Heart, Lung and Circulation (2017) 26, 926–933 REVIEW

1443-9506/04/$36.00
http://dx.doi.org/10.1016/j.hlc.2017.05.134

Pharmacological Therapy for Rate and

Rhythm Control for Atrial Fibrillation in
2017
Logan Kanagaratnam, FRACP a,b,c*, Peter Kowey, MD d,e,
David Whalley, FRACP, PhD a,b
a
Department of Cardiology, Royal North Shore Hospital, Sydney, NSW, Australia
b
University of Sydney, Sydney, NSW, Australia
c
Ryde Hospital, Sydney, NSW, Australia
d
Lankenau Heart Institute, Wynnewood, PA, USA
e
Jefferson Medical College, Philadelphia, PA, USA

In spite of the emergence of non-pharmacological approaches, medical therapy remains the primary
modality of treatment for most patients with atrial fibrillation (AF). This review will look at evidence for
rate and rhythm control approaches, and at factors that would help in choosing the appropriate treatment
strategy for individual patients.
Keywords Atrial fibrillation  Pharmacological therapy

or long standing persistent) and the likelihood of maintain-

Introduction
Atrial fibrillation (AF) is one of the commonest arrhythmias
encountered in adult cardiology practice. The incidence and
prevalence of AF increases with age. Atrial fibrillation is
associated with an increase in morbidity and mortality. Atrial
fibrillation also affects the quality of life [1].
The treating physician needs to make two main decisions
when seeing a patient with AF. The first is to assess throm-
boembolic risk and evaluate whether the patient needs anti-
coagulation. The CHA2DS2VASc score helps with this
decision-making, and the HAS-BLED score may help to
assess the risk of anticoagulation therapy.
The next decision is whether to embark on a rhythm
control strategy or primary rate control strategy. Even
patients with a primary objective of obtaining and maintain-
ing sinus rhythm (SR) will require rate control until SR is
achieved. Many factors influence whether one should aim for
rhythm control or rate control, and it may be necessary to
change from one approach to other due to changing clinical
circumstances.
The main factors that influence this decision would include
the patient’s symptoms, type of AF (paroxysmal, persistent
ing SR. Patient age, co-morbidities and left atrial size also
need to be factored into this decision.
This review will examine the available clinical trial data for
each of these approaches and look at specific patient groups
that may benefit from each approach. This review will focus
on pharmacological therapies, however rhythm control and
rate control may also be achieved by non-pharmacological
means (such as ablation and device therapies).
Reappraisal of the Traditional
Approach
Traditionally rhythm control was looked at as the first option
and only when rhythm control failed were patients delegated
to rate control strategy. However, the results of the AF
Follow-up Investigation of Rhythm Management (AFFIRM)
and the Rate Control versus Electrical Cardioversion for
Persistent Atrial Fibrillation (RACE) trials have led to a
reconsideration of this approach.
In the AFFIRM trial, 4,060 patients who were thought to be
at risk of recurrent AF were enrolled and had a mean follow-

