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trial fibrillation, a frequent compli-cation following cardiothoracic surgery (CTS), occurs in 20–50% of pa-tients.1The incidence of post-CTS atrial fibrillation peaks on the second to third postoperative day.2Results of one study showed that patients who developed post-CTS atrial fibrillation had a 2.6 day longer hospital length of stay, which contributed an additional $1616 to the overall cost of surgery.3A more recent analysis showed that atrial fibrillation contributed a 1- to 1.5-day increase in length of stay, perhaps reflecting advances in preventive strate-gies.4Although post-CTS atrial fibrillation is primarily self limiting, hemodynamic instability and thromboembolic events are more prevalent in these patients. Lahtinen et al.5evaluated 2630 patients undergoing CTS, 52 (2%) of whom had postoperative stroke. Of these patients, 36.5% developed atrial fibrillation prior to their stroke. Giv-en the high prevalGiv-ence and potGiv-entially se-vere consequences of post-CTS atrial fib-rillation, intensive research has investigat-ed pharmacologic and nonpharmacologic prevention modalities. We present an overview of the etiology, risk factors, and preventive strategies of post-CTS atrial fibrillation.

Data Sources

A search of MEDLINE (1966–March

2007) was conducted using the MeSH terms atrial fibrilla-tion, cardiothoracic surgery, cardiac surgery, etiology,

neu-rohormonal, sympathetic, volume, fluid, inflammation, risk factors, operative, pacing, β-adrenergic blockers, amiodarone, sotalol, calcium-channel blockers, magne-sium, HMG-CoA reductase inhibitors, statins, fatty acids, PUFA, steroids, and nonsteroidal antiinflammatory drugs.

Post-Cardiothoracic Surgery Atrial Fibrillation:

A Review of Preventive Strategies

William L Baker and C Michael White

Cardiology

Author information provided at the end of the text.

OBJECTIVE:To review the available literature addressing preventive strategies of post-cardiothoracic surgery atrial fibrillation (post-CTS atrial fibrillation).

DATA SOURCES: Pertinent articles related to the etiology, risk factors, and preventive strategies were identified through a MEDLINE search (1966–March 2007) using the MeSH terms atrial fibrillation, cardiothoracic surgery, cardiac surgery, etiology, neurohormonal, sympathetic, volume, fluid, inflammation, risk factors, operative, pacing, β-adrenergic blockers, amiodarone, sotalol, calcium-channel blockers, magnesium, HMG-CoA reductase inhibitors, statins, fatty acids, PUFA, steroids, and nonsteroidal antiinflammatory drugs.

STUDY SELECTION AND DATA EXTRACTION:Articles evaluated were limited to human studies, published in the English language, with a Jadad score greater than 3. References of identified articles were reviewed for additional pertinent articles. DATA SYNTHESIS:Post-CTS atrial fibrillation most commonly occurs on the second or third postoperative day, with an incidence of 20–50%. Etiology theories include neurohormonal activation, volume overload, and inflammation. Studies examining nonpharmacologic therapies have shown that maintenance of the anterior epicardial fat pad is not a viable prophylactic strategy. Biatrial cardiac pacing, especially in combination with amiodarone, is a viable preventive option. Withdrawal of preoperative β-blockers places patients at higher risk for atrial fibrillation; these drugs should be continued postoperatively. Evidence exists supporting the use of amiodarone, sotalol, and magnesium in addition to β-blockers. Since most of these strategies work by attenuating neurohormonal activation, adverse events, including hypotension and bradycardia, are of concern. Adding agents with antiinflammatory properties, including hydroxymethylglutaryl coenzyme A reductase inhibitors or corticosteroids, may prove to be of benefit. Additional studies using novel therapies are needed in addition to established preventive strategies.

CONCLUSIONS:Available evidence supports the continuation of preoperative β-blockers, as well as prophylactic amiodarone, sotalol, and magnesium. Other novel therapies, mostly targeting inflammation, are under investigation and may provide additional strategies.

KEY WORDS:atrial fibrillation, cardiothoracic surgery.

Ann Pharmacother2007;41:587-98.

Published Online, 20 Mar 2007, www.theannals.com, DOI 10.1345/aph.1H594

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Etiology

Moe6proposed that post-CTS atrial fibrillation resulted from multiple reentry wavelets circulating within the atria. Why wavelets are initiated and propagated is not well un-derstood, but multiple mechanisms have been proposed in-cluding neurohormonal activation, volume overload, and inflammation. One or more of these mechanisms may un-derlie the onset of atrial fibrillation in a patient.

NEUROHORMONAL ACTIVATION

Patients undergoing CTS with cardiopulmonary bypass (CPB) have increased plasma norepinephrine and epineph-rine concentrations that correlate with increases in mean blood pressure readings.7,8Hogue et al.9showed that pa-tients developing post-CTS atrial fibrillation have either higher or lower RR interval variability than the majority of subjects, suggesting that either heightened sympathetic or vagal tone occurs prior to arrhythmia onset. Increased sympathetic and parasympathetic activation of atrial tis-sues reduces atrial refractoriness (eg, a shortening of the atrial effective refractory period), possibly facilitating the development of atrial fibrillation.10This suggests that sym-pathetic/parasympathetic balance is better than dominance of either of the autonomic components.

