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Article Annals of Internal Medicine Amiodarone Prophylaxis Reduces Major Cardiovascular Morbidity and Length of Stay after Cardiac Surgery: A Meta-Analysis Johan D. Aasbo, DO; Andrew T. Lawrence, MD; Kousik Krishnan, MD; Michael H. Kim, MD; and Richard G. Trohman, MD Background: Although evidence supports the prophylactic use of -blockade in cardiac surgery, postoperative atrial fibrillation or flutter occurs in 40% to 60% of patients. Trials that assessed whether amiodarone prophylaxis decreases the incidence of postoperative atrial tachyarrhythmias have had mixed results and were not specifically powered to detect changes in cardiovascular morbidity, length of stay, or mortality. Purpose: To see whether prophylactic administration of amiodarone decreases the incidence of major cardiovascular events, length of stay, and mortality after cardiac surgery. Data Sources: English-language and non–English-language publications listed in the MEDLINE, EMBASE, and CINAHL databases and the Cochrane Central Register of Controlled Trials, and bibliographies of published reviews. Sources were searched from the earliest possible dates through February 2005. Study Selection: Double-blind, randomized studies comparing amiodarone with placebo that reported the incidence of supraventricular arrhythmia, atrial fibrillation, or atrial flutter as the primary end point. Data Extraction: Two investigators independently collected all data. Discrepancies were resolved by consensus. patients, amiodarone therapy was found to decrease the incidence of atrial fibrillation or flutter (relative risk, 0.64 [95% CI, 0.55 to 0.75]), ventricular tachycardia and fibrillation (relative risk, 0.42 [CI, 0.28 to 0.63]), stroke (relative risk, 0.39 [CI, 0.21 to 0.76]), and length of stay (weighted mean difference, ⴚ0.63 day [CI, ⴚ1.03 to ⴚ0.23 days]). All studies reported adverse events, but none indicated how these events were assessed. Three studies found significantly more adverse events with amiodarone therapy, including nausea permitting continuation of therapy, bradycardia of unclear clinical significance, and increased intensive care monitoring and support. Limitations: Not all studies used -blockade, and regimens were not uniform among trials. Few trials met the stringent inclusion criteria, some did not report each type of cardiovascular event, and none reported completeness of follow-up. Conclusions: Amiodarone prophylaxis decreases the occurrence of atrial fibrillation, ventricular tachyarrhythmias, and stroke and length of stay after cardiac surgery. To further evaluate the potential benefits of concomitant prophylaxis with -blockers and amiodarone, a multicenter, randomized, double-blind trial with cardiovascular outcomes that compares amiodarone with placebo in patients already receiving -blocker prophylaxis is needed. Data Synthesis: After DerSimonian–Laird random-effects models were used to combine data from 10 trials involving 1744 Ann Intern Med. 2005;143:327-336. For author affiliations, see end of text. A noncompetitive -receptor antagonism. Sinus bradycardia develops more gradually as a function of time while receiving a constant dose (11). Short-term amiodarone administration also blocks sodium channels (making the threshold voltage for activation more positive), thereby reducing automaticity (ectopic triggers) and prolonging conduction velocity (length of the tachycardia cycle) (12–14). Amiodarone may also reduce automaticity by decreasing the recruitment of voltage-dependent inward current (the “pacemaker current”) during spontaneous depolarization, reducing the slope of phase 4 of the action potential (14). Long-term therapy (weeks to months) results in prolongation of atrial and ventricular effective refractory periods because of potassium blockade (11, 15). trial fibrillation and atrial flutter are common after cardiac surgery. Studies have estimated their incidence to be as high as 40% to 60% after coronary artery bypass grafting or cardiac valve surgery (1, 2). These arrhythmias most often develop between the second and fifth postoperative day (3), with a peak incidence in the first 2 to 3 days (4). Atrial fibrillation and atrial flutter increase the occurrence of postoperative stroke (4), perioperative myocardial infarction, heart failure, and readmission to the intensive care unit (and reintubation) (5); length of stay; and total cost of hospitalization (6, 7). Recent data suggest that atrial fibrillation and atrial flutter are independent risk factors for inpatient and long-term mortality after open-heart surgery (8). Amiodarone has complex pharmacokinetics and pharmacodynamics. Although it is categorized as a Vaughn– Williams class III agent, amiodarone combines anti–-adrenergic effects (9) with sodium-, calcium-, and potassiumchannel blocking properties (10). Striking pharmacologic and therapeutic differences between short-term and longterm administration are not readily accounted for by plasma, tissue, or membrane levels of drug. The most rapid electrophysiologic effects of amiodarone are prolongation of AV nodal refractoriness and conduction time. These effects probably result from calcium-channel blockade and www.annals.org See also: Print Editors’ Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328 Summary for Patients. . . . . . . . . . . . . . . . . . . . . . . I-26 Web-Only Appendix Tables Conversion of figures and tables into slides © 2005 American College of Physicians 327 Article Amiodarone Prophylaxis Reduces Morbidity after Cardiac Surgery Context Tachyarrhythmias are common after