*Corresponding author at: Department of Cardiology, Royal North Shore Hospital, Pacific Highway St Leonards, NSW 2065, Australia.,
Email: Logan.Kanagaratnam@health.nsw.gov.au
© 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ).
Published by Elsevier B.V. All rights reserved.
Rate and Rhythm Control for Atrial Fibrillation
up of 3.5 years [2]. In this group with mean age of 69.7 years,
rhythm control strategy was mostly with amiodarone or
sotalol and rate control was mainly with a beta blocker
(BB), calcium channel blocker (CCB) — diltiazem or verapa-
mil, or with digoxin. In the rhythm control group, the prev-
alence of SR was 82.4%, 73.3% and 62.6% at one-, three- and
five-year follow-up, respectively. In this study, a rhythm
control strategy did not offer a survival advantage over
the rate control strategy. In the rate control group there were
less drug-related side effects. There was no difference in
stroke rates. Most strokes occurred after anticoagulation
withdrawal or in patients with sub-therapeutic INR. In the
rate control strategy group, about one third were in SR on
follow-up.
In the RACE trial, 522 patients with persistent AF were
randomised to rhythm control or rate control after cardio-
version [3]. Both groups received anticoagulation. The
rhythm control group had serial cardioversions and antiar-
rhythmic (AA) medications. After a mean follow-up of
2.3+/ 0.6 years, 39% in the rhythm control strategy group
and 10% in the rate control strategy group were in SR. The
endpoints of death, heart failure, thromboembolic complica-
tions were similar in both groups.
These two trials were pivotal in establishing that a strategy
of rate control is not inferior to a strategy of pharmacological
rhythm control in patients with mean age of 68–69 years. The
results of these trials should not be interpreted as showing an
equivalence of SR and AF with respect to stroke risk and
mortality. Rather, they show that with available antiarrhyth-
mic drug therapies, the ability to maintain SR is modest and
their potential benefits may be counterbalanced by signifi-
cant cardiac and non-cardiac side effects including pro-
arrhythmia [4]. There is great interest awaiting the results
of ongoing large randomised trials of catheter ablation for AF
such as the CABANA study (Clinicaltrials. gov.
NCT00911508) to determine whether a non-pharmacological
approach to rhythm control will decrease stroke risk and
mortality.
Rate Control for AF – How Strict
Should We Be?
An important question to consider when implementing rate
control for AF is how strictly to reduce the ventricular rate.
Fast ventricular rates may be associated with palpitations,
fatigue, chest discomfort and dyspnoea and may truncate
diastolic filling and reduce cardiac output. A proportion of
patients with sustained fast ventricular rates have also been
documented to have a poor ejection fraction (tachycardia-
induced cardiomyopathy), which has been noted to improve
with better rate control or rhythm control.
In the RACE II trial, 610 patients with permanent AF were
randomiaed to strict rate control (resting heart rate less than
80 beats per minute (bpm) and with moderate exercise <110
bpm) or lenient rate control (resting HR <110 bpm) [5]. At
three-year follow-up, there was no difference in death, stroke
927
and heart failure hospitalisations. At the end of a three-year
period, the resting heart rate of the aggressive rate control
group was 76+/ 14 bpm, and in the lenient rate control
group it was 85+/ 14 bpm. Resting heart rate target was
achieved in 98% of the lenient group and only in 75% of strict
rate control group. As expected, the number of medications
required and the dosage used were higher in the strict rate
control group, and they had a higher incidence of drug
related side effects. However, it is important to note that
the observed mean heart rate difference between the groups
was small (9 bpm).
A subsequent combined analysis of the AFFIRM and
RACE cohorts showed that the AFFIRM patients with a
resting heart rate in AF of less than 80 bpm and the RACE
patients with a heart rate <100 bpm had better outcomes
compared with patients with a resting heart rate greater than
100 bpm, with odds ratios of 0.7 and 0.66, respectively [6].
A meta-analysis of all rate control and rhythm control
studies showed similar long-term outcomes, including all-
cause mortality, cardiac mortality and stroke with either
approach [7].
The current ESC guidelines recommend targeting a resting