Volume Overload

The impact of volume overload on the development of post-CTS atrial fibrillation has been suggested.11A sub-study of the AFIST II (Atrial Fibrillation Suppression Trial II) showed that patients who developed post-CTS atrial fibrillation received 1.3 L more fluid than those without post-CTS atrial fibrillation over 5 postoperative days. Net fluid balance on postoperative day 2 was an independent predictor of post-CTS atrial fibrillation among amiodarone-naïve pa-tients (OR 6.4; 95% CI 1.4 to 29.1). The net fluid balance on postoperative day 2 is important since most post-CTS atrial fibrillation occurs on this day. Excess fluid volume could ele-vate intraatrial pressures, resulting in atrial dilation, which, in animal studies, increases atrial fibrillation vulnerability.12,13

INFLAMMATION

An inflammatory response is seen in patients undergo-ing CTS, which is initiated by the exposure of blood to ab-normal bypass circuit surfaces. This contact increases plas-ma levels of acute phase proteins such as C-reactive pro-tein (CRP), interleukin (IL)-1 and 6, and complement components.14,15Bruins et al.16proposed a biphasic activa-tion of the complement system, with CRP and comple-ment-CRP complexes peaking on the second and third postoperative days. Post-CTS arrhythmias peaked at the same times. White blood cell count has recently been

shown to be an independent predictor of post-CTS atrial fibrillation, with peak levels seen on and after postopera-tive day 2.17,18Inflammation has been shown to alter atrial conduction, setting the stage for reentry, predisposing pa-tients to development of post-CTS atrial fibrillation.19,20

RISK FACTORS

Numerous risk factors for the development of post-CTS atrial fibrillation have been identified, although conflicting results have been seen (Table 1).3,21-26Increasing age, histo-ry of prior atrial fibrillation, male sex, decreased left-ven-tricular ejection fraction, valvular heart surgery, chronic obstructive pulmonary disease, chronic renal insufficiency, diabetes mellitus, and rheumatic heart disease have been shown in multivariate logistic regression modeling to in-crease the risk of post-CTS atrial fibrillation.3,21-26For ev-ery 5 year increase in patient age, the risk of post-CTS atri-al fibrillation increases 24– 48%; the increase slows in pa-tients after ages 75– 80.3,22 Intraoperative factors that

Table 1. Univariate and Multivariate Risk Factors for

Development of Post-CTS Atrial Fibrillation3,21-26

Univariate Multivariate

Characteristic Analysis Analysis

Increased age X X

Prior atrial fibrillation X X

Male X X

Decreased LVEF X X

Valvular surgery X X

COPD X X

Chronic renal insufficiency X X

Diabetes mellitus X X

Rheumatic heart disease X X

Preoperative digoxin use X X

Increased aortic cross-clamp time X X

Increased SAPD X X

White X

MI X

Chronic heart failure X

Unstable angina X

No preoperative β-blockers X Previous cardiac operations X Peripheral vascular disease X

Hypertension X Neurologic disease X Previous stroke X Smoking history X Increased LVEDP X Increased CPB time X Withdrawal of β-blockers X

Withdrawal of ACE inhibitors X

Postoperative NSAID use X

ACE = angiotensin converting enzyme; COPD = chronic obstructive pulmonary disease; CPB = cardiopulmonary bypass; CTS = cardio-thoracic surgery; LVEDP = left-ventricular end-diastolic pressure; LVEF = left-ventricular ejection fraction; MI = myocardial infarction; NSAID = nonsteroidal antiinflammatory drug; SAPB = signal-averaged P-wave duration.

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increase risk include increased aortic cross-clamp and car-diopulmonary bypass time, while type of cardioplegia does not increase risk.21,22,27,28One trial showed that withdrawal of β-blocker therapy postoperatively increased the odds of developing atrial fibrillation by 91%.23However, when the β-blocker was continued or started postoperatively, post-CTS atrial fibrillation risk was significantly reduced by 51–68%. Thus, continuation of preoperative β-blockade is an important preventive measure in patients undergoing CTS. Conversely, preoperative digoxin use is associated with increased risk for post-CTS atrial fibrillation.21,24

Preventive Strategies

INTRAOPERATIVE

Recent post-CTS atrial fibrillation guidelines published by the American College of Chest Physicians (ACCP) have recommended mild hypothermia, the use of posterior pericardiotomy, and heparin-coated CPB circuits as possi-ble options for reducing the incidence of post-CTS atrial fibrillation.29The mechanism behind the benefit of mild hypothermia (ie, 34

˚

C) versus moderate hypothermia (ie, 28

˚

C) for preventing post-CTS atrial fibrillation is unclear. However, it has been speculated that mild hypothermia suppresses sympathetic nerve activity seen during rewarm-ing followrewarm-ing CTS, thus preventrewarm-ing neurohormonally me-diated atrial fibrillation.30 Posterior pericardiotomy is sometimes used to allow blood to drain away from the heart into the chest cavity and out a chest tube. Studies have shown that this surgical technique reduces the risk of pericarditis and supraventricular tachyarrhythmias.31-33 Heparin-coated CPB circuits have been developed to help attenuate the systemic inflammatory response associated with CPB, thus reducing post-CTS atrial fibrillation inci-dence.29No recommendations could be made regarding in-terventions such as using off-pump coronary artery bypass graft (CABG), thoracic epidural anesthesia, various forms of cardioplegia, or perioperative glucose–insulin–potassi-um solutions due to a lack of sufficient supportive evi-dence.

Recently, research has focused on the retention of the anterior epicardial fat pad (AFP) as a means of decreasing post-CTS atrial fibrillation. A few small, randomized trials have examined the effect of retaining the AFP on post-CTS atrial fibrillation rate, with conflicting results.34-37The recently completed AFIST-III (Atrial Fibrillation Suppres-sion Trial III) study examined the effect of AFP mainte-nance on post-CTS atrial fibrillation incidence in 180 pa-tients undergoing CABG.38Prophylaxis with β-blockers (85%) and amiodarone (28%) was allowed per the providers’ discretion. No significant effect on post-CTS atrial fibrillation incidence or total hospital cost was seen. We conducted a meta-analysis using the results of

AFIST-III38with the results of other randomized AFP trials34-37 us-ing a random-effects model. We found that the odds of de-veloping post-CTS atrial fibrillation were not significantly reduced by AFP maintenance (OR 0.40; 95% CI 0.12 to 1.32). As such, AFP retention is not a viable option for prevention of post-CTS atrial fibrillation.

