Review

© Future Drugs Ltd. All rights reserved. ISSN 1478-7210 187

CONTENTS

β-blockers

Sotalol

Amiodarone

Comparisons between different agents

Pacing

Prevention of postoperative atrial fibrillation & LOS

Summary

Expert opinion

Five-year view

Key issues

References

Affiliaton

www.future-drugs.com

Atrial fibrillation after cardiac surgery: evidence on prophylactic interventionsEugene CrystalPostoperative atrial fibrillation after heart surgery is frequent and may increase the length of hospital stay and costs of postoperative care of patients after heat surgery. Pharmacological and pacing interventions were evaluated in the large number of relatively small trials with often contradictory results. Conventional β-blockers, sotalol, amiodarone and pacing were shown to be equally effective in the prevention of postoperative atrial fibrillation. Amiodarone and bi-atrial pacing were also effective in decreasing the length of hospital stay.

Expert Rev. Cardiovasc. Ther. 1(2), 187–190 (2003)

Faculty of Medicine, University of Toronto, Electrophysiology Program, Schulich Heart Centre, Sunnybrook and Womens’ College Health Science Centre, 2075 Bayview Ave, Toronto, Ontario M4N 3M5, CanadaTel.: +1 416 480 6100 ext. 7370 Fax: +1 416 480 5099eugene.crystal@sw.ca

KEYWORDS:atrial fibrillation, complication, heart surgery, prevention

Postoperative atrial fibrillation (POAF) is afrequent complication of cardiac surgery. Itoccurs in 25–40% of patients after open heartsurgery [1–3]. POAF has been associated with acomplicated postoperative course, increasedincidence of stroke [4–6], increased length ofhospital stay (LOS) and increased hospitalcosts [2,5,7,8]. This paper focuses on recentdevelopments in prophylactic interventionsfor POAF.

Morphologic proarrhythmic substrate forthe development of POAF remains uncertain.Altered expression of connexins, the key pro-teins of gap junctions, is a determinant of apredisposition to POAF [9]. Decreased activityof K+ currents, which are determinants of cel-lular repolarization, were also significantlyassociated with the onset of human POAF [10].Sympathetic activation in the immediate post-operative period is associated with POAF. Theefficacy of β-blockers (BB) also suggests animportant role of adrenergic stimulation in theetiology of POAF. Sympathetic activation ishighest during the first 24 h after surgery butthe typical onset of POAF is in the second andthird postoperative day.

Inflammation is another proven cause. Differ-ent anti-inflammatory drugs are effective in theprevention of POAF in clinical and experimentalsettings [11–13]; the clinical correlation of POAFwith occurrence of pericarditis is well known.

Common clinical risk factors for POAFinclude: old age, history of prior atrial fibril-lation (AF), hypertension, decreased left ven-tricular function, left main disease or multi-vessel disease, grafting of right coronaryartery, significant left atrial enlargement, val-vular disease, obstructive disease in thesinoatrial nodal and atrioventricular nodalarteries, chronic lung disease, and chronicrenal failure [8,14,15]. Intraoperative risk fac-tors that were also associated with increasedprevalence of POAF include: prolonged aor-tic cross-clamp time, cold blood cardiople-gia, pulmonary vein venting and bicavalvenous cannulation [8,16].

The numerous risk-factors associated withPOAF suggest a multifactorial pathogenesis ofthis disorder. POAF is probably a result of bothsubstrate (preoperative heart disease) and trigger(factors associated with operation itself ).

Since the association of POAF with pooreroutcome has been demonstrated, the issue ofprophylaxis became important and many stud-ies were conducted with end points set as adecrease in the burden of POAF. These trialsincluded different agents such as digoxin, vera-pamil, conventional BB, sotalol, amiodarone,magnesium and many others, as well as tem-porary pacing more recently. Prior meta-analy-ses revealed that verapamil and digoxin failedto affect the occurrence of POAF effectively

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188 Expert Rev. Cardiovasc. Ther 1(2), (2003)

[17,18]. Magnesium remains controversial, failing to be effectivein some trials [19], but successful in others [20,21].

However, most of the recent trials have evaluated conven-tional BBs, sotalol, amiodarone and pacing. This brief reviewwill focus primarily on these interventions.

