Ann Thorac Surg 2005;79:728-740
© 2005 The Society of Thoracic Surgeons
Review
Pharmacologic Strategies for Prevention of Atrial Fibrillation After Open Heart Surgery
Robert J. DiDomenico, PharmDa,
Malek G. Massad, MDb,*
a Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA
b Department of Surgery, Division of Cardiothoracic Surgery, University of Illinois at Chicago, Chicago, Illinois, USA
* Address reprint requests to Dr Massad, University of Illinois at Chicago, Division of Cardiothoracic Surgery, 840 S Wood St, CSB Ste 417 (M/C 958), Chicago, IL 60612, USA
mmassad{at}uic.edu
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Abstract
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Postoperative atrial fibrillation is a common complication after open heart surgery; it increases morbidity, hospital stay, and costs. In an analysis of 8 large cardiac surgery trials totaling 20,193 patients, the incidence of postoperative atrial fibrillation was estimated to be 26% and ranged from 17% to 35%. We reviewed the results of 52 studies published between 1966 and 2003 that evaluated pharmacologic strategies to prevent postoperative atrial fibrillation in nearly 10,000 patients undergoing open heart operations. Supraventricular tachyarrhythmias, including atrial fibrillation, after open heart operations occurred in 29% of patients who did not receive prophylactic drugs, compared with 12% in patients who received intravenous followed by oral amiodarone, 15% in those given sotalol, 16% in those given oral amiodarone, and 19% in those given ß-blockers. Pharmacologic strategies and regimens aimed at preventing postoperative atrial fibrillation are necessary to optimize the postoperative care of patients undergoing open heart operations. Although no strategy has consistently been shown to be superior to another, the most effective approach to preventing postoperative atrial fibrillation likely involves multiple interventions. In the absence of contraindications, all patients should receive ß-blocker therapy before and after the operation. For patients with 1 or more risk factors for postoperative atrial fibrillation, regimens consisting of either sotalol (ß-blocker with class III antiarrhythmic properties) alone or ß-blockers in combination with amiodarone seem to be the safest, most effective pharmacologic strategies for preventing postoperative atrial fibrillation.
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Introduction
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Postoperative cardiac dysrhythmias are a frequent complication of open heart operations. Supraventricular tachyarrhythmia (SVT), particularly atrial fibrillation (AF), is the most common dysrhythmia to develop after operation in these patients. In an analysis of 8 large cardiac surgery trials totaling 20,193 patients, the incidence of postoperative AF was estimated to be 26% and ranged from 17% to 35% [1]. Even though postoperative AF is often a short-lived, self-limiting complication, morbidity is increased in patients with this complication. The incidence of postoperative stroke, the hospital length of stay (LOS), the incidence of ventricular arrhythmias, and the need for a permanent pacemaker are all increased in patients in whom postoperative AF develops after cardiac operations [2–4]. Thus, to improve the care of patients undergoing open heart operations, effective prophylactic strategies should be adopted to prevent postoperative AF.
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Material and Methods
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A systematic literature search was conducted to identify studies evaluating pharmacologic strategies to prevent AF after open heart operations published between 1966 and November 2003. The search technique included computerized MEDLINE searches that used the following search terms: "atrial fibrillation," "tachycardia," "supraventricular," "thoracic surgery," "cardiac surgical procedures," "coronary artery bypass graft," "digoxin," "adrenergic beta antagonists," "calcium-channel blockers," "antiarrhythmia agents," "sotalol," and "amiodarone." Additional studies were identified by reviewing the bibliographies of published reports and the authors' knowledge of the current literature. To be included in this review, studies must have been (1) peer-reviewed articles published in the English language and (2) randomized, controlled clinical trials assessing the safety and efficacy of drug therapy in the prevention of AF or SVT after cardiac operations. Studies that did not meet these criteria were excluded from this review. Altogether, 52 studies were identified that met these criteria.
The rate of SVT or postoperative AF was extracted from these studies, and safety variables were assessed. Additionally, the cumulative incidence of postoperative AF or SVT from each of the pharmacologic strategies was calculated to allow for comparisons among the various drug therapies. This was performed by adding the cumulative number of patients in whom postoperative SVT or AF developed with a given strategy and dividing this by the cumulative number of patients treated with this strategy.
