7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials : Kapil Kumar, MD, Peter J Zimetbaum, MD : 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: Jan 09, 2023. INTRODUCTION Long-term outcomes, such as survival or rate of thromboembolism, are similar with either rhythm or rate control strategies in patients with atrial fibrillation (AF) ( figure 1A-B). In addition, anticoagulation is required with both in most patients [1,2]. Thus, the main goal of therapy is to reduce symptoms by decreasing the frequency and duration of episodes [3,4]. When the rhythm control strategy is chosen, the recommended drugs for maintenance of sinus rhythm vary with the clinical setting ( table 1 and algorithm 1) [3,5]. Optimal antiarrhythmic drug therapy should be both effective and have a low incidence of toxicity, including proarrhythmia [6-8]. Most patients for whom rhythm control is chosen will require rate control, both prior to its initiation and after, as many patients will have breakthrough episodes of AF. (See "Control of ventricular rate in patients with atrial fibrillation who do not have heart failure: Pharmacologic therapy".) The studies describing the efficacy and toxicity (including proarrhythmia) of the different antiarrhythmic drugs used to maintain sinus rhythm in patients with AF will be reviewed here. Recommendations concerning the use of pharmacologic therapy, the choice between a rhythm and a rate control strategy, and the role of alternative methods to maintain sinus rhythm in selected patients who are refractory to conventional therapy, including surgery and radiofrequency ablation, are discussed separately. (See "Antiarrhythmic drugs to maintain sinus https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 1/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate rhythm in patients with atrial fibrillation: Recommendations" and "Management of atrial fibrillation: Rhythm control versus rate control" and "Atrial fibrillation: Catheter ablation" and "Atrial fibrillation: Surgical ablation".) This topic will also address the issue of whether other medications are associated with a decreased frequency of recurrent AF. (See 'Other therapies' below.) META-ANALYSIS The safety and efficacy of a number of antiarrhythmic drugs was assessed in a 2019 meta- analysis, which included 59 trials (n = 20,981) in which an antiarrhythmic drug for the treatment of atrial fibrillation (AF) was compared against a placebo, another antiarrhythmic, or untreated controls [9]. The following findings were noted: Compared with controls, disopyramide, quinidine, flecainide, propafenone, amiodarone, dofetilide, dronedarone, and sotalol lowered the recurrence rate of AF (risk ratios [RR] 0.77, 0.83, 0.65, 0.67, 0.52, 0.72, 0.85, and 0.83, respectively). Metoprolol also lowered the risk (RR 0.83). All-cause mortality was increased (compared with controls) with sotalol (2.23, 95% CI 1.03- 4.81). Mortality may be increased with other antiarrhythmic drugs, but the evidence was of moderate certainty or weak. These data support the general observation (as summarized in the following sections) that antiarrhythmics can reduce AF recurrences, but their overall value is limited by adverse effects. All of the antiarrhythmic drugs used to maintain sinus rhythm in AF have the potential to provoke ventricular arrhythmias. (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring" and "Sustained monomorphic ventricular tachycardia: Clinical manifestations, diagnosis, and evaluation", section on 'Drugs'.) CLASS IA ANTIARRHYTHMIC DRUGS Quinidine, disopyramide, and procainamide are class IA antiarrhythmic drugs ( table 2). These drugs act by modifying the sodium channel and inhibiting the outward potassium current resulting in QT prolongation. They also have important vagolytic effects. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) Quinidine is the most widely studied class IA agent for the maintenance of sinus rhythm in AF [10,11]. Although studies have shown that quinidine can reduce the rate of recurrent AF https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 2/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate compared to placebo, it is associated with an increase in mortality, particularly in patients with heart failure [7,8,12,13]. The use of quinidine for the maintenance of sinus rhythm has declined largely because other drugs are both more effective and safer. Disopyramide also seems to have some benefit in the prevention of recurrent AF [14], although it must be used with caution since it can significantly worsen underlying heart failure. The efficacy of oral procainamide has been evaluated in older and poorly controlled trials or in patients who recently underwent coronary artery bypass surgery [15-17]. Oral procainamide is not readily available in the US. CLASS IC ANTIARRHYTHMIC DRUGS Flecainide and propafenone are classified as class IC antiarrhythmic agents, although they are known to have significantly different electrophysiologic and other properties. The following observations have been made regarding their efficacy: Compared to placebo, both