CARDIAC PACING

Pacing is thought to favorably influence intraatrial con-duction and atrial refractoriness while reducing episodes of symptomatic bradycardia.39,40 Studies evaluating both chronic single-site and dual-site atrial pacing in patients with drug-refractory atrial fibrillation not undergoing CTS have shown prolonged arrhythmia-free intervals.41,42 Meta-analysis of clinical trials have evaluated the effect of tem-porary pacing on the incidence of post-CTS atrial fibrilla-tion.43-45Right and left atrial pacing alone have not been shown to significantly reduce atrial fibrillation. However, most of the studies analyzed included small patient num-bers and varying pacing protocols. Atrial septal pacing, alone or in combination with amiodarone, was studied in the AFIST II trial.40The combination of pacing and amio-darone was superior to placebo with or without pacing, but not to amiodarone alone for reduction of post-CTS atrial fibrillation. Thus, the increased complexity of cardiac pac-ing may negate its utility as a preventive strategy. In con-trast, biatrial pacing has been consistently shown to reduce the relative risk for post-CTS atrial fibrillation by up to 2.6-fold.43-45Biatrial pacing is supported by the ACCP guidelines as a potential preventive strategy.46

ββ-ADRENERGIC ANTAGONISTS

β-Blockers (eg, propranolol, atenolol, metoprolol) exert their effect by blocking the positive chronotropic and in-otropic actions of catecholamines at β1-receptors, resulting in decreased heart rate and myocardial contractility. Given the increased sympathetic tone seen in patients undergoing CTS, it is theorized that β-blocker therapy may be useful in protecting the heart.8,9

Numerous clinical trials have been conducted examin-ing the effects of various β-blockers on the incidence of post-CTS atrial fibrillation (Table 2).47-53These trials varied widely in their study design, including various degrees of background β-blocker use. Meta-analysis of these clinical trials has shown that β-blockers reduce post-CTS atrial fib-rillation by 61– 64%.43,45In each analysis, significant het-erogeneity was seen between trials. In an effort to assess the reason for heterogeneity, Crystal et al.43separately evaluated each β-blocker used, study sample size, preoper-ative β-blocker use, and study source, but could find no ra-tionale. Another group of investigators reported that with-drawal of the nonstudy β-blocker in the control group was

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responsible for much of the heterogeneity.45In trials in which the nonstudy β-blocker was withdrawn at the time of surgery in the comparator groups, a much larger reduc-tion in post-CTS atrial fibrillareduc-tion was seen (OR 0.30; 95% CI 0.22 to 0.40) compared with trials that allowed non-study β-blocker therapy to be continued post-CTS (OR 0.69; 95% CI 0.54 to 0.87).45

Three studies prospectively examined the effect of β-blockers on length of stay.51,53,54Coleman et al.54conducted a prospective cohort evaluation of 1660 patients undergo-ing CTS at a sundergo-ingle US hospital. Patients receivundergo-ing β-blockers were matched (1:1) for age, sex, history of atrial fibrillation, valvular surgery, and preoperative use of β-blockers or digoxin with those not receiving β-β-blockers. The results of the study showed that patients receiving β-blocker therapy had a reduction in post-CTS atrial fibrilla-tion (23.5% vs 28.4%; p = 0.02) and length of stay (mean ± SD 10.22 ± 11.38 vs 12.40 ± 15.67; p = 0.001) versus those not receiving β-blockers. However, the BLOS (β-Blocker Length of Stay) study, which compared 1000 pa-tients undergoing CTS who were receiving either metopro-lol 100 mg daily or placebo, showed no reduction in hospi-tal length of stay (mean ± SD 155 ± 90 vs 152 ± 61,

respectively; p = 0.79), despite a 20% reduction in post-CTS atrial fibrillation.53Differing risk factors for develop-ing post-CTS atrial fibrillation, includdevelop-ing baseline atrial fibrillation history, preoperative digoxin use, and concomi-tant valve surgery, may explain the differences in length of stay between these studies.54

Preoperative β-blocker use may reduce mortality rates in patients undergoing CTS. An observational study was conducted of more than 600 000 patients using the Society of Thoracic Surgeons National Adult Cardiac Surgery Database.55Patients were evaluated using both direct risk adjustment and a matched-pairs analysis based on propen-sity for preoperative β-blocker therapy. The investigators showed that β-blockers reduced unadjusted 30 day mortal-ity rates versus the rate in those not receiving β-blockers (2.8% vs 3.4%; OR 0.80; 95% CI 0.78 to 0.82; p < 0.001). The use of propensity score matching yielded similar re-sults (OR 0.92; 95% CI 0.89 to 0.94).

