Flecainide

Of the 128 articles evaluated on the overall topic of atrial fibrillation (AF) after cardiac surgery, only 19 studies dealing with pharmacologic heart rhythm control were relevant for inclusion in this analysis, indicating the relative paucity of evidence-based studies addressing this topic. We found limited data on guiding treatment for the rhythm control of AF following cardiac surgery in patients who do not require urgent cardioversion; therefore, the choice of an antiarrhythmic drug needs to be guided by patient characteristics. Based on limited available evidence, amiodarone is recommended for pharmacologic conversion of postoperative AF and AFL in patients with depressed left ventricular function who do not need urgent electrical cardioversion. This recommendation is made largely because of the effectiveness of amiodarone and also because of its relatively favorable side-effects profile. Sotalol and class 1A antiarrhythmic drugs are reasonable choices for patients with coronary artery disease who do not have congestive heart failure. There are currently no definitive data to guide the decision about the duration of antiarrhythmic drug therapy for patients with AF following cardiac surgery. Most protocols continue therapy with the antiarrhythmic drug for 4 to 6 weeks following surgery, but evidence from randomized studies is lacking.

Key words: antiarrhythmic drug; atrial fibrillation; atrial flutter

Abbreviations: AF = atrial fibrillation; AFL = atrial flutter; CABG = coronary artery bypass graft; RCT = randomized controlled trial

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Over 400,000 coronary artery bypass graft (CABG) and valvular surgical procedures are performed annually in the United States. (1) Atrial fibrillation (AF) or atrial flutter (AFL) complicate CABG surgery in about 30% of cases, (2) and in up to 60% of cases involving valve replacement. (3) Postoperative AF may be complicated by significant symptoms, hemodynamic instability, and an increased risk of stroke. (4) Postoperative AF is also associated with increased length of stay both in the ICU and in low-acuity rooms, and incurs additional costs averaging several thousand dollars per patient. (5) Currently, there is no consensus supporting a strategy for the conversion of AF and the maintenance of sinus rhythm (rhythm control) vs rate control and anticoagulation therapy in the post-cardiac surgery patient. Clinical factors that favor rhythm control include significant symptoms, hemodynamic instability associated with these dysrhythmias, and contraindication to anticoagulation therapy. Available data from 19 studies on the use of antiarrhythmic drugs for patients with post-cardiac surgery AF were reviewed and graded, and have provided the basis for the clinical practice guidelines set forth in this article.

SUMMARY OF EVIDENCE REVIEW

Although a modicum of the literature addresses antiarrhythmic drug use in the post-cardiac surgery patient to convert AF, there are very few studies that address the maintenance of sinus rhythm after cardiac surgery. Therefore, recommendations for antiarrhythmic maintenance of sinus rhythm were extrapolated from recommendations for the patients with AF in the nonoperative state. (6,7) After a review of 128 abstracts, 19 studie (8-26) were eligible for inclusion in our review of post-cardiac surgery rhythm control. The results of these studies are reported below using the Vaughan-Williams antiarrhythmic drug classification system. The conversion rates for the various antiarrhythmic agents are summarized in Table 1. The doses and toxicity of the drugs used for AF conversion are shown in Table 2, and the doses and toxicity of drugs for the maintenance of sinus rhythm after conversion are given in Table 3. A summary of the evidence grade, net benefit, and overall strength of the recommendations for pharmacologic rhythm control of AF or AFL is given in Table 4. Figure 1 outlines a management strategy for the pharmacologic conversion of AF after cardiac surgery. Below are general summaries of the studies of each drug for which data are available, "along with the associated evidence grades.

Class IA Drugs

Procainamide: Two small randomized controlled trials (RCTs) with important study limitations have suggested that procainamide is less efficacious than propafenone (8) for conversion of AF and is no more efficacious than digoxin. (9) Nine percent of the procainamide-treated group stopped receiving the drug due to severe hypotension, compared to 2% in the propafenone-treated group. There were no reported differences in the number of adverse events compared to the group treated with digoxin, and there were no proarrhythmic effects in either group. We identified no adequate placebo-controlled trials using procainamide for the treatment of postsurgical AF.

Quinidine: One randomized crossover trial (10) reported that quinidine was more likely than amiodarone to restore sinus rhythm in patients with AF. This trial included 80 patients but had important study limitations, with an overall quality score of 68%. No adequate placebo-controlled trials using quinidine for the treatment of postsurgical AF were identified. Quinidine may be more efficacious than amiodarone in achieving conversion, but the evidence is limited and weak.

