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Rhythm control versus rate control in atrial fibrillation

Authors: Kapil Kumar, MD, Warren J Manning, MD

Section Editor: Peter J Zimetbaum, MD
Deputy Editor: Gordon M Saperia, MD, FACC

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2017. | This topic last updated: Oct 10, 2016.

INTRODUCTION — Atrial fibrillation (AF) is the most common sustained arrhythmia. It may cause
significant symptoms and impair both functional status and quality of life. Without therapeutic
intervention, affected patients are at increased risk for mortality (1.5- to 1.9-fold in the Framingham
Heart Study) and morbidity (thromboembolic events and limiting symptoms).

In AF, the loss of the regular and organized contraction of the left atrium as well as the subsequent
increase in ventricular rate, lead to both immediate and long-term adverse consequences:
deterioration in hemodynamics secondary to increased heart rate and loss of atrioventricular (AV)
synchrony, an increased risk for stroke and other embolic events from left atrial thrombi, and
progressive dysfunction of the left atrium and left ventricle [1,2]. (See "Hemodynamic consequences of
atrial fibrillation and cardioversion to sinus rhythm" and "Arrhythmia-induced cardiomyopathy".)

For each patient with AF, the two principal goals of therapy are symptom control and the prevention of
thromboembolism. (See "Atrial fibrillation: Anticoagulant therapy to prevent embolization" and
"Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm", section on
'Adverse hemodynamics in AF'.)

Rate- and rhythm-control strategies improve symptoms, but neither has been conclusively shown to
improve survival compared to the other. (See 'Definitions' below.)

For each patient with AF, a decision should be made as to which approach will be used for long-term
management. The following points should be kept in mind irrespective of strategy:

● Both strategies can fail both in the short and long terms. As a consequence many patients need
to be reconsidered for the alternate strategy as the natural history of their disease progresses.

● All patients with AF, irrespective of strategy chosen/rhythm, should have their thromboembolic
risk assessed and be managed accordingly. (See 'Thromboembolic risk' below.)

● For patients who are managed with a rhythm-control strategy, rate control is necessary due to the
possibility of the recurrence of AF.
The advantages and disadvantages of rhythm and rate control, as well as whether there are
subgroups of patients in whom one or the other should be preferred, will be discussed here. The
methods to achieve rhythm or rate control are discussed separately. (See "Antiarrhythmic drugs to
maintain sinus rhythm in patients with atrial fibrillation: Clinical trials" and "Antiarrhythmic drugs to
maintain sinus rhythm in patients with atrial fibrillation: Recommendations" and "Control of ventricular
rate in atrial fibrillation: Pharmacologic therapy" and "Control of ventricular rate in atrial fibrillation:
Nonpharmacologic therapy".)

Patients with recent onset — For patients who present with recent onset AF, relatively rapid
decisions, including the choice between rhythm and rate control, often need to be made. This issue is
discussed in detail separately. (See "Management of new onset atrial fibrillation".)

DEFINITIONS — A rhythm-control strategy uses antiarrhythmic drug therapy, radiofrequency catheter

ablation, and/or a surgical procedure performed at the time of open heart surgery to maintain sinus
rhythm (SR). Many patients who remain in SR require rate slowing drugs (in the event of return to
atrial fibrillation [AF]) long term as well as chronic antithrombotic therapy. (See 'Thromboembolic risk'
below.)

A rate-control strategy uses drugs that block (slow conduction through) the atrioventricular (AV) node
such as beta blockers, rate-slowing calcium channel blockers, or digoxin. AV nodal ablation plus
ventricular pacing to control symptoms is also considered when pharmacologic therapy is ineffective.
Rate control goals are discussed elsewhere. (See "Control of ventricular rate in atrial fibrillation:
Pharmacologic therapy", section on 'Rate control goals'.)

THROMBOEMBOLIC RISK — Thromboembolism is the most important adverse outcome of atrial

fibrillation (AF). Unfortunately, clinical maintenance of sinus rhythm (SR) does not reduce the
frequency of clinical thromboembolization. The AFFIRM and RACE trials demonstrated that embolic
events occurred with equal frequency regardless of whether a rate control or rhythm-control strategy
was pursued; furthermore, most embolic events (113 of 157 ischemic strokes in AFFIRM and 29 of 35
embolic events in RACE) occurred after warfarin had been stopped or when the International
Normalized Ratio (INR) was subtherapeutic (less than 2.0) [3,4]. These findings indicate that at-risk
patients in whom a rhythm-control strategy is pursued still require chronic anticoagulation, even if it
seems that SR is maintained. (See "Atrial fibrillation: Anticoagulant therapy to prevent embolization".)

There are at least three explanations for the failure of rhythm control to reduce embolic risk:

● Despite successful cardioversion and antiarrhythmic drug therapy, the recurrence rate of either
intermittent (paroxysmal) or persistent (chronic) AF is 35 to 60 percent at one year with
intermittent monitoring (figure 1) [5,6] and up to 88 percent with continuous monitoring
(permanent pacemaker with AF detection function and electrogram storage) for more than 18
months [7]. In the AFFIRM trial described below, there was a high crossover rate from rhythm to
rate control (17 and 38 percent of patients at one and five years), due primarily to inability to
maintain SR and drug intolerance [3].

Up to 90 percent of recurrences are asymptomatic [8] (likely because of the use of rate controlling
medications) and asymptomatic episodes lasting more than 48 hours are not uncommon,
occurring in 17 percent of patients in a report using continuous monitoring [7]. During these
 prolonged episodes of AF, left atrial thrombi can form that may cause clinical thromboembolism.
The continuous monitoring study also showed that 40 percent of patients had episodes of AF-like
symptoms in the absence of AF [7]. Even very brief episodes of AF can increase stroke risk. In a
study using pacemakers for arrhythmia detection in patients without a history of AF, AF duration
for greater than five minutes increased the risk of thromboembolic events sixfold compared with
patients with similar or greater CHADS2 score and no detected AF [9].

● Patients with nonvalvular AF that is not due to a reversible disease (eg, hyperthyroidism, cardiac
surgery) often have other predisposing factors for thromboembolism even when they are in SR.
These include complex aortic plaque and left ventricular systolic dysfunction. (See
"Antithrombotic therapy in patients with heart failure" and "Embolism from aortic plaque:
Thromboembolism".)

There may be discordance between the body of the left atrium, demonstrating sinus mechanism, while
the atrial appendage displays an AF contraction pattern [10].

● Thus, the implementation of either strategy requires the assessment of the need for
antithrombotic therapy. Issues related to risk stratification and the approach to antithrombotic
therapy in patients with AF are discussed in detail separately. (See "Atrial fibrillation: Risk of
embolization" and "Atrial fibrillation: Anticoagulant therapy to prevent embolization".)

A separate issue from chronic antithrombotic therapy is anticoagulation related to cardioversion. The
recommended approach to such patients is presented separately. (See "Prevention of embolization
prior to and after restoration of sinus rhythm in atrial fibrillation".)

COMPARATIVE STUDIES — At least seven randomized trials have compared rate and rhythm
control approaches in the broad population of patients with atrial fibrillation (AF) and demonstrated
equivalent outcomes (such as the rates of death or embolism) in both arms [3,4,11-13]. Two large
trials, AFFIRM and RACE, will be discussed in detail. One trial demonstrated improved quality-of-life
scores with rhythm control [14]. A large, 2012 observational study found a lower risk of death at both
five and eight years of follow-up with rhythm control [15].

AFFIRM trial — AFFIRM, the largest trial, randomly assigned 4060 patients with recurrent AF to rate
control (using digoxin, beta blocker, and/or calcium channel blocker) and anticoagulation with warfarin
or to rhythm control with the most effective antiarrhythmic drug, with the use of warfarin left up to the
discretion of the investigator [3]. Patients had to be at least 65 years of age (mean age 70) or have
other risk factors for stroke or death and there could be no contraindications to antiarrhythmic or
anticoagulation therapy. All patients were initially anticoagulated, but those in the rhythm control arm
who maintained sinus rhythm (SR) could be withdrawn from warfarin.

In the rate control arm of the study, the goals were a ventricular rate of 80 beats per min at rest and
110 beats per minute during a six-minute walk test. At five years, 35 percent of patients were in SR
(compared to 63 percent with rhythm control), while over 80 percent of those still in AF had "adequate
heart rate control." Over 85 percent of patients in the rate control arm were treated with warfarin.
Radiofrequency ablation of the atrioventricular node (AV) was required in 105 patients (5 percent) (see
"Control of ventricular rate in atrial fibrillation: Nonpharmacologic therapy").

In the rhythm control arm of the study, SR was maintained in 82 and 63 percent of patients at one and
five years; only 1 percent underwent nonpharmacologic therapy to maintain rhythm control. The most
frequently used initial antiarrhythmic drugs were amiodarone (38 percent) and sotalol (31 percent). By
the end of 3.5 years of follow-up, 63 percent of patients had had at least one trial of amiodarone.

Among patients initially assigned to rhythm control, crossover to rate control occurred in 17 and 38
percent of patients at one and five years, primarily due to inability to maintain SR and drug
intolerance. In those originally assigned to rate control, the crossover rate to rhythm control was lower
at 8 and 15 percent, primarily due to failure to control symptoms due to AF and heart failure.