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Pathophysiology
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The pathophysiology of postoperative AF is complex and multifactorial. Patients undergoing open heart operations generally have the substrate for development of AF: a diseased myocardium. AF commonly occurs in patients with long-standing hypertension, valvular heart disease, coronary artery disease, cardiomyopathy, and left ventricular hypertrophy [5]. In addition to these factors, other processes are believed to contribute to the development of postoperative AF. After open heart operations, patients experience increased sympathetic tone, which leads to increased premature atrial contractions, which commonly trigger AF [6, 7]. Inflammation is also thought to contribute to postoperative AF. Damage incurred by pericardiotomy often leads to pericarditis and may increase the likelihood of postoperative AF [6, 7]. Atrial ischemia may play a role in the development of postoperative AF [1, 6, 7]. Finally, electrolyte abnormalities, particularly hypomagnesemia, have been implicated as precipitating factors [6, 7].
It is important to recognize the time course of postoperative AF. When AF develops after cardiac operations, it typically does so within the first 72 postoperative hours. One analysis found that in 73% of patients in whom postoperative AF eventually developed, it did so within the first 3 postoperative days [4]. Consequently, this is the period when strategies aimed at preventing postoperative AF are useful. In patients in whom postoperative AF developed, persistence or recurrence of the arrhythmia for longer than 4 to 6 weeks after operation is rare [7]. As a result, long-term therapy is generally unnecessary.
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Risk Factors
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Various risk factors for the development of postoperative AF have been identified over the years (Tables 1 and 2). History of AF, valvular heart disease, heart failure, vascular disease, chronic obstructive pulmonary disease, stroke, myocardial infarction, advanced age, and nonuse of ß-blockers are all preoperative characteristics that have been shown in univariate analyses to increase the risk of postoperative AF [2, 3, 8]. It is interesting to note that preoperative use of digoxin, which has been studied as a strategy to prevent postoperative AF, has also been associated with an increased risk of AF after cardiac operations [2]. The reason for this is unknown, but it is plausible that preoperative digoxin use reflects the presence of advanced heart disease such as AF or heart failure—both known to increase the risk of postoperative AF—and that the increased risk of AF is not a direct effect of the drug itself. Perioperative and postoperative risks for the development of postoperative AF include valve operation, combined coronary artery bypass graft (CABG) and valve operation, prolonged cross-clamp time, and postoperative inotropic support [2, 3, 8]. In multivariate analyses, the largest predictors of postoperative AF seemed to be advanced age; history of AF, heart failure, rheumatic heart disease, and chronic obstructive pulmonary disease; preoperative digoxin use; absence of preoperative ß-blocker therapy; pulmonary vein venting; bicaval venous cannulation; prolonged cross-clamp time; and postoperative atrial pacing [2, 3, 8]. Although many of the intraoperative and postoperative risk factors cannot be predicted, clinicians may be able to use the preoperative clinical characteristics of patients to stratify their risk of postoperative AF and to design a prophylactic regimen in accordance with the anticipated risk.
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Table 1. Preoperative Univariate and Multivariate Risk Factors for the Development of Postoperative Atrial Fibrillation
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Table 2. Intraoperative and Postoperative Univariate and Multivariate Risk Factors for the Development of Postoperative Atrial Fibrillation
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Prophylactic Strategies Studied
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Although postoperative AF is a troublesome complication of open heart operations for both patients and health-care providers, there are effective strategies to prevent its occurrence. Several drug therapies have been investigated (Tables 3 and 4). Although these studies provide useful information regarding the incidence of postoperative AF and the various prophylactic drug regimens used to prevent it, most are limited by small sample sizes and weak statistical methods to appropriately test the research hypotheses. The remainder of this review summarizes the prophylactic therapies studied in this setting.