β-blockersThe effectiveness of BBs for the prevention of POAF has beenproven in multiple randomized controlled trials [22]. The bene-ficial effect of BBs in controlled randomized trials was alsoconfirmed in the most recent meta-analysis [22]. In this meta-analysis the use of BBs decreased prevalence of AF with oddsratio (OR) of 0.39 (95% CI: 0.28–0.52). In the largest availa-ble BBs prevention trial [23], metoprolol decreased prevalenceof POAF from 39% of patients to 31% of patients (relativereduction of 20%; p = 0.01).

A more recent, intriguing discovery was that in the post hoc anal-ysis of the largest POAF prevention trial. This study demonstratedthat the positive effects of prophylactic BBs on POAF were essen-tially confined to the subgroup of patients on BBs preoperatively.Patients not on BBs preoperatively also demonstrated differenthemodynamic response to the administration of BBs [24].

The attractiveness of BBs is not only efficacy but also in therelatively low occurrence of significant side effects [23]. In fact,in most patients undergoing open heart surgery receiving BBspreoperatively, these agents may by safely re-administered inthose patients postoperatively.

SotalolSotalol is a class III antiarrhythmic drug with prominent BBactivity. Its prophylactic efficacy against POAF was evaluated inseveral trials, recently summarized in meta-analysis [22]. The over-all prevalence of POAF decreased with an OR of 0.35 (95% CI:0.26–0.49). Another two trials, published after this meta-analysiswas locked, showed results in the same range [20,25].

AmiodaroneAmiodarone has been evaluated as an effective prophylacticagent against POAF in several trials [22]. In meta-analysis, ninetrials, including 1384 patients, were analyzed. Amiodaronereduced the proportion of patients with AF from 37% in thecontrol group to 22.5% in the amiodarone group: OR: 0.48,(95% CI: 0.37–0.61), with no significant heterogeneitybetween trials (p = 0.54). Since this meta-analysis was per-formed, four other trials on the efficacy of amiodarone preven-tion for POAF were published [26–29], all with positive results inthe same range of efficacy.

One of these amiodarone trials compared the ability of twodifferent regimens to reduce the risk of POAF. Patients receiv-ing the slow-load amiodarone regimen had a significant reduc-tion in the risk of AF (48.4%; p = 0.013), AF lasting morethan 24 h (76.5%; p = 0.003), symptomatic AF (90.0%;p = 0.002) and recurrent AF (64.5%; p = 0.025) comparedwith placebo. Patients receiving the fast-load amiodarone regi-men had significant reductions in the risk of AF lasting more

than 24 h (52.6%; p = 0.038) and symptomatic AF (65.0%;p = 0.024) but the incidence of any AF or any recurrence ofAF only showed a trend toward significance (34.0% and45.5%; p = 0.054 and 0.09, respectively). Therefore, slow oralloading with amiodarone pre-operatively is preferable to thebrief intravenous prophylaxis [27].

Despite the problems of administration (long oral protocolor potentially complicated intravenous administration), amio-darone is an effective alternative for patients with contraindica-tions to BBs. Amiodarone also has an excellent safety record inischemic heart disease patients and in those with decreased leftventricular function.

Comparisons between different agentsThe direct comparison of sotalol against conventional BBs hasbeen performed in several trials [30–33]. Meta-analysis of thesetrials showed superiority of sotalol over conventional BB [22]. Inthe most recent meta-analysis, the results of eight prophylacticsotalol trials including 1294 patients were summarized.

Another meta-analysis compared the efficacy of sotalol andamiodarone for the prevention of POAF. No significant differ-ences were noted between amiodarone and sotalol for efficacy(sotalol: -21.5%; 95% CI: -28.3 to -14.6; amiodarone:-14.1%; 95% CI: -20.1 to -8.1), or adverse drug reactionscausing drug termination (sotalol: 9.7%; 95% CI: 0.086 to19.3; amiodarone: 1.95%; 95% CI: -0.48 to 4.38) [34].

PacingMore recently, atrial pacing has been evaluated for the preven-tion of POAF. Intervention protocols in these trials used differ-ent locations of pacing electrodes (right atrial, left atrial, bi-atrial pacing). The pacing algorithms were also different: eithersimple overdrive at a fixed heart rate, or complex overdrivealgorithms based on the atrial sensed rhythm. Patients in thecontrol groups received atrial demand pacing at low rates. Pac-ing from all three pacing locations showed a decrease in AFoccurrence: bi-atrial OR: 0.46; 95% CI: 0.30–0.71; right atrialOR: 0.68; 95% CI: 0.39–1.19; left atrial OR: 0.57; 95% CI:0.28–1.16. Overdriving algorithms (compared as fixed over-drive vs. others) showed similar efficacy: OR 0.58 (95% CI:0.32–1.07) for pacing at fixed rates versus OR 0.62 (95% CI:0.38–1.01) for flexible pacing algorithms [35].