After a mean follow-up of 3.5 years, the following findings were observed:

● There was a trend toward a decrease in the rate of occurrence of the primary end point (all-cause
mortality) with rate control (21.3 versus 23.8 percent, hazard ratio [HR] 0.87, 95% CI 0.75-1.01)
(figure 2). There was no difference between the two groups in the incidence of cardiac death,
arrhythmic death, or deaths due to ischemic or hemorrhagic stroke [16]. Two prespecified
subgroups had a significant reduction in mortality with rate control: those without a history of heart
failure (adjusted HR 0.69) and those aged 65 years or older (HR 0.76) [17].

● There was no significant difference in the composite secondary end point of death, ischemic
stroke, anoxic encephalopathy, major bleeding, or cardiac arrest.

● There was no significant difference in global functional status or quality of life in the initial report.

● The number of patients requiring hospitalization during follow-up was significantly lower in the
rate control group than in the rhythm control group (73 versus 80 percent).

A subsequent report provided evidence that the trend toward increased mortality with rhythm control
was due to the deleterious effects of antiarrhythmic drugs [18]. In this analysis, the use of
antiarrhythmic drugs was associated with a significant increase in mortality (HR 1.49), while the
presence of SR was associated with a significant reduction in mortality (hazard ratio 0.53). It could not
be determined if the latter effect was due to SR itself or to AF being a marker for a confounding factor
or factors that affect survival, such as heart failure [19].

RACE trial — The RACE trial enrolled 522 patients (mean age 68) with recurrent persistent AF or
atrial flutter less than one year in duration who had required one to two cardioversions within the prior
two years [4]. (See "Overview of atrial fibrillation", section on 'Classification'.)

Patients were randomly assigned to rate control using the same AV nodal blocking drugs as used in
AFFIRM or to rhythm control. Successful rate control was defined as a ventricular rate below 100
beats/min and no symptoms. Initial therapy for rhythm control was sotalol. If AF recurred within six
months, antiarrhythmic drug therapy was changed; if AF again recurred within six months, amiodarone
was substituted. A late recurrence, after more than six months of therapy, was treated with repeat
cardioversion and continuation of the same antiarrhythmic agent.

The primary end point was a composite of cardiovascular death, admission for heart failure,
thromboembolic event, severe bleeding, pacemaker implantation, or severe side effects from
antiarrhythmic drugs. After a mean 2.3-year follow-up, the following findings were observed:

● Significantly fewer patients were in SR in the rate control group (10 versus 39 percent).
 ● There was an almost significant trend toward a lower incidence of the primary end point with rate
control (17.2 versus 22.6 percent with rhythm control, HR 0.73, 90% CI 0.53-1.01) (figure 3).
There was no difference in cardiovascular mortality (6.8 versus 7 percent). However, there was a
trend toward a higher incidence of nonfatal end points among patients assigned to rhythm control,
including heart failure, thromboembolism, pacemaker insertion, and adverse drug reactions.

● There were no significant differences in quality of life between the rate and rhythm control groups,
a finding similar to that in AFFIRM [20]. Improvement in quality of life was associated with
symptomatic AF at baseline, a short duration of AF, and the presence of SR at the end of follow-
up, rather than the assigned strategy.

It has been thought that restoration and maintenance of SR may be of particular importance in
patients with cardiomyopathy and symptomatic heart failure who have AF, based upon the expectation
that hemodynamics would improve and heart failure would be more easily controlled in such patients if
they were in sinus rhythm. This issue is discussed in detail elsewhere. (See "The management of
atrial fibrillation in patients with heart failure", section on 'Rhythm versus rate control'.)

Limitations of trial data — Limitations of the RACE and AFFIRM trials should be kept in mind:

● The mean ages in AFFIRM and RACE were 70 and 68 years, respectively [3,4]. It is therefore
uncertain if younger healthy patients might benefit from more aggressive rhythm control [21,22].

● Approximately one-half of patients in AFFIRM who had a detailed history had symptomatic
episodes of AF that occurred less often than once per month [23]. Such patients would be
expected to derive little symptomatic benefit from rhythm control, and the results may not directly
apply to patients with frequent episodes of symptomatic AF [19].

● The use of antiarrhythmic drugs in AFFIRM was associated with a significant increase in mortality
(HR 1.49), which was due to non-cardiovascular causes, while the presence of SR was
associated with a significant reduction in mortality (HR 0.53) [16,18]. A similar benefit from being
in sinus rhythm (relative risk 0.44) was noted in the DIAMOND trial that compared dofetilide to
placebo in patients with reduced left ventricular systolic function [24]. (See "The management of
atrial fibrillation in patients with heart failure".)

One interpretation of these data is that maintenance of SR might be beneficial if there were a
safer and more effective approach than current antiarrhythmic drugs [19,25]. (See "Overview of
atrial fibrillation", section on 'Long-term outcome'.)

● The AFFIRM and RACE data were largely gathered before catheter-based pulmonary vein
isolation was common. The potential impact of this procedure (versus chronic antiarrhythmic
therapy) remains incompletely explored. (See "Catheter ablation to prevent recurrent atrial
fibrillation: Clinical applications".)

● Both trials allowed for cessation of anticoagulant therapy four weeks after documentation of SR,
leading to a higher rate of stroke. It has been postulated that continued anticoagulation might
have led to a lower mortality in the rhythm control group [26].

Canadian health care database study — One additional caveat about the RACE and AFFIRM trials
is that, while randomized trials are generally the best study design to compare outcomes with two or
more differing interventions, the generalizability of their results to “real world” populations can be
questioned. For example, risk profiles and adherence to therapy may differ between those enrolled in
randomized trials and those in large observational studies.

Using a population-based database from Quebec, Canada, a 2012 observational study evaluated the
comparative effectiveness in reducing mortality between a rhythm or a rate control strategy in 26,130
patients 66 years or older who were hospitalized with AF [15]. These individuals had not received rate
or rhythm control drugs in the year before hospitalization and received a prescription within seven
days of discharge. After a mean follow-up of 3.1 years, the following findings were noted:

● Death occurred in 49.5 percent of the entire cohort (the mean age at baseline was 79 years).

● Antiarrhythmic medication was prescribed in 24.5 percent.

● During the first six months, there was a small increase in the risk of death for patients treated with
rhythm control (HR 1.07, 95% CI 1.01-1.14).

● Mortality was similar between the two groups until year four. However, the relative risk of death,
comparing rhythm to rate control, fell thereafter and the risk was lower at five and eight years (HR
0.89, 95% CI 0.81-0.96 and 0.77, 95% CI 0.62-0.95, respectively).

CHOICE OF THERAPY — The data from the clinical trials suggest that both rate and rhythm control
are acceptable approaches, with comparable rates of mortality and stroke [11,12,20]. As discussed
below, we prefer a rate-control strategy in most relatively asymptomatic patients with rhythm control in
symptomatic patients.

However, an individual patient may do better with one or the other, and in many cases only after trying
one strategy is utility known. When choosing a strategy, the major factors that should be considered
are the relative ability of each strategy to control symptoms and the relative burdens imposed by each.

Preference for rate control — In most asymptomatic patients with atrial fibrillation (AF), particularly
recurrent AF, we prefer rate control as the initial approach [19,21,22,27]. This is based upon the
following factors:

● The results from AFFIRM and RACE show equivalent and perhaps better outcomes with rate
control (figure 2 and figure 3) as well as a similar requirement for anticoagulation [3,4]. A meta-
analysis of above five trials, in which AFFIRM accounted for 77 percent of the patients, found a
strong trend toward a reduction in all-cause mortality with rate control (13.0 versus 14.6 percent
with rhythm control, odds ratio 0.87, 95% CI 0.74-1.02) [28]. The proportion of patients who had
an ischemic stroke was similar with the two approaches (3.5 versus 3.9 percent).

● Important side effects, especially proarrhythmia, are associated with antiarrhythmic drugs [18,29-
31]. In addition pulmonary vein isolation using radiofrequency catheter ablation is associated with
important complications. (See "Catheter ablation to prevent recurrent atrial fibrillation: Clinical
applications", section on 'Complications'.)

● There is an appreciable rate of recurrent AF and frequent crossover to a rate-control strategy

when antiarrhythmic drugs are used for maintenance therapy after conversion to sinus rhythm
 (SR). Recurrence is detected clinically in 20 to 60 percent at one year (figure 1) [32].
Furthermore, a continuous monitoring study found that recurrent episodes occurred in
approximately 90 percent of patients; many of these episodes were asymptomatic, including
some lasting more than 48 hours [7]. The risk of recurrent AF is highest in patients who have
hypertension, an enlarged left atrium, AF for more than one year, or heart failure [33].

Rate control is generally preferred in symptomatic patients, especially those with heart failure. This
issue is discussed in detail separately. (See "The management of atrial fibrillation in patients with heart
failure", section on 'Rhythm versus rate control'.)

Newly detected AF — We agree with the American Academy of Family Practice/American College
of Physicians guideline recommendation that maintenance antiarrhythmic drug therapy not be
routinely used after cardioversion in patients with their first presentation with AF [21,27]. (See
"Management of new onset atrial fibrillation", section on 'Antiarrhythmic therapy after reversion to
sinus rhythm'.)

Very elderly — Patients over age 80 account for approximately 35 percent of patients with AF and
the prevalence of AF is about 10 percent (figure 4) [34]. These individuals are underrepresented in
clinical trials. Rhythm control is less often preferred in such patients for the following reasons:

● They are more sensitive to the proarrhythmic effects of drugs

● AF is often permanent

Preference for rhythm control — While it seems intuitive that an individual patient would feel better
in SR than in AF (even with rate control) not all such patients feel better. Demonstrating that SR
improves symptoms and quality of life has been difficult for two reasons, related in large part by
limitations of antiarrhythmic drug therapy:

● Limited efficacy: a substantial percentage of patients in whom a rhythm-control strategy is chosen

continue to have AF.

