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 "Atrial fibrillation: Atrioventricular node ablation".)
RATIONALE — There are two established reasons to prevent a prolonged 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".)
There are two other reasons to consider rate control:
●Potential mortality benefit – 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.
●Spontaneous conversion to sinus rhythm – Some patients whose rate has been slowed and who then tolerate AF may spontaneously convert without the need for planned cardioversion. Spontaneous conversion is most likely to occur in patients with a duration of AF of less than 48 hours, or in patients with a history of short, self-limited episodes [1,2]. The rate of spontaneous conversion has been reported to be around 50 percent at 48 hours [1].
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 "Atrial fibrillation: Overview and management of new-onset atrial fibrillation".)
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 "Cardiac excitability, mechanisms of arrhythmia, 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. Although this relates to AV node dysfunction, AF with slow rates is generally included as a manifestation of sinus node dysfunction.
A ventricular rate above 200 beats/min suggests one or more of the following:
●Catecholamine excess
●Enhanced AV nodal conduction
●Parasympathetic withdrawal
●Hyperthyroidism
●An accessory pathway as occurs in the preexcitation syndrome. (See "Atrioventricular reentrant tachycardia (AVRT) associated with an accessory pathway".)
Long-term rate control goals — The optimal rate goal for patients with AF has not been determined [3]. 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 [4]. (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) [5]. 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:
●Similar efficacy of lenient and strict rate control – 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).
●Less people in strict versus lenient group met heart rate target – 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 [6]. However, there was no significant difference in the primary outcome (12.1 versus 14.2 versus 15 percent).
●More medical visits in strict rate control group – 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 "Sinus node dysfunction: 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 upstairs may provide sufficient information. Wearable devices, such as an electronic watch that connects with a smartphone app, also can provide heart rate data.
In the assessment of heart rate control, average heart rate is considered the most important parameter. Heart rates during peak exercise may also be valuable. Assessment of rate control can be confusing when using monitors that display continuous beat-to-beat heart rate rather than average heart rate.
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 immediate goals are to stabilize hemodynamics (if necessary) and to improve symptoms. Thus, 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".)
●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 – This management strategy consists of cardioversion, often followed by maintenance of sinus rhythm with arrhythmic drugs.
●Rate control – This management strategy is usually with drugs that slow conduction through the AV node.
The advantages and disadvantages of rhythm and rate control, as well as whether there are subgroups of patients for whom one or the other should be preferred, are discussed 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. The drug of choice in the acute setting is intravenous procainamide. (See "Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome", section on 'When to avoid AV nodal blockers'.)
Long-term therapy in preexcited AF includes ablation of the accessory pathway. (See "Treatment of 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. 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.
These agents slow atrioventricular (AV) nodal conduction based upon the following physiologic mechanisms (figure 2) [7,8]:
●Calcium channel blockade – Blockade of the calcium channel with the nondihydropyridine calcium channel blockers verapamil and diltiazem.
●Beta blockade – Decreased sympathetic tone and slowed atrioventricular nodal conduction with beta blockers.
●Enhancement of parasympathetic tone – This is done 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 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) [9-11]. 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 mcg/kg per minute. If, after four minutes, the response is inadequate, another bolus is given followed by an infusion of 100 mcg/kg per minute. If, after four minutes, the response is still inadequate, a third and final bolus can be given followed by an infusion of 150 mcg/kg per minute. If necessary, the infusion can be increased to a maximum of 200 mcg/kg per minute after another four minutes.
Alternatively, an infusion can be started at 50 mcg/kg per min without a bolus, and the rate of administration can be increased by 50 mcg/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. Beta blockers decrease the resting heart rate and blunt the heart rate response to exercise. Most beta blockers appear to have similar efficacy. There is the most supporting evidence for metoprolol, atenolol, and nadolol. There are some data that indicate labetalol is less effective than other beta blockers for reducing heart rate at rest [12]. 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. However, atenolol takes longer to clear, especially in the setting of kidney disease; therefore, we generally use this medication if a patient has side effects to metoprolol. 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 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 "Initial pharmacologic therapy of heart failure with reduced ejection fraction in adults".)