Disopyramide: One RCT (11) with 40 patients and important study limitations (ie, differences in ancillary medications between groups and suboptimal outcome measures) compared therapy with disopyramide plus digoxin to therapy with sotalol for patients with AF after cardiac surgery. This study suggested that therapy with sotalol was similarly efficacious to the combination therapy of disopyramide and digoxin. An additional trial (12) with serious limitations studied the combination therapy of disopyramide plus digoxin and compared it to therapy with flecainide for the treatment of postoperative AF. This trial suggested that the combination therapy was as efficacious as that with flecainide in achieving conversion of AF. There have been no adequate placebo-controlled trials using disopyramide for the treatment of postsurgical AF. Insufficient evidence exists to determine the efficacy and safety of disopyramide in combination with digoxin for the treatment of post-cardiac surgery AF.

Class IC Drugs

Flecainide: Two RCTs have suggested that flecainide therapy is as safe and efficacious as the combination therapy of disopyramide and digoxin, (12) and that it may be more efficacious than therapy with digoxin alone in achieving the conversion of AF. (13) The studies each had important study limitations, and the total number of patients was 85 in the combined trials. There have been no adequate placebo-controlled trials using flecainide for the treatment of postsurgical AF. We conclude that therapy with flecainide may be as efficacious as therapy with digoxin with or without the addition of disopyramide, but the evidence is limited and weak.

Propafenone: One small randomized crossover trial (14) has suggested that propafenone is efficacious in achieving the conversion of AF when compared to placebo. Patients in the propafenone group had a small but statistically significant decrease in BP. This study had important limitations with an overall quality score of 60%. Propafenone was also studied in three RCTs (8,15,16) with a total of 186 patients, each with at least one important study limitation. These studies suggested that propafenone therapy may be more efficacious than therapy with amiodarone and procainamide in achieving the conversion of AF. None of these trials reported a difference in the occurrence of adverse events among groups. Propafenone therapy may be effective in achieving the conversion of postoperative AF to sinus rhythm, but the evidence is weak. It is important to note that neither flecainide nor propafenone should be used in patients with coronary artery disease because of their proarrhythmic effects.

Class II Drugs

Beta-blockers: One small RCT (17) with an overall quality score of 63% compared therapy with esmolol to therapy with diltiazem and found that esmolol achieved a higher rate of conversion of AF at 6 h, but that there was no difference in conversion rates at 24 h. This study was marked by limitations, notably that 50% of patients in the diltiazem group had their beta-blocker therapy discontinued. Another small study (18) marked by serious limitations and an overall quality score of 55% compared therapy with metoprolol to therapy with sotalol for the treatment of AF. The authors reported no significant difference in time to conversion. There have been no adequate placebo-controlled trials using beta-blockers for the treatment of post-cardiac surgery AF. We conclude that beta-blockers may be efficacious in achieving AF conversion, but that the evidence is limited and weak.

Class III Drugs

Amiodarone: Three RCTs (15,16,19) and one randomized crossover trial (10) compared the use of amiodarone to the use of multiple agents. These studies had a total of 234 patients, and each had at least one important study limitation. These trials suggested that amiodarone might be less efficacious than propafenone and quinidine but more efficacious than digoxin in achieving the conversion of AF. The studies reported no significant differences in the occurrence of adverse outcomes. There have been no adequate placebo-controlled trials using amiodarone for the treatment of postsurgical AF. Based on data using comparisons with other drugs that are efficacious in treating postoperative AF, and due to the safety profile, we conclude that amiodarone may be efficacious in the rhythm control of patients with postoperative AF, but that the evidence is both indirect and weak. It should be noted that amiodarone, like many other antiarrhythmic agents, is not currently approved by the US Food and Drug Administration for use in the treatment AF or AFL because it has not been formally evaluated for this indication.

Dofetilide: One RCT (20) compared therapy with dofetilide to placebo. The authors reported that dofetilide at two different doses showed no improved efficacy in rhythm conversion at 3 h when compared to placebo. Four patients in the high-dose dofetilide group had nonsustained ventricular tachycardia. We concluded that dofetilide may not be efficacious in the management of postoperative AF or AFL for the achievement of conversion, and may be associated with more toxicity than placebo; however, the evidence is weak.

Ibutilide: VanderLugt et al (21) compared therapy with ibutilide to placebo in an RCT and reported a significantly higher conversion rate in the ibutilide-treated group. This study, although relatively large, had serious limitations, including differences in ancillary medications between study groups and suboptimal outcome assessment procedures, resulting in an overall quality score of 39%. We conclude that ibutilide may be efficacious in the management of postoperative AF or AFL, but the evidence is weak.