● Side effects: proarrhythmia and inconveniences (eg, monitoring tests and dose adjustments), that
have a negative impact on quality of life.

Among patients in whom SR is successfully maintained, exercise capacity and quality of life are
improved [35,36]. Thus, many experts see the failure to demonstrate improved outcomes with rhythm-
control strategies as a reflection of the inadequacies of available therapies, rather than a clinical
equivalence between AF with rate control and sinus rhythm.

Despite the general preference for a rate-control strategy, and the difficulty in demonstrating improved
outcomes with rhythm control, there are several situations in which rhythm control is preferable [21].

Failure of rate control — There are two manifestations of failure of rate control:

● Persistent symptoms (palpitations, dyspnea, lightheadedness, angina, and near syncope) despite
adequate rate control. (See "Hemodynamic consequences of atrial fibrillation and cardioversion to
sinus rhythm".)

● An inability to attain adequate rate control as defined above. In these patients, alternatives to
 rhythm control with antiarrhythmic drug therapy include radiofrequency ablation of the AV node
with pacemaker insertion or radiofrequency catheter ablation. (See "Control of ventricular rate in
atrial fibrillation: Nonpharmacologic therapy" and "Catheter ablation to prevent recurrent atrial
fibrillation: Clinical applications".)

Younger patients — Younger individuals (less than 65 years), or those who need to carry out
activities requiring optimal cardiac performance, generally do not tolerate AF. When antiarrhythmic
drugs are used in this setting, patients should be well informed of the benefits and risks of this therapy.

Patients early in their natural history — There is some evidence that suggests it is easier to
maintain SR earlier in the natural history of AF [37]. Therefore, patients for whom a rhythm-control
strategy is chosen should have AF restored to SR early once adequate thromboembolic prophylaxis
has been achieved.

We consider cardioversion to SR in most patients (particularly younger patients) with a first episode of
AF in whom the arrhythmia is of recent onset and the risk for recurrence appears to be low based
upon the following findings:

● Left atrial dimension less than 4.5 to 5 cm.

● A reversible underlying disorder such as hyperthyroidism, pericarditis, pulmonary embolism, or
postoperative AF.
● Absence of hypertension.
● Normal left ventricular systolic function.

Cardioversion should only be attempted when the risk of embolization has been lowered to an
acceptable level. (See "Prevention of embolization prior to and after restoration of sinus rhythm in
atrial fibrillation".)

RECOMMENDATIONS OF OTHERS — Recommendations regarding the choice between rate and

rhythm control are available from the American Heart Association/American College of Cardiology
(2014) and the European Society of Cardiology (2016) [38-40].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from

selected countries and regions around the world are provided separately. (See "Society guideline
links: Atrial fibrillation" and "Society guideline links: Arrhythmias in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The
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the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have
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sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and
are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-
mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on “patient info” and the keyword(s) of interest.)
 ● Beyond the Basics topic (see "Patient education: Atrial fibrillation (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● For each patient with atrial fibrillation (AF), the two principal goals of therapy are symptom control
and the prevention of thromboembolism. (See "Atrial fibrillation: Anticoagulant therapy to prevent
embolization" and "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus
rhythm", section on 'Adverse hemodynamics in AF'.)

● Rhythm- and rate-control strategies are associated with similar rates of mortality and serious
morbidity, such as embolic risk, which is best addressed using anticoagulation based on the
CHADS2 or CHA2DS2-VASc criteria. (See 'Thromboembolic risk' above.)

In addition, assessments of quality of life have not shown significant differences between the two
in most studies. (See 'Definitions' above.)

A rate-control strategy generally uses drugs that block the atrioventricular (AV) node, such as
beta blockers, rate-slowing calcium channel blockers, or digoxin. AV nodal ablation plus
ventricular pacing is another option.

The principal reasons to prefer a rate-control strategy include simplification of the medical
regimen, lower cost, and less concern about the risks of antiarrhythmic drug therapy (such as
torsades de pointes) or radiofrequency catheter ablation. (See 'Preference for rate control'
above.)

● Patients managed by either rate or rhythm control must be assessed for their thromboembolic
risk. Therapy should be initiated when appropriate. (See 'Thromboembolic risk' above.)

● For asymptomatic or mildly symptomatic AF patients who are 65 years or older, we suggest a
rate-control as opposed to a rhythm-control strategy using medical therapy (Grade 2B). This
recommendation places a high priority on concerns about side effects of antiarrhythmic drug
therapy or radiofrequency catheter ablation. Patients for whom a rhythm-control strategy may be
reasonable include those who continue with clinically significant symptoms on a rate-control
strategy. (See 'Preference for rate control' above.)

● For most patients with AF younger than age 65, particularly those who are symptomatic, we
suggest a rhythm control as opposed to a rate-control strategy (Grade 2B). This recommendation
places a high priority on relief of symptoms as well as the potential, but as of yet unproven
benefit, from remaining in sinus rhythm over long periods of time. For younger, asymptomatic
patients who are concerned about the potential side effects of antiarrhythmic drug therapy, and
who are not inclined to undergo radiofrequency catheter ablation, a rate-control strategy is
reasonable. In these patients, an informed discussion of the benefits and risks of antiarrhythmic
drug therapy is critically important. (See 'Preference for rhythm control' above.)

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mortality on dofetilide (diamond) substudy. Circulation 2001; 104:292.
25. Waldo AL. A perspective on antiarrhythmic drug therapy to treat atrial fibrillation: there remains
an unmet need. Am Heart J 2006; 151:771.
26. Dewland TA, Marcus GM. Rate vs rhythm control in atrial fibrillation: can observational data
trump randomized trial results? Arch Intern Med 2012; 172:983.
27. McNamara RL, Tamariz LJ, Segal JB, Bass EB. Management of atrial fibrillation: review of the
evidence for the role of pharmacologic therapy, electrical cardioversion, and echocardiography.
Ann Intern Med 2003; 139:1018.
28. de Denus S, Sanoski CA, Carlsson J, et al. Rate vs rhythm control in patients with atrial
fibrillation: a meta-analysis. Arch Intern Med 2005; 165:258.
29. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of
Patients With Atrial Fibrillation A Report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines and the European Society of Cardiology
Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the
Management of Patients With Atrial Fibrillation). J Am Coll Cardiol. 2006; 48:e149.
30. Coplen SE, Antman EM, Berlin JA, et al. Efficacy and safety of quinidine therapy for
maintenance of sinus rhythm after cardioversion. A meta-analysis of randomized control trials.
Circulation 1990; 82:1106.
31. Flaker GC, Blackshear JL, McBride R, et al. Antiarrhythmic drug therapy and cardiac mortality in
atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators. J Am Coll Cardiol 1992;
20:527.
32. Roy D, Talajic M, Dorian P, et al. Amiodarone to prevent recurrence of atrial fibrillation. Canadian
Trial of Atrial Fibrillation Investigators. N Engl J Med 2000; 342:913.
 33. Dittrich HC, Erickson JS, Schneiderman T, et al. Echocardiographic and clinical predictors for
outcome of elective cardioversion of atrial fibrillation. Am J Cardiol 1989; 63:193.
34. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national
implications for rhythm management and stroke prevention: the AnTicoagulation and Risk
Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001; 285:2370.
35. Chung MK, Shemanski L, Sherman DG, et al. Functional status in rate- versus rhythm-control
strategies for atrial fibrillation: results of the Atrial Fibrillation Follow-Up Investigation of Rhythm
Management (AFFIRM) Functional Status Substudy. J Am Coll Cardiol 2005; 46:1891.
36. Singh SN, Tang XC, Singh BN, et al. Quality of life and exercise performance in patients in sinus
rhythm versus persistent atrial fibrillation: a Veterans Affairs Cooperative Studies Program
Substudy. J Am Coll Cardiol 2006; 48:721.
37. Cosio FG, Aliot E, Botto GL, et al. Delayed rhythm control of atrial fibrillation may be a cause of
failure to prevent recurrences: reasons for change to active antiarrhythmic treatment at the time
of the first detected episode. Europace 2008; 10:21.
38. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of
patients with atrial fibrillation: a report of the American College of Cardiology/American Heart
Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014;
130:e199.
39. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of
patients with atrial fibrillation: executive summary: a report of the American College of
Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm
Society. Circulation 2014; 130:2071.
40. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial
fibrillation developed in collaboration with EACTS. Eur Heart J 2016; 37:2893.

Topic 1045 Version 20.0

GRAPHICS

The rate of recurrent atrial fibrillation is lowest with amiodarone

The Canadian Trial of Atrial Fibrillation randomized 403 patients with at least one episode of
atrial fibrillation (AF) during the prior six months to low-dose amiodarone, propafenone, or
sotalol. After a mean follow-up of 16 months, the likelihood of being free from recurrent AF
was highest with amiodarone (65 versus 37 percent for sotalol and propafenone) and the
median time to recurrence was longer (>468 versus 98 days).

Data from: Roy D, Talajic M, Dorian P, et al. N Engl J Med 2000; 342:913.

Graphic 69285 Version 3.0

Rate control versus rhythm control in AFFIRM

Results of the AFFIRM trial in which 4060 patients with atrial fibrillation (AF) that
was likely to be recurrent were randomly assigned to rhythm or rate control. The
primary end point was overall mortality. There was an almost significant trend
toward lower mortality with rate control (21.3 versus 23.8 percent, hazard ratio
0.87, 95 percent CI 0.75 to 1.01).

Data from Wyse DG, Waldo AL, DiMarco JP, et al. N Engl J Med 2002; 347:1825.

