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 7/5/23, 9:14 AM 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 7/5/23, 9:14 AM 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 7/5/23, 9:14 AM 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 blocker with persistently high ventricular rates, the combination of a beta blocker and a calcium channel blocker can be tried in most patients. In a post-hoc analysis of the AFFIRM trial of rate versus rhythm control in patients with AF, this combination 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.) Adding digoxin In patients who do not achieve adequate rate control on maximum- tolerated doses of a beta blocker and nondihydropyridine calcium channel blocker together, we suggest adding digoxin if AV nodal ablation, pharmacologic rhythm control, or catheter ablation of AF are not being considered. (see "Atrial fibrillation: Atrioventricular node ablation", section on 'Indications'). When digoxin is added to either a beta blocker or calcium channel blocker or to both, patients should be carefully monitored for bradycardia and hypotension. Also, patients with significant left ventricular dysfunction may not tolerate triple therapy ( table 2). Digoxin levels should be obtained periodically for the purpose of detecting potentially high levels. We attempt to keep the level in the lower half of the normal range. Digoxin toxicity is discussed in detail separately. (See "Digitalis (cardiac glycoside) poisoning" and "Cardiac arrhythmias due to digoxin toxicity".) Combination therapy with digoxin was studied in a post-hoc analysis of the AFFIRM rate versus rhythm control trial. The overall effectiveness (meeting both rest and exertion ventricular rate goals) of combination therapy with digoxin was described as follows: Beta blocker plus digoxin 68 percent https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 15/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Calcium channel blocker plus digoxin 60 percent Beta blocker plus calcium channel blocker plus digoxin 76 percent The AFFIRM trial is discussed in greater detail separately. (See 'Choice of nonurgent therapy' above.) In patients with AF, the following summarizes evidence regarding the efficacy and safety of digoxin as a combination drug for rate control: Three large observational studies of digoxin use among patients with AF have yielded mixed results, with at least two finding an increase in all-cause mortality of about 20 percent [29,30] and one finding no increase [31]. The best available evidence regarding the relationship between digoxin use in AF patients (either alone or in combination with a beta blocker or calcium channel blocker) and mortality comes from a post-hoc subgroup analysis of the ARISTOTLE trial of anticoagulant therapy [32]. The following findings were reported: Baseline digoxin use was not associated with an increased risk of death (adjusted hazard ratio [HR] 1.09; 95% CI 0.96-1.23) Digoxin concentration 1.2 ng/mL was associated with an increased risk of death (adjusted HR 1.56; 95% CI 1.20-2.04) New digoxin use was associated with a higher risk of death (adjusted HR 1.78; 95% CI 1.37-2.31) Having heart failure versus not having heart failure did not change these effects. 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'.) Alternative medications Amiodarone For patients with AF, there is a limited role for amiodarone as a long-term agent for rate control. Due to the increased 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 [33,34]. We agree with this guideline, and for patients treated with amiodarone for long-term rate control of AF, we require careful follow-up, including monitoring for known medication side effects. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 16/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Data supporting the use of amiodarone as a rate-control agent for AF are more limited compared with evidence supporting its use for pharmacologic rhythm control of AF. In one study, IV amiodarone (7 mg/kg), flecainide, or placebo were given to 98 patients with recent-onset AF (0.5 to 72 hours) [35]. 