Sotalol: Two trials evaluated the use of sotalol. One trial (11) compared therapy with sotalol to therapy with disopyramide plus digoxin, and the other trial (18) compared therapy with sotalol to therapy with metoprolol or placebo for the treatment of AF. One was an BCT with a total of 40 patients, (11) and the other was a randomized, open-label, controlled trial with only 18 patients, (18) with each having important study limitations (ie, differences in ancillary medications and nonobjective outcome measures). These studies found sotalol to be as efficacious as therapy with metoprolol or the combination therapy of disopyramide plus digoxin. We conclude that sotalol may be as efficacious as metoprolol or the combination of disopyramide and digoxin in the conversion of postoperative AF or AFL, but the evidence is insufficient.

Class IV Drugs

Diltiazem: Two small trials with a total of 70 patients found that diltiazem therapy was less efficacious than esmolol therapy (17) and was similar in efficacy to therapy with digoxin (22) in achieving AF conversion. There have been no adequate placebo-controlled trials using diltiazem for the treatment of postsurgical AF. We conclude that insufficient evidence exists on the efficacy of diltiazem in the conversion of AF/AFL following cardiac surgery.

Verapamil: Three randomized crossover trials, (23-25) each with important study limitations, showed a slight benefit or equal efficacy to that of verapamil in the conversion of AF to sinus rhythm compared to placebo. One study (24) reported a significant decrease in BP with verapamil. There is insufficient evidence on the efficacy of verapamil in achieving conversion of postoperative AF/AFL.

Miscellaneous Pharmacologic Interventions

Digoxin: Four small RCTs (11,13,19,22) reported on the use of digoxin (not in combination with disopyramlde). (9,13,19,22) These studies included a total of 129 patients, and each study had important limitations. The studies suggested that therapy with digoxin alone was less efficacious than that with amiodarone or flecainide, (13,19) and was no more efficacious than therapy with diltiazem or procainamide in achieving AF/AFL conversion. (9,22) No trial reported a difference in the occurrence of adverse events. There have been no adequate placebo-controlled trials using digoxin for the treatment of postsurgical AF. We conclude that digoxin may not be efficacious for converting postoperative AF/AFL, but that the evidence was limited and weak.

Conversion vs Rate Control: One RCT (26) with 50 patients reported little difference in the time to conversion between a rate-controlling strategy and a strategy to restore sinus rhythm. This trial was limited by its small size and the lack of standard treatment protocols in the study groups but must be considered in the context of deciding to pursue a rate-control or rhythm-control strategy for the treatment of AF following cardiac surgery.

DISCUSSION

It is advisable to restore and maintain sinus rhythm in patients with post-cardiac surgery AF that is complicated by significant symptoms, hemodynamic instability, or contraindication to anticoagulation therapy. In the absence of these clinical conditions, a strategy of rate control may be equivalent to one of rhythm control. (26)

In general, antiarrhythmic drugs are moderately successful for the conversion of AF to sinus rhythm. However, few randomized placebo-controlled data exist supporting the effectiveness of these medications in the post-cardiac surgery state. The antiarrhythmic drugs that are available in the United States and their potential toxicities are outlined in Tables 2 and 8.

Limitations

Little evidence exists to identify the best pharmacologic strategy to achieve rhythm control in patients with AF or AFL following cardiac surgery. We are unable to definitively state the relative efficacy of various agents because of the inability to ensure comparable subjects, comparable outcome measures, and comparable monitoring methods. Additionally, many of the trials were underpowered to achieve definitive conclusions. Recommendations should be considered in light of these data limitations. The summary of the evidence grade, net benefit, and overall recommendations are listed in Table 4. The final recommendations have evolved from a consensus using those studies that are available for data extraction.