Graphic 61608 Version 3.0

Rate control versus rhythm control in RACE

Results of the RACE trial in which 522 patients with recurrent persistent atrial
fibrillation (AF) were randomly assigned to rhythm or rate control. The primary
end point was a composite of cardiovascular death, heart failure,
thromboembolism, bleeding, pacemaker placement, and antiarrhythmic drug
side effects. There was an almost significant trend toward a lower incidence of
the primary end point with rate control (17.2 versus 22.6 percent with rhythm
control, hazard ratio 0.73, 90 percent CI 0.53 to 1.01).

Data from Van Gelder IC, Hagens VE, Bosker HA, et al. N Engl J Med 2002;
347:1834.

Graphic 74434 Version 3.0

Prevalence of atrial fibrillation with age

In a cross-sectional study of almost 1.9 million men and women, the prevalence of atrial
fibrillation increases with age, ranging from 0.1 for those <55 years of age to over 9
percent in those ≥85 years of age. At all ages, the prevalence is higher in men than
women.

Data from Go AS, Hylek EM, Phillips K, et al. Prevalence of diagnosed atrial fibrillation in adults:
National implications for rhythm management and stroke prevention: The AnTicoagulation and
Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001; 285:2370.

Graphic 77268 Version 5.0

Contributor Disclosures
Kapil Kumar, MD Speaker’s Bureau: St. Jude Medical [ICD therapy, CRT implantation, atrial flutter
ablation (Pacemakers, ICDs, ablation catheters, EP mapping system)]. Warren J Manning,
MD Patent Holder: Samsung Electronics [MRI]. Equity Ownership/Stock Options: Pfizer
[Anticoagulants]. Equity Ownership/Stock Options (Spouse): General Electric [Cardiac
imaging]. Peter J Zimetbaum, MD Consultant/Advisory Boards: Medtronic [Atrial fibrillation
(Linq)]. Gordon M Saperia, MD, FACC Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found,
these are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

 Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Control of ventricular rate in atrial fibrillation: Pharmacologic therapy

Author: Leonard I Ganz, MD, FHRS, FACC

Section Editor: Bradley P Knight, MD, FACC
Deputy Editor: Gordon M Saperia, MD, FACC

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2017. | This topic last updated: Apr 13, 2016.

INTRODUCTION — In patients with atrial fibrillation (AF), the ventricular rate is controlled by the conduction properties of
the atrioventricular (AV) node. In the typical patient with untreated AF, the ventricular rate can reach 150 beats/min or
higher.

The use of pharmacologic therapies to achieve rate control in AF will be reviewed here. Nonpharmacologic therapies for
rate control in AF are discussed separately. (See "Control of ventricular rate in atrial fibrillation: Nonpharmacologic
therapy".)

RATIONALE — There are two established reasons to prevent a rapid ventricular response in patients with atrial fibrillation:

● Avoidance of hemodynamic instability and/or symptoms. (See "Hemodynamic consequences of atrial fibrillation and
cardioversion to sinus rhythm".)

● Avoidance of a tachycardia-mediated cardiomyopathy. (See "Arrhythmia-induced cardiomyopathy".)

In addition, there is some evidence to suggest a mortality benefit from rate control. In a large, population-based cohort study
in Taiwan, mortality in individuals receiving beta blockers (43,879), nondihydropyridine calcium channel blockers (18,466),
and digoxin (38,898) was compared with mortality in individuals not taking a rate control drug. Patients were excluded if
they were taking more than one rate slowing drug. After adjustment for baseline differences, the risk of death was lower in
patients receiving beta blockers (adjusted hazard ratio [HR] 0.76, 95% CI 0.74-0.78) and calcium channel blockers
(adjusted HR 0.93, 95% CI 0.90-0.96). However, the risk of death was higher in the group receiving digoxin (adjusted HR
1.12, 95% CI 1.10-1.14). We recommend caution in applying to clinical practice the findings in this non-randomized study.

GENERAL PRINCIPLES — The initial management of patients with atrial fibrillation (AF) and a rapid ventricular response
involves two decisions:

● Determining the urgency of initial therapy (eg, intravenous versus oral rate control therapy, and/or immediate versus
elective cardioversion).

● Choosing between a rate control and a rhythm control strategy. (See "Rhythm control versus rate control in atrial
fibrillation".)

These decisions are not independent, and the options are not mutually exclusive. As an example, a patient for whom rate
control may be the appropriate long-term strategy may require urgent cardioversion in the acute setting due to
hemodynamic instability. On the other hand, a patient for whom a chronic rhythm control strategy is chosen may require
initial rate control for three to four weeks to permit appropriate anticoagulation prior to cardioversion. (See "Overview of
atrial fibrillation", section on 'Treatment issues'.)

When a rate control strategy is chosen, most patients can be successfully managed with pharmacologic therapy. Selection
of an appropriate regimen is guided by an understanding of the determinants of the ventricular rate in AF and a structured
method for assessing the adequacy of rate control.

Determinants of ventricular rate — During AF, electrical activity in the atria can exceed 400 beats/min. The majority of
these impulses do not conduct to the ventricles because of the electrical properties of the atrioventricular (AV) node. (See
"Mechanisms of atrial fibrillation", section on 'Role of the atrioventricular node'.)

AV nodal tissue consists of so-called "slow response" fibers. In most myocardial tissue, the initial depolarizing phase of the
action potential (phase 0) is mediated by rapid sodium channels. In contrast, in the slow response fibers of the AV node,
phase 0 is mediated by an inward calcium current, which uses a kinetically slow channel. (See "Myocardial action potential
and action of antiarrhythmic drugs".)

The relatively slow kinetics of the inward calcium current limits conduction velocity through the AV node, and therefore the
ventricular rate during AF. In addition to these intrinsic properties, the AV node is also richly supplied and affected by both
components of the autonomic nervous system. AV conduction is enhanced by sympathetic fibers and slowed by
parasympathetic fibers (figure 1).

In the typical patient with untreated AF, the ventricular rate during the day varies between 90 and 170 beats/min. The
ventricular rate may be slower (eg, less than 60 beats/min) in the following settings:

● Increased vagal tone.

● Drugs that affect AV nodal conduction.
● AV nodal disease, which should be suspected if the ventricular rate is below 60 beats/min in the absence of a drug that
slows AV conduction.

A ventricular rate above 200 beats/min suggests one of the following:

● Catecholamine excess
● Parasympathetic withdrawal
● Hyperthyroidism
● An accessory pathway as occurs in the preexcitation syndrome. (See "Atrioventricular reentrant tachycardia (AVRT)
associated with an accessory pathway".)

Rate control goals — The optimal rate goal for patients with AF has not been determined [1]. Achieving rates similar to
those recommended for patients in sinus rhythm with heart disease has been advocated: resting heart rate ≤80 beats/min
and ≤110 beats/min during moderate exercise such as with the six-minute walk. Goals similar to these were used in many of
the trials of rate versus rhythm control, such as AFFIRM [2]. (See "Rhythm control versus rate control in atrial fibrillation".)

This issue was directly addressed in the RACE II trial, which randomly assigned 614 physically active patients with
permanent AF to either a lenient rate control strategy (resting heart rate <110 beats per minute) or a strict rate control
strategy (resting heart rate <80 beats per minute and heart rate during moderate exercise <110 beats per minute) [3]. The
primary outcome was a composite of cardiovascular death, hospitalization for heart failure, and stroke, systemic embolism,
bleeding, and life-threatening arrhythmic events. The following findings were noted:

● With regard to the three-year estimated cumulative incidence of the primary outcome, lenient control was non-inferior to
strict rate control (12.9 versus 14.9 percent, respectively; hazard ratio 0.84; 90% CI 0.58-1.21).

● In the lenient and strict rate control groups, 98 and 75 percent of patients, respectively, met their resting heart rate
target. This target required use of more than one rate slowing agent (AV blocking) in 30 and 69 percent of patients,
respectively. When the data were analyzed from the end of the dose-adjustment phase until the end of follow-up
(median 2.9 years), the average heart rates in the lenient control group, strict control group patients who met the target,
and strict control group patients who failed to meet the target were significantly different at 93, 72, and 86 beats per
minute, respectively [4]. However, there was no significant difference in the primary outcome (12.1 versus 14.2 versus
15 percent).

● There were nearly nine times as many visits (684 versus 75) to achieve rate the control target(s) in those assigned to
strict control. Rate control was “stricter” than anticipated in the lenient control group. Though the target rate was less
than 110 beats per minute at rest, mean resting rates in this group at the after one year, two years, and at the end of
follow-up were 86+15, 84+14, and 85+14 beats per minute, respectively. By comparison, mean resting rates in the
strict control group were 75+12, 75+12, and 76+14 beats per minute, respectively.

The results of the RACE II trial must be tempered given that the lenient control group was in fact treated more aggressively
than the protocol required. In addition, RACE II included only patients with permanent AF, so extrapolation to patients with
paroxysmal AF is difficult.

Based upon the results of the RACE II trial, we believe that achieving strict heart rate control may not be necessary in many
physically active patients with AF who are minimally symptomatic. A more lenient rate control strategy offers the advantages
of less medication (fewer drug side effects, lower cost) and fewer outpatient visits to achieve heart rate control. For patients
in whom a lenient strategy is chosen, we suggest a goal of less than 85 beats per minute (85 beats per minute was the
mean in the lenient group in RACE II).

The prevention of symptoms during normal activities or exercise is a primary goal of therapy. It is important to consider that
symptoms may be due to either inadequate rate control or relative bradycardia (eg, in patients with tachy-brady syndrome).
(See "Sick sinus syndrome: Epidemiology, etiology, and natural history".)