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Table 3. Studies Evaluating Drug Therapies to Prevent Atrial Fibrillation and Other Supraventricular Arrhythmias After Open Heart Surgery
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Table 4. Summary of Studies Evaluating Drug Therapies to Prevent Atrial Fibrillation and Other Supraventricular Arrhythmias After Open Heart Surgery
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Negative Chronotropic Drugs
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Digoxin
Digoxin is a cardiac glycoside that enhances vagal tone, thereby slowing conduction through the atrioventricular node. It has been studied alone and in combination with ß-adrenergic blockers for the prevention of SVT, including postoperative AF, in patients undergoing CABG surgery [9–14]. Monotherapy with digoxin has produced conflicting results in terms of preventing SVT. Johnson and colleagues [9] demonstrated that patients undergoing CABG who received prophylactic digoxin had dramatically lower rates of SVT compared with those who did not receive prophylaxis (5.6% vs 25.8%, respectively; p < 0.01). In contrast, Roffman and Fieldman [11] found that the incidence of postoperative SVT was unchanged in patients who received postoperative digoxin compared with the control group. A subsequent study suggested that digoxin prophylaxis may actually increase the risk of postoperative SVT [10].
Although the efficacy of digoxin as monotherapy to prevent postoperative AF is questionable, when it is used in combination with ß-blocking drugs, digoxin has been shown to be effective. When initiated either before the operation or in the immediate postoperative period along with ß-blockers, postoperative SVT occurred in 2.1% to 5% of patients, compared with 25% to 30% of the corresponding control groups [11, 12, 14]. These data are encouraging, but the role of digoxin in the prevention of postoperative AF remains unclear.
ß-Blockers
Because patients recovering from open heart operations often have heightened sympathetic tone, the risk of postoperative SVT is increased. ß-Blockers antagonize the effects of catecholamines on the myocardium and have been studied extensively as prophylactic agents in this setting [15–26].
Propranolol was one of the first ß-blockers to be studied in this setting. Most of the trials evaluating the efficacy of propranolol for the prophylaxis of SVT after open heart surgery have demonstrated favorable results. Postoperative initiation of propranolol has been shown to markedly reduce the incidence of postoperative AF after CABG surgery [15, 19]. However, other studies suggest that propranolol is ineffective in preventing SVT after CABG surgery [17, 22].
Other ß-blockers have been studied in this setting as well. Both timolol and acebutolol, initiated after operation, dramatically decreased the frequency of AF, atrial flutter, or both compared with placebo [18, 21]. Three days of atenolol prophylaxis before CABG was effective in decreasing the rate of SVT to 3%, compared with 37% in patients who received no atenolol (p = 0.001) [23].
ß-Blockers have also been compared with one another as prophylactic therapy. Sotalol, a ß-blocker with class III antiarrhythmic activity, was superior to metoprolol in preventing postoperative SVT, and both drugs were superior to no ß-blocker when initiated after CABG surgery (2.4% vs 15.3% vs 36%, respectively) [20]. In another study, carvedilol was more effective than either metoprolol or atenolol in preventing postoperative AF after CABG with or without valve operations [26].
The largest and, perhaps, best-designed study evaluating the effect of ß-blockers on postoperative AF was the ß-Blocker Length of Stay study [25]. This study enrolled 1,000 patients and was powered to detect a 10% difference in hospital LOS (secondary to a lower incidence of postoperative AF) between patients who received metoprolol (initiated after open heart operations) and control subjects. Metoprolol was associated with a 20% relative risk reduction in the development of postoperative AF (31% vs 39%; p = 0.01). However, LOS between groups was not different.
The timing of ß-blocker therapy may be an important factor in the development of postoperative AF. Patients who received long-term preoperative propranolol followed by low-dose postoperative propranolol had a lower rate of SVT (5%) compared with patients who received propranolol only before operation (40%; p < 0.001) or only after operation (27%; p < 0.01) [16]. Although Shafei and colleagues [22] did not find a marked reduction in SVT in patients given propranolol prophylaxis, SVT was less frequent in patients who received preoperative ß-blockers when propranolol was given after operation than in patients who received no postoperative ß-blocker (9.9% vs 13.8%; not significant). Likewise, Ali and colleagues [24] demonstrated that in patients treated before operation with ß-blockers (metoprolol, atenolol, sotalol, or propranolol), continuation of postoperative ß-blocker therapy was associated with a lower rate of postoperative AF compared with patients in whom ß-blocker therapy was not continued after operation (17.1% vs 38.1%; p < 0.02). These data suggest that ß-blockers are more effective in preventing postoperative AF when administered both before and after open heart operations. Additionally, we hypothesize that ß-blocker withdrawal plays a role in the development of postoperative AF.