Class IA Drugs: Procainamide, Quinidine, and Disopyramide

Sparse data exist to support the use of class IA antiarrhythmic medications for the restoration or maintenance of sinus rhythm in the post-cardiac surgery patient. Procainamide is the only class IA antiarrhythmic drug that is available in the United States in both the IV and oral formulations. Quinidine and disopyramide may be used for patients who are able to absorb oral medications in the postoperative state. IV procainamide may be limited by hypotension and should be avoided in the presence of renal insufficiency. All class IA medication use may be complicated by ventricular arrhythmias (see below). (27,28)

Class IC Drugs: Propafenone and Flecainide

Both of these agents have been tested in an IV formulation (not available in the United States) and an oral formulation. Although agents in this class are reasonably efficacious, flecainide has been associated with significantly increased mortality in patients with coronary artery disease and ventricular ectopy, and therefore this class of medication is not recommended for the treatment of post-cardiac surgery AF. (29)

Class III Drugs

Class III agents are widely used for the management of AF and, with the exception of amiodarone, are similar in their rates of conversion and the maintenance of sinus rhythm. Amiodarone is slightly more effective than other antiarrhythmic drugs for the maintenance of sinus rhythm in the non-postsurgical setting, but no specific data exist for the post-cardiac surgery clinical setting. (30) Amiodarone is available in the oral and IV formulations in the United States; however, as stated before, it has not yet been approved by the US Food and Drug Administration for use in patients with atrial arrhythmias. IV amiodarone is an effective rate-controlling agent, but it is not highly effective for use in short-term cardioversion and may be complicated by the occurrence of hypotension. (10) Oral loading of amiodarone (ie, [greater than or equal to] 600 mg/d) may restore sinus rhythm, and continued therapy is highly effective for the maintenance of sinus rhythm. Therapy with oral amiodarone is a good choice for patients with AF after undergoing CABG or valve surgery, because it is relatively safe for use in patients with structural heart disease and does not cause hypotension. However, some controversy exists regarding the potential risk of acute pulmonary toxicity in patients receiving amiodarone whose lungs have been exposed to physical insults such as those associated with cardiac surgery. (31) Additional research is needed to address this potential risk of amiodarone.

Sotalol is only available in the oral formulation in the United States. Minimal data exist to define its efficacy in the oral preparation for the treatment of AF following cardiac surgery.

Ibutilide is only available in the IV form in the United States. It has a similar efficacy to that of class IA drugs and sotalol. It may be slightly more efficacious for use in the conversion of AFL than for the conversion of AF. (33) It is also a useful pretreatment for patients with a previous lack of response to electrical cardioversion. (34)

Dofetilide is available only in the oral formulation in the United States. It has demonstrated efficacy for the restoration and maintenance of sinus rhythm in patients with coronary artery disease and congestive heart failure. (35) However, in the post-cardiac surgery patient, efficacy has not been demonstrated, and some evidence of toxicity may be present. Dofetilide requires dose adjustment in the setting of renal insufficiency and 3 days of in-hospital monitoring during drug initiation because of the risk of inducing ventricular arrhythmias.

Class II and IV Drugs and Digoxin

In the non-postoperative setting, beta-blockers, calcium channel blockers, and digoxin are useful agents for rate control or as adjunctive agents for atrioventricular node slowing in conjunction with antiarrhythmic agents, but are not considered as appropriate therapy for the conversion of AF or the maintenance of sinus rhythm. (6,7) For patients who experience AF after cardiac surgery, beta-blockers and calcium channel blockers are the most useful agents for achieving rate control, while digoxin has little efficacy because of the heightened adrenergic tone present postoperatively. Although the trials reviewed for this report suggested that some patients converted to sinus rhythm after receiving digoxin, the time to conversion generally was delayed. The findings thus are consistent with the often self-limited natural history of postoperative AF rather than yielding evidence of the efficacy of digoxin for AF conversion. None of these trials compared therapy with digoxin to placebo, and the literature in the nonoperative setting (6) rates digoxin equal to placebo in terms of conversion rates.

Antiarrhythmic Drug Proarrhythmia

The two major proarrhythmic complications of antiarrhythmic drugs include torsades de pointes ventricular tachycardia and bradycardia. Torsades de pointes is a form of polymorphic ventricular tachycardia associated with QT-interval prolongation on the baseline ECG. Risk factors for torsades de pointes associated with therapy with antiarrhythmic drugs include electrolyte depletion, bradycardia, or pauses. The diuresis that often occurs in the postoperative state may lead to electrolyte depletion. It is important to replenish potassium levels (maintenance level, [greater than or equal to] 4.0 mEq/L) and magnesium levels prior to the initiation of therapy with antiarrhythmic drugs.

The conversion of AF to sinus rhythm is frequently associated with a sinus pause and is a high-risk setting for the development of torsades de pointes ventricular tachycardia. (36) It is therefore necessary that patients be monitored closely (eg, with continuous telemetry and immediate access to a defibrillator) when therapy with antiarrhythmic drugs is started during AF. Sinus bradycardia may also be a significant side effect of antiarrhythmic drugs and may necessitate the dose adjustment of concomitantly administered drugs (eg, calcium channel blockers, beta-blockers, or digoxin). Epicardial or transvenous pacing may be helpful to prevent bradycardia, pauses, and torsades de pointes ventricular tachycardia.