Thus, for those patients in whom a lenient strategy is chosen but who remain symptomatic, an attempt should be made to
decrease symptoms by setting a lower rate goal.

Documenting rate control — In practice, the efficacy of heart rate control therapy can be assessed by measurement of
both the resting heart rate and use of either a six-minute walk test (at moderate exercise) or submaximal or maximal
exercise electrocardiogram (ECG) testing. A 24-hour ambulatory monitor can also be used to evaluate efficacy. For young
active patients, we recommend either an exercise ECG test or a Holter during exercise. For older or sedentary patients,
measuring heart rate after walking briskly around the office or up stairs may provide sufficient information.

Tachycardia-mediated cardiomyopathy — Persistently increased ventricular rates in AF have been associated with a
left ventricular cardiomyopathy. (See "Arrhythmia-induced cardiomyopathy".)

While this issue has not been well studied, we believe that this phenomenon is unlikely to occur if the ventricular rate is kept
below 110 beats/min, which is the recommended heart rate goal. Some experts perform an echocardiogram every two to
three years in asymptomatic patients with higher average ventricular rates while others do not.

Urgency of therapy — In a patient with new or recurrent AF with a rapid ventricular response, the intensity of initial therapy
depends upon the clinical scenario:

● Emergent therapy – In patients who are clinically or hemodynamically unstable (eg, myocardial ischemia, pulmonary
edema, hypotension) due to AF and a rapid ventricular response, treatment options include intravenous rate control
medications and/or immediate cardioversion. In patients with an adequate blood pressure, pharmacologic rate control
with intravenous calcium channel blockers or beta blockers may be attempted, while arrangements are made for
cardioversion. If the patient responds to rate control therapy but remains unstable, an explanation other than AF with a
rapid ventricular response should be sought. (See "Atrial fibrillation: Cardioversion to sinus rhythm".)

● Urgent therapy – In patients with AF and a rapid ventricular response who are symptomatic but not unstable, initial
therapy usually involves intravenous rate control medications. Patients who are chronically managed with a rhythm
control strategy can undergo cardioversion if they have been adequately anticoagulated or are considered to have a
low thromboembolic risk.

● Elective therapy – Patients who have mild or no symptoms, and whose ventricular rate is mildly to moderately elevated
(eg, ≤120 beats/min) can be managed with the addition or increase of oral rate control medications.

Rhythm versus rate control — The two main therapeutic strategies in patients with AF are:

● Rhythm control, which consists of cardioversion, often followed by maintenance of sinus rhythm with arrhythmic drugs.

● Rate control, usually with drugs that slow conduction through the AV node.

In the past, many physicians preferred a rhythm control strategy because of presumed improvements in symptoms,
hemodynamics, and embolic risk. However, the expected advantages of rhythm control were not confirmed in AFFIRM,
RACE, and other randomized trials [2,5]. As a result, a rate control strategy is now preferred in most asymptomatic patients
[6,7]. The data supporting this conclusion are discussed in detail separately. (See "Rhythm control versus rate control in
atrial fibrillation".)

Caution in preexcitation syndrome — Among patients with AF and preexcitation, initial therapy is aimed at reversion to
sinus rhythm. Intravenous procainamide or ibutilide should be given if hemodynamics are stable, and direct current
cardioversion should be performed if the patient is unstable.

The AV nodal blocking drugs (calcium channel blockers, beta blockers, and digoxin) can paradoxically increase the
ventricular response in patients with AF and preexcitation by impairing conduction via the normal AV node-His-Purkinje
system. This decreases retrograde concealed conduction in the accessory pathway, thereby improving antegrade
conduction over the pathway. Intravenous adenosine, amiodarone, digoxin, verapamil, and diltiazem are therefore
contraindicated with pre-excited AF; data are limited with intravenous beta blockers but theoretically pose the same risk.
(See "Treatment of symptomatic arrhythmias associated with the Wolff-Parkinson-White syndrome", section on 'Avoidance
of AV nodal blockers'.)

Long-term therapy in preexcited AF includes ablation of the accessory pathway. (See "Treatment of symptomatic
arrhythmias associated with the Wolff-Parkinson-White syndrome", section on 'Catheter ablation'.)

PHARMACOLOGIC TREATMENT — The ventricular rate in atrial fibrillation (AF) is slowed using beta blockers or calcium
channel blockers, and to a lesser extent digoxin or amiodarone. These agents slow atrioventricular (AV) nodal conduction
based upon the following physiologic mechanisms (figure 2) [8,9]:

● Blockade of the calcium channel with the nondihydropyridine calcium channel blockers verapamil and diltiazem.

● Decreased sympathetic tone resulting from beta blockers.

● Enhancement of parasympathetic tone with vagotonic drugs, the most important of which is digoxin.

Beta blockers — Beta blockers are commonly used for both the acute and chronic control of ventricular rates in patients
with AF.

Acute control with beta blockers — For the acute control of ventricular rate, intravenous beta blockade with
metoprolol, propranolol, or esmolol can be effective. Beta blockers may be particularly useful in states of high adrenergic
tone (eg, postoperative AF).

Metoprolol is given as an intravenous bolus of 2.5 to 5.0 mg over two minutes. The dose may be repeated at five-minute
intervals up to a total of 15 mg as needed. While subsequent doses can be given intravenously, the optimal regimen is not
well defined, and oral administration is preferable.

Esmolol is a rapidly acting intravenous beta blocker that is metabolized by red blood cell esterase, resulting in a short
duration of action (10 to 20 minutes) [10-12]. Esmolol may be particularly useful if it is uncertain that a beta blocker will be
tolerated, since its short half-life permits a therapeutic trial to be performed at reduced risk. If esmolol is tolerated, then a
long-acting beta blocker can be given.

The following esmolol regimen is recommended for acute rate control:

● A bolus of 0.5 mg/kg is infused over one minute, followed by 50 µg/kg per min.
● If, after four minutes, the response is inadequate, another bolus is given followed by an infusion of 100 µg/kg per min.
● If, after four minutes, the response is still inadequate, a third and final bolus can be given followed by an infusion of 150
µg/kg per min.
● If necessary, the infusion can be increased to a maximum of 200 µg/kg per min after another four minutes.

Alternatively, an infusion can be started at 50 µg/kg per min without a bolus, and the rate of administration can be increased
by 50 µg/kg per min every 30 minutes.

Intravenous propranolol, 1 mg over one minute, can be given and repeated up to three doses at two-minute intervals.

Chronic beta blocker therapy — Oral beta blockers are widely used as primary therapy for rate control in chronic AF
(table 1). Beta blockers decrease the resting heart rate and blunt the heart rate response to exercise. Most beta blockers
appear to have similar efficacy, although atenolol, metoprolol, timolol, pindolol, and nadolol have the most supporting
evidence. There are some data that labetalol is less effective than other beta blockers for reducing heart rate at rest [7].
Bisoprolol and carvedilol are also used.

Atenolol and nadolol have the advantages of a long half-life and are typically given once daily. In our experience, atenolol
has the additional advantage of producing less central nervous system side effects than other beta blockers. Long-acting
propranolol and metoprolol preparations are also effective if tolerated. We generally begin with 25 mg of atenolol per day
and gradually increase the daily dose to 100 mg, and sometimes 200 mg, if necessary.

Beta blockers have additional properties that may make them preferred to other rate control drugs in some AF patients:

● Patients with chronic heart failure due to systolic dysfunction – A retrospective analysis from the United States
Carvedilol Trials Program evaluated 1094 heart failure patients with AF [13]. In this population, carvedilol therapy led to
a statistically significant improvement in left ventricular ejection fraction. In addition, there was a trend toward a
decrease in the combined end point of death or hospitalization for heart failure. (See "The management of atrial
fibrillation in patients with heart failure" and "Use of beta blockers in heart failure with reduced ejection fraction".)

● Beta blockers may reduce the incidence of AF recurrence in patients with episodes of AF that are triggered by surges
in sympathetic activity [14].

Beta blockers also have a variety of adverse effects. Some of these complications that may be important in patients with AF
include (see "Major side effects of beta blockers"):

● Worsening heart failure

● Hypotension
● Bronchospasm
● Reduced exercise tolerance [15,16]
● High-degree AV block
● Bradycardia

Some patients with paroxysmal AF also have sinus node dysfunction, with the tachycardia-bradycardia syndrome. In such
patients, beta blockers with intrinsic sympathomimetic activity may be useful since they are less likely to worsen bradycardia
than standard beta blockers (table 1). (See "Sick sinus syndrome: Epidemiology, etiology, and natural history".)

Calcium channel blockers — The nondihydropyridine calcium channel blockers verapamil and diltiazem are useful in the
management of AF in the absence of preexcitation. These drugs can be used intravenously for acute rate control and can
produce long-term rate slowing when used orally. (See "Calcium channel blockers in the treatment of cardiac arrhythmias".)

● Verapamil increases refractoriness and decreases conduction velocity in the AV node [17-24]. Although it is often used
in combination with digoxin, monotherapy with oral verapamil is often possible [22-24].

● Diltiazem may have a less pronounced negative inotropic effect than verapamil [25]. The intravenous preparation is
effective for acute control of the ventricular rate in AF [26-28], while oral therapy is effective for chronic rate control
[29,30].