●Patients with AF triggered by sympathetic dysfunction – 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. (See "Sinus node dysfunction: 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 – 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 – 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, and as tolerated by blood pressure.
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. Some experts use a lower bolus dose of 5 to 15 mg.
The efficacy of this regimen was evaluated in a report of 84 consecutive patients with AF, atrial flutter, or both [28]. 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 — 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.
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. Higher doses are limited by the development of constipation and edema.
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:
●Variable effect on sinoatrial (SA) nodal function – 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 sinus node dysfunction may be particularly sensitive to the effects of calcium channel blockers. (See "Sinus node dysfunction: Epidemiology, etiology, and natural history".)
●Negative ionotropic effects – 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.
●Interaction between verapamil and digoxin – 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].
●Side effects in older patients – 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 or a procedure that slows atrioventricular nodal conduction (see "Atrial fibrillation: Atrioventricular node ablation", section on 'Indications'). It is not as effective as these two categories of drug and its use is associated with higher mortality in patients at higher digoxin levels. 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].
The best available evidence regarding the relationship between digoxin use in AF patients and mortality comes from a post-hoc subgroup analysis of the ARISTOTLE trial of anticoagulant therapy [44]. While baseline digoxin use was not associated with an increased risk of death (adjusted hazard ratio [HR] 1.09, 95% CI 0.96-1.23), patients with a serum digoxin concentration ≥1.2 ng/mL had a 56 percent increased risk of death (adjusted HR 1.56, 95% CI 1.20-2.04) compared with those not taking the drug. In patients with baseline digoxin level >0.9 but less than 1.2 ng/mL, there was a trend towards higher mortality; in patients with baseline digoxin level <0.9 ng/mL, there was no excess mortality. In addition, the risk of death was higher in new digoxin users (adjusted HR 1.78, 95% CI 1.37-2.31). These effects were not significantly different between those with and without heart failure.
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 [45,46]. 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 [9,17,18,47-52]. (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 in heart failure with reduced ejection fraction'.)
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 [49,53]. However, beta blockers, if tolerated, are now a standard component of therapy for all patients with heart failure due to systolic dysfunction. (See "Initial pharmacologic therapy of heart failure with reduced ejection fraction in adults".)
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"):
●Inability to achieve rate control targets – Patients who do not achieve rate control targets on beta blockers alone.
●Side effects from beta blockers – Patients who cannot tolerate the addition of or increased doses of a beta blocker due to acute decompensated heart failure.
●Heart failure symptom control – 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 "Secondary pharmacologic therapy in heart failure with reduced ejection fraction (HFrEF) in adults".)
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 <0.9 ng/mL. For patients in whom additional rate control is needed and the level is <0.9 ng/mL, a small increase in the dose can be made. (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.
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) [54]. 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 [55].
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 [45,46]. 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 "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".)
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 [56]. 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. Furthermore, 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, and magnesium was associated with side effects such as flushing and hypotension. A separate meta-analysis of six trials and 745 patients showed similar results [57]. Nonetheless, we do not use IV magnesium for control of ventricular rate in AF because very few patients are refractory to other therapy.
Combination therapy — In patients who do not achieve adequate chronic 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 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 is not being considered. If digoxin is used, digoxin levels should be obtained periodically. We attempt to keep the level in the lower half of the normal range. (See "The management of atrial fibrillation in patients with heart failure", section on 'Rate control in heart failure with reduced ejection fraction' and "The management of atrial fibrillation in patients with heart failure", section on 'Rate control in heart failure with preserved ejection fraction'.)
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.
Once an effective rate control regimen has been developed, it is reasonable to periodically assess adequacy of rate control. It is also reasonable to monitor left ventricular function in patients treated with a pharmacologic rate control strategy to make sure that a tachycardia-related cardiomyopathy has not developed.
COMPARATIVE EFFICACY — There are few studies directly comparing the efficacy of beta blockers, calcium channel blockers, and digoxin:
●Digoxin plus atenolol was highly effective at rate control – 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 [47]. 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).