In addition to being effective in preventing postoperative AF in patients undergoing open heart operations, ß-blockers have also been shown to decrease postoperative mortality in patients undergoing surgical procedures [27, 28]. In 200 patients undergoing elective noncardiac operations, the administration of atenolol immediately before operation and for up to 7 days after operation was associated with a 55% lower mortality (9.1% vs 20.8%; p = 0.019) at 2 years [27]. Observational data from more than 600,000 patients in the Society of Thoracic Surgeons National Adult Cardiac Surgery Database reveal that patients treated with preoperative ß-blockers have a small, but statistically significant, reduction in overall mortality at 30 days compared with those not pretreated with ß-blockers (2.8% vs 3.4%; unadjusted odds ratio, 0.80; 95% confidence interval, 0.78 to 0.82; p < 0.001) [28]. Thus, because ß-blockers are effective in decreasing the frequency of postoperative AF and, more importantly, are associated with lower mortality, all patients undergoing open heart operation should be started on preoperative ß-blockers, and these should be continued after operation unless otherwise contraindicated.
Calcium-Channel Blockers
The nondihydropyridine calcium-channel blockers, verapamil and diltiazem, have several beneficial effects on the cardiovascular system. Because their cardiac effects are similar to those of ß-blockers, both drugs have been studied as alternatives to ß-blockers in the prevention of postoperative AF [29–31]. Oral verapamil after CABG was ineffective in decreasing the incidence of postoperative AF or atrial flutter compared with control [29]. In contrast, perioperative infusions of diltiazem were associated with fewer cardiac complications after CABG. Two studies comparing 24-hour continuous infusions of diltiazem with nitroglycerin after operation demonstrated a lower incidence of postoperative AF in diltiazem-treated patients [30, 31]. These data suggest that diltiazem may have a role in the prevention of postoperative AF, whereas oral verapamil is ineffective. However, given the paucity of data compared with ß-blockers and given the mortality benefits of ß-blockers in surgical patients, prophylaxis of postoperative AF with diltiazem is best reserved for patients with contraindications to ß-blockers (eg, severe bronchospastic airway disease).
Magnesium
Electrolyte deficiencies, including hypomagnesemia, are common complications after open heart operations [5, 7]. Many have hypothesized that prophylactic magnesium supplementation in patients undergoing cardiac operations may decrease the incidence of postoperative arrhythmias, including postoperative AF. Some studies have documented rather dramatic reductions in the incidence of AF after operation compared with placebo [32, 33]. However, in other studies, magnesium supplementation failed to reduce the incidence of postoperative AF [34, 35]. Therefore, routine magnesium supplementation is not advised. However, close monitoring for the development of electrolyte deficiencies should be performed, and magnesium supplementation should be given to patients with hypomagnesemia.
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Class I and III Antiarrhythmic Drugs
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Antiarrhythmic drugs are effective in terminating both supraventricular and ventricular tachyarrhythmias. However, their efficacy must be balanced with the risk of toxicity. The results of the Cardiac Arrhythmia Suppression Trial (CAST) revealed that the use of antiarrhythmic drugs increased mortality in patients with ischemic cardiomyopathy secondary to an increased incidence of ventricular proarrhythmia (eg, torsades de pointes) [36, 37]. Bradycardia is also a common side effect of several of these drugs (eg, sotalol and amiodarone). In addition, amiodarone may cause several noncardiac adverse effects, including thyroid dysfunction, hepatotoxicity, and pulmonary fibrosis. Therefore, the potential role of these drugs in the prevention of postoperative AF has been tempered with their potential for harm, particularly because most patients being studied have 1 or more risk factors (eg, ischemic heart disease) for proarrhythmia. Nevertheless, several studies have investigated the role of antiarrhythmic drugs for the prophylaxis of postoperative AF, and these are discussed below.