Acute control with calcium channel blockers — We prefer intravenous diltiazem to intravenous verapamil. However,
intravenous verapamil can be given acutely in a dose of 5 to 10 mg over two to three minutes; this dose can be repeated
every 15 to 30 minutes, as necessary. Once rate control is achieved with intravenous bolus (often one or two are
necessary), we start a maintenance infusion at a rate of 5 mg/hour; higher infusion rates, perhaps up to 20 mg per hour,
may be necessary for rate control [31,32]. The onset of action is within two minutes and the peak effect occurs in 10 to 15
minutes. Control of the ventricular response is lost in approximately 90 minutes if repeated boluses or a maintenance
infusion are not given.

The suggested regimen for intravenous diltiazem is derived from the Diltiazem Atrial Fibrillation/Atrial Flutter Study Group
[26-28]. Diltiazem is given as an intravenous bolus of 0.25 mg/kg (average adult dose 20 mg) over two minutes; in 15
minutes, if the first dose is tolerated but does not produce the desired response (20 percent reduction in heart rate from the
baseline or a heart rate less than or equal to 100 beats/min) a second bolus of 0.35 mg/kg (average adult dose 25 mg) is
given over two minutes; in those who respond to the first or second bolus, a continuous infusion at a rate of 5 to 15 mg/h is
initiated. This regimen usually controls the ventricular rate within four to five minutes.

The efficacy of this regimen was evaluated in a report of 84 consecutive patients with AF, atrial flutter, or both [28]. The
following findings were noted:
 ● The overall response rate was 94 percent.

● The continuous infusion maintained adequate rate control for 10 hours or longer in a dose-dependent fashion – 47
percent at 5 mg/h; 68 percent after titration to 10 mg/h; and 76 percent after titration to 15 mg/h (figure 3).

● Hypotension occurred in 13 percent and was symptomatic in almost 4 percent. All such patients responded to isotonic
saline.

Chronic calcium channel blocker therapy — The initial dose of oral verapamil is 40 mg three or four times per day
increased to a maximum of 360 mg/day in divided doses. The equivalent dose of sustained release verapamil can be used
once per day, but a divided dose often must be used to maintain rate control.

Oral diltiazem is started at 30 mg four times daily. The usual maximum dose is a total of 360 to 480 mg daily (ie, 90 to 120
mg four times per day). For conversion to the sustained release form of diltiazem, the same total daily dose is given in a
single tablet or divided into two doses.

Clinical cautions — Calcium channel blockers have a number of characteristics that need to be considered when they
are administered to patients with AF:

● The effect on sinoatrial (SA) nodal function is variable. Although both verapamil and diltiazem have an inhibitory effect
on the sinus node, their vasodilator effects cause a reflex release of catecholamines that usually maintains or slightly
accelerates the SA nodal rate. However, patients with the sick sinus syndrome may be particularly sensitive to the
effects of calcium channel blockers. (See "Sick sinus syndrome: Epidemiology, etiology, and natural history".)

● Both verapamil and diltiazem have negative inotropic effects, although this is less pronounced with diltiazem. As a
result, these drugs should be used with caution in patients with heart failure and in patients taking other negative
inotropes, such as beta blockers. They should not be given if the patient is hypotensive.

● Verapamil interacts with digoxin, resulting in an increase in serum digoxin. This interaction is dose-related (often
occurring when verapamil doses are over 240 mg/day) and generally occurs after seven days of therapy with both
agents. Similar to the digoxin-quinidine interaction, verapamil reduces the renal clearance of digoxin; it may also
interfere with its hepatic metabolism [33-35].

● With either verapamil or diltiazem, it should be remembered that older patients are more likely to develop side effects,
especially cardiac. Although the same maximum doses may be tolerated, it is usually appropriate to titrate more slowly.

In summary, diltiazem and verapamil should not be given to patients with severe heart failure (New York Heart Failure class
III or IV), the preexcitation syndrome, or significant hypotension. In addition, these drugs should be given with caution to
patients with sinus node dysfunction, significant liver disease, mild hypotension, marked first-degree heart block, or the
concurrent intake of other drugs that inhibit SA nodal function or slow AV nodal conduction.

Digoxin — We generally reserve digoxin for patients whose rate has not adequately been controlled with the use of a beta
blocker and/or a calcium channel blocker. It is not as effective as these two categories of drug and there is some concern
about its use being associated with higher mortality. It may not be appropriate for use in older patients.

Older, small observational studies and post-hoc analyses of clinical trials have reached differing conclusions, with some
showing an increase in mortality [36-38] and others not [39,40]. Similarly, more contemporary large observational studies
have reached differing conclusions, with at least two finding an increase in all-cause mortality of about 20 percent [41,42]
and one finding no increase [43].

Although the mechanism by which digoxin could increase mortality, if real, is not known, there is a concern it might be linked
to higher serum concentrations. Our recommendations for dosing are discussed below. (See 'Dosing and monitoring'
below.)

There are additional reasons that digoxin should not be used as a first-line drug for rate control in most settings [44,45].
Digoxin slows the ventricular rate during AF primarily by vagotonic inhibition of AV nodal conduction. Digoxin is generally
less effective for rate control than beta blockers or calcium channel blockers, particularly during exercise when vagal tone is
low and sympathetic tone is high [10,17,18,46-51]. (See 'Comparative efficacy' below.) Furthermore, digoxin has no ability to
terminate AF.
The use of digoxin in patients with AF and heart failure is discussed separately. (See "The management of atrial fibrillation
in patients with heart failure", section on 'Rate control'.)

Left ventricular dysfunction — In patients with heart failure due to systolic dysfunction and AF, digoxin has two
potential benefits: reduction in the ventricular rate and improvement in contractility. For these reasons, digoxin was in the
past considered a reasonable first-line therapy for rate control in such patients [48,52]. However, beta blockers, if tolerated,
are now a standard component of therapy for all patients with heart failure due to systolic dysfunction. (See "Pharmacologic
therapy of heart failure with reduced ejection fraction", section on 'Beta blocker'.)

Thus, in patients with left ventricular dysfunction, the use of digoxin is limited to the following settings (see "The
management of atrial fibrillation in patients with heart failure"):

● Patients who do not achieve rate control targets on beta blockers alone.

● Patients who cannot tolerate the addition of or increased doses of a beta blocker due to acute decompensated heart
failure.

● Patients in whom digoxin would be added for improved control of heart failure symptoms independent of AF. Many such
patients will already be treated with a beta blocker, and care must be taken to avoid excessive bradycardia. (See "Use
of digoxin in heart failure with reduced ejection fraction", section on 'Summary and recommendations'.)

Dosing and monitoring — Digoxin can be administered orally, intravenously, or intramuscularly, although we do not use
the intramuscular route because absorption is erratic. Intravenous digoxin begins to act within 15 to 30 minutes, with a peak
effect attained in one to five hours. (See "Treatment with digoxin: Initial dosing, monitoring, and dose modification".)

If digoxin is used, levels should be obtained periodically. Although the correlation between drug concentration and
ventricular rate control is poor, the presence of a low serum digoxin concentration is useful in that it allows a higher dose to
be administered. However, because of concerns about an increase in mortality in patients taking the drug, we attempt to
keep the level below 1.0 ng/mL (1.28 nmol/L). (See 'Digoxin' above.)

Junctional escape beats (detected by the equality of all of the longest observed R-R intervals on the electrocardiogram) are
common when digitalis has successfully slowed the ventricular rate. Giving more digoxin in this setting will increase the
degree of AV nodal block and produce periods of a regular junctional escape rhythm. The change from single junctional
escapes to periodic junctional rhythm usually signifies the development of digoxin toxicity. AF with a slow, regular ventricular
response generally reflects complete AV block, which may be due to digoxin excess. (See "The electrocardiogram in atrial
fibrillation", section on 'Effect of high degrees of AV nodal block and exit block on ventricular response'.)

Amiodarone — Amiodarone is commonly used to maintain sinus rhythm in AF patients in whom a rhythm control strategy is
chosen. However, amiodarone can also slow the ventricular rate in patients who remain in AF. In one study, for example,
intravenous amiodarone (7 mg/kg), flecainide, or placebo was given to 98 patients with recent onset AF (0.5 to 72 hours)
[53]. Even when AF did not revert to sinus rhythm, amiodarone promptly slowed the ventricular rate during the eight-hour
observation period (figure 4). In addition, in critically ill patients, amiodarone may be less likely to cause systemic
hypotension than intravenous diltiazem [54].

Because of the long-term risk of side effects, the 2014 American Heart Association/American College of Cardiology/Heart
Rhythm Society AF guideline states that amiodarone can be used as second-line therapy for chronic rate control only when
other therapies are unsuccessful or contraindicated [44,45]. We agree with this very limited role for amiodarone as a chronic
rate control agent and recommend that patients treated with amiodarone receive careful follow-up, including monitoring for
known side effects. (See "Monitoring and management of amiodarone side effects".)

Magnesium sulfate — Magnesium has physiologic properties suggesting that it might have efficacy for rate control in AF.
Initial small studies provided the rationale for a clinical trial in which 199 patients presenting with rapid AF (mean baseline
ventricular rate 142 beats per min) were treated with usual therapy for rate control, most often digoxin, and randomly
assigned to intravenous magnesium sulfate (2.5 g over 20 minutes followed by 2.5 g over two hours) or placebo [55].
Magnesium therapy increased the likelihood of achieving a ventricular rate <100 beats/min (65 versus 34 percent with
placebo) and conversion to sinus rhythm (27 versus 12 percent with placebo). However, the difference in mean ventricular
rate never exceeded 12 beats/min.
Important limitations to the results of the study include the following:

● The benefit of magnesium was modest.

