7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy : Rachel Kaplan, MD, MS : Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jun 27, 2023. INTRODUCTION In patients with atrial fibrillation (AF), the ventricular rate is modulated 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".) Further information regarding the overall management of patients with AF, including anticoagulation and choice of rhythm versus rate control, is discussed separately: (See "Atrial fibrillation in adults: Use of oral anticoagulants".) (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation".) (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation".) (See "Management of atrial fibrillation: Rhythm control versus rate control".) The control of ventricular rate of AF in patients with heart failure is discussed separately; thus, this topic focuses only on patients with AF who do not have heart failure. (See "The management of atrial fibrillation in patients with heart failure".) https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/p 1/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate PATHOPHYSIOLOGY Atrial fibrillation 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 electrophysiologic properties of the AV node. (See "Mechanisms of atrial fibrillation", section on 'Role of the atrioventricular node'.) AV nodal tissue consists of so-called "slow response" fibers, giving it decremental conduction properties. 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 limit 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 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".) Drug mechanisms of action The ventricular rate in AF is slowed using beta blockers or calcium channel blockers, and to a lesser extent digoxin or amiodarone. In general, calcium https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/p 2/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate channel blockers are effective at rest and during exercise, beta blockers are similarly effective at rest but more effective during exercise, and digoxin is reasonably effective at rest but less effective than the other drugs during exercise. Thus, it is particularly important to assess ventricular rate with exertion in patients treated with digoxin alone. These agents slow AV nodal conduction based upon the following physiologic mechanisms ( figure 2) [1,2]: Calcium channel blockade Blockade of the calcium channel with the nondihydropyridine calcium channel blockers verapamil and diltiazem. Beta blockade Decreased sympathetic tone and slowed AV nodal conduction with beta blockers. Enhancement of parasympathetic tone This is done with vagotonic drugs, the most important of which is digoxin. RATIONALE FOR RATE LOWERING Specific reasons for slowing the ventricular rate in patients with AF include the following: Hemodynamic instability This may be acute and may require urgent therapy. This is discussed in detail separately. (See "Hemodynamic consequences of atrial fibrillation and cardioversion to sinus rhythm".) Symptoms Patients with AF may or may not have associated symptoms, and the spectrum of symptoms is broad. Typical symptoms include palpitations, tachycardia, fatigue, weakness, dizziness, lightheadedness, reduced exercise capacity, increased urination, or mild dyspnea. Symptoms of AF are discussed in detail separately. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Symptoms'.) Tachycardia-mediated cardiomyopathy Persistently increased ventricular rates in AF have been associated with left ventricular 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 ventricular rate goal. This is discussed in detail separately. (See "Arrhythmia-induced cardiomyopathy".) 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 https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/p 3/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate 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 nonrandomized study. Spontaneous conversion to sinus rhythm Some patients whose rate has been slowed and who then tolerate AF may spontaneously convert to normal sinus rhythm without the need for electrical 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 [3]. The rate of spontaneous conversion has been reported to be around 50 percent at 48 hours [3]. In a retrospective study of 438 patients with AF, if the AF onset was <48 hours, spontaneous conversion occurred in 77 percent compared with 36 percent in the group with first onset AF >48 hours [4]. In a separate study of 943 patients, spontaneous conversion was shown to occur most frequently in patients with first-onset AF <24 hours, a lower body mass index, and normal left atrial size [5]. EVALUATION AND GOAL VENTRICULAR RATE Evaluation and monitoring of ventricular rate In practice, the ventricular rate can be assessed by measurement of both the resting ventricular rate and use of one of the following to assess exercise: Six-minute walk test (at moderate exercise) ( table 1). Either submaximal or maximal exercise electrocardiogram (ECG) testing. (See "Exercise ECG testing: Performing the test and interpreting the ECG results".) A 24-hour ambulatory monitor can also be used to evaluate efficacy. (See "Ambulatory ECG monitoring".) For patients with an implantable pacemaker or defibrillator, device interrogation provides useful diagnostic data to assess rate control, including a ventricular rate histogram during episodes of AF. For young active patients, we recommend either an exercise ECG test or ambulatory monitoring during exercise. For older or sedentary patients, measuring ventricular rate after walking briskly around the office or upstairs may provide sufficient information. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/p 4/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Wearable devices, such as an electronic watch that connects with a smartphone application, also can provide ventricular rate data. Caution is advised with relying entirely on photoplethysmography, which may undersense individual beats in AF and report an inaccurately low heart rate [6]. Heart rate reports should be verified with ECG strips, which may also be obtainable from some wearable technologies. These methods of assessing ventricular rate can be used both at the start of therapy and for long-term follow-up. In the assessment of ventricular rate control, average ventricular rate is considered the most important parameter. Ventricular rates during peak exercise may also be valuable. Assessment of rate control can be confusing when using monitors that display continuous beat-to-beat ventricular rate rather than average ventricular rate. Goal ventricular rate The optimal long-term ventricular rate for patients in AF has not been firmly established [7]. For most symptomatic patients with AF, we suggest a ventricular rate goal of 85 beats/min. In general, the goal is to control the rate during activity to prevent or treat symptoms. If the ventricular rate during AF is faster than would be expected during sinus rhythm and occurs at a time that correlates with the patient's symptoms, then rate control medications are usually titrated upwards. In the subset of patients with AF who are asymptomatic and have permanent AF, a less strict rate control goal of <110 beats/min may be reasonable. These patients should be monitored for the development of tachycardia-mediated cardiomyopathy. (See "Arrhythmia-induced cardiomyopathy".) Alternative goal rates that are similar to those recommended for patients in sinus rhythm with heart disease can also be used: 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 [8]. The AFFIRM study is discussed in detail separately. (See "Management of atrial fibrillation: Rhythm control versus rate control", section on 'High cardiovascular risk'.) 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 tachycardia-bradycardia 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. A more https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/p 5/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate lenient rate-control strategy offers the advantages of less medication (fewer drug side effects, lower cost) and fewer outpatient visits to achieve ventricular rate control. The recommended goal rate is based on the observation that 85 beats/min was the mean achieved rate for patients assigned lenient rate control in the RACE study [9]. In this trial of patients with permanent AF, adhering to a strict rather than lenient rate-control strategy did not improve cardiovascular or safety outcomes. This study also supports our practice in which achieving strict rate control is not necessary in many physically active patients with AF who are minimally symptomatic. In the RACE study, 614 physically active patients with permanent AF were randomly assigned either lenient rate control (resting heart rate <110 beats/min) or a strict rate control (resting heart rate <80 beats/min and heart rate during moderate exercise <110 beats per minute). Patients were followed for the primary outcome of cardiovascular death, hospitalization for heart failure, stroke, systemic embolism, bleeding, and life-threatening arrhythmic events. The following findings were noted: Similar efficacy of lenient and strict rate control After three years, the estimated cumulative incidence of the primary outcome was similar in both groups (12.9 versus 14.9 percent, respectively; hazard ratio [HR] 0.84; 90% CI 0.58-1.21). Fewer people in strict versus lenient group met heart rate target The percentage of patients was 98 and 75 percent, respectively [10]. More medical visits in strict rate-control group There were nearly nine times as many visits (684 versus 75) to achieve rate control target(s) in the strict control. Low resting heart rates were achieved in the lenient group too In patients assigned to lenient rate control, the mean resting rates at the end of follow-up was 85+14 beats/min compared with 76+14 beats/min in those assigned to strict control. The results of the RACE trial must be tempered given that the lenient-control group was in fact treated more aggressively than the protocol required. In addition, RACE included only patients with permanent AF, so the results are not generalizable to those with paroxysmal or persistent AF. INITIAL CONSIDERATIONS The initial management of patients with AF and a rapid ventricular response involves the following: Determining if urgent therapy is needed. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/p 6/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Choosing between a rate and rhythm control strategy. Determining if there is preexcitation. Determining urgency 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 rate control therapy (eg, inpatient versus outpatient or oral versus intravenous therapy) depends upon the clinical scenario. Urgent 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. (See 'Urgent therapy' below.) 