Recommended Follow-up

The use of antiarrhythmic drugs for the maintenance of sinus rhythm requires a strategy for follow-up once the patient leaves the hospital, and the choice of antiarrhythmic drug will depend on patient characteristics (Fig 1). Patients should be monitored closely with immediate access to a defibrillator when therapy with antiarrhythmic drugs is started during AF. In addition, patients should have an ECG at least once in the first 2 weeks following discharge from the hospital. If there is specific concern for QT prolongation or bradycardia, the patient should have more frequent ECGs or daily monitoring with a transtelephonic event monitor. This is particularly true for patients in whom antiarrhythmic drug therapy is initiated within 24 to 48 h of hospital discharge. If the patient leaves the hospital in AF with therapeutic anticoagulation and remains in AF at the 1-month follow-up, cardioversion should be considered.

Summary of Recommendations

In patients who do not require emergent cardioversion, pharmacologic agents for control of postoperative AF and AFL are selected for use due to their efficacy in converting AF to normal sinus rhythm in the immediate postoperative period and in maintaining normal sinus rhythm postoperatively (Table 4). Antiarrhythmic drugs that are administered to maintain normal sinus rhythm are customarily continued for 4 to 6 weeks postoperatively. Because of a dearth of high-quality evidence regarding pharmacologic therapy for the maintenance of postoperative normal sinus rhythm after conversion of postoperative AF or AFL, recommendations for the pharmacologic maintenance of normal sinus rhythm postoperatively were extrapolated from recommendations for nonsurgical patients with AF. In all instances, the choice of a drug or drugs to convert postoperative AF or AFL and subsequently to maintain normal sinus rhythm must be determined for each patient based on individual clinical characteristics. It is advisable to restore and maintain sinus rhythm for patients with postoperative AF or AFL that is complicated by significant symptoms or hemodynamic instability. Early cardioversion within 48 h should be considered in patients with a contraindication to anticoagulation therapy. When these clinical conditions are absent, a strategy of rate control may be equivalent to one of rhythm control.

Torsades de pointes and bradycardia are major complications of antiarrhythmic therapy. Patients should be monitored closely by continuous telemetry and should have access to a defibrillator when therapy with antiarrhythmic drugs is started during AF. Epicardial or transvenous pacing may be helpful to prevent torsades de pointes, pauses, or bradycardia.

Table 1 summarizes the various agents used for rhythm control in AF with conversion and relapse rates. Tables 2 and 3 list the doses and toxicities for drugs used for the conversion to and maintenance of sinus rhythm, respectively. Finally, Table 4 provides a summary of the evidence and strength of recommendations for each intervention.

1. In patients with depressed left ventricular function in whom maintaining sinus rhythm is important, we recommend therapy with amiodarone (strength of recommendation, E/C; evidence grade, low; net benefit, intermediate).

2. In patients without heart failure, we recommend therapy with amiodarone, sotalol, or ibutilide, or, alternatively, class IA agents for the conversion of AF following cardiac surgery (strength of recommendation, C [E/C for amiodarone]; evidence grade, low; net benefit, intermediate).

3. In patients with AF after cardiac surgery, we recommend 4 to 6 weeks of antiarrhythmic therapy (strength of recommendation, E/C; evidence grade, low; net benefit, small/weak).

4. In patients with AF following cardiac surgery, we cannot at this time recommend using flecainide, digoxin, or calcium channel blockers for the purpose of conversion to sinus rhythm (strength of recommendation, I; evidence grade, low; net benefit, none).

5. In patients with AF following cardiac surgery, we recommend against therapy with dofetilide and class 1C agents for conversion to sinus rhythm (strength of recommendation, D; evidence grade, low; net benefit, negative)

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Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml).

Correspondence to: Peter Zimetbaum, MD, Division of Cardiology, Beth Israel Deaconess Medical Center, 1 Deaconess Rd, Boston, MA 02215; e-mail: pzimetba@bidmc.harvard.edu

* From the Departments of Anesthesia (Dr. Martinez) and Medicine (Dr. Bass), The Johns Hopkins University School of Medicine, Baltimore, MD; and the Department of Medicine (Dr. Zimetbaum), Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard University, Boston, MA.

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