● Preferred primary therapies (calcium channel blocker, beta blocker) were used in only 12 to 13 percent of the patients.

● Magnesium was associated with side effects such as flushing and hypotension.

COMPARATIVE EFFICACY — There are few studies directly comparing the efficacy of these drugs. In general, calcium
channel blockers are effective at rest and during exercise, beta blockers are similarly effective at rest, but more effective
during exercise, and digitalis is reasonably effective at rest but less effective than the other drugs during exercise. Thus, it is
particularly important to assess heart rate with exertion in patients treated with digoxin alone.

In a small crossover study of 12 patients with chronic AF, patients were treated for two-week intervals with five different drug
regimens: digoxin 0.25 mg daily, diltiazem-CD 240 mg daily, atenolol 50 mg daily, digoxin plus diltiazem, and digoxin plus
atenolol [46]. Digoxin plus atenolol was the most effective regimen for controlling the mean ventricular rate and reducing the
peak heart rate during exercise; digoxin and diltiazem as single agents were the least effective (figure 5).

AFFIRM trial — Among evaluations of rate control drugs, the study with the largest sample size and longest follow-up is a
post-hoc analysis from the AFFIRM trial [56]. In AFFIRM, which compared rate control and rhythm control strategies, 2027
patients were randomly assigned to the rate control arm. Adequate rate control at rest and exercise was defined according
to predetermined criteria. (See 'Rate control goals' above.)

The overall effectiveness (meeting both rest and exertion goals) of initial therapy was as follows:

● Beta blocker alone – 59 percent

● Calcium channel blocker alone – 38 percent
● Digoxin alone – 58 percent
● Beta blocker plus digoxin – 68 percent
● Calcium channel blocker plus digoxin – 60 percent
● Beta blocker plus calcium channel blocker – 59 percent
● Beta blocker plus calcium channel blocker plus digoxin – 76 percent

At five-year follow-up, adequate rate control increased from approximately 60 to 80 percent of patients. Only 58 percent of
patients had adequate rate control with the first drug or combination used. Patients initially treated with a beta blocker were
significantly less likely than those treated with calcium channel blockers or digoxin to have their drug regimen changed.

Several important limitations to this study need to be considered:

● Once randomized to the rate control arm of the trial, drug selection was not randomized. There were significant
differences between patients treated with different regimens; beta blockers were more commonly used in patients with
coronary disease, calcium channel blockers were more often given to patients with pulmonary disease and to women,
while digoxin was used more often in patients with cardiomyopathy and in nonwhite patients. Whether these baseline
differences had an impact on the adequacy of rate control is not known.

● Only 361 (18 percent) of the patients assigned to the rate control strategy had an initial assessment of the adequacy of
rate control at rest and with exertion. This is because many patients spontaneously reverted to sinus rhythm (and
therefore, rate control could not be assessed), and also because of the limited number of patients in atrial fibrillation
(AF) who had heart rate assessed with exertion.

Systematic review — A systematic review of the overall management of AF included a discussion of 54 trials that
evaluated 17 different agents used for rate control [7]. The studies were all relatively small (6 to 239 patients), and had
follow-up periods of eight weeks or less. Most compared single agents to placebo. Due to extensive variability in methods
and outcome assessments, a summary analysis of the trials could not be performed. However, the following observations
were noted:

● Diltiazem, verapamil, and most beta blockers (atenolol, metoprolol, timolol, pindolol, and nadolol) were all effective in
reducing the ventricular rate during rest and exercise. The beta blockers labetalol, xamoterol, and celiprolol were less
effective at rest, but did reduce ventricular rates during exercise.
 ● Trials comparing digoxin to placebo reported inconsistent results, particularly when heart during exercise was
assessed.

● The combination of digoxin with a beta blocker or calcium channel blocker reduced heart rate both at rest and with
exertion.

Thus, pharmacologic therapy can achieve adequate rate control in approximately 80 percent of patients. However,
achieving this goal requires close monitoring, medication adjustments, and often combination therapy. Although there are
differences in the efficacy of the various drugs, it is likely that monitoring and adjustments to therapy are more important
components of successful rate control strategies than is the initial drug selection (algorithm 1).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and
regions around the world are provided separately. (See "Society guideline links: Atrial fibrillation" and "Society guideline
links: Arrhythmias in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the
Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they
answer the four or five key questions a patient might have about a given condition. These articles are best for patients who
want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are
longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best
for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to
your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the
keyword(s) of interest.)

● Basics topic (see "Patient education: Medicines for atrial fibrillation (The Basics)")

● Beyond the Basics topic (See "Patient education: Atrial fibrillation (Beyond the Basics)".)

SUMMARY AND RECOMMENDATIONS — The following summary and recommendations are in general agreement with
the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society AF guideline [44,45].

This discussion applies to AF patients in whom a chronic rate control strategy has been chosen, or to any AF patient
requiring acute rate control. A discussion of the relative risks and benefits of rate versus rhythm control strategies is
presented in detail separately. (See 'Rhythm versus rate control' above and "Rhythm control versus rate control in atrial
fibrillation".)

Acute rate control — In patients with AF and a rapid ventricular response, acute heart rate control is usually achieved with
intravenous medications. (See 'Urgency of therapy' above.)

In such patients, we suggest the following approach:

● In patients without significant heart failure or hypotension, we suggest intravenous beta blockers or nondihydropyridine
calcium channel blockers (Grade 2B). (See 'Acute control with beta blockers' above and 'Acute control with calcium
channel blockers' above.)

● Intravenous diltiazem, using the regimen described above, is our preferred drug in this setting. (See 'Acute control with
calcium channel blockers' above.) However, comparative data are limited and intravenous verapamil or intravenous
beta blockers such as metoprolol, propranolol, or esmolol are reasonable alternatives (see 'Comparative efficacy'
above) [57].

● If it is uncertain whether such therapy will be tolerated by the patient, esmolol may be cautiously administered since its
very short half-life permits a therapeutic trial to be performed at reduced risk. (See 'Acute control with beta blockers'
above.)

● In patients who do not adequately respond to initial therapy with either an intravenous beta blocker or intravenous
calcium channel blocker, we suggest the addition of intravenous digoxin as the second drug in combination therapy
(Grade 2C). (See 'Digoxin' above.) Some patients have a greater degree of rate control with a beta blocker than with a
calcium channel blocker, and vice versa. Thus, in patients who have an inadequate response to one of these drugs,
 switching to a drug from the other class is an alternative to adding digoxin.

If rate control is achieved, we try to use the second drug as a single agent and to avoid using beta blockers and
calcium channel blockers as combination therapy for rate control. However, in selected patients who do not have
hypotension or significant left ventricular dysfunction, these classes may be used together, and in some cases all three
agents (ie, a beta blocker, a calcium channel blocker, and digoxin) may be necessary to achieve adequate rate control.

● In patients with advanced HF or significant hypotension, we suggest intravenous digoxin as initial therapy (Grade 2C).
(See 'Digoxin' above.)

● In patients who do not respond to or are intolerant of intravenous calcium channel blockers, beta blockers, and/or
digoxin, we suggest intravenous amiodarone for acute control of the ventricular rate (Grade 2C). (See 'Amiodarone'
above.) In such patients, the use of amiodarone for rate control is a short-term strategy (eg, hours to days). The drug
should not be used if pre-excitation is present.

Chronic rate control — Using drugs that block atrioventricular (AV) conduction, at least 75 percent of AF patients can
achieve a rate control target of ≤80 beats/min and over 90 percent a target of ≤110 beats/min. However, achieving this goal
requires close monitoring, medication adjustments, and often combination therapy. In such patients, adjustments can often
be made in the outpatient setting. (See 'Urgency of therapy' above and 'Rate control goals' above.)

Although there are differences in the efficacy of the various drugs used for rate control, it is likely that monitoring and
adjustments to therapy are more important components of successful rate control strategies than is the initial drug selection
(algorithm 1).

● We suggest a rate control goal of <85 beats/min, for symptomatic patients in AF in whom a rate control strategy has
been chosen (Grade 2C). For patients who continue with unacceptable symptoms at this goal, an attempt should be
made to see if a lower rate goal lessens symptoms. (See 'Rate control goals' above.) For asymptomatic patients with
permanent AF, a more lenient rate control goal of <110 beats/min may be reasonable, as long as patients do not
develop LV dysfunction. Careful monitoring for symptoms and/or development of LV dysfunction is imperative.

● In patients who require chronic rate control therapy, we suggest initial therapy with an oral beta blocker or
nondihydropyridine calcium channel blockers (Grade 1B). (See 'Chronic beta blocker therapy' above and 'Chronic
calcium channel blocker therapy' above.)

• Beta blockers are preferred in patients with coronary heart disease, heart failure due to systolic dysfunction, and in
patients in whom the ventricular rate increases inappropriately during exercise. In the first two settings, beta
blockers improve patient survival. (See "Acute myocardial infarction: Role of beta blocker therapy" and "Use of
beta blockers in heart failure with reduced ejection fraction".)

Despite these advantages, beta blockers are contraindicated or relatively contraindicated in some patients, and
others cannot tolerate the side effects. (See "Major side effects of beta blockers".)

• A nondihydropyridine calcium channel blocker is preferred in patients with chronic lung disease and in patients
who do not tolerate a beta blocker. Among the calcium channel blockers, verapamil has a somewhat greater
blocking effect on the AV node than diltiazem, and the choice between these drugs is often dictated by side
effects. Diltiazem may be preferred in patients with mild heart failure if a beta blocker is contraindicated or not
tolerated.

