COMPARISON OF INTRAVENOUS METOPROLOL VERSUS AMIODARONE IN THE PREVENTION OF AF AFTER CARDIAC SURGERY

We found no difference in the occurrence of postoperative AF in patients treated with intravenous metoprolol or amiodarone after cardiac surgery. Atrial fibrillation occurred in 23.9% and 24.8% of patients in the metoprolol and amiodarone groups, respectively.

However, the wide range of the confidence intervals does not satisfy the hypothesized definition of equivalence (between -5 and 5 percentage points) and therefore does not allow us to conclude that the two treatments are equally effective in preventing AF after cardiac surgery. According to current guidelines, beta-blockers should be the first-line preventive treatment of AF in patients having cardiac surgery. Amiodarone should be reserved for patients in whom beta-blocker therapy fails or is contraindicated (Dunning et al. 2006).

Despite this, according to a recent survey, 19% of physicians reported using amiodarone as the first-line prophylactic strategy for postoperative AF (Price et al. 2009). This nonadherence to guidelines may be because amiodarone is considered to be the most potent drug in the prevention of AF (Lee et al. 2000) and data directly comparing the efficacy and safety of intravenous beta-blockers and amiodarone in preventing postoperative AF are lacking.

Several studies (Study I, Crystal et al. 2002, Burgess et al. 2006, Andrews et al. 1991, Kowey et al. 1991) have demonstrated the effectiveness of beta-blockers in preventing AF after cardiac surgery. A meta-analysis of 27 prospective randomized trials and 3840 patients reported a 61% decrease in the incidence of postoperative AF with beta-blocker therapy (Crystal et al.

2002). In the largest randomized trial, oral amiodarone decreased the incidence of postoperative AF after CABG by 39% compared with placebo (Mitchell et al. 2005). In a meta-analysis of 18 randomized trials, amiodarone decreased the incidence of postoperative AF by 62% (Burgess et al. 2006).

Indeed, only a few studies have compared beta-blockers and amiodarone in a head-to-head setting. In a recent report by Sleilaty and colleagues (Sleilaty et al. 2009), oral bisoprolol and amiodarone were equally effective for the prophylaxis of AF after CABG. Auer and coworkers (Auer et al. 2004) compared oral amiodarone plus metoprolol with oral sotalol, oral metoprolol, and placebo in patients having cardiac surgery. The combination of amiodarone and metoprolol reduced the incidence of AF significantly (44%) compared with placebo, whereas no significant differences were found between the active groups. In these trials, the study drugs were administered orally, whereas the drugs were given intravenously in our study. The bioavailability of oral drugs is markedly reduced when administered in oral form during the early phase after CABG (Valtola et al. 2007). Only one earlier trial compared intravenous beta-blockers with intravenous amiodarone. Solomon and colleagues

(Solomon et al. 2001) randomly assigned patients to either intravenous amiodarone for 48 hours followed by oral amiodarone until discharge, or intravenous propranolol for 48 hours followed by oral propranolol until discharge, in 102 patients undergoing cardiac surgery.

Amiodarone was superior to propranolol in preventing postoperative AF, but beta-blocker treatment was continued throughout the study in the patients assigned to amiodarone who took beta-blockers before surgery. Thus, in many cases, the true comparison was amiodarone plus beta-blocker versus beta-blocker alone, rather than amiodarone versus beta-blocker.

With regard to serious adverse events in our study, one patient in each group died during the 48-hour follow-up. In addition, one patient in the metoprolol group had a stroke. In all of these cases, the study medication was unlikely to be related to these adverse events. Both treatments seemed to be well tolerated. No patients required crossover to the other treatment. The only symptomatic adverse effect was venous thrombophlebitis in 11 patients in the amiodarone group. The study drug infusion was temporarily interrupted because of hypotension more often in the metoprolol group than in the amiodarone group and because of bradycardia more often (although nonsignificantly) in the amiodarone group than in the metoprolol group. These findings are in line with those of an earlier study reporting that amiodarone infusion was associated with bradycardia and interruption of the infusion in 18% of patients (Jafari-Fresharaki et al. 1998).

An obvious limitation in our study is that although the incidence of AF was similar (38 and 39 patients in the metoprolol and amiodarone groups, respectively) and did not differ between the study groups, we lacked sufficient power to demonstrate equality. Even after adjustment for potential confounders, the wide range in the confidence intervals (95% CI, 0.67–1.76) does not allow us to conclude that the two treatments were equally effective in preventing postoperative AF. Thus, we cannot exclude the possibility that true differences in efficacy exist between amiodarone and beta-blockers in the prevention of AF. For example, it is possible that the withdrawal of established beta-blocker therapy for patients allocated to amiodarone may have precipitated AF. Although we doubt this was the case, because amiodarone has beta-blocking properties (Singh 2008), we cannot exclude the possibility that this may have biased our results against amiodarone. The blocking effect of amiodarone is supported by our finding that bradycardia (<60 beats/min) developed more frequently in patients treated with amiodarone than in those treated with metoprolol. Our patients were not considered to be at particularly elevated risk for AF and were hemodynamically stable, were off pressors, and were free of mechanical ventilation within 24 hours of cardiac surgery.

Thus, our results cannot be safely applied to sicker patients or those at higher risk for AF, such as patients with a history of AF or undergoing mitral valve repair.

The study period of 48 hours starting from the first postoperative morning may be thought to be too short. The incidence of AF is highest on the second and third postoperative days (Arankiet al. 1996, Hakal et al. 2002). A great majority of this time period was well covered in our study. As many as 17% of the patients developed AF after the study period but before hospital discharge. However, the occurrence of AF after the study period did not differ between the groups.

It could also be argued that the amiodarone dose in our study was not sufficient.

Amiodarone has been shown to be efficient in various doses and in oral and intravenous administration (Crystal et al. 2002, Burgess et al. 2006, Aasbo et al. 2005, Gillespie et al. 2005, Mitchell et al. 2005, Buckley et al. 2007). In the largest randomized trial, the amiodarone dose was 10 mg/kg, whereas it was 50% more in our study, 15 mg/kg per day (Mitchell et al. 2005).

Thus, an insufficient dose is unlikely to explain the results of our study.

Although we did not find any difference in the incidence of AF, larger multicenter trials or meta-analyses are needed to confirm the equality of metoprolol and amiodarone in preventing postoperative AF. In addition, comparisons of metoprolol and amiodarone are needed in patient cohorts with higher risk for AF, such as patients undergoing mitral

after operation. Until more data are available, we recommend adherence to current guidelines, namely the use of beta-blockers as first-line prophylaxis of postoperative AF.

We conclude that while the observed incidence of AF during 48 hours of treatment with intravenous metoprolol or amiodarone after cardiac surgery was similar, we cannot conclude that the treatments are equally effective.