are more effective in maintaining sinus rhythm at six months and in prolonging the time to atrial fibrillation (AF) recurrence [18-26]. Flecainide and propafenone appear to have equal efficacy [27,28]. In a randomized, open- label study of 200 patients, for example, the probability of a safe and effective response (maintenance of sinus rhythm or fewer episodes of paroxysmal AF) at one year was 77 and 75 percent with flecainide and propafenone, respectively [27]. A meta-analysis evaluated trials of patients with AF resistant to class I drugs or sotalol who were treated with flecainide or amiodarone after cardioversion [29]. Maintenance of sinus rhythm at 12 months was significantly more likely with amiodarone (60 versus 34 percent with flecainide). Despite the apparent benefit for the prevention of recurrent AF, the toxicity associated with these drugs has restricted their use. The cardiac complications of the class IC drugs include worsening of heart failure, bradycardia, and presumably drug-induced atrial and ventricular arrhythmias in 7 to 27 percent of cases. In up to 13 percent of patients AF recurs as, or converts to, persistent atrial flutter [30]. Radiofrequency ablation of the atrial flutter, with continuation of the antiarrhythmic agent, is an effective approach for reducing arrhythmia recurrence and duration [30,31]. (See 'Hybrid therapy in patients who develop atrial flutter' below and "Atrial flutter: Maintenance of sinus rhythm".) https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 3/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate The use of flecainide is restricted to those patients who have no structural heart disease, particularly coronary heart disease. The concern about the use of the class IC agents is primarily the result of the Cardiac Arrhythmia Suppression Trial (CAST), which showed that flecainide increased the number of deaths among patients with drug-suppressible ventricular premature beats in the year following a myocardial infarction ( figure 2) [32]. It is not known if these findings can be extrapolated to other types of heart disease. (See "Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management", section on 'Class I agents'.) Propafenone has some mild beta-blocking activity in addition to its effects on the sodium channel. Thus, its toxicity may not be identical to that of flecainide and, in patients with ventricular arrhythmia, propafenone appears to be less proarrhythmic. In a study of 480 patients with supraventricular arrhythmia treated with propafenone for 14 months, 59 percent of patients experienced at least one side effect; the drug was discontinued due to an adverse reaction in only 15 percent, while 17 percent required a reduction in dose [33]. Arrhythmia aggravation occurred in 2 percent of patients; the incidence was higher in those with structural heart disease compared to those without (3 versus 1 percent). CLASS III ANTIARRHYTHMIC AGENTS Amiodarone, dronedarone, sotalol, dofetilide, and ibutilide are classified as class III antiarrhythmic agents. There are, however, many dissimilarities among these drugs, and they should be considered separately. (See "Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs".) Amiodarone Amiodarone is the most effective antiarrhythmic drug for the prevention of atrial fibrillation (AF), as demonstrated in the following randomized trials [34-39]: The Canadian Trial of Atrial Fibrillation (CTAF) randomly assigned 403 patients who had at least one episode of AF within six months of entry to low-dose amiodarone, sotalol, or propafenone [34]. After a mean follow-up of 16 months, amiodarone was associated with a significantly greater likelihood of being free from recurrent AF (65 versus 37 percent for sotalol and propafenone) and a longer median time to recurrence (>468 versus 98 days) ( figure 3). There was no difference among the three therapies in mortality, but there was an almost significant trend toward an increased incidence of side effects resulting in drug discontinuation with amiodarone (18 versus 11 percent for sotalol or propafenone). (See "Amiodarone: Adverse effects, potential toxicities, and approach to monitoring".) Similar relative efficacies were noted in a substudy from the AFFIRM trial [37]. Patients in the rhythm control arm were randomly assigned to amiodarone or sotalol (256 patients), https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 4/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate amiodarone or a class I drug (222 patients), or sotalol and a class I drug (183 patients). The one-year endpoint was defined as the patient being alive, being in sinus rhythm at follow- up visits, still taking the drug (ie, no discontinuation for episodes of highly symptomatic AF), and needing no electrical or pharmacologic cardioversions. The likelihood of achieving the endpoint was significantly higher with amiodarone compared to sotalol (60 versus 38 percent) or a class I drug (62 versus 23 percent). In comparison to CTAF, amiodarone was not associated with a higher risk than sotalol of cessation of therapy for adverse effects (13 versus 16 percent). The SAFE-T trial compared amiodarone, sotalol, and placebo in patients with persistent AF for both conversion to sinus rhythm and maintenance of sinus rhythm [35]. The rate of maintenance of sinus rhythm was significantly higher at one year with amiodarone than sotalol or placebo and with sotalol than placebo (52 versus 32 and 13 percent on intention to treat analysis and 65 versus 40 and 18 percent on treatment received analysis). The primary endpoint, the median time to recurrence beginning after day 28, was 487, 74, and 6 days in the three groups. However, among the approximately 25 percent of patients with ischemic heart disease, the median time to recurrence with amiodarone was not significantly different from sotalol (569 versus 428 days). There was no difference among the study groups in terms of adverse effects except for a small increase in minor bleeding among patients treated with amiodarone. The mortality rate was not significantly higher with amiodarone and sotalol combined compared to placebo (4.36 versus 2.84 per 100 person-years), but trials of patients with heart failure or myocardial infarction have not shown an increase in mortality with amiodarone [40,41]. Nonrandomized studies of patients with chronic or paroxysmal AF refractory to most other antiarrhythmic agents have shown that amiodarone maintained sinus rhythm in 53 to 79 percent of cases during a 15 to 27 month follow-up [42-45]. Amiodarone is less effective in patients who have AF for over one year or who have an enlarged LA. However, even in this group, the success rate with amiodarone may be as high as 50 to 60 percent [42,43]. Amiodarone has also been evaluated as a prophylactic therapy to prevent AF after cardiac surgery. This issue is discussed separately. (See "Early noncardiac complications of coronary artery bypass graft surgery".) Sotalol Sotalol is not very effective in converting AF to sinus rhythm, but is useful in preventing recurrent episodes [46-48]. As an example, one study randomly assigned 253 patients with AF or atrial flutter to placebo or three doses of sotalol (80, 120, or 160 mg BID); the recurrence rate at one year was 72, 70, 60, and 55 percent, respectively, and the median times to https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 5/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate recurrence were 27, 106, 119, and 175 days, respectively [48]. As noted with other drugs, predictors of AF recurrence were the presence of coronary disease, duration of AF >2 months before reversion, LA size >60 mm, and older age. A number of studies have compared the efficacy of sotalol to other antiarrhythmic drugs for preventing recurrent AF. As noted above, randomized controlled trials and a substudy analysis from AFFIRM demonstrated that sotalol was less effective than amiodarone [34-37]. After a mean follow- up of 16 months in CTAF, for example, amiodarone was associated with a significantly greater likelihood of being free from recurrent AF (65 versus 37 percent for sotalol and propafenone) and a longer median time to recurrence (>468 versus 98 days) ( figure 3) [34]. Similar findings were noted in SAFE-T [35]. (See 'Amiodarone' above.) Sotalol appears to have equal efficacy to propafenone [34,49,50]. The best data come from CTAF, which randomly assigned 403 patients who had at least one episode of AF within six months of entry to low-dose amiodarone, sotalol, or propafenone [34]. After a mean follow-up of 16 months, the proportion of patients free from recurrent AF was 37 percent with both sotalol and propafenone ( figure 3). (See 'Amiodarone' above.) Dofetilide Dofetilide is a class III antiarrhythmic drug ( table 2). The SAFIRE-D trial evaluated 204 patients with AF who were successfully cardioverted electrically or pharmacologically with dofetilide and maintained on a dose of 125, 250, or 500 g twice daily or placebo [51]. The probability of remaining in sinus rhythm at one year was significantly greater for dofetilide compared to placebo (40, 37, and 58 versus 25 percent). The all-cause mortality was the same in the four groups. (See "Atrial fibrillation: Cardioversion", section on 'Specific antiarrhythmic drugs'.) The results were similar in the EMERALD trial, which randomly assigned patients who were pharmacologically or electrically cardioverted to therapy with one of three doses of dofetilide (125, 250, or 500 g twice daily), sotalol (80 mg twice daily), or placebo [52]. After 12 months of therapy, AF recurred in 79 percent of placebo patients, 34 percent of those receiving the highest dose of dofetilide, and between 48 and 60 percent in the other groups. (See "Clinical use of dofetilide".) It is of concern that nonfatal torsades de pointes (TdP) or sudden death occurred in four patients in the high-dose dofetilide group [52]. However, a pooled analysis of 1346 patients receiving dofetilide and 677 treated with placebo in randomized clinical trials of the treatment of supraventricular arrhythmias found that dofetilide was not associated with an increase in mortality (adjusted hazard ratio 1.1) [53]. https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 6/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate The lack of an increase in mortality with dofetilide is reassuring. However, because drug-induced TdP is relatively rare and can be treated if it occurs in a monitored setting, the impact of this complication may not be seen in analyses limited to overall survival. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) Dronedarone Dronedarone is a derivative of amiodarone. In patients with AF, randomized trials with up to 12 months of follow-up have found that dronedarone prevents recurrent AF and was safe (including no increased risk of serious arrhythmias) [54-56]. However, in the ANDROMEDA trial in patients with advanced heart failure from LV systolic dysfunction, there was an increased risk of death with dronedarone and the trial was stopped early [57]. As a result, dronedarone is contraindicated in this population of patients. (See "The management of atrial fibrillation in patients with heart failure", section on 'Antiarrhythmic drugs'.) In the ATHENA trial 4628 patients with AF were randomly assigned to either dronedarone or placebo [58]. Patients with New York Heart Association (NYHA) class II or III heart failure comprised 21 percent of the study population, but patients with NYHA class IV heart failure were excluded. After a mean follow-up period of 21 months, dronedarone significantly reduced the primary outcome of death or cardiovascular hospitalization (31.9 versus 39.4 percent, hazard ratio 0.76, 95% CI 0.69-0.84) and the secondary outcome of cardiovascular death (2.7 versus 3.9 percent, hazard ratio 0.71, 95% CI 0.51-0.98). Dronedarone is the only antiarrhythmic drug that has shown a salutary effect on mortality. Maintenance of sinus rhythm was not one of the endpoints in ATHENA. The DIONYSOS study was a short-term (median duration of seven months) comparison between amiodarone and dronedarone to assess the differences in drug tolerability and AF recurrence in 504 patients [59]. Sixty percent of the patients had persistent AF. The authors found that the composite primary endpoint of AF recurrence or premature study drug discontinuation occurred in 75.5 percent of patients taking dronedarone, but only 58.8 percent of patients taking amiodarone. This endpoint was primarily driven by AF recurrence on dronedarone compared to amiodarone (63.5 versus 42.0 percent, respectively). Drug discontinuation and the main safety endpoints of extra-cardiac toxicity only tended to be less with dronedarone, but did not reach statistical significance. It is possibly that with longer follow-up periods there would have been a greater difference in noncardiac side effects, since the toxicity with amiodarone is typically manifest after several months to years of use. In a meta-analysis of dronedarone trials prior to the DIONYSOS study, where the effect of amiodarone versus dronedarone was estimated with the use of indirect comparison and normal logistic meta-analysis models, a similar conclusion was reached [60]. Amiodarone was found to https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 7/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate be more effective in maintaining sinus rhythm, but at the expense of greater drug discontinuation secondary to adverse events. The PALLAS trial, which was stopped early due to an increase in adverse events in patients taking dronedarone, evaluated the potential use of dronedarone to improve cardiovascular outcomes in patients with permanent AF. This trial is discussed elsewhere. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Concerns about dronedarone'.) Ibutilide Ibutilide is only available for intravenous use and therefore is useful for the acute reversion of AF, not for long-term prevention [61]. (See "Atrial fibrillation: Cardioversion".) Vernakalant Vernakalant is considered a relatively atrially-selective antiarrhythmic agent since one of its main actions is to inhibit the ultrarapid potassium current (IKur) and the acetylcholine potassium current (IKAch), both of which are predominantly found in the atria. Vernakalant also mildly inhibits other potassium channels and, to a much lesser extent, the sodium current. The program for vernakalant drug development in the US has been terminated. The drug is available in an intravenous form to terminate AF in Europe. BETA BLOCKERS There is no evidence to support the use of beta blockers (aside for sotalol), in the absence of other antiarrhythmic drugs, for the prevention of atrial fibrillation (AF). In patients with heart failure (HF) due to systolic dysfunction, chronic treatment with certain beta blockers reduces mortality. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.) There is evidence that beta blockers may also reduce the likelihood of the development of AF in patients with HF. A systematic review including seven randomized trials of 11,952 patients evaluated the efficacy of beta blockers for this purpose [62]. Among patients who were in sinus rhythm at baseline and were followed for six months to two years, the incidence of new onset AF was significantly lower in patients treated with beta blockers than those assigned to placebo (28 versus 39 per 1000 patient years). (See "The management of atrial fibrillation in patients with heart failure".) A separate issue is whether beta blockers, which are felt to have some antiarrhythmic properties ( table 2), are effective for preventing recurrent atrial fibrillation in patients with no heart disease. The evidence to support their use for this purpose is scant, and any reduction in the https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 8/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate reported frequency of AF may be attributable to improved rate control that may render recurrent AF silent. VERAPAMIL The calcium channel blocking agents verapamil and diltiazem impair conduction and prolong refractoriness in the AV node. They have been used both acutely and chronically to slow the ventricular response in atrial fibrillation (AF). Verapamil has also been investigated for its effectiveness in maintaining sinus rhythm after cardioversion. The rationale for this approach is the observation that the electrical remodeling that occurs during AF is thought to be due, at least in part, to abnormal calcium loading during rapid atrial rates. In studies in animals and humans, verapamil has been shown to prevent electrical remodeling [63,64]. (See "Mechanisms of atrial fibrillation", section on 'Electrical remodeling'.) Verapamil as a single agent was not effective in preventing AF recurrence in the VERDICT trial, in which 97 patients with persistent AF were randomly assigned to either verapamil or digoxin [65]. There was no difference in AF recurrence rates at one month. It was suggested that verapamil may be effective only when given with a sodium or potassium channel blocking agent [66]. Verapamil with another agent Based upon the observations cited above, several studies evaluated the benefit of verapamil with another agent in preventing recurrences of AF. In the small VEPARAF trial, the addition of verapamil to either amiodarone or flecainide significantly reduced the incidence of recurrent AF within three months of cardioversion compared with either agent alone [67]. The larger PAFAC and SOPAT trials found the combination of verapamil and quinidine to be comparable to sotalol, and superior to placebo, in preventing AF recurrence. In PAFAC, 848 patients with persistent AF were cardioverted and then randomly assigned to sotalol, quinidine and verapamil, or placebo [68]. Patients used an event recorder to record and transmit at least one ECG daily during a mean of nine months of follow-up. The incidence of death or any AF recurrence was significantly lower for both sotalol and for quinidine plus verapamil than for placebo (67 and 65 versus 83 percent). Serious adverse events were not more common with quinidine plus verapamil than with sotalol, and the only episodes of torsades de pointes occurred with sotalol. In the SOPAT trial, 1033 patients with recurrent symptomatic paroxysmal AF were randomly assigned to placebo, sotalol, or one of two dose combinations of quinidine plus verapamil [69]. As in the PAFAC trial, patients recorded and transmitted at least one ECG daily with an event https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 9/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate recorder. The mean time to first AF recurrence was prolonged significantly in all three active treatment groups compared to placebo. At a mean of eight months of follow-up, the number of days of symptomatic AF was reduced significantly for all three active treatment arms compared to placebo. There was no difference between the sotalol and the two quinidine plus verapamil treatment groups in either of these efficacy endpoints or in the incidence of serious adverse side effects. OTHER THERAPIES In addition to conventional antiarrhythmic drugs, a number of other agents have been investigated for the purpose of suppressing atrial fibrillation (AF). ACE inhibitors, angiotensin II receptor blockers Both angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) reduce the incidence of atrial fibrillation in selected patient populations. In a recent meta-analysis of 26 randomized trials that evaluated the effect of ACE inhibitors and ARBs on the prevention of AF, it was demonstrated that both classes of drugs had a similar beneficial effect on AF [70]. The effect was more potent for recurrent AF compared to primary prevention of AF (OR 0.45 versus 0.80, respectively). ACE inhibitor or ARB effect on AF was additive to that of amiodarone when used concurrently and endured even in patients with depressive LV function. This issue is discussed in further detail separately. (See "ACE inhibitors, angiotensin receptor blockers, and atrial fibrillation".) Magnesium Although not a primary antiarrhythmic agent, magnesium affects atrial electrophysiologic properties. Some studies, particularly those in patients undergoing coronary artery bypass surgery, have found that magnesium deficiency is associated with AF and that magnesium supplementation reduces its