Combination therapy — In patients who do not achieve adequate rate control with a single agent, we attempt
combination therapy with a beta blocker and a calcium channel blocker. When these are used together, patients should be
carefully monitored for bradycardia and hypotension. Digoxin is reserved for patients with preserved left ventricular systolic
function who do not achieve rate control with a beta blocker and a calcium channel blocker and when an interventional
procedure such as catheter ablation or atrioventricular nodal ablation in is not being considered. If digoxin is used, digoxin
levels should be obtained periodically. We attempt to keep the level below 1.0 ng/mL (1.28 nmol/L). (See "The management
of atrial fibrillation in patients with heart failure", section on 'Our approach to rate control'.)

● In patients who have inadequate rate control on maximum tolerated doses of either a beta blocker or a calcium channel
blocker, we suggest the addition of digoxin (Grade 2C). (See 'Digoxin' above.)
 ● In patients who do not achieve adequate rate control on maximum tolerated doses of two atrioventricular nodal
blocking agents, we suggest digoxin if atrioventricular nodal ablation or catheter ablation of AF is not being considered
(Grade 2C). Careful follow-up for side effects such as bradycardia is imperative.

Although some patients may not tolerate a beta blocker and a calcium channel blocker (eg, those with left ventricular
systolic dysfunction or hypotension), the combination can be tried in most patients. As an alternative, patients who appear
unlikely to tolerate both a beta blocker and calcium channel blocker can be switched from one class to the other before
trying both in combination.

Some patients will not achieve adequate heart rate control with pharmacologic therapy due to poor response to or
intolerance of the medications. In such cases, options include reconsideration of a rhythm control strategy and
nonpharmacologic therapies to control the ventricular rate (algorithm 1). These issues are discussed separately. (See
"Rhythm control versus rate control in atrial fibrillation" and "Control of ventricular rate in atrial fibrillation: Nonpharmacologic
therapy".)

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Topic 938 Version 40.0

GRAPHICS

Physiology of the AV node in AF

The atrioventricular (AV) node modulates the response between the atrium
and the ventricle. In atrial fibrillation, the atrial rate is up to 600 beats per
minute while the ventricular rate in response is 90 to 170 beats per minute;
this difference in the rate results from several properties of the AV node that
impede impulse conduction. The AV node generates a slow action potential
(AP) that is mediated by calcium (Ca++) ion currents; the node is therefore
slow response tissue. Parasympathetic innervation via the vagus nerve also
slows conduction, while activation of the sympathetic nervous system speeds
conduction.

Graphic 75699 Version 1.0

Effect of drugs on AV function in AF

Various drugs can slow conduction through the atrioventricular node in atrial
fibrillation by altering its physiology. The calcium (Ca++) channel blockers,
primarily diltiazem and verapamil, block the influx of calcium and therefore
slow conduction by reducing the upstroke of the action potential; digoxin,
carotid massage, Valsalva maneuver, and edrophonium are vagotonic and slow
conduction by increasing parasympathetic effects on the node; beta blockers
slow conduction by offsetting sympathetic inputs; and adenosine slows
conduction only transiently by increasing potassium conduction and decreasing
calcium influx.

Graphic 51932 Version 1.0

Beta blocker properties

Alpha Beta-1 Usual Half life,

Drug ISA MSA Lipophilicity Elimination
blockade selectivity dose* hours ¶

Acebutolol No Yes Yes Yes Low 100 to 400 mg 3 to 4 Hepatic

twice per day (primary)
Renal
(secondary)

Atenolol No Yes No No Low 50 to 200 mg 6 to 9 Renal

once daily

Betaxolol No Yes No Yes Low 10 to 20 mg 14 to 22 Hepatic

once daily (primary)
Renal
(secondary)

Bisoprolol No Yes No No Moderate 2.5 to 20 mg 9 to 12 Renal and

once daily hepatic

Carteolol No No Yes No Low 2.5 to 5 mg 6 Renal

once daily

Carvedilol Yes No No Yes High 3.125 to 25 7 to 10 Biliary

mg twice per (primary)
day
Hepatic
(secondary)

Esmolol No Yes No No Low IV only 250 to 9 minutes Blood

500 esterases
micrograms/kg
over one
minute then
25 to 50
micrograms/kg
per minute as
IV infusion;
titrate
incrementally
up to
maximum of
300
microgram/kg
per minute Δ

Labetalol Yes No Yes Low Moderate IV 20 mg Δ 3 to 4 Hepatic

(Beta 2 )
Orally 100-400
mg two or
three times
per day

Metoprolol No Yes No Low Moderate IV 1.25 to 5 3 to 4 Hepatic via

tartrate mg Δ (7 to 9 hours CYP2D6
in poor (polymorphic)
Orally 25 to
metabolizers)
100 mg two or
three times
per day

Metoprolol No Yes No Low Moderate Orally 50 to Apparent Hepatic via

succinate 400 mg once half-life CYP2D6
(extended daily prolonged by (polymorphic)
release) continuous
osmotic
release over
~20 hours

Nadolol No No No No Low 40 to 160 mg 20 to 24 Renal

once daily

Nebivolol No Yes No No High 5 to 40 mg 10 to 12 Hepatic

 once daily (19 to 32
poor
metabolizers)

Oxprenolol ◊ No No Yes Yes Moderate 40 to 80 mg 1.5 Hepatic

three times
per day

Penbutolol No No Yes No High 10 to 40 mg 5 Hepatic

once daily

Pindolol No No Yes Low Moderate 5 to 30 mg 3 to 4 Hepatic

twice per day (primary)
Renal
(secondary)

Propranolol No No No Yes High IV 1 to 5 mg Δ 3 to 4 Hepatic

Orally 10 to 80
mg two to four
times daily

Sotalol § No No No No Low 80 to 160 mg 12 Renal

twice per day

Timolol No No No No Moderate 10 to 30 mg 4 to 5 Hepatic

twice per day (primary)
Renal
(secondary)

ISA: intrinsic sympathomimetic activity; MSA: membrane stabilizing activity; IV: intravenous.
* Range of usual, oral, anti-hypertensive dose, unless "IV" noted.
¶ Duration of hypotensive effect, in general, is longer than may be predicted by serum half-life.
Δ Usual initial IV dose. Subsequent dosing generally needed. See drug monograph for detail.
◊ Not available in US.
§ Sotalol has independent class III antiarrhythmic activity.

Prepared with data from:​

1. Frishman WH, Alwarshetty M. β-Adrenergic blockers in systemic hypertension pharmacokinetic considerations related to
current guidelines. Clin Pharmacokinet 2002; 41:505.
2. Brubacher JR. β-Adrenergic Antagonists. In: Goldfrank's Toxicologic Emergencies, 9th ed, Nelson LS (Ed), McGraw-Hill, New
York 2010.

Graphic 82571 Version 9.0

Dose response to diltiazem for rate control in atrial
fibrillation

Kaplan-Meier analysis of the percentage of patients maintaining a therapeutic

rate control response to each dose level of intravenous diltiazem infusion in
patients who initially responded to bolus diltiazem. Maintenance of rate
control was greater at doses of 10 to 15 mg/h.

Data from Ellenbogen KA, Dias VC, Cardello FP, et al. Am J Cardiol 1995; 75:45.

Graphic 80630 Version 3.0

Efficacy of amiodarone in rate control for atrial fibrillation

Effect of intravenous placebo, amiodarone, and flecainide on the ventricular

response to atrial fibrillation in patients who failed to revert to sinus rhythm
after the initiation of therapy. Amiodarone slowed the ventricular response,
an effect that was not seen with flecainide or placebo. Although flecainide
was less effective for rate control, it was associated with earlier reversion to
sinus rhythm than amiodarone or placebo. Note that the time scale is
nonlinear.

Data from Donovan KD, Power BM, Hockings GE, et al. Am J Cardiol 1995; 75:693.

Graphic 81119 Version 3.0

Atenolol plus digoxin is most effective for rate control in
AF

In a study of 12 patients which compared the effect of various

atrioventricular nodal drugs on heart rate during atrial fibrillation (AF),
digoxin plus atenolol was the most effective therapy for attenuating the
circadian rhythmicity of heart rate (upper panel) and the peak heart rate
with exercise (bottom panel). The least effective therapies were digoxin or
diltiazem administered as single agents.

Data from Farshi R, Kistner D, Sarma JS, et al. J Am Coll Cardiol 1999; 33:304.

Graphic 73989 Version 2.0

Management algorithm of permanent atrial fibrillation - rate
control

Graphic 75491 Version 1.0

Contributor Disclosures
Leonard I Ganz, MD, FHRS, FACC Speaker’s Bureau: Amgen [Heart failure (Ivabradine)]; Pfizer, BMS [Anticoagulation
(Apixaban)]; St. Jude Medical, Biotronik [Cardiac rhythm (Pacemaker/ICD)]; Lundbeck [Orthostatic hypotension (Northera)].
Consultant/Advisory Boards: Unequal Technologies [Commotio cordis (Protective equipment)]. Equity Ownership/Stock
Options: Unequal Technologies [Commotio cordis (Protective equipment/apparel)]. Bradley P Knight, MD,
FACC Grant/Research/Clinical Trial Support: BSCI; MDT; SJM; Biotronik; Biosense Webster [EP (implantable devices and
ablation tools)]. Speaker's Bureau: BSCI; MDT; SJM; Biotronik; Biosense Webster [EP (implantable devices and ablation
tools)]. Consultant/Advisory Boards: BSCI; MDT; SJM; Biotronik; Biosense Webster; Apama Medical [EP (implantable
devices and ablation tools)]. Gordon M Saperia, MD, FACC Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by
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