heart surgery and are associated with increased morbidity. Contribution This meta-analysis of 10 randomized, double-blind trials involving 1744 patients undergoing open-heart surgery found that, compared with placebo, amiodarone reduced atrial and ventricular arrhythmias, stroke, and length of hospital stay. Side effects included nausea and bradycardia that was not always deemed clinically important. Cautions Trial participants did not always receive prophylaxis with -blockers. Dosages and timing of amiodarone and length of follow-up varied across studies. Implications Amiodarone may benefit some patients undergoing heart surgery. We now need trials of prophylaxis with both -blockers and amiodarone. –The Editors Clinical trials of varying size and design have evaluated the efficacy of amiodarone in reducing the incidence of atrial fibrillation and atrial flutter after cardiac surgery (16 –22). No prospective studies have intentionally been powered to detect decreases in major cardiovascular morbidity or mortality. Current American College of Cardiology/American Heart Association/European Society of Cardiology guidelines recommend -blocker therapy for all patients (without contraindications) before cardiac surgery and reserve therapy with amiodarone for patients at increased risk for postoperative atrial fibrillation and atrial flutter (those with a history of atrial fibrillation, left atrial enlargement, or valvular heart disease) (23). We performed a meta-analysis to compare the effect of treatment with amiodarone or placebo on the incidence of atrial fibrillation and atrial flutter, the incidence of major cardiovascular morbidity (ventricular tachycardia or fibrillation, stroke, or myocardial infarction), length of stay, and death. Subgroup analyses were done to compare patients who began amiodarone prophylaxis up to 13 days before surgery with those who received amiodarone intraoperatively or immediately postoperatively, and patients who received oral amiodarone with those who received intravenous amiodarone. METHODS Literature Search We conducted this review in accordance with recommendations put forth by the QUOROM Group (24). We searched the English-language and non–English-language literature by using MEDLINE, EMBASE, and CINAHL 328 6 September 2005 Annals of Internal Medicine Volume 143 • Number 5 databases and the Cochrane Central Register of Controlled Trials from the earliest searchable dates through February 2005. Search terms were atrial fibrillation, amiodarone, and surgery. We also searched the bibliographies of published reviews but excluded unpublished data. Data Collection Inclusion criteria for the meta-analysis were established before the literature search. Studies had a randomized, controlled, double-blind design to compare amiodarone with placebo; included patients who underwent coronary artery bypass grafting or cardiac valve surgery (or both); measured the occurrence of atrial fibrillation, atrial flutter, or supraventricular tachycardia as a primary outcome; and clearly described drug administration, comorbid conditions, the risk profile of study cohorts, study design, and methods. One author screened titles and abstracts before manuscript retrieval. Three authors read all retrieved manuscripts and made the final decision on which studies met the inclusion criteria. All data were abstracted independently and in duplicate by 2 of the authors by using a standardized data collection form. Discrepancies in the data abstracted were resolved by consensus among all authors. We assessed reported randomization methods and completeness of follow-up but avoided use of a formal or aggregated score for quality assessment because such use can produce inconsistent results (25). Statistical Analysis Incidences of atrial fibrillation, atrial flutter, stroke, ventricular tachycardia or fibrillation, myocardial infarction, and death were treated as dichotomous variables. Summary effects for the dichotomous variables were calculated as relative risks. Length of stay was treated as a continuous variable. The summary effect for data on length of stay was calculated as the weighted mean difference. Data on length of stay were included in calculating the summary effect only if both the mean and standard deviation were specified. We pooled data by using the DerSimonian–Laird random-effects model (26). Statistical heterogeneity for all variables was assessed by using the I2 measure because this measure is independent of the number of studies that are pooled and of the effect-size metric (27). To assess for possible publication bias, we used the test proposed by Egger and colleagues (28), which provides an assessment of funnel-plot asymmetry (expressed as a P value) by applying an inverse-variance weighted approach. For each variable, studies were assigned a Mantel–Haenszel weight that was directly proportional to the sample size and inversely proportional to the variance of each study. For subgroup analysis, studies were organized into 2 categories according to when amiodarone or placebo was initially administered. Studies were categorized as “preoperative” if administration of amiodarone or placebo began before surgery or “perioperative” if drug or placebo was www.annals.org Amiodarone Prophylaxis Reduces Morbidity after Cardiac Surgery administered during or immediately after surgery. To compare the efficacy of oral versus intravenous administration of amiodarone, we excluded trials in which both routes were used. Publication bias was assessed by using StatsDirect software, version 2.3.1 (StatsDirect Ltd., Sale, United Kingdom). All other