcg/kg per
minute infusion. Infusions may be titrated by
50 mcg/kg per minute increments as needed
every 4 minutes up to a relative maximum dose
of 300 mcg/kg per minute. Esmolol is a popu-
lar agent of choice in situations where flexible
control of -blockade is necessary because of
its rapid onset and short duration. Platia and
colleagues6 studied esmolol compared with
verapamil in the short-term treatment of AF
with RVR (heart rate of at least 120 beats per
minute), demonstrating the value of -blocker
use for rate control. The authors reported that
heart rate declined from 139 to 100 beats per
minute (P  .001) with esmolol and from 142
to 97 beats per minute (P  .001) with vera-
pamil. Moreover, the AFFIRM trial showed
that more than 70% of patients achieved rate
control with the use of -blockers, compared
with 54% with the use of calcium channel
blockers.4
In patients for whom emergent rate con-
trol is not indicated, the oral dosage forms
of -blockers provide another alternative for
their use. However, -blockers may not be
the optimal choice for every patient, because
-blockers can result in excessive bradycardia,
lethargy, and shortness of breath. Although the
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NCI200194.indd 123
Drug Update
effects of -blockers on 2 receptors are less
pronounced, the effects of vasoconstriction on
the vascular bed are still of concern because
of the negative inotropic and chronotropic ac-
tions. In patients who experience bradycardia,
hypotension, or heart block, -blockers are
not the drug of choice. However, these adverse
effects may be avoided by using -blockers with
intrinsic sympathomimetic activity (ISA). These
ISA agents work by exhibiting a low level of
agonist activity at the  site, while producing
antagonistic effects. Pindolol and acebutolol are
the most common agents used, at oral doses of
15 to 20 mg daily and 200 to 1200 mg once or
twice daily, respectively. Although these agents
are potential options, more trials and clinical
evidence support the use of -blockers without
ISA activity. Because -blockers without ISA
have a long and successful history of use, they
should be considered safe and effective options
both in the emergent setting and for the long
term to control rate.
Calcium Channel Blockers
Calcium channel blockers exhibit their mecha-
nism of action by blocking the voltage-gated
calcium channels in cardiac and blood vessels.
Decreased intracellular calcium reduces muscle
contraction. Less contractility in the vascular
smooth muscle can result in vasodilation, which
can lead to afterload reduction (pressure against
which the heart pumps). Afterload reduction
ameliorates symptoms of ischemic heart disease
and angina pectoris.
Both verapamil and diltiazem are nondihy-
dropyridine calcium-channel blocking options
for patients with AF. Verapamil exerts most
of its effects on the myocardium, with minimal
afterload reduction, whereas diltiazem exhib-
its effects on both myocardium and vascular
smooth muscle. The 2006 American College
of Cardiology, American Heart Association,
and European Society of Cardiology guidelines,
“Recommendation for Rate Control During
Atrial Fibrillation,” suggest the use of diltiazem
in the instance of emergent AF.7 The most ef-
ficacious and safe dose of diltiazem is still up
for debate. According to these guidelines,7 the
current recommended dose of diltiazem to be
given intravenously in emergency situations is
a load of 0.25 mg/kg over 2 minutes.7 A recent
study suggests that lower doses of diltiazem
are safer, producing less hypotension. In their
study, Lee and colleagues8 evaluated low-dose
diltiazem in patients with AF with RVR. The
09/04/12 6:00 PM
 Drug Update
study compared 3 different doses of diltiazem
in the emergent setting to control rate: low dose
( 0.2 mg/kg), standard dose (0.25 mg/kg), and
high dose ( 0.3 mg/kg). The study reported no
therapeutic benefits to using lower doses of dil-
tiazem, but low doses were statistically signifi-
cant for producing fewer hypotensive adverse
effects (18%, 34.9%, and 41.7%, respectively;
P  .037).8 Limitations to this study include
its retrospective nature and small sample size.
Perhaps differences in efficacy may have been
noted if more patients had been compared. This
low-dose strategy may be considered with clini-
cal judgment for instances in which hypoten-
sion may lead to adverse outcomes.
Emergent Rate Control
Although long-term management of AF is the
primary goal for patient care, emergent situ-
ations require a quick resolution on the basis
of short-term goals. Long-term goals can be
developed and adjusted later as needed. When a
patient with signs of symptomatic AF arrives at
the emergency department but is hemodynami-
cally stable, the main goal for short-term man-
agement is rate control. Rate control is achieved
by the use of atrioventricular nodal-blocking
agents, which are the mainstay of therapy. Di-
goxin has been the favored drug in years past to
control rate, but over time it has become a less-
popular option. Diltiazem has become a stan-
dard therapy and drug of choice for acute care
settings. The study that brought diltiazem to
the forefront compared intravenous diltiazem
with intravenous digoxin in controlling acute
AF with RVR. The study used a dose of intra-
venous digoxin bolus of 0.25 mg initially and
then another 0.25 mg at 30 minutes, compared
with a diltiazem bolus of 0.25 mg/kg followed
by a dose of 0.35 mg/kg and then a titratable
infusion at a rate of 10 to 20 mg/h to maintain
heart rate control at a ventricular rate of less
than 100 beats per minute. The authors con-
cluded that for emergency management of rate
control in AF, diltiazem is the drug of choice
because of its rapid onset within 5 minutes (P 
.037).9 The study used an unconventional dose
of digoxin; the standard dose is usually 0.5 mg
given intravenously once, followed by 0.25 mg
every 6 hours for 2 doses.