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Class I Antiarrhythmic Agents
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Class Ia and Ic antiarrhythmic drugs decrease conduction velocity and suppress the automaticity of myocardial cells. Therefore, they are effective in terminating and preventing automatic tachyarrhythmias such as postoperative AF and have been studied in the setting of open heart surgery. Neither quinidine nor propafenone has been shown to be effective in preventing postoperative AF [38, 39]. Two studies demonstrated lower rates of postoperative AF in patients treated prophylactically with procainamide after CABG surgery; however, because of relatively small sample sizes, the differences were not statistically significant [40, 41]. It is interesting to note that the incidence of postoperative AF was significantly lower than with placebo (13% vs 38%; p < 0.05) when therapeutic procainamide levels were achieved, compared with an overall incidence of 26% in the entire procainamide cohort (not significant), suggesting that efficacy is improved when therapeutic serum levels are attained [41]. Because of uncertain efficacy coupled with the risk of proarrhythmia, class Ia and Ic antiarrhythmic drugs cannot be recommended as prophylactic therapy for postoperative AF in patients undergoing open heart operations.
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Class III Antiarrhythmic Agents
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The class III antiarrhythmic drugs prolong the refractory period of myocytes, thus terminating tachyarrhythmias and maintaining normal sinus rhythm. Some of these drugs have additional pharmacologic properties that may afford antiarrhythmic benefit. Sotalol possesses ß-blocking properties as well. Amiodarone has antiarrhythmic activity consistent with each of the antiarrhythmic classifications: sodium channel blockade (class I), ß-blockade (class II), the class III effects described previously, and calcium-channel blockade (class IV). These drugs have been studied extensively and offer the most promise as prophylactic agents against postoperative AF in patients undergoing open heart operations.
Sotalol
Numerous studies have investigated the role of prophylactic sotalol therapy in open heart patients [42–49]. Unlike studies with negative chronotropes and magnesium, in which efficacy has been inconsistent, sotalol prophylaxis has consistently reduced the incidence of postoperative AF. Pfisterer and colleagues [45] randomized 255 patients having CABG with or without valve replacement to receive sotalol (administered 2 hours before the induction of anesthesia) or placebo (for 3 months). Sotalol reduced the incidence of postoperative AF by 43% and reduced LOS by 0.4 days [45]. Other studies have shown that postoperative sotalol prophylaxis may reduce the incidence of AF by 50% or more compared with no sotalol prophylaxis [43, 46, 48, 49]. Sotalol may be even more effective when it is initiated before the operation and continued after the operation. When sotalol was initiated up to 48 hours before the operation and was continued after operation, the incidence of AF was reduced by more than 65% [44, 47]. These studies provide compelling evidence for the use of sotalol as a prophylactic agent in patients undergoing open heart operations.
Although sotalol is effective as a prophylactic strategy, the incidence of adverse effects seems to be dose related. Suttorp and colleagues [42] compared high- and low-dose sotalol (240 vs 120 mg daily) with high- and low-dose propranolol. Patients who received high-dose therapy (either sotalol or propranolol) had a higher incidence of adverse drug events that necessitated cessation of therapy (10.7% vs 2.9%; p < 0.02), despite a trend toward less postoperative AF in sotalol-treated patients [42]. In another study, 22% of patients who received high-dose sotalol therapy (target dose of 320 mg daily) experienced bradycardia that necessitated dosage reduction (12%) or discontinuation (10%) [44]. It is worth noting that 42% of the patients treated with sotalol in this study also received concomitant ß-blocker therapy. This may have contributed to the relatively high rate of adverse effects [44]. Adverse events in this setting were less common when sotalol was given in doses of less than 240 mg daily [43–49]. Because sotalol is cleared renally, similar concerns exist when sotalol is used in patients with marked renal insufficiency. In fact, sotalol is contraindicated for supraventricular arrhythmias in patients with a creatinine clearance less than 40 mL/min [50].