statistical calculations were performed by using Review Manager (RevMan) statistical software, version 4.2.7 for Windows (The Cochrane Collaboration, Oxford, United Kingdom). Continuous data are expressed as the mean and standard deviation, unless otherwise specified. A 2-sided P value less than 0.05 was considered significant. Article Figure 1. Flow diagram of study selection. Role of the Funding Source We received no intramural or extramural funding for this study. RESULTS Figure 1 shows the trial selection process. Searches identified 1989 potentially relevant citations. Of these, we considered and retrieved 17 citations for possible inclusion in the meta-analysis (16 –22, 29 –38). We excluded 4 studies because they were not double-blind (16 –18, 22), 1 because it compared amiodarone with propranolol rather than placebo (19), 1 because the characteristics of the participants and details of the study methods were not provided (20), and 1 because the amiodarone regimen (a single oral dose of 1.2 g) differed markedly from those used in other studies (21). Table 1 provides information on the patients and design of the included studies. One thousand seven hundred forty-four patients were included. In 4 studies, amiodarone or placebo was administered before surgery. In 6 studies, therapy was given during or immediately after surgery. Five studies included patients who underwent coronary artery bypass grafting only, and 5 included patients who had coronary artery bypass grafting or valve surgery. All patients received at least 2 g of amiodarone by the second postoperative day. Amiodarone was administered orally in 5 studies, intravenously in 2 studies, and both orally and intravenously in 3 studies. Eight studies reported ventricular tachycardia and fibrillation, 8 reported stroke, and 4 reported myocardial infarction. Follow-up data were limited to inpatient stay for all studies except that by Giri and associates (34), which included information on death at 30 days. No study included in our analysis gave data on adequacy of patient follow-up (dropout rate). Table 2 shows medical and surgical data for the included patients. The mean patient age was 64.4 years, and the mean left ventricular ejection fraction was 0.492. At the time of surgery, a mean of 61.1% of patients were receiving a -blocker. Four studies excluded patients with a history of supraventricular tachycardia. In the studies that included such patients, only 6.5% in total had supraventricular tachycardia. Eight of ten studies excluded patients www.annals.org VF ⫽ ventricular fibrillation; VT ⫽ ventricular tachycardia. who were taking any Vaughn–Williams class I or III antiarrhythmic drug. Of the studies including patients taking antiarrhythmic drugs, 1 study (35) excluded patients with a history of supraventricular tachycardia, and the other (30) excluded patients taking amiodarone. Appendix Table 1 and Appendix Table 2 (available at www.annals.org) describe the cohorts of each study in greater detail. Compared with placebo, amiodarone decreased the incidence of atrial fibrillation and atrial flutter (relative risk, 0.64 [95% CI, 0.55 to 0.75]; P ⬍ 0.001) (Figure 2). The decrease in the incidence of atrial fibrillation and atrial flutter was similar regardless of whether amiodarone therapy was initiated preoperatively or perioperatively (relative risk, 0.62 [CI, 0.49 to 0.78] and 0.65 [CI, 0.53 to 0.81], respectively). Oral administration of amiodarone yielded similar results to intravenous administration (relative risk, 0.62 [CI, 0.49 to 0.78] and 0.67 [CI, 0.51 to 0.88], respectively). Amiodarone therapy decreased the incidence of ventricular tachycardia and fibrillation (relative risk, 0.42 [CI, 0.28 to 0.63]; P ⬍ 0.001) (Figure 3). Elimination of the studies that did not differentiate between sustained and nonsustained ventricular tachycardia or fibrillation (30, 33) did not markedly change the results (relative risk, 0.34 [CI, 0.18 to 0.66]). Amiodarone therapy also decreased the incidence of stroke (relative risk, 0.39 [CI, 0.21 to 0.76]; 6 September 2005 Annals of Internal Medicine Volume 143 • Number 5 329 Article Amiodarone Prophylaxis Reduces Morbidity after Cardiac Surgery Table 1. Randomized, Controlled Trials Included in the Meta-Analysis* Study, Year (Reference) Patients, n Type of Surgery Timing of Amiodarone or Placebo Administration Total Amiodarone Dose, g Dose and Route of Amiodarone Administration Primary Arrhythmia Butler et al., 1993 (30) 120 CABG Perioperative 4.5 Any SVT Daoud et al., 1997 (32) 124 CABG or valve, or both Preoperative Indeterminate Intravenous, 15 mg/kg of body weight (maximum of 1.5 g) over 24 h, initiated intraoperatively; then oral, 200 mg TID for 5 d Oral, 200 mg TID for 7 d, then 200 mg daily until discharge; dose halved if patient was receiving digoxin or warfarin concomitantly† Redle et al., 1999 (33) 143 CABG Preoperative 6.2 Oral, 2-g load over 5 d before surgery; then 400 g daily after surgery for 7d AF or AFL Guarnieri et al., 1999 (31) 300 CABG or valve, or both‡ Perioperative 2.0 Intravenous, 2-g load over 48 h, started within 3 h of ICU arrival AF or AFL Treggiari-Venzi, et al., 2000 (35) 100 CABG Perioperative 2.7 Intravenous, 2.7 g over 72 h, started within 1 h of ICU arrival AF or AFL Giri et al., 2001 (34) 220 CABG or valve, or both Preoperative Method 1, 7.5 Method 2, 6.0 AF or AFL White et al., 2002 (29) 220 CABG or valve, or both Preoperative Method 1: 7.5 Method 2: 6.0 Yazigi et al., 2002 (36) 200 CABG Perioperative 4.65 Method 1: Oral, 200 mg TID for 5 d before surgery, then 400 mg BID on day of surgery and on postoperative