heart rate of <110 bpm then adjusting therapy if the patient
remains symptomatic. They emphasise the importance of try-
ing to avoid excessive bradycardia (Figure 1, from ESC guide-
lines [8]). However, as the lenient rate control group in RACE II
had a mean heart rate of 85 bpm, in clinical practice it would be
reasonable to aim for a resting heart rate of 80–90 bpm.
Pharmacological Agents for Rate Control
The main agents used for rate control are BB, non-dihydro-
pyridine CCB, and digoxin. Most of the evidence for effec-
tiveness of these drugs come from small studies. The choice
of drugs depends on patient co-morbidities, symptoms, ejec-
tion fraction, lifestyle and the target heart rate.
Beta Blockers
The common BBs used are metoprolol, atenolol and, to a
lesser extent, carvedilol and bisoprolol. Beta blockers may
have additional benefit in patients with hypertension, ischae-
mia, and heart failure. The side effects of BBs include fatigue,
sexual dysfunction, bronchospasm, vivid dreams and altered
mood. Commonly used BBs and dosages are listed in Table 1.
Calcium Channel Blockers
The non-dihydropyridine CCBs are used for rate control
(Table 2). They may have negative inotropic effect, and are
best avoided in patients with systolic dysfunction. The CCBs
can cause vasodilation, oedema, headache and constipation.
Digoxin
Cardiac glycosides like digoxin have been used for more than
200 years for the treatment of AF. Despite lack of clinical trial
evidence, digoxin is still used widely for rate control in AF.
Although digoxin can control ventricular rate at rest, it is less
effective when there is higher sympathetic tone (that is, with
exercise). Recently, the safety of digoxin for rate control in AF
has been called into question.
928
Figure 1 Rate control Therapy for AF from ESC guidelines [8].
In The Retrospective Evaluation and Assessment of Ther-
apies in AF (TREAT-AF) study, which was a retrospective
review of a large data base of predominantly male veterans,
with propensity matching, treatment of newly diagnosed AF
was associated with increased mortality (hazard ratio, 1.21),
independent of renal function, cardiac co-morbidities and
concomitant therapy [9].
In one of the AFFIRM post-hoc analyses, digoxin use was
associated with higher all-cause mortality in a propensity-
adjusted analysis [10]. However, in a subsequent propensity
matched analysis where baseline heart failure was taken into
account, digoxin use did not cause excess mortality [11]. In
the Digitalis Investigation Group (DIG) study digoxin had a
neutral effect on mortality with an improvement in morbid-
ity [12].A recent large systematic review and meta-analysis
by Ziff et al., concluded that digoxin use was not associated
with any excess mortality [13].
In patients with long-standing AF and cardiac failure,
addition of digoxin to carvedilol was associated with better
ventricular rate control, lower symptoms and slightly better
ejection fraction but there was no difference in the six-minute
walk test [14].
Table 1 Beta Blockers.
BETA BLOCKER USUAL DOSAGE
Metoprolol 25 mg–100 mg twice daily
Atenolol 25–100 mg once daily
Carvedilol 3.125–50 mg twice daily
Nebivolol 1.25–10 mg daily
Bisoprolol 1.25–10 mg daily
L. Kanagaratnam et al.
The usual maintenance dose of digoxin is 62.5 mcg–250
mcg daily. The dose is often determined by the renal func-
tion and concurrent use of other medications, and is guided
by serum digoxin level to avoid toxicity. Lower serum
digoxin concentrations are now recommended in heart
failure [15,16].
Antiarrhythmic agents including amiodarone, dronedar-
one and sotalol can also control ventricular rates in AF.
However, due to their side effect profile, they are not used
for primary rate control in routine practice. In critically ill
patients with AF who need rate control amiodarone can be
used for short periods [17].
Challenges in Rate Control
In patients with low BP, the use of an adequate dose of BB or
CCB may be difficult, and alternative agents such as digoxin
or amiodarone may need to be considered. It may also be
difficult to achieve rate control in some patients whose high
ventricular response is being driven by the use of beta-ago-
nist therapies for asthma or chronic obstructive pulmonary
disease, or in thyrotoxic patients. In those patients with both
fast rates and a propensity at times to bradycardia or
INTRA-VENOUS DOSE – (where available)
Initial 5 mg (at 1–2 mg/min); May be repeated at
5 minute intervals- up to 15 mg
Rate and Rhythm Control for Atrial Fibrillation 929