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 IV diltiazem [36]. Digoxin monotherapy In patients without hypotension or severe heart failure, we do not generally use digoxin as a single agent for the following reasons [33,34]: Association with higher mortality in patients with high digoxin levels. It may not be appropriate for use in older patients. There are additional reasons that digoxin should not be used as an initial drug for rate control in most settings Generally less effective rate control compared with beta blockers or calcium channel blockers, particularly during exercise when vagal tone is low and sympathetic tone is high [37]. This is because the drug slows the ventricular rate during AF, primarily by vagotonic inhibition of AV nodal conduction. Digoxin is only rarely effective at terminating AF. One study suggests that digoxin may have a similar efficacy for rate control as bisoprolol [38]. However, the higher toxicity profile and risk of mortality prevent us from using it as monotherapy. Refractory to rate-control medications Some patients will not achieve adequate ventricular rate control with pharmacologic therapy due to poor response to or intolerance of initial, combination, and alternative medications. In such cases, the options are as follows: AV nodal ablation with permanent pacemaker placement If a patient has high refractory ventricular rates despite initial therapy, combination, and other pharmacotherapies, they may be referred for AV nodal ablation with pacemaker placement to achieve adequate rate control of their AF. This is discussed in detail separately. (See "Atrial fibrillation: Atrioventricular node ablation".) Switching to rhythm control In some patients, it is prudent to reconsider a rhythm- control strategy to control the ventricular rate. This is discussed in detail separately. (See "Management of atrial fibrillation: Rhythm control versus rate control" and "Atrial fibrillation: Atrioventricular node ablation".) https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 17/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Monitoring and adjustments These are more important components of successful rate- control strategies than initial drug selection. Once an effective rate control regimen has been developed, it is reasonable to periodically assess adequacy of rate control; monitoring for both bradycardia and tachycardia is important. (See "Atrial fibrillation: Overview and management of new-onset atrial fibrillation", section on 'Additional cardiac testing' and 'Evaluation and goal ventricular rate' above.) 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. Some experts perform an echocardiogram every two to three years in asymptomatic patients with higher average ventricular rates while others do not. (See "Tests to evaluate left ventricular systolic function".) 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. th th The Basics patient education pieces are written in plain language, at the 5 to 6 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 th th sophisticated, and more detailed. These articles are written at the 10 to 12 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)".) https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 18/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate SUMMARY AND RECOMMENDATIONS Rationale and rate goal We slow the ventricular rate in patients with atrial fibrillation (AF) to treat symptoms, stabilize hemodynamics symptoms, and/or to avoid tachycardia- mediated cardiomyopathy. (See 'Rationale for rate lowering' above.) We target a mean rate-control goal of <85 beats/min for symptomatic patients with AF. For asymptomatic patients with permanent AF, a more lenient mean rate-control goal of <110 beats/min may be reasonable. (See 'Evaluation and goal ventricular rate' above.) Caution in preexcitation syndrome In these patients, initial therapy is aimed at reversion to sinus rhythm rather than rate control. Amiodarone, digoxin, verapamil, diltiazem, and adenosine are contraindicated with preexcited AF, and beta blockers also should not be used. (See "Treatment of arrhythmias associated with the Wolff-Parkinson- White syndrome", section on 'When to avoid AV nodal blockers'.) Urgent therapy Normotensive patients In these patients, we suggest intravenous nondihydropyridine calcium channel blockers such as diltiazem ( table 2) (Grade 2B). (See 'Urgent therapy' above and 'Normotensive patient' above.) 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 (Grade 2C). (See 'Combination therapy' above.) Asymptomatic hypotensive patients who do not require vasopressor We typically start oral metoprolol tartrate (short-acting) until the rate is controlled. In patients who do not adequately respond to initial therapy with either IV calcium channel blocker or IV beta blocker, we suggest the addition of IV digoxin as the second drug in combination therapy ( table 2). (See 'Asymptomatic and not on a vasopressor' above.) In patients who do not respond to or are intolerant of IV calcium channel blockers, beta blockers, and/or digoxin, we suggest IV amiodarone as a short-term rate- control strategy ( table 2). Careful attention to anticoagulation is also necessary because there is a small chance of cardioversion with amiodarone. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 19/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate 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 appropriate anticoagulation strategy). Symptomatic hypotensive patients and/or those requiring vasopressors 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 anticoagulation strategy). (See 'Symptomatic hypotension and/or on a vasopressor' above and "Prevention of embolization prior to and after restoration of sinus rhythm in atrial fibrillation".) Elective and long-term management We start an oral beta blocker or nondihydropyridine calcium channel blocker. (See 'Choice of nonurgent therapy' above.) Combination therapy We try a combination of oral beta blocker and calcium channel blocker if monotherapy is not effective. (See 'Combination therapy' above.) Alternative short-term 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 (Grade 2C). (See 'Alternative medications' above.) Refractory to rate control In patients who have a poor response or intolerance to pharmacologic therapy, options are: Atrioventricular (AV) nodal ablation with permanent pacemaker placement. (See "Atrial fibrillation: Atrioventricular node ablation".) Switching to rhythm control. (See "Management of atrial fibrillation: Rhythm control versus rate control" and "Atrial fibrillation: Atrioventricular node ablation".) Monitoring Careful follow-up for side effects such as bradycardia or persistent tachycardia is imperative. (See 'Monitoring and adjustments' above.) ACKNOWLEDGMENT The UpToDate editorial staff acknowledges Leonard Ganz, MD, FHRS, FACC, who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 20/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate REFERENCES 1. Pritchett EL. Management of atrial fibrillation. N Engl J Med 1992; 326:1264. 2. Atrial fibrillation: current understandings and research imperatives. The National Heart, Lung, and Blood Institute Working Group on Atrial Fibrillation. J Am Coll Cardiol 1993; 22:1830. 3. Mariani MV, Pierucci N, Piro A, et al. Incidence and Determinants of Spontaneous Cardioversion of Early Onset Symptomatic Atrial Fibrillation. Medicina (Kaunas) 2022; 58. 4. Lindberg S, Hansen S, Nielsen T. Spontaneous conversion of first onset atrial fibrillation. Intern Med J 2012; 42:1195. 5. Pluymaekers NAHA, Dudink EAMP, Weijs B, et al. Clinical determinants of early spontaneous conversion to sinus rhythm in patients with atrial fibrillation. Neth Heart J 2021; 29:255. 6. Knight S, Lipoth J, Namvari M, et al. The Accuracy of Wearable Photoplethysmography Sensors for Telehealth Monitoring: A Scoping Review. Telemed J E Health 2023; 29:813. 7. Dorian P. Rate control in atrial fibrillation. N Engl J Med 2010; 362:1439. 8. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347:1825. 9. Van Gelder IC, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010; 362:1363. 10. Groenveld HF, Tijssen JG, Crijns HJ, et al. Rate control efficacy in permanent atrial fibrillation: successful and failed strict rate control against a background of lenient rate control: data from RACE II (Rate Control Efficacy in Permanent Atrial Fibrillation). J Am Coll Cardiol 2013; 61:741. 11. B hm M, Schwinger RH, Erdmann E. Different cardiodepressant potency of various calcium antagonists in human myocardium. Am J Cardiol 1990; 65:1039. 12. Salerno DM, Dias VC, Kleiger RE, et al. Efficacy and safety of intravenous diltiazem for treatment of atrial fibrillation and atrial flutter. The Diltiazem-Atrial Fibrillation/Flutter Study Group. Am J Cardiol 1989; 63:1046. 13. Ellenbogen KA, Dias VC, Plumb VJ, et al. A placebo-controlled trial of continuous intravenous diltiazem infusion for 24-hour heart rate control during atrial fibrillation and atrial flutter: a multicenter study. J Am Coll Cardiol 1991; 18:891. 14. Ellenbogen KA, Dias VC, Cardello FP, et al. Safety and efficacy of intravenous diltiazem in atrial fibrillation or atrial flutter. Am J Cardiol 1995; 75:45. 15. Steinberg JS, Katz RJ, Bren GB, et al. Efficacy of oral diltiazem to control ventricular response in chronic atrial fibrillation at rest and during exercise. J Am Coll Cardiol 1987; 9:405. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 21/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate 16. Roth A, Harrison E, Mitani G, et al. Efficacy and safety of medium- and high-dose diltiazem alone and in combination with digoxin for control of heart rate at rest and during exercise in patients with chronic atrial fibrillation. Circulation 1986; 73:316. 17. Lan Q, Wu F, Han B, et al. Intravenous diltiazem versus metoprolol for atrial fibrillation with rapid ventricular rate: A meta-analysis. Am J Emerg Med 2022; 51:248. 18. Posen A, Bursua A, Petzel R. DOsing Strategy Effectiveness of Diltiazem in Atrial Fibrillation With Rapid Ventricular Response. Ann Emerg Med 2023; 81:288. 19. Davey MJ, Teubner D. A randomized controlled trial of magnesium sulfate, in addition to usual care, for rate control in atrial fibrillation. Ann Emerg Med 2005; 45:347. 