days 1–4; method 2: Oral, 400 mg QID for 1 d, then 600 mg BID on day of surgery, then 400 mg BID on postoperative days 1–4 Method 1: 400 mg QID for 1 d, then 600 mg BID on day of surgery, then 400 mg BID on postoperative days 1–4; method 2: 200 mg TID for 5 d before surgery, then 400 mg BID on day of surgery and postoperative days 1–4 Oral, load of 15 mg/kg of body weight, then 7 mg/kg daily until discharge; therapy initiated within 4 h of ICU arrival Yagdi et al., 2003 (38) 157 CABG Perioperative Indeterminate AF White et al., 2003 (37) 160 CABG or valve, or both Perioperative 6.9 (oral equivalents) Intravenous, 10 mg/kg of body weight daily for 48 h; then oral, 600 mg TID for 5 d; then 400 mg BID for 5 d; then 200 mg for 20 d; initiated within 2 h of ICU arrival Intravenous, 1050-mg load over 24 h, then oral, 400 mg TID on postoperative days 1–4 AF or AFL AF or AFL AF or AFL AF or AFL * AF ⫽ atrial fibrillation; AFL ⫽ atrial flutter; BID ⫽ twice daily; CABG ⫽ coronary artery bypass grafting; CT ⫽ computed tomography; CVA ⫽ cerebrovascular accident; ICU ⫽ intensive care unit; MRI ⫽ magnetic resonance imaging; NA ⫽ not applicable; NS ⫽ not specified; QID ⫽ 4 times daily; SVT ⫽ supraventricular tachycardia; TIA ⫽ transient ischemic attack; TID ⫽ 3 times daily. † Average presurgical stay was 13 days (SD, 7). ‡ One patient had atrial septal defect repair at the time of bypass surgery. P ⫽ 0.005) (Figure 4) and length of stay (weighted mean difference, ⫺0.63 day [CI, ⫺1.03 to ⫺0.23 days]; P ⫽ 0.002) (Figure 5). No statistically significant differences in mortality between the amiodarone and placebo cohorts were seen (relative risk, 0.84 [CI, 0.43 to 1.65]). For these estimates, we found no evidence of statistical heterogeneity or publication bias (P ⫽ 0.169, 0.133, 0.317, 0.230, and 0.959 for the incidence of atrial arrhythmias, ventricular 330 6 September 2005 Annals of Internal Medicine Volume 143 • Number 5 arrhythmias, stroke, length of stay, and mortality, respectively). The incidence of myocardial infarction did not significantly differ between groups (relative risk, 0.71 [CI, 0.31 to 1.62]). Twenty-two myocardial infarctions were reported in the 4 trials that documented their occurrence. We found no statistical heterogeneity for this outcome and could not assess publication bias because there were too few studies. www.annals.org Amiodarone Prophylaxis Reduces Morbidity after Cardiac Surgery Article Table 1—Continued Method and Duration of Patient Monitoring Randomization Methods and Blinding Funding Sources Intention-toTreat Analysis? Definition of Ventricular Tachycardia Definition of Stroke Description of Myocardial Infarction Mortality Assessment Holter monitor, 6 d postoperatively NS Pharmaceutical support Yes NS New Q waves Inpatient Telemetry, 7.2 d (SD, 3.6) NS Pharmaceutical support Yes Sustained (⬎30 s) or nonsustained (⬎3 beats) NS NS Inpatient Telemetry, not less than 96 h postoperatively Stratified/ factorial NS Yes NS Continuous ambulatory monitor, duration not specified Holter monitor, during 72 h of amiodarone infusion Telemetry, duration not specified NS Pharmaceutical support Yes Sustained (⬎30 s) or nonsustained (⬎3 beats) NS Right ventricular infarction and sepsis NA NS NA Inpatient Stratified/ factorial Pharmaceutical support No NA NS NA Inpatient Stratified/ factorial NS Yes Sustained (⬎30 s) or requiring termination TIA (focal defect ⬍24 h) or CVA (lasting ⬎24 h, with CT or MRI confirmation) NA 30 d Telemetry, duration not specified Stratified/ factorial Financial support from hospital research foundation Yes Sustained (⬎30 s) or requiring termination TIA (focal defect ⬍24 h) or CVA (lasting ⬎24 h, with CT or MRI confirmation) NA Inpatient Telemetry for 72 h, then vital checks every 4 h and electrocardiography every 12 h Telemetry until discharge NS NS Yes NS NA NA Inpatient NS NS NS NS NS NS Inpatient Stratified/ factorial Pharmaceutical support NS NA TIA (focal defect ⬍24 h) or CVA (lasting ⬎24 h, with CT or MRI confirmation) NS Inpatient Telemetry, duration not specified All 10 studies reported adverse events, but none indicated whether these events were reported incidentally or determined as end points a priori. Three studies reported significantly higher rates of adverse events that may have been related to amiodarone therapy. Butler and coworkers (30) noted a significantly higher incidence of bradycardia among amiodarone recipients (P ⫽ 0.005). The clinical significance of these bradycardia episodes was not eluciwww.annals.org Inpatient dated. Treggiari-Venzi and associates (35) reported a significantly increased duration of catecholamine support (P ⬍ 0.01), use of pulmonary artery catheters (P ⬍ 0.01), and stay in the intensive care unit (P ⬍ 0.05) among amiodarone recipients. White and colleagues (29) found a significantly increased incidence of nausea (not requiring termination of therapy) with a higher-dose, shorter-duration amiodarone loading regimen (P ⫽ 0.018). 