Table 2 CCB.

Calcium Channel Blockers DOSAGE DOSAGE FOR EXTENDED INTRA-VENOUS DOSE

RELEASE PREPARATION (where available)

Verapamil 40–120 mg three 120–480 mg once daily Initial 2.5–5 mg over 2 minutes; May be
times daily repeated every 10 minutes up to a
maximum of 20 mg
Diltiazem 60–120 mg three 120–360 mg once daily
times daily

prolonged pauses (tachy-brady syndrome), pacemaker Currently Available Antiarrhythmic

implantation may be needed to permit use of rate control
agents.
Rhythm Control Strategy
Principles of Management
Once appropriately rate-controlled and, when indicated,
anticoagulation has been implemented, antiarrhythmic
drug therapy with the aim of achieving rhythm control
can be commenced. This may be in the context of reverting
acute onset AF, prior to and following direct current car-
dioversion to assist in the long-term maintenance of SR, and
as adjuvant therapy in patients undergoing catheter abla-
tion of AF.
The aim of drug therapy is to alleviate symptoms whilst
minimising side-effects. Safety should be the overriding pri-
ority. Although complete abolition of AF episodes would be
an ideal goal, the modest efficacy of available drugs means
that breakthrough of AF is often encountered and a signifi-
cant reduction in symptomatic AF burden is a more realistic
and achievable goal in most patients. A single recurrence of
AF despite drug therapy should not be regarded as thera-
peutic failure but rather an opportunity to examine and, if
possible, titrate drug dosage.
It is important to recognise the synergistic therapeutic role
played by addressing lifestyle factors such as obesity and
treating co-morbidities, including hypertension and obstruc-
tive sleep apnoea, when pursuing a rhythm control strategy
for AF [18].
Drug Therapy in Australia
Antiarrhythmic drugs exert their predominant effects via
blockade of one or more ion channels and/or via modulation
of adrenoreceptors. Currently, in Australia, the available
agents are the Class 1C agent flecainide, the Class III agents
amiodarone and sotalol, and the class 1A agent disopyra-
mide (Table 3). In the US and Europe, the additional agents
dofetilide, propafenone, dronedarone and procainamide are
available.
Amiodarone is the most effective agent for maintenance of
SR but also carries the greatest potential for causing cardiac
and non-cardiac toxicity [2,19,20]. It blocks sodium (Na) and
calcium channels and a variety of potassium (K) channels,
and is a non-competitive blocker of alpha- and beta-adrenor-
eceptors. It inhibits the Na-K ATPase and influences cellular
thyroid metabolism. Intravenous (IV) administration is effec-
tive for rate control via early beta blockade, however, the
class III effects are delayed and are time- and dose-depen-
dent. For this reason, it has been found to be less effective for
acute reversion of new onset AF when compared with oral or
IV flecainide [21].
Its long half-life of six to seven weeks necessitates oral
loading and dose titration. It may produce a variety of non-
cardiac side effects including tremor, sleep disturbance,
flushing, photosensitivity, thyroid dysfunction, hepatic dys-
function, corneal deposits and, rarely, pulmonary toxicity
(pneumonitis, pulmonary fibrosis).
Cardiac effects include sinus bradycardia and prolonga-
tion of the corrected QT interval, although it is rarely associ-
ated with torsades de pointes.

Table 3 Anti Arrhythmic Medications.