AMIODARONE

Amiodarone is a class III antiarrhythmic drug with com-bined potassium channel, sodium channel, calcium

chan-Table 2. Selected β-Blocker Clinical Trials

Reference Design Pts. Regimen Results Comments

Salazar R, DB, PC N = 42 propranolol 1 mg iv q4h post-CTS AF pts. continued preop β-blocker until 10 h preop (1979)47 CABG immediately postop, β-blocker 5/20 (25%)

then 10 mg po q6h control 11/22 (50%) control (p < 0.05)

Stephenson R, DB, PC, N = 223 propranolol 10 mg po post-CTS AF 72% treatment group and 63% control group on (1980)48 CABG q6h, started on arrival β-blocker 9/87 (10%) β-blockers preop; pts. who developed AF within

to ICU control 31/136 (23%) 18 h postop were excluded control (p < 0.05)

Ali (1997)49 R, DB, PC N = 210 preop β-blocker post-CTS AF all pts. on preop β-blocker; duration of AF shorter

CABG (metoprolol, atenolol, β-blocker 40/105 (38%) in β-blocker pts. sotalol, propranolol) placebo 18/105 (17%)

placebo (p < 0.02)

Gun R, DB, PC N = 500 propranolol 20 mg po post-CTS AF pts. underwent isolated aorta–coronary bypass (1998)50 CABG q8h started postop β-blocker 33/250 (13.2%) grafting

placebo placebo 58/250 (23.2%) (p = 0.003)

Wenke R, DB, PC N = 200 metoprolol 1 mg/kg, SVT measured SVT as primary endpoint; β-blocker (1999)51 CABG beginning on day 1 β-blocker 4/100 (4%) decreased hospital LOS by average 1.4 days

after surgery placebo 37/100 (37%) (p < 0.01) placebo (p < 0.0001)

Lucio R, OL, PC N = 200 metoprolol 100–300 mg SVT measured both AF and SVT as primary endpoint (2004)52 CABG (divided 2–3 doses/day) β-blocker 11/100 (11%)

from 12th h to 7th placebo 24/100 (24%) postop day (p = 0.02)

placebo

Connolly R, DB, PC N = 1000 metoprolol 50 mg bid post-CTS AF no significant difference in hospital or ICU LOS; (2003)53 OHS (increased to tid after β-blocker 156/500 (31%) nonstudy β-blocker given to 40% placebo vs

enrollment of placebo 195/500 (39%) 29% β-blocker pts; metoprolol increased ventilator

411 pts.) (p = 0.01) time vs placebo

placebo

AF = atrial fibrillation; CABG = coronary artery bypass graft; CTS = cardiothoracic surgery; DB = double-blind; ICU = intensive care unit; LOS = length of stay; OHS = open heart surgery; OL = open label; PC = placebo-controlled; postop = postoperatively; preop = preoperatively; R = randomized; SVT = supraventricular tachycardia.

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nel, and antiadrenergic properties.56,57The ability of amio-darone to block the rapid component of the delayed rectifi-er potassium channel (Ikr) within cardiac myocytes results in prolongation of the effective refractory period in both atrial and ventricular tissues. However, unlike other cur-rently available class III antiarrhythmics, amiodarone blocks the slow component of the delayed rectifier potassi-um channel (Iks), which reduces transmural dispersion of repolarization and lessens the risk of torsade de pointes. Hohnloser et al.58 studied patients undergoing CABG surgery and found that amiodarone significantly prolonged the QTc interval by 19% within the first 24 hours of thera-py (p < 0.001). Amiodarone has also been reported to at-tenuate sympathetic overstimulation seen in patients un-dergoing CTS via its antiadrenergic properties.59

Clinical trials using various doses and routes of admin-istration have evaluated the effect of amiodarone on post-CTS atrial fibrillation rates (Table 3).40,58,60-64Study

conclu-sions vary widely concerning the best time to initiate thera-py, the necessity of loading doses, and optimum route of amiodarone administration. Daoud et al.60were the first to report the clinical effects of amiodarone on atrial fibrilla-tion incidence in 124 patients undergoing heart surgery with CPB. Patients were randomized to receive either a 7 day preoperative amiodarone load followed by daily thera-py until hospital discharge or placebo. Postoperative β-blockers were used in 28% of placebo patients and 39% of amiodarone patients. Overall atrial fibrillation rates (during and after hospitalization) were reduced from 53% with placebo to 25% with amiodarone (p = 0.003). In-hospital atrial fibrillation rates were also significantly reduced from 42% with placebo to 23% with amiodarone use (p = 0.03), most commonly occurring on postoperative day 2.

The AFIST II trial randomized 160 patients, using a 2 × 2 factorial design, to receive amiodarone or placebo and then to pacing or no pacing.40Amiodarone was given

intra-Table 3. Selected Amiodarone Clinical Trials

Reference Design Pts. Regimen Results Comments

Hohnloser R, PC N = 77 amiodarone 300 mg iv post-CTS SVT amiodarone decreased ventricular (1991)58 CABG postop, then 1200 mg/ amiodarone 2/39 (5%) arrhythmias vs placebo (p < 0.05)

day iv for 2 days, then placebo 8/38 (21%) 900 mg/day iv for 2 days (p < 0.05) placebo

Daoud (1997)60 R, DB, PC N = 124 amiodarone 200 mg po post-CTS AF amiodarone reduced hospital LOS by

CABG ± tid for 7 days, then amiodarone 16/64 (25%) 1.4 days vs placebo (p = 0.04), valve 200 mg/day until placebo 32/60 (53%) as well as total hospital cost (p = 0.03)

discharge (p = 0.003) placebo

ARCH R, DB, PC N = 300 amiodarone 1 g/day iv for post-CTS AF no significant difference in hospital LOS (1999)61 CABG ± 2 days starting within amiodarone 56/158 (35.4%) between groups (p = 0.34)

valve 3 h from arrival in ICU placebo 67/142 (47.2%)

placebo (p = 0.01)