6 September 2005 Annals of Internal Medicine Volume 143 • Number 5 331 Article Amiodarone Prophylaxis Reduces Morbidity after Cardiac Surgery Table 2. Medical and Surgical Characteristics of Patient Cohorts* Study, Year (Reference) Patients, n Mean Age, y Men, % History of Supraventricular Tachycardia, % History of Myocardial Infarction, % History of Hypertension, % Butler et al., 1993 (30) Daoud et al., 1997 (32) Redle et al., 1999 (33) Guarnieri et al., 1999 (31) Treggiari-Venzi et al., 2000 (35) Giri et al., 2001 (34) White et al., 2002 (29) Yazigi et al., 2002 (36) Yagdi et al., 2003 (38) White et al., 2003 (37) Mean (SD) 120 124 143 300 100 220 220 200 157 160 59.5 59 63.8 63.6 65 72.6 72.6 60.6 61.1 65.9 64.4 (4.9) 85.3 67.8 82.5 75.5 86.1 76.2 76.4 65.0 77.1 75.8 76.8 (6.8) NS 7.3 None in past 6 mo None† 3.0 9.7 10 None† None† 2.5 6.5 (3.6) 53.4 30.7 NS 40.2 45.3 34.6 35.5 16.0 46.5 25.6 36.4 (11.5) 38.4 50.0 53.3 73.2 41.2 70.7 70.5 39.0 57.8 NS 54.9 (14.0) * Appendix Tables 1 and 2 (available at www.annals.org) describe the cohorts in greater detail. NS ⫽ not specified. † Supraventricular tachycardia was an exclusion criterion. DISCUSSION incidence of atrial fibrillation and atrial flutter (16, 18, 22), and 1 reported that it decreased the incidence of ventricular arrhythmias (18). Two studies reported no significant difference in length of stay between amiodarone recipients and placebo recipients (16, 22), 3 studies reported no significant difference in mortality (16 –18), and 1 study (22) did not report on mortality. No study found a significant reduction in the incidence of stroke, and no occurrence of myocardial infarction was reported. No study included in our analysis provided a subgroup analysis of patients with low ejection fraction. However, Butler and coworkers (30) and Redle and associates (33) found that depressed ejection fraction did not predict atrial fibrillation and atrial flutter. Giri and colleagues (34) found left atrial enlargement and clinical history of heart The pivotal finding of our meta-analysis is that treatment with amiodarone decreases the incidence of major postoperative cardiovascular events (ventricular tachycardia, ventricular fibrillation, and stroke). Previous metaanalyses suggest that amiodarone therapy decreases the incidence of atrial fibrillation and atrial flutter after openheart surgery (39 – 41). Our analysis confirms that amiodarone prophylaxis decreases rates of these tachyarrhythmias and shortens the length of hospitalization. Whereas previous meta-analyses included unblinded studies, we excluded such trials in an attempt to minimize bias. In the 4 unblinded studies that we excluded (16 –18, 22) the results of amiodarone prophylaxis varied. Three studies reported that amiodarone prophylaxis decreased the Figure 2. Incidence of atrial fibrillation or flutter with amiodarone or placebo. Random RR Weight, % Random RR (95% CI) Study, Year (Reference) Amiodarone Group, n/n Placebo Group, n/n Butler et al., 1993 (30) 12/60 12/60 4.43 1.00 (0.49–2.05) Daoud et al., 1997 (32) 15/64 25/60 7.95 0.56 (0.33–0.96) Redle et al., 1999 (33) 18/73 23/70 8.32 0.75 (0.45–1.27) Guarnieri et al., 1999 (31) 56/158 67/142 30.46 0.75 (0.57–0.99) 7/49 14/51 3.39 0.52 (0.23–1.18) Giri et al., 2001 (34) 28/120 38/100 13.53 0.61 (0.41–0.92) White et al., 2002 (29) 27/120 38/100 13.13 0.59 (0.39–0.90) Yazigi et al., 2002 (36) 12/100 25/100 5.72 0.48 (0.26–0.90) Yagdi et al., 2003 (38) 8/77 20/80 3.95 0.42 (0.19–0.89) White et al. (AFIST II), 2003 (37) 17/77 32/83 9.09 0.57 (0.35–0.94) 100.00 0.64 (0.55–0.75) Treggiari-Venzi et al., 2000 (35) Total 898 846 0.1 0.2 0.5 Favors Amiodarone 1 2 5 10 Favors Placebo AFIST ⫽ Atrial Fibrillation Suppression Trial; RR ⫽ relative risk. 332 6 September 2005 Annals of Internal Medicine Volume 143 • Number 5 www.annals.org Amiodarone Prophylaxis Reduces Morbidity after Cardiac Surgery Article Table 2—Continued History of Diabetes Mellitus, % Left Ventricular Ejection Fraction Use of -Blocker, % Duration of Cardiopulmonaary Bypass, min Patients Who Received Valve Surgery, % Duration of Cross-Clamping, min Mean Vessels Grafted, n 7.5 14.5 25.9 30.0 19.2 32.6 NS 26.0 28.7 NS 23.1 (8.6) 0.63 0.48 0.485 0.445 0.575 0.427 0.427 NS 0.475 0.482 0.492 (0.068) 79.2 35.3 58.8 51.6 59.9 72.4 89.1 66.5 25.6 72.4 61.1 (19.5) 55.8 151.0 77.0 97.8 152.5 119.3 119.1 99.0 67.4 NS 104.3 (34.4) None 50.9 None 14.7 None 26.9 18.2 None None 21.2 26.4 (14.4) 34.0 100.5 NS NS 101.5 88.8 88.7 50.0 42.5 96.2 75.3 (28.1) 2.7 2.6 3.3 4.1 3.0 2.4 NS 2.8 3.0 3.4 3.0 (0.5) failure symptoms to be predictive of atrial fibrillation and atrial flutter (P ⬍ 0.001 and 0.032, respectively). Daoud and coworkers (32) found that valve surgery independently predicted atrial fibrillation and atrial flutter (P ⫽ 0.04). Adverse events possibly related to amiodarone therapy occurred significantly more often in the amiodarone groups of 3 studies (29, 30, 35). These events warrant consideration, but the data are not conclusive. One study reported an increased occurrence of clinically unimportant nausea (29). In the studies that reported a higher incidence of bradycardia and increased duration of catecholamine support, use of pulmonary artery catheters, and intensive care unit stay (30, 35), the blinding code was broken when the primary end point of arrhythmia occurred, possibly before the occurrence of the adverse event. This decision raises the question of whether bias occurred. None of the trials were specifically designed to assess adverse events due to amiodarone therapy. Of note, patients who underwent amiodarone loading during or immediately after surgery had similar reductions in the incidence of atrial fibrillation and atrial flutter compared with those who underwent loading days before surgery. This finding suggests that prescribing oral amiodarone days before surgery is unnecessary. Prolonged amiodarone prophylaxis may increase length of hospitalization, costs, and patient inconvenience. On the other hand, perioperative intake and absorption of oral amiodarone may be limited. Administration of the more expensive intravenous preparation may counterbalance any cost benefit of abbreviated regimens. Two meta-analyses found no difference in the incidence of stroke