incidence. (See "Significance of hypomagnesemia in cardiovascular disease" and "Atrial fibrillation and flutter after cardiac surgery", section on 'Ineffective or possibly effective therapies'.) The role of oral magnesium therapy in the prevention of recurrent AF after cardioversion was evaluated in one study of 301 patients who were followed for at least six months after the restoration of sinus rhythm; magnesium therapy alone or in combination with sotalol was ineffective for preventing recurrent AF [71]. Statins There is some evidence that statins may prevent recurrences in patients with lone AF [72,73], ischemic heart disease [73,74] and after cardiac bypass surgery [73,75]. Aldosterone Blockers These drugs have been useful in the treatment of heart failure. Spironolactone and eplerenone have effects on atrial electrophysiologic properties in https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 10/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate experimental animals, but no studies in patients with AF have been done. DRUG-REFRACTORY ATRIAL FIBRILLATION Some patients are refractory to individual antiarrhythmic agents plus an AV nodal blocker or develop side effects on doses necessary for arrhythmia prevention. There are limited data to support the use of combination antiarrhythmic drug therapy, and this approach may expose the patient to a greater risk of proarrhythmia and other side effects. As a result, combination therapy is not recommended. Such patients can be treated with a rate control strategy or referred for nonpharmacologic therapy of atrial fibrillation (AF). These options include: Radiofrequency catheter ablation (RFA), which is the most common of these approaches. (See "Atrial fibrillation: Catheter ablation".) Surgical procedures such as the maze operation, particularly for patients undergoing cardiac surgery for another indication. Some centers also offer mini-maze operations using limited bilateral thoracotomies as standalone procedures as well. (See "Atrial fibrillation: Surgical ablation".) HYBRID THERAPY IN PATIENTS WHO DEVELOP ATRIAL FLUTTER Atrial flutter can occur after the initiation of antiarrhythmic drug therapy in patients with atrial fibrillation (AF), especially with the use of class IC agents or amiodarone. One approach to managing this situation has been a hybrid approach that involves ablation of atrial flutter by creating a block across the cavotricuspid isthmus and then continuation of the antiarrhythmic drug. Although this approach may be helpful in maintaining sinus rhythm in the short term, data (articles below) suggest that in the long term, there is a high recurrence of AF [76,77]. Therefore, the development of atrial flutter on an antiarrhythmic drug may be considered failure of therapy. SUMMARY Recommendations for the use drug therapy to maintain sinus rhythm in patients with atrial fibrillation (AF) are found elsewhere. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".) https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials/print 11/27 7/5/23, 9:02 AM Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials - UpToDate The following are the important points made in this topic: The main goal of drug therapy to maintain sinus rhythm is to reduce symptoms by decreasing the frequency and duration of episodes. The primary endpoint of many clinical trials involving antiarrhythmic drugs has been time to first recurrence of AF. However, there is great variation in efficacy of antiarrhythmic drugs from patient to patient. Although a drug may be shown to significantly prolong the time to recurrence of AF in a clinical trial, some patients will experience no benefit and others will experience a dramatic reduction in AF frequency. Other outcomes are also important. These include the effect of the drug on overall AF burden, AF episode duration, symptoms, ventricular rate control, and hospitalizations. A single recurrence of AF on a drug does not necessarily indicate treatment failure or require a change in therapy. When the rhythm control strategy is chosen, the recommended drugs for maintenance of sinus rhythm vary with the clinical setting ( table 1 and algorithm 1). Optimal antiarrhythmic drug therapy should be both effective and have a low incidence of toxicity, including proarrhythmia. Amiodarone, sotalol, dofetilide, dronedarone, flecainide, and propafenone are effective in the maintenance of sinus rhythm. Of these, amiodarone is the most effective, but is associated with the development of more frequent side effects. Dronedarone is also associated with the development of significant side effects as well as worse outcomes in some groups of patients with AF. (See 'Amiodarone' above and 'Dronedarone' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. 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. 2. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002; 347:1834. 3. Falk RH. Atrial fibrillation. N Engl J Med 2001; 344:1067. 4. Connolly SJ. Appropriate outcome measures in trials evaluating treatment of atrial fibrillation. 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