AFIST R, DB, PC N = 220 amiodarone (slow) post-CTS AF amiodarone slow load (n = 120) >5 days (2001)62 CABG ± 200 mg po tid for 5 days amiodarone 28/120 (23.3%) preop, rapid load (n = 100) 1–5 days

valve preop, then 400 mg bid placebo 38/100 (38%) preop; 89% of pts. received postop days 1–4; (rapid) 400 mg (p = 0.01) β-blocker; no significant difference in po qid for 1 day preop, hospital LOS between groups (p = 0.86) then 600 mg bid day 0,

then 400 mg bid days 1–4

placebo

Yazigi R, DB, PC N = 200 amiodarone 15 mg/kg po post-CTS AF postop β-blockers not used; no significant (2002)63 CABG for 4 h postop, then 7 amiodarone 12/100 (12%) difference in hospital LOS between

mg/kg po until discharge placebo 25/100 (25%) groups (p = 0.38)

placebo (p = 0.016)

AFIST II R, DB, PC, N = 160 amiodarone 1050 mg iv post-CTS AF treatment started within 6 h postop; (2003)40 2 × 2 CABG ± over 24 h, then 400 mg amiodarone 17/77 (22.1%) 80–83% pts. on postop β-blockers;

factorial valve po tid days 1–4 ± atrial placebo 32/83 (38.6%) pacing + amiodarone better than pacing

design pacing (p = 0.037) alone (p = 0.040)

placebo ± atrial pacing

PAPABEAR R, DB, PC 601 amiodarone 10 mg/kg/day post-CTS AF atrial tachyarrhythmias (93.4% of AF): no (2005)64 CABG ± bid starting 6 days amiodarone 48/299 (16.1%) significant difference in hospital LOS

valve preop, continuing 6 days placebo 89/302 (29.5%) between groups (p = 0.11) postop (p < 0.001)

placebo

AF = atrial fibrillation; AFIST = Atrial Fibrillation Suppression Trial; CABG = coronary artery bypass graft; CTS = cardiothoracic surgery; DB = dou-ble-blind; ICU = intensive care unit; LOS = length of stay; PAPABEAR = Prophylactic Amidarone for the Prevention of Arrhythmias that Begin Early Af-ter Revascularization, Valvular Repair, or Replacement; PC = placebo-controlled; R = randomized; SVT = supraventricular tachycardia.

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venously (1050 mg total) over the first 24 hours, followed by oral therapy (4800 mg total) for 4 days postoperatively. Concomitant β-blockers were used in 83.1% of placebo pa-tients and in 80.5% of amiodarone papa-tients, which is signifi-cantly more than seen in prior studies. The investigators showed that amiodarone significantly reduced post-CTS atri-al fibrillation incidence by 43% versus placebo. The reduc-tions in atrial fibrillation seen in AFIST II were similar to those achieved with the slow-loading oral regimen in the original AFIST study.62This finding is important since the same cumulative dose (the oral equivalent of 7 g of drug) was used in both trials; however, in AFIST it was given over 10 days, while in AFIST II it was administered over 5 days.40 Multiple meta-analyses have examined amiodarone’s effect on post-CTS atrial fibrillation.43,45,65-67One of these investigations combined data from 10 trials and reported significant reductions in the incidence of post-CTS atrial fibrillation or flutter (RR 0.64; 95% CI 0.55 to 0.75), ven-tricular tachycardia and fibrillation (RR 0.42; 95% CI 0.28 to 0.63), and stroke (RR 0.39; 95% CI 0.21 to 0.76) with amiodarone therapy versus placebo.65Hospital length of stay was also significantly reduced with amiodarone use (weight-ed mean difference [WMD] – 0.63 days; 95% CI –1.3 to – 0.23). Many of the endpoints evaluated were secondary outcomes, some of which were post hoc. More recently, Gillespie et al.66examined 15 trials, showing a 50% reduc-tion in post-CTS atrial fibrillareduc-tion with amiodarone versus placebo (OR 0.50; 95% CI 0.42 to 0.60). Interestingly,

surgery type, β-blocker use, and route of administration did not have significant effects on the overall results of the anal-ysis. These authors also showed a significant 0.75 day re-duction in hospital length of stay with prophylactic amio-darone use (WMD –0.73 days; 95% CI –0.95 to –0.51).

The overall safety of amiodarone was recently evaluated in a meta-analysis of 18 randomized controlled trials in-cluding a total of 3408 patients (1736 receiving amio-darone, 1672 receiving placebo).67 The investigators showed that amiodarone use was significantly associated with increased risk of bradycardia and hypotension, al-though risk of heart block, nausea, and myocardial infarc-tion were not significantly increased. Rates of bradycardia (OR 2.33; 95% CI 1.41 to 3.61) and hypotension (OR 1.79; 95% CI 1.04 to 3.09) were higher in studies using in-travenous amiodarone-based regimens versus those using oral amiodarone. These effects may be exacerbated when β-blockers are used concomitantly with amiodarone.

SOTALOL

Sotalol is a class III antiarrhythmic agent with β-receptor and potassium channel blocking properties. These properties theoretically prevent post-CTS atrial fibrillation by prolong-ing refractoriness and blockprolong-ing neurohormonal activation. Studies have shown sotalol to reduce heart rate and cardiac index in patients undergoing CABG compared with baseline.68

Table 4. Selected Novel Therapy Clinical Trials

Reference Design Pts. Regimen Results Comments

Marin P, O N = 234 statin pretreatment multivariate analysis showed specific statins/doses not specified; no (2006)90 CABG (medium 31 days) 48% RRR with preop statin use difference between development of AF

control (OR 0.52; 95% CI 0.29 to 0.96) and statin used

ARMYDA-3 R, DB, PC N = 200 atorvastatin 40 mg daily, post-CTS AF OL atorvastatin continued in all pts. after (2006)91 CABG starting 7 days preop atorvastatin 35/101 (35%) hospital discharge

placebo placebo 56/99 (57%) (p = 0.003)