Amiodarone
Multiple studies have investigated the use of both oral [51–58] and intravenous (IV) [59–65] amiodarone as a preventive strategy for postoperative AF. The use of oral amiodarone to prevent postoperative AF was first described by Daoud and colleagues [51]. Patients undergoing elective open heart operations were identified more than a week before the scheduled operation and were randomized to placebo or a 7-day preoperative load of oral amiodarone followed by postoperative amiodarone. The incidence of postoperative AF during hospitalization was 23% in the amiodarone group, compared with 43% in the placebo group (p = 0.03). One week after hospital discharge, the reduction of postoperative AF rates was even greater (25% in the amiodarone group vs 53% in the placebo group; p = 0.003). Although the incidence of postoperative AF was relatively high in the placebo group (43% to 53%), patients in this study were at higher risk for the development of postoperative AF: nearly 50% of patients in both groups had either valvular operation or combined CABG and valve operation. In patients in whom postoperative AF developed, the maximal heart rate during these episodes was significantly lower in the amiodarone group (112 ± 21 bpm) compared with placebo (135 ± 31 bpm; p = 0.03). Hospital LOS and total costs were also significantly less in patients treated with amiodarone. There was, however, a relatively low incidence of both preoperative and postoperative ß-blocker use, and this could have contributed to the higher rates of postoperative AF.
The successful use of oral amiodarone for the prophylaxis of postoperative AF in patients undergoing open heart operations has been described in several other studies [53, 54, 56–58]. The largest of these studies was recently presented at the American Heart Association annual meeting (Orlando, FL; November 2003) [58]. The PAPABEAR study (Prophylactic Amiodarone for the Prevention of Arrhythmias That Begin Early After Revascularization, Valvular Repair, or Replacement) randomized 601 patients undergoing open heart operations to either oral amiodarone or placebo. Patients in the amiodarone group were given 10 mg · kg–1 · d–1 in 2 divided doses starting 6 days before operation and continuing for 6 days after operation. More than half of the patients in each treatment group also received preoperative ß-blockers. Amiodarone was associated with a 52% relative risk reduction in the incidence of either AF or atrial flutter compared with placebo (16.1% vs 29.6%; hazard ratio, 0.48; 95% confidence interval, 0.34 to 0.69; p < 0.001). Patients in the amiodarone group in whom postoperative SVT developed had lower heart rates compared with patients in whom SVT developed while they were receiving placebo (105 ± 24 bpm vs 131 ± 25 bpm; p < 0.001). Amiodarone-treated patients did, however, experience more adverse events that necessitated discontinuation of therapy compared with placebo (11.4% vs 5.3%; p = 0.02).
The concomitant use of oral amiodarone and perioperative ß-blocker therapy may afford the greatest benefit. In patients undergoing CABG, Redle and colleagues [52] found that preoperative amiodarone did not significantly decrease the incidence of postoperative AF compared with no amiodarone prophylaxis (24.7% vs 32.8%; p = 0.30). It is interesting to note that patients who received both amiodarone and ß-blockers showed a trend toward lower rates of postoperative AF compared with patients given either therapy alone or no prophylaxis (16.7% with combination therapy vs 31.9% in the remainder of the cohort; p = 0.10) [52]. The Atrial Fibrillation Suppression Trial randomized 220 patients having open heart operations to preoperative and postoperative amiodarone or placebo [54]. More than 90% of the patients in both groups also received preoperative ß-blockers, and more than 60% received ß-blockers after operation [54]. Amiodarone reduced the risk of postoperative AF by 41% in this study [54]. For patients with contraindications to or intolerance of postoperative ß-blockers, the reduction in postoperative AF was even more dramatic when amiodarone was used. AF occurred in 35% of amiodarone-treated patients (compared with 70% who received placebo) [54]. As mentioned previously, more than 50% of the patients in the PAPABEAR study were receiving preoperative ß-blockers in addition to amiodarone, and the risk reduction was more than 50% [58].
Although oral amiodarone seems to be very effective in the prevention of postoperative AF after open heart operations, patients who require more urgent operation may not have the luxury of preoperative prophylaxis with several days of oral amiodarone. Because IV amiodarone has a rapid pharmacologic effect, several investigators have evaluated its use in the prevention of postoperative AF. Initial studies using IV amiodarone for the prophylaxis of postoperative AF yielded conflicting results. The Amiodarone Reduction in Coronary Heart study compared 2 days of postoperative IV amiodarone with placebo in 300 patients undergoing CABG and demonstrated a reduction in postoperative AF from 47% in the placebo group to 35% in patients given amiodarone (p = 0.01) [60]. Similarly, Lee and associates [61] found that IV amiodarone given for 3 days before operation and 5 days after operation significantly decreased the incidence of postoperative AF. Maximal heart rates during postoperative AF episodes and the duration of postoperative AF episodes were also significantly less in patients treated with IV amiodarone [61]. However, in other studies, IV amiodarone failed to appreciably reduce the incidence of postoperative AF and was associated with an increased incidence of bradycardia [59, 62].