●Digoxin and bisoprolol were equally effective – In the 2020 RATE-AF open-label trial, 160 patients with permanent AF, who were 60 years of age or older, and who had symptoms of heart failure were randomly assigned to digoxin (dose range 62.5 to 250 micrograms daily) or bisoprolol (1.25 to 15 mg daily) [58]. The baseline resting heart rate was approximately 100 beats per minute. At 12 months, there was no difference in the resting heart rate (75 versus 74 beats per minute, respectively) or the primary outcome of normalized SF-36 PCS quality-of-life score (31.9 versus 29.7, respectively). However, some secondary outcomes such as European Heart Rhythm Association symptom class and median NT-proBNP level were better with digoxin.
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 [59]. 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 'Long-term 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:
●Non-random assignment of specific rate control medication – 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 non-White patients. Whether these baseline differences had an impact on the adequacy of rate control is not known.
●Inadequate baseline assessment of heart rate – 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 [12]. 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:
●Beta blockers and calcium channel blockers were effective at rate control – 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.
●Mixed results for digoxin versus placebo – Trials comparing digoxin to placebo reported inconsistent results, particularly when heart during exercise was assessed.
●Digoxin was effective when added to beta blocker or calcium channel blocker – 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
●Rate control goal – We target a rate control goal of <85 beats/min for symptomatic patients with atrial fibrillation (AF) in whom a rate control strategy has been chosen. 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 'Long-term rate control goals' above.)
For asymptomatic patients with permanent AF, a more lenient rate control goal of <110 beats/min may be reasonable. These patients should be monitored for the development of tachycardia-mediated cardiomyopathy. (See 'Tachycardia-mediated cardiomyopathy' above.)
●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:
•Initial therapy – In patients without significant heart failure or hypotension, we suggest intravenous nondihydropyridine calcium channel blockers or beta blockers (Grade 2B). (See 'Acute control with calcium channel blockers' above and 'Acute control with beta blockers' above.)
-Intravenous diltiazem, using the regimen described above, is our preferred drug in this setting. (See 'Acute control with calcium channel blockers' above.)
-Intravenous verapamil or intravenous beta blockers such as metoprolol, propranolol, or esmolol are reasonable alternatives. (See 'Comparative efficacy' above.)
-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 relatively safe therapeutic trial. (See 'Acute control with beta blockers' above.)
•Combination therapy – In patients who do not adequately respond to initial therapy with either an intravenous calcium channel blocker or intravenous beta blocker, we suggest the addition of intravenous digoxin as the second drug in combination therapy (Grade 2C) (see 'Digoxin' above).
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 calcium channel blocker, a beta blocker, and digoxin) may be necessary to achieve adequate rate control.
•Alternative short-term therapy – 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.
•Patients with hypotension – In patients with advanced heart failure or significant hypotension, we suggest digoxin as initial therapy (Grade 2C). (See 'Digoxin' above.)
●Chronic rate control – Monitoring and adjustments to therapy are more important components of successful rate control strategies than initial drug selection (algorithm 1).
•Initial therapy – In patients who require chronic rate control therapy, we suggest initial therapy with an oral beta blocker or nondihydropyridine calcium channel blocker (Grade 1B). (See 'Chronic beta blocker therapy' above and 'Chronic calcium channel blocker therapy' above.)
Beta blockers are preferred in patients with acute myocardial infarction, 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 "Initial pharmacologic therapy of heart failure with reduced ejection fraction in adults".)
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".)
•Alternative therapy – In patients who do not achieve adequate rate control on maximum-tolerated doses of a beta blocker and non-dihydropyridine calcium channel blocker together, we suggest adding digoxin if atrioventricular (AV) nodal ablation, pharmacologic rhythm control, or catheter ablation of AF are not being considered (Grade 2C).
●Monitoring – Careful follow-up for side effects such as bradycardia is imperative. (See 'Combination therapy' above.)
●Switching to rhythm control – 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 "Atrial fibrillation: Atrioventricular node ablation".)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review.