Calo R, OL N = 160 n-3 PUFA 2 capsules post-CTS AF PUFA = 850–882 mg eicosapentaenoic (2005)97 CABG daily, starting PUFA 12/79 (15.2%) acid and docosahexaenoic acid as

immediately postop control 27/81 (33.3%) ethyl esters, average ratio 1:2 until 5 days postop (p = 0.013)

control

Cheruku R, OL N = 100 ketorolac 30 mg iv q6h, post-CTS AF treatment started on pts.’ arrival to ICU; (2004)98 CABG then ibuprofen 600 mg NSAID 5/51 (9.8%) NSAIDs significantly reduced hospital

tid for 7 days or until control 14/49 (28.6%) LOS vs control (p = 0.009) discharge (p = 0.017)

control

Prasongsukarn R, DB, PC N = 88 methylprednisolone 1 g post-CTS AF β-blockade an inclusion criterion; 2 pts. (2005)100 CABG iv preop, then steroid 9/43 (20.9%) excluded after having off-pump CABG

dexamethasone 4 mg iv placebo 22/43 (51.2%) q6h for 1 day (p = 0.003)

placebo

AF = atrial fibrillation; CABG = coronary artery bypass graft; CTS = cardiothoracic surgery; DB = double-blind; ICU = intensive care unit; LOS = length of stay; NSAID = nonsteroidal antiinflammatory drug; O = observational; OL = open label; P = prospective; PC = placebo-controlled; PUFA = polyun-saturated fatty acids; R = randomized; RRR = relative risk reduction.

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Numerous studies have evaluated the use of sotalol in patients undergoing CTS, both as monotherapy68-70and combination therapy with magnesium.69These trials have shown that sotalol reduces the incidence of post-CTS atrial fibrillation by 41–93% versus control. These results must be interpreted cautiously, however, because preoperative β-blockers were not continued in the control groups in some of the studies,68,69predisposing them to higher rates of atrial fibrillation. Meta-analyses have reported similar results.43,45Burgess et al.45reported an overall 63% reduc-tion in atrial fibrillareduc-tion incidence (OR 0.37; 95% CI 0.29 to 0.48) with use of sotalol. No significant heterogeneity was seen in an analysis of 8 clinical trials (p = 0.25).43 These analyses found that more patients withdrew from sotalol treatment due to adverse events than placebo (6.0 vs 1.9%; p = 0.004).45A majority of patients withdrew due to bradycardia and hypotension, which may be exacerbat-ed in patients taking background β-blockers in addition to sotalol.

In comparison with β-blockers, meta-analysis has shown sotalol to significantly reduce the incidence of post-CTS atrial fibrillation by 58% (OR 0.42; 95% CI 0.26 to 0.65).45That meta-analysis also showed that there was no significant difference in the incidence of adverse effects between sotalol and β-blockers (7.2 vs 4.8%; p = 0.25). Forlani et al.69compared the effects of low-dose sotalol versus magnesium, the combination of sotalol and magne-sium, or control on the incidence of post-CTS atrial fibril-lation. Sotalol significantly reduced atrial fibrillation inci-dence versus control (p = 0.002) but was inferior to the combination of sotalol plus magnesium (p = 0.04), sug-gesting that combination therapy may be more effective.

CALCIUM-CHANNEL BLOCKERS

Non-dihydropyridine calcium-channel blockers (ie, ver-apamil, diltiazem) have been examined in CTS, often in comparison with β-blockers. Early studies suggested that calcium-channel blockers might be effective in lowering the ischemic burden of patients with CTS.71In one trial, when adequate serum diltiazem concentrations were achieved during the most stressful events of surgery, heart rate, mean arterial pressure, and inotropy were decreased.71 Clinical studies have been conducted evaluating the ef-fects of calcium-channel blockers on the incidence of atrial fibrillation in CTS as well as general thoracic surgery.72,73 Amar et al.72randomized 330 patients undergoing thoracic surgery (lobectomy, pneumonectomy) to receive diltiazem (intravenous followed by oral administration) or placebo, starting in the postanesthesia care unit. Patients taking pre-operative β-blockers continued therapy postpre-operatively to avoid withdrawal. Diltiazem was shown to reduce the inci-dence of postoperative atrial arrhythmias (including fibril-lation and flutter) from 25% to 15% versus placebo (p =

0.03). In patients undergoing CABG, diltiazem reduced post-CTS atrial fibrillation incidence by 50 –74% com-pared with placebo, depending on whether diltiazem was initiated as an intravenous infusion.73

Diltiazem was compared with propranolol and control in 103 patients undergoing CABG surgery.74Treatment was given from the onset of anesthesia until 72 hours after the end of aortic cross-clamping. Despite no difference in any measured hemodynamic parameter, patients receiving propranolol had a significantly lower risk of developing a postoperative arrhythmia versus either diltiazem (p < 0.05) or control (p value not reported). A meta-analysis showed that calcium-channel blockers not only reduced supraven-tricular tachyarrhythmia risk (OR 0.62; 95% CI 0.41 to 0.93), but also myocardial infarction (OR 0.58; 95% CI 0.37 to 0.91) and myocardial ischemia (OR 0.53; 95% CI 0.39 to 0.72).75However, significant heterogeneity was found among the studies reviewed. Calcium-channel blockers may have a role in post-CTS atrial fibrillation prophylaxis; however, larger studies including high use of β-blockers (plus or minus amiodarone) are required before their routine use can be recommended.