in patients who received amiodarone ther- Figure 3. Incidence of ventricular tachycardia or fibrillation with amiodarone or placebo. Weight, % Random RR (95% CI) 38.17 0.45 (0.24–0.88) 2/60 1.81 0.19 (0.01–3.83) 13/70 22.31 0.52 (0.22–1.22) 2/142 1.79 0.18 (0.01–3.72) 2/120 7/100 6.85 0.24 (0.05–1.12) White et al., 2002 (29) 2/120 7/100 6.85 0.24 (0.05–1.12) Yazigi et al., 2002 (36) 1/100 0/100 1.62 3.00 (0.12–72.77) Yagdi et al., 2003 (38) 6/77 20.59 0.42 (0.17–1.02) 100.00 0.42 (0.28–0.63) Study, Year (Reference) Amiodarone Group, n/n Placebo Group, n/n Butler et al., 1993 (30) 10/60 22/60 Daoud et al., 1997 (32) 0/64 Redle et al., 1999 (33) 7/73 Guarnieri et al., 1999 (31) 0/158 Giri et al., 2001 (34) Total 772 Random RR 15/80 712 0.1 0.2 0.5 Favors Amiodarone 1 2 5 10 Favors Placebo RR ⫽ relative risk. www.annals.org 6 September 2005 Annals of Internal Medicine Volume 143 • Number 5 333 Article Amiodarone Prophylaxis Reduces Morbidity after Cardiac Surgery Figure 4. Incidence of stroke with amiodarone or placebo. Study, Year (Reference) Amiodarone Group, n/n Placebo Group, n/n Butler et al., 1993 (30) 1/60 0/60 Daoud et al., 1997 (32) 1/64 Guarnieri et al., 1999 (31) 2/158 Giri et al., 2001 (34) 4/120 White et al., 2002 (29) Random RR Weight, % Random RR (95% CI) 4.24 3.00 (0.12–72.20) 0/60 4.24 2.82 (0.12–67.80) 3/142 13.62 0.60 (0.10–3.53) 12/100 35.45 0.28 (0.09–0.83) 2/120 7/100 17.88 0.24 (0.05–1.12) Yazigi et al., 2002 (36) 0/100 1/100 4.22 0.33 (0.01–8.09) Yagdi et al., 2003 (38) 2/77 4/80 15.41 0.52 (0.10–2.75) White et al. (AFIST II), 2003 (37) 0/77 3/83 4.94 0.15 (0.01–2.93) 100.00 0.39 (0.21–0.76) 776 Total 725 0.1 0.2 0.5 1 2 Favors Amiodarone 5 10 Favors Placebo AFIST ⫽ Atrial Fibrillation Suppression Trial; RR ⫽ relative risk. apy (40, 41). Our apparent discrepant results may be due to the fact that we included recent studies (29, 36 –38) that were not included in the earlier reviews. The annual incidence of stroke associated with atrial fibrillation and atrial flutter in nonsurgical patients is approximately 5%. On the basis of this value, it seems unlikely that decreasing the incidence of postoperative atrial fibrillation and atrial flutter would cause a measurable decrease in the incidence of stroke solely by diminishing embolization of atrial thrombi. Indeed, the incidence of embolization due to atrial fibrillation and atrial flutter may be lower in postsurgical patients than in nonsurgical patients (42). The reduc- tion in stroke observed may also be attributable to prevention of low cardiac output states, increased sympathetic tone, and other factors associated with postoperative atrial fibrillation and atrial flutter. Amiodarone was synthesized in 1962 as a potent antianginal agent (43). Its antiarrhythmic effects were first noted in 1967 (44), but it was not approved by the U.S. Food and Drug Administration as an antiarrhythmic agent until 1985 (45). Although amiodarone therapy reduced the relative risk for myocardial infarction in our analysis, this finding was not statistically significant. Unfortunately, only 4 trials reported 22 myocardial infarctions. The decrease Figure 5. Length of hospitalization with amiodarone or placebo. Patients, n Mean Stay (SD), d Random Weighted Mean Difference Placebo Group Amiodarone Group Study, Year (Reference) Patients, Mean Stay (SD), d n Weight, % Random Weighted Mean Difference (95% CI) 64 6.50 (2.60) 60 7.90 (4.30) 9.43 –1.40 (–2.66 to –0.14) Guarnieri et al., 1999 (31) 158 7.60 (5.90) 142 8.20 (6.20) 8.02 –0.60 (–1.97 to 0.77) Giri et al., 2001 (34) 120 9.16 (8.20) 100 9.35 (7.80) 3.47 –0.19 (–2.31 to 1.93) White et al., 2002 (29) 120 9.10 (7.80) 100 9.40 (7.80) 3.63 –0.30 (–2.37 to 1.77) Yazigi et al., 2002 (36) 100 6.80 (1.30) 100 7.10 (2.00) 49.84 –0.30 (–0.77 to 0.17) Yagdi et al., 2003 (38) 77 6.80 (1.70) 80 7.80 (2.90) 24.55 –1.00 (–1.74 to –0.26) White et al. (AFIST II), 2003 (37) 77 7.88 (6.16) 83 11.30 (16.83) 1.06 –3.42 (–7.29 to 0.45) Daoud et al., 1997 (32) Total 716 100.00 665 –4 –2 Favors Amiodarone 0 2 –0.63 (–1.03 to –0.23) 4 Favors Placebo AFIST ⫽ Atrial Fibrillation Suppression Trial. 334 6 September 2005 Annals of Internal Medicine Volume 143 • Number 5 www.annals.org Amiodarone Prophylaxis Reduces Morbidity after Cardiac Surgery we noted may have been due in part to the -blocking effects of amiodarone. Amiodarone also inhibits calcium channels and may prevent vasospastic ischemia and infarction. Vasospasm has been described as a cause of perioperative myocardial infarction after coronary artery bypass grafting with internal mammary arteries (46 – 48). A recent large retrospective study indicated that atrial fibrillation and atrial flutter are independent predictors of inpatient and long-term mortality (8). Although the incidences of atrial fibrillation and atrial flutter and major cardiovascular events were decreased, amiodarone therapy did not significantly alter the risk for death in our study. Mortality data in the studies included in our analysis were limited to inpatient death in 9 studies and death within 30 days of discharge in 1 study. Demonstration of a mortality benefit might require data obtained from follow-up weeks to months after discharge. It is also possible that modern aggressive treatment of postoperative illnesses has already had an important impact on the overall mortality rate, limiting its correlation with postoperative ventricular tachycardia or fibrillation, stroke, or myocardial infarction. Whether a mortality benefit would be demonstrated in a prospective study that is powered specifically to answer this question remains uncertain. Our