20. Ramesh T, Lee PYK, Mitta M, Allencherril J. Intravenous magnesium in the management of rapid atrial fibrillation: A systematic review and meta-analysis. J Cardiol 2021; 78:375. 21. Chan YH, Hai JJ, Wong CK, et al. Ventricular rate control with ivabradine in patients with permanent atrial fibrillation. J Interv Card Electrophysiol 2022; 65:597. 22. Fontenla A, L pez-Gil M, Tamargo-Men ndez J, et al. Ivabradine for chronic heart rate control in persistent atrial fibrillation. Design of the BRAKE-AF project. Rev Esp Cardiol (Engl Ed) 2020; 73:368. 23. Sorrentino MJ. Switching from drip to oral diltiazem therapy. Postgrad Med 1998; 104:37. 24. Drug Class Review: Calcium Channel Blockers: Final Report, Oregon Health & Science Univer sity. 25. 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. 26. Olshansky B, Rosenfeld LE, Warner AL, et al. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study: approaches to control rate in atrial fibrillation. J Am Coll Cardiol 2004; 43:1201. 27. Park CS, Lee HY. Clinical utility of sympathetic blockade in cardiovascular disease management. Expert Rev Cardiovasc Ther 2017; 15:277. 28. Dobrev D, Aguilar M, Heijman J, et al. Postoperative atrial fibrillation: mechanisms, manifestations and management. Nat Rev Cardiol 2019; 16:417. 29. Turakhia MP, Santangeli P, Winkelmayer WC, et al. Increased mortality associated with digoxin in contemporary patients with atrial fibrillation: findings from the TREAT-AF study. J Am Coll Cardiol 2014; 64:660. 30. Washam JB, Stevens SR, Lokhnygina Y, et al. Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 22/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Lancet 2015; 385:2363. 31. Allen LA, Fonarow GC, Simon DN, et al. Digoxin Use and Subsequent Outcomes Among Patients in a Contemporary Atrial Fibrillation Cohort. J Am Coll Cardiol 2015; 65:2691. 32. Lopes RD, Rordorf R, De Ferrari GM, et al. Digoxin and Mortality in Patients With Atrial Fibrillation. J Am Coll Cardiol 2018; 71:1063. 33. 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. 34. 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. 35. Donovan KD, Power BM, Hockings BE, et al. Intravenous flecainide versus amiodarone for recent-onset atrial fibrillation. Am J Cardiol 1995; 75:693. 36. Delle Karth G, Geppert A, Neunteufl T, et al. Amiodarone versus diltiazem for rate control in critically ill patients with atrial tachyarrhythmias. Crit Care Med 2001; 29:1149. 37. Van Gelder IC, Rienstra M, Crijns HJ, Olshansky B. Rate control in atrial fibrillation. Lancet 2016; 388:818. 38. Kotecha D, Bunting KV, Gill SK, et al. Effect of Digoxin vs Bisoprolol for Heart Rate Control in Atrial Fibrillation on Patient-Reported Quality of Life: The RATE-AF Randomized Clinical Trial. JAMA 2020; 324:2497. Topic 938 Version 69.0 https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 23/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate 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 https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 24/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate 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 https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 25/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate [2,3] Six-minute walk test technique Flat, straight corridor 30 m (100 feet) in length Turnaround points marked with a cone Patient should wear comfortable clothes and shoes Patient rests in chair for at least 10 minutes prior to test (ie, no warm-up period) Heart rate and pulse oxygen saturation (SpO ) should be monitored throughout the test 2 If the patient is using supplemental oxygen, record the flow rate and type of device [1] Have patient stand and rate baseline dyspnea and overall fatigue using Borg scale* Set lap counter to zero and timer to six minutes Instruct the patient: Remember that the object is to walk AS FAR AS POSSIBLE for 6 minutes, but don't run or jog. Pivot briskly around the cone. Standardized encouragement statements should be provided at one minute intervals, such as "You are doing well. You have _ minutes to go" and "Keep up the good work. You have _ minutes to go." At the end of the test, mark the spot where the patient stopped on the floor If using a pulse oximeter, measure the pulse rate and SpO and record 2 [1] After the test record the Borg* dyspnea and fatigue levels Ask, "What, if anything, kept you from walking farther?" Calculate the distance walked and record Refer to UpToDate table on the modified Borg Scale. Reference: 1. Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc 1982; 14:377. 2. American Thoracic Society. ATS statement: Guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002; 166:111. 