MAGNESIUM

Hypomagnesemia has been demonstrated in patients un-dergoing CTS and has been associated with development of atrial fibrillation.76,77Thus, prophylactic use of magne-sium during CTS to correct magnemagne-sium deficiency may prevent the development of atrial fibrillation. A recent study suggested that hypomagnesemia seen in this popula-tion results in increased serum epinephrine and norep-inephrine concentrations, potentiating the development of post-CTS atrial fibrillation.78Wilkes et al.79reported that correction of low magnesium levels with intravenously ad-ministered magnesium given during CPB resulted in sig-nificantly reduced ventricular arrhythmia rates versus placebo (p < 0.01), although the incidence of atrial arrhyth-mias did not differ significantly between groups. Other studies in patients undergoing both on-pump CABG80and off-pump81CABG surgery have shown magnesium sup-plementation to significantly reduce atrial fibrillation rates, with resulting reductions in hospital length of stay.81

Meta-analyses have shown magnesium to reduce post-CTS atrial fibrillation risk by 23–36%.82,83Two of these re-ported no effect of magnesium on hospital length of stay,82,84while the other reported a significant 0.3 day re-duction (WMD – 0.29; 95% CI – 0.54 to – 0.05).84Lower cumulative magnesium doses (6.5–9 g) significantly re-duced post-CTS atrial fibrillation rates (OR 0.36; 95% CI 0.23 to 0.56), whereas no significant effect was seen with moderate-to-high doses (12–18 g) (OR 0.99; 95% CI 0.70 to 1.42).84The same meta-analysis also showed that mag-nesium was most effective when administered

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preopera-tively (OR 0.46; 95% CI 0.31 to 0.67). Magnesium was well tolerated, with no significant bradycardia or hypoten-sion seen in clinical trials.82-84Significant heterogeneity was seen among the trials. Further randomized clinical tri-als comparing various doses and administration times are necessary before routine incorporation of magnesium into clinical practice can be recommended.

Novel Therapies

HMG-CoA REDUCTASE INHIBITORS

Large clinical trials have suggested that hydroxymethyl-glutaryl coenzyme A reductase inhibitors (statins) reduce CRP levels in patients with coronary artery disease, an ef-fect that has been maintained after 24 weeks of therapy.85,86 Given the role of inflammation in the development of atri-al fibrillation, statin therapy has been proposed as a possi-ble therapeutic option. Studies have shown the ability of statins to prevent recurrent atrial fibrillation following elec-trical cardioversion,87,88as well as preventing atrial fibrilla-tion after noncardiac thoracic surgery.89 Amar et al.89 showed that the reduction in atrial fibrillation following noncardiac thoracic surgery was independent of CRP and IL-6 reduction, although this was a nonrandomized obser-vational study, confirming a multi-mechanistic etiology of postoperative atrial fibrillation.

A prospective observational study evaluated 234 pa-tients who underwent CABG surgery, 144 of whom re-ceived preoperative statin therapy (Table 4).90Patients not receiving preoperative statins were at increased risk for de-veloping post-CTS atrial fibrillation (p = 0.038). However, when statins were continued postoperatively, a significant reduction in atrial fibrillation was seen (p = 0.024). The au-thors proposed that statin therapy protected against atrial fibrillation effecting atrial remodeling of the extracellular matrix, as measured by altered plasma levels of matrix metalloproteinase-1 and its inhibitor.

The recently published ARMYDA-3 (Atorvastatin for Reduction of Myocardial Dysrhythmia After Cardiac Surgery) study randomized 200 patients undergoing CTS to receive either atorvastatin or placebo starting 7 days pre-operatively.91Open-label atorvastatin was given to all pa-tients after hospital discharge and continued indefinitely. Atorvastatin was shown to significantly reduce post-CTS atrial fibrillation risk versus placebo (p = 0.003). Hospital length of stay was also significantly reduced by atorva-statin use (p = 0.001). Multivariable analysis suggested that the combination of statin plus β-blockers reduced post-CTS atrial fibrillation by 90% (OR 0.19; 95% CI 0.08 to 0.44). These results must be interpreted carefully. Up to one-half of patients were not receiving concomitant β-blocker therapy, and even fewer received amiodarone pro-phylactically. As such, the patients in this study were not receiving optimal preventive therapy.

Statin use was also associated with reduced cardiac mortality (OR 0.25; 95% CI 0.07 to 0.87) in patients un-dergoing CABG in a prospective, longitudinal study.92 Thus, statins seem to have a potential role in preventing post-CTS atrial fibrillation, although further confirmatory research is needed.

OMEGA-3 FATTY ACIDS

Polyunsaturated omega-3 fatty acids (PUFAs) are pri-marily used to reduce plasma levels of triglycerides and in-crease levels of high-density lipoprotein in patients with dyslipidemia. PUFAs have been suggested to have direct effects on cardiac microsomal calcium/magnesium adeno-sine triphosphatase and voltage-gated sodium channels.93 Clinical studies have shown PUFAs to reduce the inci-dence of atrial fibrillation as well as ventricular arrhyth-mias, whether by increased fish intake94or as an oral sup-plement95,96in patients with myocardial infarction95and im-planted cardioverter/defibrillators.96

Calo et al.97randomized 160 patients undergoing CABG to receive either PUFA 2 g/day or control for at least 5 days postoperatively (Table 4). Approximately 56–58% of patients were taking β-blockers preoperatively, which were continued postoperatively. PUFAs were shown to reduce the incidence of post-CTS atrial fibrillation by 65% versus con-trol (OR 0.35; 95% CI 0.16 to 0.76). This was associated with a significant reduction in hospital length of stay versus control (mean ± SD, 7.3 ± 2.1 days, 95% CI for mean 6.8 to 7.7 vs 8.2 ± 2.6 days; 95% CI for mean 7.6 to 8.7; p = 0.017). The results of this trial need to be confirmed using standard-ized, commercially available PUFA preparations in the US, in combination with β-blocker and amiodarone therapy, be-fore this therapy can be adopted into clinical practice.