study has several limitations. First, the incidence of ventricular tachycardia or fibrillation, stroke, and myocardial infarction and length of stay were all secondary end points in the trials in our analysis. These secondary end points were predefined in some studies but not in others. Definitions of these end points varied and were not explicitly stated in some trials. Second, the time span of the trials was 1993 to 2003. Surgical techniques and postoperative care improved during this period. Third, -blockers, the only agents whose effectiveness as prophylaxis is proven, were not given to all patients or a uniform fraction of patients in each trial. It is unclear whether the prophylactic effects of amiodarone would have been blunted if all study patients had received -blockade. Finally, although all trials were randomized and double-blind, details of the randomization methods, the concealment of treatment allocation, and the handling of patients who dropped out or were withdrawn from analysis were not always provided. Our findings suggest that amiodarone prophylaxis reduces major cardiovascular morbidity and decreases length of hospitalization after open-heart surgery. We believe that all patients undergoing open-heart surgery should receive prophylaxis with a -blocker unless it is contraindicated, in accordance with current guidelines (23). The value of routine use of amiodarone as an additional first-line prophylactic agent remains uncertain. To further evaluate the potential benefits of concomitant prophylaxis with both -blockers and amiodarone, we recommend a multicenter, randomized, double-blind trial with cardiovascular outcomes that compares amiodarone with placebo in patients already receiving prophylaxis with a -blocker. This study should assess the optimal dosing regimen for amiodarone, www.annals.org Article the degree of additional protection it provides beyond that of -blockade, whether amiodarone offers sufficient prophylaxis in patients intolerant of -blockers, the true incidence of clinically significant adverse events due to amiodarone therapy, and whether amiodarone decreases the incidence of myocardial infarction or death. From Rush University Medical Center, Chicago, Illinois. Potential Financial Conflicts of Interest: Consultancies: M.H. Kim, R.G. Trohman (Guidant CRM Business Strategy Advisory Board); Honoraria: M.H. Kim, R.G. Trohman (St. Jude Medical, Inc., Guidant CRM); Grants received: M.H. Kim, R.G. Trohman (St. Jude Medical, Inc., Medtronic, Inc., Guidant CRM, Wyeth-Ayerst). Requests for Single Reprints: Richard G. Trohman, MD, Rush Uni- versity Medical Center, 1750 West Harrison, Suite 983 Jelke, Chicago, IL 60612; e-mail, [email protected]. 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European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation). North American Society of Pacing and Electrophysiology. Circulation. 2001;104:211850. [PMID: 11673357] 24. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet. 1999; 354:1896-900. [PMID: 10584742] 25. Juni P, Witschi A, Bloch R, Egger M. The hazards of scoring the quality of clinical trials for meta-analysis. JAMA. 1999;282:1054-60. [PMID: 10493204] 26. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177-88. [PMID: 3802833] 27. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539-58. [PMID: 12111919] 28. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629-34. [PMID: 9310563] 29. White CM, Giri S, Tsikouris JP, Dunn A, Felton K, Reddy P, et al. A comparison of two individual amiodarone regimens to placebo in open heart surgery patients. Ann Thorac Surg. 2002;74:69-74. [PMID: 12118806] 30. Butler J, Harriss DR, Sinclair M, Westaby S. Amiodarone prophylaxis for tachycardias after coronary artery surgery: a randomised, double blind, placebo controlled trial. Br Heart J. 1993;70:56-60. [PMID: 8038000] 31. Guarnieri T, Nolan S, Gottlieb SO, Dudek A, Lowry DR. Intravenous amiodarone for the prevention of atrial fibrillation after open heart surgery: the 336 6 September 2005 Annals of Internal Medicine Volume 143 • Number 5 Amiodarone Reduction in Coronary Heart (ARCH) trial. J Am Coll Cardiol. 1999;34:343-7. [PMID: 10440143] 32. Daoud EG, Strickberger SA, Man KC, Goyal R, Deeb GM, Bolling SF, et al. Preoperative amiodarone as prophylaxis against atrial fibrillation after heart surgery. N Engl J Med. 1997;337:1785-91. [PMID: 9400034] 33. Redle JD, Khurana S, Marzan R, McCullough PA, Stewart JR, Westveer DC, et al. Prophylactic oral amiodarone compared with placebo for prevention of atrial fibrillation after coronary artery bypass surgery. Am Heart J. 1999;138(1 Pt 1):144-50. [PMID: 10385778] 34. Giri S, White CM, Dunn AB, Felton K, Freeman-Bosco L, Reddy P, et al. Oral amiodarone for prevention of atrial fibrillation after open heart surgery, the Atrial Fibrillation Suppression Trial (AFIST): a randomised placebo-controlled trial. Lancet. 2001;357:830-6. [PMID: 11265951] 35. Treggiari-Venzi MM, Waeber JL, Perneger TV, Suter PM, Adamec R, Romand JA. Intravenous amiodarone or magnesium sulphate is not cost-beneficial prophylaxis for atrial fibrillation after coronary artery bypass surgery. Br J Anaesth. 2000;85:690-5. [PMID: 11094581] 36. Yazigi A, Rahbani P, Zeid HA, Madi-Jebara S, Haddad F, Hayek G. Postoperative oral amiodarone as prophylaxis against atrial fibrillation after coronary artery surgery. J Cardiothorac Vasc Anesth. 2002;16:603-6. [PMID: 12407614] 37. White CM, Caron MF, Kalus JS, Rose H, Song J, Reddy P, et al. Intravenous plus oral amiodarone, atrial septal pacing, or both strategies to prevent post-cardiothoracic surgery atrial fibrillation: the Atrial Fibrillation Suppression Trial II (AFIST II). Atrial Fibrillation Suppression Trial II. Circulation. 