More recent studies suggest that IV amiodarone given for 1 to 2 days after operation followed by oral amiodarone decreases the incidence of postoperative AF by 40% or more [63–65]. Amiodarone given IV for 2 days after operation followed by oral therapy was superior to metoprolol (before and after operation) plus digoxin (after operation) and to controls in preventing postoperative AF in patients undergoing CABG surgery (8.3% vs 16.8% vs 33.6%; p < 0.001 for amiodarone vs control; p < 0.01 for metoprolol plus digoxin vs control) [63]. Yagdi and colleagues [64] found that a 2-day course of IV amiodarone followed by oral therapy for 30 days dramatically decreased the incidence of postoperative AF compared with placebo (10.4% vs 25%; p = 0.017). It was also associated with a slower ventricular response in patients in whom postoperative AF developed (106 ± 19 bpm vs 126 ± 18 bpm; p = 0.016) and with a shorter LOS (6.8 ± 1.7 days vs 7.8 ± 2.9 days; p = 0.014).
Perhaps the most sophisticated study evaluating IV amiodarone for prophylaxis of postoperative AF in open heart patients was the Atrial Fibrillation Suppression Trial II study [65]. In this study, 2 treatment strategies were compared in a 2 x 2 factorial design: amiodarone therapy (IV after operation for 1 day followed by 4 days of oral therapy) and atrial septal pacing. More than 70% of the patients received ß-blockers both before and after operation in all treatment groups. Amiodarone reduced the incidence of postoperative AF by 43% (22.1% in the amiodarone group vs 38.6% in patients without amiodarone; p = 0.037), whereas atrial septal pacing had no effect. The combination of amiodarone and atrial septal pacing had an even greater reduction in postoperative AF, nearly 60%, compared with only pacing and with neither amiodarone nor pacing. These studies suggest that a short course of IV amiodarone initiated after operation and followed by oral therapy is an effective strategy to reduce the incidence of postoperative AF. The effectiveness of this approach may be enhanced if combined with atrial septal pacing.
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Comparisons of Prophylactic Strategies
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Although both sotalol and amiodarone seem to be effective in considerably reducing the incidence of postoperative AF in patients undergoing open heart operations, they have not been compared with each other in a randomized clinical trial. They were, however, compared in a meta-analysis by Wurdeman and associates [66]. This evaluation included 539 patients who received sotalol and 764 patients who received amiodarone. Both drugs effectively reduced the rate of postoperative AF or atrial flutter compared with placebo (–21% for sotalol vs placebo; –14.1% for amiodarone vs placebo; p < 0.001 for both comparisons). Although the magnitude of reduction was greater with sotalol compared with amiodarone, the difference between these strategies was not statistically significant, thus suggesting that neither drug is superior to the other. In the sotalol studies, significantly more patients experienced adverse effects that necessitated discontinuation (weighted mean rate difference, 9.7%; p = 0.048). However, this was not true in the amiodarone pooled data (weighted mean rate difference, 1.95%; p = 0.12). Neither drug resulted in a significant reduction in LOS. Although not specifically addressed in this study, the incidence of proarrhythmia (torsades de pointes) was estimated to be more than twice as common in nonsurgical patients treated with sotalol compared with amiodarone (2.5% vs < 1% for sotalol and amiodarone, respectively).
Crystal and associates [67] performed a metaanalysis that included 42 pharmacologic studies evaluating ß-blockers, sotalol, and amiodarone as prophylactic strategies for postoperative AF in patients undergoing open heart operations. Each of these therapies was associated with a relative risk reduction of greater than 50% relative to control subjects. Sotalol was associated with a 50% relative risk reduction when compared with conventional ß-blockers, but it was not compared with amiodarone.