MEDICATION USUAL ORAL DOSAGE COMMENTS

AMIODARONE Usual maintenance dose 100–200 mg/day-following Monitor thyroid function, liver function and lung function
oral loading
SOTALOL 80–160 mg bd Reduce dose if renal impairment; Avoid QTc prolongation
more than 500 msec
FLECAINIDE 50–150 mg bd Use with AV nodal blocking agent
DISOPYRAMIDE 100–200 mg tds Monitor QTc
930
As it has no adverse effects on cardiac contractility, amio-
darone is the preferred antiarrhythmic drug for patients with
impaired left ventricular function or cardiac failure. Drone-
darone, a de-iodinated derivative of amiodarone is available
in the US and Europe but has demonstrated inferior efficacy
to the parent drug, and is contraindicated in patients with
congestive cardiac failure [22,23].
Sotalol is a beta blocker and a potassium channel (IKr)
blocker. It appears to be equivalent in efficacy to flecainide
for maintenance of SR but is inferior to amiodarone. The drug
is renally excreted, and dosage adjustment and careful mon-
itoring of the QTc interval should be undertaken for patients
with reduced renal function, and especially for elderly
females. The most common side-effects are gastrointestinal
intolerance, fatigue, loss of libido and impaired exercise
capacity. It can be administered orally or IV. Sotalol should
be avoided in patients with decompensated cardiac failure
and used with caution in those with LVEF <30% because of
an increased risk of torsades de pointes [24].
Sotalol is less effective than amiodarone for the mainte-
nance of SR but appears to be equivalent in efficacy to
amiodarone for reversion of recent onset AF [20,25]. A recent
meta-analysis has suggested that sotalol use is associated
with an increased all-cause mortality [4].
Flecainide is a potent Na channel blocker and is also a
weak blocker of IKr. It has mild negative inotropic effects.
Flecainide is available in intravenous (IV) and oral form, and
is effective for reversion of recent onset AF and maintenance
of SR post-cardioversion. It is contraindicated in patients
with a past history of myocardial infarction, structural heart
disease or left ventricular dysfunction because of an
increased risk of ventricular tachyarrhythmias [26]. It should
be used in conjunction with an atrioventricular (AV) nodal
blocking agent to minimise the risk of 1:1 conduction of atrial
flutter which can occur due to slowing of atrial conduction.
Flecainide can be used as a ‘‘pill in the pocket” approach to
revert recent onset AF in patients with no history of struc-
tural or ischaemic heart disease [27,28]. The regimen, which
consists of a single oral dose of 200–300 mg, administered
30 minutes after an AV nodal blocking agent, can be self-
administered in an outpatient setting provided it has first
been shown to be safe and effective for the patient in a
monitored inpatient setting. The most common side effects
are headache, dizziness, and visual disturbance on lateral
gaze.
Disopyramide blocks Na channels and IKr, and has anti-
cholinergic properties. It has a limited role in treatment of
vagally-induced AF. It has negative inotropic properties and
should be avoided in patients with heart failure, prostatism
or narrow-angle glaucoma. A recent meta-analysis has sug-
gested that disopyramide use may also be associated with
increased all-cause mortality [4].
Barriers for Rhythm Control
In young patients with significant bradycardia, it may not be
possible to use maintenance antiarrhythmic medication
which may aggravate the bradycardia. Patient co-morbidities
L. Kanagaratnam et al.
including coronary artery disease, thyroid dysfunction and
renal impairment may also limit the choice of AA medica-
tions. In some patients, AF which was initially well con-
trolled on drug therapy may become resistant, and an
alternative treatment such as catheter ablation may need
to be considered. In those whose AF has transitioned from
paroxysmal to persistent, and who are deemed unsuitable for
catheter ablation, the management strategy may need to
change from rhythm control to rate control.
Who Benefits Most from a
Pharmacological Rhythm Control
Strategy?
In a meta-analysis of 10 rate versus rhythm control studies,
there was no difference in mortality, heart failure and stroke.
It should be noted, however, that trials like AFFIRM did not
include many young patients who are active and highly
symptomatic in atrial fibrillation. A sub-analysis of patients
under 65 years of age showed that those who were assigned
to rhythm control had a lower mortality [29].
In a post-hoc analysis by the AFFIRM group, those in SR
(regardless of the treatment strategy) had lower mortality
[30]. Since SR was associated with better survival when
adjusted for other confounders, these results suggest that
the adverse effects of AAs together with an increased stroke
risk in those who discontinued their anticoagulation may be
negating this benefit [30]. Similar findings were observed in
the Danish Investigations of Arrhythmia and Mortality On
Dofetilide (DIAMOND) study [31].
Rhythm Control and Quality of Life
In the Registry on Cardiac Rhythm Disorders Assessing the
Control of Atrial Fibrillaion (RECORD-AF) sub-study which
was an observational study of 2,439 patients, both rhythm
control and rate control were associated with better quality of
life at one year, with marginal benefit in favour of the rhythm
control group [32]. In the RACE study, treatment strategy did
not affect subsequent quality of life but those who main-
tained SR had better quality of life [33].