Diltiazem, although known to have nega-
tive inotropic effects, is thought to have fewer
negative inotropic effects than verapamil. Effec-
tiveness of diltiazem has been proven in previ-
ous studies, and because of its less significant
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NCI200194.indd 124
AACN
inotropic effects compared with verapamil,
diltiazem is considered a safe choice for nondi-
hydropyridine calcium-channel blockade in the
condition of acute AF.
Intensity of Rate Control
Today, the optimal level of rate control is
unknown. A recent study titled “Rate Control
Efficacy in Permanent Atrial Fibrillation (RACE
II)” by Van Gelder and colleagues10 sought to
determine the ideal heart rate for optimal rate
control therapy. The study also evaluated the ef-
fect of preventing cardiovascular morbidity and
mortality in patients diagnosed with permanent
AF. Strict rate control was defined as a resting
heart rate of less than 80 beats per minute, and
lenient heart rate was defined as a resting heart
rate of less than 110 beats per minute. Patients
were followed for a maximum of 3 years. The
primary outcome was defined as a composite of
stroke, death from cardiovascular events, hospi-
talization for heart failure, systemic embolism,
bleeding, or life-threatening arrhythmic events.
The primary outcome after 3 years was 12.9%
in the lenient heart rate group and 14.9% in
the strict-control group (P  .001). In addition,
more patients achieved successful rate control
(as defined per group) in the lenient heart rate
group than in the strict-control group (97.7%
vs 67%, respectively; P  .001).10 Worsening
heart failure is of concern in patients with AF
with preexisting heart failure because of venous
pooling and increased preload. A limitation of
RACE II is that worsening heart failure was not
evaluated. However, the study population for
both lenient and strict groups had similar inci-
dences of heart failure at enrollment (3.8% vs
4.1%, respectively).10 The study also included
only low-risk patients who had not previously
had a stroke and were physically active. The
risk of primary outcome adverse events beyond
that of 3 years is unknown.
Although lenient heart rate control may be a
future direction for treatment goals, more stud-
ies are needed to confirm its place in therapy.
However, the newly released 2011 American
College of Cardiology, American Heart Asso-
ciation, and Heart Rhythm Society “Focused
Update on the Management of Patients With
Atrial Fibrillation (Updating the 2006 Guide-
line): A Report of the American College of
Cardiology Foundation/American Heart Asso-
ciation Task Force on Practice Guidelines” sug-
gests that strict heart rate control is unnecessary
in all patients and lenient heart rate control is
09/04/12 6:00 PM
 VOLUME 23 • NUMBER 2 • APRIL–JUNE 2012
more convenient for patients.11 The consensus
recommendation states that lenient heart rate
control may be a good option for patients with
permanently diagnosed AF with RVR.
Conclusions
Studies now confirm that rate control is an
accepted method of management of patients
with AF with RVR. Pharmacological agents such
as -blockers, digoxin, and nondihydropyridine
calcium channel blockers provide patients with
safe and efficacious options to control their symp-
toms and prevent adverse outcomes. -Blockers
have a long-standing history of efficacy and
safety demonstrated in both clinical experience
and randomized controlled trials. Over time,
digoxin has lost its popularity but still provides
value in specific populations if appropriately
monitored. In emergency situations, diltiazem is
the nondihydropyridine calcium-channel blocker
of choice. Furthermore, clinicians trying to treat
patients with AF with RVR should consider a
lenient heart rate control approach rather than
a strict-control approach, particularly in patients
with permanent AF with RVR.
REFERENCES
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of atrial fibrillation and flutter in the United States. Am J
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rheumatic atrial fibrillation. Lancet. 1987;1:526–529.
3. Olshansky B, Rosenfeld LE, Warner AL, et al. The
Atrial Fibrillation Follow-up Investigation of Rhythm
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Drug Update
Management (AFFIRM) study: approaches to control
rate in atrial fibrillation. J Am Coll Cardiol. 2004;43:
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10. Van Gelder IC, Van Veldhuisen DJ, Crijns HJ, et al. Rate
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09/04/12 6:00 PM
 Efficacy and Safety of Pharmacological Options for Rate Control in
Atrial Fibrillation
Katie O'Brien, Earnest Alexander and Lindsay Patel
AACN Adv Crit Care 2012;23 120-125 10.1097/NCI.0b013e318242fdd0
©2012 American Association of Critical-Care Nurses
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