Tables 3 and 4 list the results of 52 studies evaluating the various pharmacologic approaches to prevent postoperative AF. Overall, the incidence of postoperative AF in 4224 control subjects was 29.2%. The incidence of postoperative AF in the 1892 patients given various ß-blockers as prophylactic agents was 19.3% cumulatively. Sotalol was given to nearly 800 patients, with an average postoperative AF incidence of 15.4%. In the 1659 patients treated with either oral or IV amiodarone, postoperative AF occurred in 18.0% (12.5% in those given both IV and oral amiodarone, 16.5% in those given oral amiodarone only, and 31.4% in those who received IV amiodarone only).
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Other Drug Therapies
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Antagonism of Angiotensin II
Recently, angiotensin II has been identified as possibly playing a role in the development of atrial fibrillation in nonsurgical patients. Consequently, it has been hypothesized that antagonizing the effects of angiotensin II with drug therapy may help to prevent atrial fibrillation. In a subset of patients from the SOLVD trials, the angiotensin-converting-enzyme inhibitor (ACEI) enalapril was associated with a 78% relative risk reduction for the development of atrial fibrillation compared to placebo [68]. In another analysis, the combination of irbesartan, an angiotensin receptor blocker (ARB), plus amiodarone prevented the recurrence of atrial fibrillation more effectively than amiodarone alone [69]. Although neither of these strategies has been evaluated in patients undergoing OHS, drugs such as ACEI and ARBs may play a role in preventing POAF as well.
Nonsteroidal Antiinflammatory Drugs
Because inflammation is believed to play a big role in the development of POAF, the use of antiinflammatory drugs has also been evaluated as a preventative strategy. Cheruku and colleagues randomized 90 patients undergoing CABG surgery to receive either nonsteroidal antiinflammatory drugs (NSAIDs) or pain medications other than NSAIDs [70]. Patients receiving NSAIDs (IV ketorolac for 24 hours followed by oral ibuprofen) postoperatively had a significantly lower incidence of POAF (4.3%) compared to those not receiving NSAIDs (25.5%, p < 0.01) [70]. This trial suggests that NSAIDs may be an effective adjunct to postoperative care in reducing the risk of POAF, provided patients do not have significant renal impairment.
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Recommendations
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Postoperative AF and other SVT are common complications after open heart operations, occurring in 29.2% of patients by our estimates. When postoperative AF occurs, morbidity is often increased, LOS is prolonged, and the total cost of care is increased. Therefore, strategies aimed at preventing postoperative AF are necessary to optimize the postoperative care of patients undergoing open heart operations. No strategy has consistently been shown to be superior to another. Rather, the most effective approach to preventing postoperative AF likely involves multiple interventions (Fig 1). All patients should receive preoperative and postoperative ß-blockers unless otherwise contraindicated. Patients at high risk for the development of postoperative AF and those with intolerance of or contraindications to ß-blockers will likely benefit from antiarrhythmic therapy with either sotalol or amiodarone.
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Fig 1. Algorithm for the prophylaxis of atrial fibrillation after open heart surgery. (ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; BID = twice daily; HR = heart rate; IV = intravenous; NSAIDS = nonsteroidal antiinflammatory drugs; OHS = open heart surgery; postop = after operation; POAF = postoperative atrial fibrillation; preop = before operation; QID = 4 times daily; TID = 3 times daily.)
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The choice of antiarrhythmic therapy may depend on several variables, including the urgency of operation and renal function. Patients in whom the open heart operation is to be delayed for more than 1 day may benefit from several days of preoperative oral amiodarone followed by postoperative amiodarone in addition to ß-blocker therapy. Patients requiring urgent operation who are unable to take several days of prophylactic oral amiodarone may benefit from the combination of IV and oral amiodarone initiated immediately after operation in addition to ß-blockers. Sotalol, initiated 2 hours before anesthesia induction or the first morning after operation, is an alternative to the ß-blocker/amiodarone combination. However, in patients at high risk for postoperative AF who have concomitant renal insufficiency (creatinine clearance < 40 mL/min), the combination of ß-blockers and amiodarone is preferred because of the increased likelihood of sotalol accumulation and dose-related adverse effects. Additionally, electrolyte deficiencies, particularly hypomagnesemia, should be treated aggressively to minimize the risk of postoperative AF. Patients without contraindications may also benefit from postoperative NSAIDs. Finally, atrial septal pacing is a nonpharmacologic therapy that may be considered in addition to drug therapy to prevent postoperative AF.
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Abstract
Introduction