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. (See 'Elective and long-term management' below.) Deciding on rate control 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 "Management of atrial fibrillation: Rhythm control versus rate control".) Caution in preexcitation syndrome Among patients with AF and preexcitation, initial therapy is aimed at reversion to sinus rhythm. Usual treatments for rate control (ie, calcium channel blockers, beta blockers, digoxin, and amiodarone) should not be given because they may paradoxically increase the ventricular response in patients with AF. Intravenous procainamide or ibutilide should be given if hemodynamics are stable, and direct current cardioversion should be performed if the patient is unstable. This is discussed in detail separately. (See "Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome", section on 'When to avoid AV nodal blockers'.) The preferred long-term therapy of preexcited AF is ablation of the accessory pathway. (See "Treatment of arrhythmias associated with the Wolff-Parkinson-White syndrome", section on 'Catheter ablation'.) URGENT THERAPY https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/p 7/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate This section describes our approach to urgent ventricular rate control in patients with AF who do not have heart failure. Rate control of patients who have AF and heart failure is discussed separately. (See "The management of atrial fibrillation in patients with heart failure", section on 'Acute decompensation'.) Choice of initial urgent therapy Patients who require urgent therapy need to be in a monitored setting. In patients without symptomatic hypotension (eg, in those with ischemia without hypotension), we select diltiazem as the initial agent. Intravenous (IV) esmolol, verapamil, or other IV beta blockers such as metoprolol are reasonable alternatives to diltiazem. If it is uncertain whether the patient will become hypotensive with a beta blocker, we use esmolol since this medication has a very short half-life and can be immediately discontinued if needed. (See 'Hypotensive patient' below.) In the absence of larger randomized trials, much of the current management relies on clinical experience rather than evidence. Diltiazem may have a less pronounced negative inotropic effect than verapamil [11]. The IV preparation is convenient and effective for acute control of the ventricular rate in AF [12-14], while oral therapy is effective for chronic rate control [15,16]. In our experience, either a beta blocker or calcium channel blocker could result in hypotension, and therefore careful blood pressure monitoring is needed regardless of the choice of medication. Small, heterogenous studies of urgent control of ventricular rate in AF suggest higher efficacy for IV diltiazem versus IV beta blocker therapy: One meta-analysis of three studies including 160 patients and comparing effects of IV diltiazem versus IV metoprolol showed an average of 9 mm lower systolic blood pressure with diltiazem at 15 minutes following treatment but no differences at earlier or later timepoints (ie 5, 10, or 30 minutes) [17]. In a meta-analysis of 17 randomized and cohort studies (1214 patients), patients given IV diltiazem compared with IV metoprolol had higher efficacy of successful rate control (relative risk [RR] 1.11; 95% CI 1.06-1.16). Efficacy was defined differently in various studies (eg, achieving a heart rate <100 beats/min or lowering heart rate by at least 20 percent). Those treated with IV diltiazem also had shorter average onset time (RR per minute of onset -1.13; 95% CI -1.97 to -0.28) and lower ventricular rate (RR difference in beats/min -9.48; 95% CI -12.13 to -6.82) and less impact on (weighted mean difference 3.76 mmHg; 95% CI 0.20-7.33). There was no significant difference in adverse events between treatment regimens [17]. Normotensive patient In most normotensive patients with AF with a rapid ventricular rate, we first try IV diltiazem ( table 2). https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/p 8/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate The suggested regimen for IV diltiazem is derived from the Diltiazem Atrial Fibrillation/Atrial Flutter Study Group [12-14]. The efficacy of this regimen was evaluated in a report of 84 consecutive patients with AF, atrial flutter, or both [14]. 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/hour; 68 percent after titration to 10 mg/hour; and 76 percent after titration to 15 mg/hour ( figure 3). Hypotension occurred in 13 percent and was symptomatic in almost 4 percent. All such patients responded to an infusion of normal saline. Weight-based dosing of IV diltiazem is further supported in a study of 252 patients who received IV diltiazem for acute rate control in the emergency department. Weight-based dosing (0.25 mg/kg) was associated with higher rates of rate control without increased adverse effects [18]. Hypotensive patient Asymptomatic and not on a vasopressor If the patient is mildly hypotensive but asymptomatic and does not require a vasopressor, we typically start metoprolol tartrate (short- acting) 25 mg by mouth every six hours and up-titrate as needed and as tolerated by 12.5 mg every six hours until the rate is controlled. Other IV beta blockers and calcium channel blockers may cause worsening hypotension. Patients with inadequate response Urgent combination therapy In patients who do not adequately respond to initial therapy with either an IV calcium channel blocker or IV beta blocker, we suggest the addition of IV digoxin as the second drug in combination therapy ( table 2). Digoxin should not be used if preexcitation is present. Urgent alternative therapy In patients who do not respond to or are intolerant of IV calcium channel blockers, beta blockers, and/or digoxin, we suggest IV amiodarone for acute control of the ventricular rate ( table 2). 