Another more recent meta-analysis on postoperative pacingfor prevention of POAF also compared bi-atrial, right atrial andleft atrial pacing. In this report, both bi-atrial overdrive andfixed high-rate pacing and right atrial fixed high-rate pacingreduced the risk of new-onset AF after open heart surgery byapproximately 2.5-fold.

POAF & LOSGiven the relatively low direct detrimental effect of POAF,the issue of the LOS and cost-saving appear to be crucial fortrials on POAF prophylaxis. However, only a minority oftrials on the prevention of POAF have reported the effect ofthe treatment on LOS.

Atrial fibrillation after cardiac surgery

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In the largest BB trial [23], despite a 20% decrease in theprevalence of POAF, the LOS was not changed significantly.In meta-analysis, based essentially on the data from two trials(1200 patients together) there was no effect on the LOS. Theefficacy of BBs in decreasing LOS until recently was still notclear. In one recently published study using historical con-trols, the implementation of a novel clinical pathway based onintensive use of BBs in the postoperative period failed to showsignificant decrease in the occurrence of POAF or in LOS [36].Remarkable discrepancy exists between overall effect of BB onPOAF and a modest effect on the LOS. One probable expla-nation is that the direct benefit of POAF elimination wascounterbalanced by the side effects of pharmacological or pac-ing interventions. The other explanation would be that POAFitself does not greatly increase total LOS. Rather it may onlybe a marker of more complicated disease. An additional rea-son may be that the detrimental effect of postoperative BBson the LOS in patients who were not on BB before the opera-tion simply neutralizes the positive effect on LOS in patientswho were on BB [24].

A meta-analysis of the use of prophylactic sotalol in seventrials [22], which included a total of 808 patients, also failed toshow a significant effect on the LOS. In trials reported afterthis meta-analysis, the effect on LOS or economic impactwere not reported in comparison with control [20,25]. Whencombined with magnesium, sotalol did, however, shortenLOS significantly [20].

Amiodarone was the only agent showing significant decreaseof the LOS in meta-analysis (944 patients enrolled from fivetrials). Amiodarone reduced LOS significantly, with an averagedecrease of 0.91 days of stay (95% CI: -1.59 to -0.24) [22]. Inreports on amiodarone use that were published after this

meta-analysis, no data on the LOS were reported [28,29], or therewas no significant difference [26,27].

SummaryThe efficacy of BB, sotalol and amiodarone for the preventionof POAF is very similar. Sotalol may be superior to other BBsbased on small pull of direct comparative trials. The number ofpacing prevention trials is relatively small but is very promising.Hospital LOS may be significantly shortened by the preventionof POAF with amiodarone or bi-atrial pacing.

Expert opinionAdministration of BB should certainly be the first-line preven-tive measure in patients after heart surgery. Sotalol and amio-darone are also very effective agents, and may be able not onlyto prevent POAF but also to shorten post-operative LOS.Pacing is a promising but underevaluated modality.

Five-year viewExtensive evaluation of alternative and supportive modalitiessuch as bi-atrial pacing and anti-inflammatory agents has agood chance of being successful in bringing these modalitiesinto common practice.

Key issues

• Re-administration of BB after open heart surgery is the best proven initial strategy for prophylaxis of POAF.

• Amiodarone and sotalol are appropriate and effective alternatives.

ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest

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• Most comprehensive meta-analysis in the field.

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• Comparative meta-analysis with an in-depth breakdown of the side effects of two agents.

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Affiliaton• Eugene Crystal, MD, Assistant Professor, Faculty

of Medicine, University of Toronto, Electrophysiology Program, Schulich Heart Centre, Sunnybrook and Womens’ College Health Science Centre, 2075 Bayview Ave, Toronto, Ontario M4N 3M5, CanadaTel.: +1 416 480 6100 ext. 7370 Fax: +1 416 480 5099eugene.crystal@sw.ca