In a Canadian population based study of 26,130 patients
(sicker hospitalised patients with AF and heart failure), AA
therapy conferred a slight excess in mortality in the first six
months of initiation (odds ratio, 1.07). Subsequently, the
mortality between rate control and rhythm control groups
was similar until Year 4 from the beginning of therapy but
thereafter there was a steady decline in mortality for rhythm
control group [34].
The ESC guidelines recommend early adoption of rhythm
control strategy in highly symptomatic, young (<65 years),
new onset AF without structural heart disease.
Special Considerations
Some factors that impact the choice of rate control versus
rhythm control strategy are shown in Table 4 (From Camm
et al. [35]).
Rate and Rhythm Control for Atrial Fibrillation
Table 4 Factors that impact the choice of rate control versus rhythm control strategy (From Camm et al. [35]).
RATE CONTROL
Older
Sedentary
Asymptomatic
Late persistent or Permanent AF
Substantial atrial remodelling
Irremediable underlying heart disease
Long or indeterminate history
AF and Heart Failure
In patients with heart failure, AF increases morbidity and
mortality [36,37]. In heart failure patients (both with
impaired and preserved ejection fraction), AF reduces exer-
cise capacity [38,39].
The irregular ventricular filling and loss of atrial contrac-
tion associated with AF may exacerbate heart failure.
However, patients with impaired left ventricular function
may also be more susceptible to drug toxicity, raising the
question: Is rhythm control superior to rate control in
patients with cardiac failure?
A few trials have looked at this group of patients. However
the trial results have not been so conclusive as to make firm
recommendations.
Figure 2 Rhythm Control In Structural Heart Disease From Darby and Dimarco [46].
931
RHTYHM CONTROL
Younger
Active
Symptomatic
Paroxysmal or Early persistent AF
Little or no atrial remodelling
No or minimal underlying heart disease
Short history/Correctable cause
In a study of patients with heart failure, the strategy of
rhythm control failed to improve mortality, heart failure or
stroke outcomes [40]. In an AFFIRM sub-analysis there was
no benefit in rhythm control in heart failure patients. How-
ever, the US Veterans Affairs Congestive Heart Failure Sur-
vival Trial of Antiarrhythmic Therapy (CHF-STAT) study
found that patients who reverted to, and maintained, SR
had better survival [41]. Similarly, in the DIAMOND Study
maintenance of SR was associated with better survival [31].
In younger patients with heart failure and AF, it may
reasonable to consider a rhythm control approach as the
initial step. Even in older patients, if the AF is recent onset
and especially if the left atrial size is normal or only mildly
enlarged, initial rhythm control should be considered.
932
Meta-analysis has shown that patients with heart failure
and AF have better long-term maintenance of SR with catheter
ablation when compared with AA drugs [42]. Further larger
studies are needed to see whether catheter ablation should be
considered early in patients with heart failure and AF.
Drug Refractory AF
Multiple studies have been done in patients with drug refrac-
tory AF comparing medical therapy with AV nodal ablation
with pacing. The latter therapy has been shown to improve
quality of life measures without affecting mortality or left
ventricular ejection fraction [43].
Patients with Chronic Kidney Disease
Chronic kidney disease (CKD) is associated with a higher
prevalence of AF [44]. Patients with CKD are more prone to
arrhythmia due to, for example, electrolyte imbalances, auto-
nomic dysfunction, left ventricular hypertrophy, anaemia,
and endothelial dysfunction. Many antiarrhythmic and rate
control medications need caution and dose adjustment in
those with renal impairment. Sotalol and digoxin will need
special caution. In patients with end stage renal disease,
flecainide, verapamil and atenolol may also require dose
reduction [45].
Patients with Structural Heart Disease
Some patients with structural heart disease tolerate AF
poorly. Patients with hypertrophic cardiomyopathy and
other conditions where atrial contribution for the cardiac
output is especially important are significantly affected by
AF. However, in this group, the AA choice may be limited
due to potential contraindications. Figure 2 provides phar-
macological options for patients with structural heart disease
(from Darby and Dimarco [46]).
Conclusion
Although many non-pharmacological therapies are being
explored for treatment of AF, the vast majority of patients
require medical therapy. Initial assessment should look at
patients who are likely to benefit by achieving SR, and whether
it is likely to be feasible. It is reassuring that, for most patients,
rate control is not inferior to rhythm control and, in the absence
of symptoms, a lenient rate control should be the initial step.
Subgroup analysis shows that if rhythm control could be
successfully achieved, the longer-term quality of life may
be better. There is also some suggestion that the longer
term stroke and mortality risk may be less; however the
pro-arrhythmic potential and other side effects of AA drugs
may negate the benefit obtained by maintenance of SR.
Disclosures and Declarations
Logan Kanagaratnam and David Whalley have no disclo-
sures. Peter Kowey is an ad hoc consultant to Sanofi, Pfizer,
Gilead and Allergan
L. Kanagaratnam et al.
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