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 preexcitation is present. Careful attention to anticoagulation is also necessary because there is a small chance of cardioversion with amiodarone. If none of these therapies work, we typically opt for acute cardioversion rather than continued attempts at rate control (with evaluation of the left atrial appendage thrombus if warranted and clinically feasible and appropriate anticoagulation strategy). Symptomatic hypotension and/or on a vasopressor If the hypotension is symptomatic and requires a vasopressor, we typically opt for acute cardioversion rather than rate control (with evaluation of the left atrial appendage thrombus if warranted and appropriate https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/p 9/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate anticoagulation strategy). (See "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) If the patient is on a vasopressor that can exacerbate tachycardia (eg, epinephrine or norepinephrine), we may elect to switch the vasopressor to a vasoconstrictor (eg, phenylephrine) if this is a reasonable alternative. (See "Use of vasopressors and inotropes".) Management of patients in whom cardioversion is unsuccessful is discussed separately. (See "Atrial fibrillation: Cardioversion", section on 'Electrical cardioversion'.) Alternative therapies we do not suggest We do not use IV magnesium for control of ventricular rate in AF despite a small body of supporting evidence because very few patients are refractory to other therapies and would require it. Magnesium does have 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/min) were treated with usual therapy for rate control (most often digoxin) and randomly assigned to IV magnesium sulfate (2.5 g over 20 minutes followed by 2.5 g over two hours) or placebo [19]. 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. 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 [20]. Ivabradine blocks the pacemaker current, which is primarily thought to affect the sinoatrial node; however, some studies have shown that this current is also expressed in the atrioventricular node. Accordingly, a few studies are investigating the use of ivabradine for ventricular rate control in AF. One retrospective study of 18 patients with permanent AF showed average reduction in ventricular rate from 104.6 to 89 [21]. A randomized trial has been proposed to study ivabradine in patients with permanent AF (BRAKE-AF trial). At the present time, there is insufficient evidence to recommend the routine use of ivabradine for ventricular rate control in AF [22]. Transition to oral medications When making a transition from IV to oral therapy, we first ensure that the patient has tolerated the IV medication well. For instance, beta blockers may have a variety of adverse effects that can be important in patients with AF. (see "Major side effects of beta blockers") https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 10/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate When transitioning from IV to oral medications, we generally convert the total daily dose of the IV medication to an equivalent divided or long-acting oral dose of a medication in the same class. We often use pharmacy or pharmacist-based reference for appropriate conversion dosages. For example, if a patient is placed on IV diltiazem, we will usually convert the patient to a short or long-acting oral formulation of diltiazem that gives an equivalent daily dose of the medication. A general formula for approximate conversion from IV diltiazem to the daily oral dose is [(infusion rate x3)+3]x10 [23]. Example conversions from IV to oral dosing for diltiazem and metoprolol are shown in a table ( table 2). Other nuances of long-term rate control medications are discussed separately. (See 'Elective and long-term management' below.) ELECTIVE AND LONG-TERM MANAGEMENT Choice of nonurgent 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 the initial drug selection. Studies of specific pharmacologic agents for management of AF are small and heterogeneous. A study of 25 clinical trials showed no difference in effectiveness for different diltiazem or verapamil formulations (eg, immediate release, sustained release, or controlled delivery). There was also no evidence of differences in effectiveness for extended-release diltiazem and verapamil [24]. Long-acting or sustained-release formulations are typically preferred for chronic management to facilitate medication compliance. One study reviewed 54 trials that evaluated 17 different agents used for rate control [25]. The studies were all relatively small (6 to 239 patients) and had relatively short follow-up periods of eight weeks or less. Most compared single agents with placebo. Due to extensive variability in methods and outcome assessments, a meta-analysis of the trials could not be performed. However, the following observations were noted: Both beta blockers and calcium channel blockers were effective 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 with placebo reported inconsistent results, particularly when heart rate during exercise was assessed. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 11/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate 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 the initial drug selection. 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 [26]. The original AFFIRM trial assigned patients with AF to either rate or rhythm control, and a post-hoc analysis compared the efficacy of various rate-control medications. In this post-hoc study, over 2000 patients assigned to rate control were given medications according to physician preference. Effectiveness of rate control was defined as a resting heart rate 80 beats/minute, exertional heart rate 110 beats/min during six-minute walk test or average heart rate during 24-hour ambulatory Holter monitoring ECG 100 beats/min (at least 18 hours of interpretable monitoring), and no heart rate >110 percent maximum predicted age-adjusted exercise heart rate. The overall effectiveness (meeting both rest and exertion heart rate goals) of initial monotherapy therapy was most effective for beta blockers (59 percent), followed by digoxin (58 percent), and then calcium channel blockers (38 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. Limitations of this study included nonrandom assignment of specific rate-control medication and an inadequate baseline assessment of heart rate. Initial therapy In patients who do require elective management or in those transitioning to long-term therapy, we usually suggest an oral beta blocker or nondihydropyridine calcium channel blocker. Reasons for these preferences are discussed below. Beta blockers We prefer beta blockers in the following groups of patients: Recent myocardial infarction. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 12/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Heart failure due to systolic dysfunction. Inappropriate increase in ventricular rate during exercise. Surges in sympathetic function that trigger AF. Beta blockers may be particularly useful in states of high adrenergic tone (eg, postoperative AF) [27,28]. In the first two settings, beta blockers improve patient survival. (See "Acute myocardial infarction: Role of beta blocker therapy" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.) Oral beta blockers are widely used as primary therapy for rate control in chronic AF. Beta blockers decrease the resting ventricular rate and blunt the ventricular rate response to exercise. Most beta blockers appear to have similar efficacy. For patients with heart failure with systolic dysfunction, the preferred agents for treatment are metoprolol succinate, carvedilol, carvedilol continuous release, and bisoprolol. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.) In a post-hoc analysis of the AFFIRM trial of rate versus rhythm control in patients with AF, beta-blocker therapy was shown to be effective in achieving goal ventricular rate in 59 percent of people [26]. The AFFIRM trial is discussed in greater detail separately. (See 'Choice of nonurgent therapy' above.) There is the most supporting evidence for metoprolol, atenolol, and nadolol. Atenolol and nadolol have the advantages of a long half-life and are typically given once daily. Long- acting propranolol can be effective. Bisoprolol and carvedilol are also used ( table 2). It should be noted that beta blockers are contraindicated or relatively contraindicated in some patients, and others cannot tolerate the side effects. (See "Major side effects of beta blockers".) Beta blockers have additional properties that may make them preferred to other rate- control drugs in some AF patients: Patients with systolic dysfunction This is discussed separately. (See "The management of atrial fibrillation in patients with heart failure" and "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.) https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 13/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate 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 [27,28]. Some patients with paroxysmal AF also have sinus node dysfunction, with 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 blocker A nondihydropyridine calcium channel blocker is preferred in patients with chronic lung disease and in patients who do not tolerate beta blockers. 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 ( table 2). In a post-hoc analysis of the AFFIRM trial of rate versus rhythm control in patients with AF, calcium channel blocker therapy was shown to be effective in achieving goal ventricular rate in 38 percent of people [26]. The AFFIRM trial is discussed in greater detail separately. (See 'Choice of nonurgent therapy' above.) 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. 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 those that are cardiac in nature. Although the same maximum doses may be tolerated, it is usually appropriate to titrate more slowly. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 14/33 7/6/23, 3:08 PM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate In summary, diltiazem and verapamil should not be given to patients with severe heart failure (New York Heart Failure class III or IV), 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. Considerations for patients with heart failure are discussed separately. (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'.) Combination therapy Combination therapy In patients initially tried on a beta blocker or calcium channel