3. Holland AE, Spruit MA, Troosters T, et al. An o cial European Respiratory Society/American Thoracic Society technical standard: eld walking tests in chronic respiratory disease. Eur Respir J 2014; 44:1428. Graphic 90285 Version 4.0 https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 26/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate Medications and doses for ventricular rate control in adult patients with atrial fibrillation Medication IV dosing Oral dosing* Notes Diltiazem Bolus dosing: IR: 30 mg 4 times daily; increase as needed to IV regimen usually controls the ventricular First bolus: 0.25 achieve ventricular rate control; usual dose: 120 mg/kg (average adult dose: 20 mg) rate within 4 to 5 minutes. to 480 mg/day in 3 or 4 administered over 2 Some experts use a lower bolus dose of 5 divided doses. minutes; if dose is tolerated but does to 15 mg if there is concern for ER: 120 mg once daily or in 2 divided doses not produce desired response (ie, 20% hypotension. depending on formulation ; increase as reduction in baseline heart rate or heart rate 100 beats/min) within 15 minutes, administer a second needed to achieve ventricular rate control; usual dose: 120 to 480 mg/day. bolus. Second bolus: 0.35 mg/kg (average adult dose: 25 mg) administered over 2 minutes. In those who respond to the first or second bolus, initiate a continuous infusion at 5 to 10 mg/hour. May increase in 5 mg/hour increments as needed to a maximum of 15 mg/hour. Esmolol Rapid titration with bolus Not available as oral Due to short half-life, doses: preparation. useful when uncertain if patient will become 500 mcg/kg loading dose administered over 1 minute, hypotensive with a beta blocker. followed by a continuous infusion of 50 mcg/kg/minute. Reassess after 4 minutes. https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 27/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate If response is inadequate, administer a second bolus of 500 mcg/kg and increase infusion to 100 mcg/kg/minute. Reassess after 4 minutes. If response is inadequate, administer a third and final bolus of 500 mcg/kg and increase infusion to 150 mcg/kg/minute. Reassess after 4 minutes. If response is inadequate, may increase infusion to a maximum of 200 mcg/kg/minute. OR Slow titration without bolus doses: Initiate continuous infusion at 50 mcg/kg/minute; if needed based on clinical response, may increase in 50 mcg/kg/minute increments at 30- minute intervals to a maximum of 200 mcg/kg/minute. Verapamil Bolus dosing: 5 to 10 mg administered over 2 to 3 IR: 40 mg 3 to 4 times daily; increase as needed Rate control is often achieved with 1 or 2 minutes; may repeat every 15 to 30 minutes as to achieve ventricular rate control; maximum dose: bolus doses. With IV administration, needed and tolerated. 480 mg/day in 3 to 4 divided doses. onset of effect on AV node is within 2 Once rate control is achieved with bolus doses, minutes and peak https://www.uptodate.com/contents/control-of-ventricular-rate-in-patients-with-atrial-fibrillation-who-do-not-have-heart-failure-pharmacologic-therapy/ 28/33 7/5/23, 9:14 AM Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy - UpToDate initiate a continuous infusion at 5 mg/hour; ER : 120 or 180 mg once daily; increase as needed effect is in 10 to 15 minutes. titrate based on clinical to achieve ventricular rate Control of the ventricular response is response to a maximum of 20 mg/hour. control; maximum dose: 480 mg/day in 1 to 2 lost in approximately divided doses. 90 minutes if repeated boluses or a maintenance infusion are not given. Metoprolol Bolus dosing: 2.5 to 5 mg IR (metoprolol tartrate): administered over 2 minutes; may repeat at 5- 25 mg twice daily; increase dose gradually minute intervals up to a (eg, by 12.5 mg every 6 total dose of 15 mg. hours) as needed and tolerated to achieve While subsequent doses can be given intravenously, ventricular rate control; maximum dose: 100 mg the optimal regimen is not well defined, and oral twice daily. administration is ER (metoprolol succinate): preferable. 50 mg once daily; increase dose gradually as tolerated to achieve ventricular rate control; maximum dose: 400 mg once daily. Propranolol Bolus dosing: 1 mg IR: 10 mg 3 to 4 times administered over 1 minute; may repeat at 2- daily; increase dose gradually as tolerated to minute intervals for up to 3 achieve ventricular rate doses. control; maximum dose: 40 mg 3 to 4 times daily. ER: 60 mg once daily; increase as needed to achieve ventricular rate control up to 160 mg once daily. Digoxin TDD: 0.25 to 0.5 mg administered over several TDD: 0.5 mg once, followed by 0.25 mg every May use as add-on therapy in patients who minutes, followed by 0.25 mg every 6 hours for a 6 hours for a total loading dose of 0.75 to 1.5 mg.