2003;108 Suppl 1:II200-6. [PMID: 12970233] 38. Yagdi T, Nalbantgil S, Ayik F, Apaydin A, Islamoglu F, Posacioglu H, et al. Amiodarone reduces the incidence of atrial fibrillation after coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2003;125:1420-5. [PMID: 12830063] 39. Wurdeman RL, Mooss AN, Mohiuddin SM, Lenz TL. Amiodarone vs. sotalol as prophylaxis against atrial fibrillation/flutter after heart surgery: a metaanalysis. Chest. 2002;121:1203-10. [PMID: 11948054] 40. Crystal E, Connolly SJ, Sleik K, Ginger TJ, Yusuf S. Interventions on prevention of postoperative atrial fibrillation in patients undergoing heart surgery: a meta-analysis. Circulation. 2002;106:75-80. [PMID: 12093773] 41. Zimmer J, Pezzullo J, Choucair W, Southard J, Kokkinos P, Karasik P, et al. Meta-analysis of antiarrhythmic therapy in the prevention of postoperative atrial fibrillation and the effect on hospital length of stay, costs, cerebrovascular accidents, and mortality in patients undergoing cardiac surgery. Am J Cardiol. 2003;91:1137-40. [PMID: 12714166] 42. Arnold AZ, Mick MJ, Mazurek RP, Loop FD, Trohman RG. Role of prophylactic anticoagulation for direct current cardioversion in patients with atrial fibrillation or atrial flutter. J Am Coll Cardiol. 1992;19:851-5. [PMID: 1545081] 43. Singh BN. Amiodarone: historical development and pharmacologic profile. Am Heart J. 1983;106(4 Pt 2):788-97. [PMID: 6351575] 44. Charlier R. [Development of pharmacologic criteria for development of antianginal medications]. Brux Med. 1969;49:543-60. [PMID: 4391538] 45. Mason JW. Amiodarone. N Engl J Med. 1987;316:455-66. [PMID: 3543680] 46. Sarabu MR, McClung JA, Fass A, Reed GE. Early postoperative spasm in left internal mammary artery bypass grafts. Ann Thorac Surg. 1987;44:199-200. [PMID: 3497619] 47. Segesser L, Simonet F, Meier B, Finci L, Faidutti B. Inadequate flow after internal mammary-coronary artery anastomoses. Thorac Cardiovasc Surg. 1987; 35:352-4. [PMID: 2448904] 48. von Segesser LK, Lehmann K, Turina M. Deleterious effects of shock in internal mammary artery anastomoses. Ann Thorac Surg. 1989;47:575-9. [PMID: 2712631] www.annals.org Annals of Internal Medicine Current Author Addresses: Dr. Aasbo: Medical College of Wisconsin, Division of Cardiovascular Medicine, 9200 West Wisconsin Avenue, Suite 5100, Milwaukee, WI 53226. Drs. Lawrence, Krishnan, and Trohman: Rush University Medical Center, 1750 West Harrison, Suite 983 Jelke, Chicago, IL 60612. Dr. Kim: Health Partners, Inc., 640 Jackson Street, Mail Stop 11102M, St. Paul, MN 55101. Author Contributions: Conception and design: J.D. Aasbo, R.G. Trohman. Analysis and interpretation of the data: J.D. Aasbo, A.T. Lawrence, R.G. Trohman. Drafting of the article: J.D. Aasbo, K. Krishnan, M.H. Kim, R.G. Trohman. Critical revision of the article for important intellectual content: J.D. Aasbo, R.G. Trohman. Final approval of the article: J.D. Aasbo, A.T. Lawrence, K. Krishnan, M.H. Kim, R.G. Trohman. Statistical expertise: J.D. Aasbo. Administrative, technical, or logistic support: J.D. Aasbo. Collection and assembly of data: J.D. Aasbo, A.T. Lawrence. W-86 6 September 2005 Annals of Internal Medicine Volume 143 • Number 5 www.annals.org Appendix Table 1. Patient Characteristics, by Treatment Group* Mean Age (SD), y Study, Year (Reference) Butler et al., 1993 (30) Daoud et al., 1997 (32) Redle et al., 1999 (33) Guarnieri et al., 1999 (31) Treggiari-Venzi et al., 2000 (35) Giri et al., 2001 (34) White et al., 2002 (29) Yazigi et al., 2002 (36) Yagdi et al., 2003 (38) White et al., 2003 (37) Men, % History of Supraventricular Tachycardia, % Placebo Group History of Myocardial Infarction, % Amiodarone Group Placebo Group Amiodarone Group Placebo Group Amiodarone Group 59 (7.6) 60 (9.1) 91.7 83.3 NS 57 (14) 61 (13) 68.8 66.7 63 64.5 83.6 81.4 None in past 6 mo NS 63.3 63.9 74.1 76.8 None† 43 37.3 65‡ 65§ 87.8 84.3 2.0 3.9 59.2 31.4 72.7 (6.7) 72.6 (6.5) 72.5 (6.7) 72.5 (6.7) 78.3 78.9 74 74 13.3 13.0 6.0 6 44.2 43.9 25 25 60.6 (10.5) 60.6 (9.3) 64 66 None† 15 17 59.3 (8.9) 61.1 (9.6) 80.5 73.7 None† 41.6 51.3 66.8 (9.0) 64.9 (8.3) 76.8 74.7 2.6 24.7 26.5 7.8 6.7 2.4 Amiodarone Group Placebo Group 50 56.7 31.3 30 * NS ⫽ not specified. † Supraventricular tachycardia was an exclusion criterion. ‡ Range, 44 to 78 years. § Range, 37 to 88 years. Appendix Table 2. Patient History, by Treatment Group* Study, Year (Reference) Butler et al., 1993 (30) Daoud et al., 1997 (32) Redle et al., 1999 (33) Guarnieri et al., 1999 (31) Treggiari-Venzi et al., 2000 (35) Giri et al., 2001 (34) White et al., 2002 (29) Yazigi et al., 2002 (36) Yagdi et al., 2003 (38) White et al., 2003 (37) History of Hypertension, % History of Diabetes Mellitus, % Amiodarone Group Placebo Group Amiodarone Group Amiodarone Group Placebo Group 35 41.7 8.33 6.7 0.65 (0.12) 0.61 (0.15) 78.3 80 50 50 15.6 13.3 0.48 (0.12) 0.48 (0.13) 40.6 30 47.9 58.6 28.8 22.9 0.49 0.48 58.9 58.6 69.6 76.8 29.7 30.3 0.43 (0.28) 0.46 (0.26) 52.5 50.7 49 33.3 26.5 11.8 0.58 (0.14) 0.57 (0.13) 55.1 64.7 68.3 67.5 73 73 29.2 NS 36 0.423 (0.11) 0.436 (0.102) 0.431 (0.12) 0.431 (0.117) 70.8 87.7 74 91 40 38 25 27 ⬍0.4 in 8 patients ⬍0.4 in 7 patients 67 66 50.6 65 26 31.3 NS NS Placebo Group Use of -Blocker, % Mean Left Ventricular Ejection Fraction (SD) Amiodarone Group Placebo Group 0.47 (0.99) 0.479 (0.104) 29.9 21.3 0.483 (0.123) 0.48 (0.127) 70.1 74.7 * NS ⫽ not specified. www.annals.org 6 September 2005 Annals of Internal Medicine Volume 143 • Number 5 W-87