ANTIINFLAMMATORY AGENTS

As was stated earlier, inflammation plays a major role in the etiology of post-CTS atrial fibrillation as evidenced by increased serum concentrations of inflammatory biomark-ers such as CRP, IL-1, IL-6, and complement components, as well as white blood cells.15-18As such, the potential role of antiinflammatory agents, such as nonsteroidal inflam-matory drugs (NSAIDs) and corticosteroids, has been pro-posed. Cheruku et al.98tested this theory by randomizing 100 patients undergoing CABG surgery to receive either ketorolac followed by ibuprofen or control (Table 4). NSAIDs were found to significantly reduce both the inci-dence of post-CTS atrial fibrillation (p = 0.017) and hospi-tal length of stay (p = 0.009) versus control. However, oth-er recent evidence has aroused soth-erious concoth-ern about the use of NSAIDs in patients undergoing CTS. One trial ran-domized 1671 patients undergoing CTS to receive cy-clooxygenase 2 (COX-2) inhibitors (parecoxib followed

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by valdecoxib) or placebo for 10 days postoperatively.99 The COX-2 inhibitors significantly increased the patients’ risk of cardiovascular events (including myocardial infarc-tion, cardiac arrest, stroke, pulmonary embolism) versus placebo (p = 0.03). Thus, future studies of NSAIDs in this population are unlikely.

Corticosteroid use in CTS has been investigated, mainly focusing on reducing intubation time. Only one study ex-amining the effect of corticosteroid use in CTS with atrial fibrillation reduction as a primary endpoint has been pub-lished (Table 4).100That trial randomized 88 patients to re-ceive either methylprednisolone followed by dexametha-sone for 24 hours postoperatively or placebo. For inclusion into the study, patients were required to receive β-blocker therapy. The steroids significantly reduced the incidence of post-CTS atrial fibrillation (p = 0.003), as well as hospital length of stay (p = 0.002) versus placebo. Increased glu-cose levels, as well as infection, are concerns with corti-costeroid use. This study was too small to evaluate compli-cation rates, although more steroid patients had high blood glucose levels versus patients receiving placebo. Thus, cor-ticosteroids have a potentially beneficial role in the preven-tion of post-CTS atrial fibrillapreven-tion.

Summary

Atrial fibrillation remains a significant postoperative complication of CTS. Current evidence strongly suggests the continuation of perioperative β-blocker therapy in pa-tients and initiation of β-blockers in naïve papa-tients. Adding amiodarone can be done safely and reduces post-CTS atri-al fibrillation by an additionatri-al 50%. Adding magnesium supplementation and or a drug to prevent inflammation (eg, statins or corticosteroids) may also further reduce post-CTS atrial fibrillation. However, the impact of a triple-therapy regimen including β-blockers, amiodarone, and ei-ther statins, magnesium, or corticosteroids has not been eval-uated. As further data on pharmacologic and other preventive methods become available, their optimal and effective use may ameliorate this frequent and complicated condition.

William L Baker PharmD BCPS, Cardiovascular Pharmacology

Fellow, School of Pharmacy, University of Connecticut; Divisions of Cardiology and Drug Information, Hartford Hospital, Hartford, CT

C Michael White PharmD FCP FCCP, Associate Professor of

Phar-macy Practice, School of PharPhar-macy, University of Connecticut; Co-Director, Arrhythmia and Cardiac Pharmacology Research, Divisions of Cardiology and Drug Information, Hartford Hospital

Reprints: Dr. White, Divisions of Cardiology and Drug Information,

Hartford Hospital, 80 Seymour St., Hartford, CT 06102, fax 860/545-2277, cmwhite@harthosp.org

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EXTRACTO

OBJETIVO:Revisar la literatura disponible que discute estrategias para prevenir fibrilación atrial luego de cirugía cardiotorácica (FA post-CCT). FUENTES DE INFORMACIÓN:Se identificaron artículos pertinentes relacionados a la etiología, factores de riesgo y estrategias de prevención a través de una búsqueda MEDLINE (1966–marzo 2007) usando los términos fibrilación atrial, cirugía cardiotorácica, etiología,

neurohormonal, simpatético, volumen, fluido, inflamación, factores de riesgo, operativo, bloqueadores β-adrenérgicos, amiodarona, sotalol, bloqueadores de canales de calcio, magnesio, estatinas, inhibidores de la reductasa HMG-CoA, ácidos grasos, PUFA, esteroides, y

antiinflamatorios no-esteroidales.

SELECCIÓN DE FUENTES DE INFORMACIÓN:Se seleccionaron artículos de estudios en humanos, publicados en inglés y con una puntuación Jadad mayor de 3. Se revisaron las referencias de los artículos identificados para artículos pertinentes adicionales.

SÍNTESIS:La FA post-CCT más comúnmente ocurre en el segundo o tercer día postoperatorio, con una incidencia de entre 20–50%. Las teorías para la etiología incluyen activación neurohormonal, sobrecarga de volumen e inflamación. Estudios que evalúan terapias no-farmacológicas han demostrado que mantener la grasa epicardial anterior no es una opción preventiva viable. Marcar el ritmo cardiaco biatrial, especialmente en combinación con amiodarona, es una opción

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preventiva viable. Descontinuar el uso de bloqueadores β-adrenérgicos preoperatorios coloca al paciente en un mayor riesgo de fibrilación atrial por lo que se debe continuar su uso postoperatorio. Existe evidencia apoyando el uso de amiodarona, sotalol y magnesio en adición a los bloqueadores β-adrenérgicos. Debido a que la mayoría de estas estrategias trabajan afectando la activación neurohormonal, los efectos adversos incluyendo hipotensión y bradicardia son preocupantes. Añadir agentes con propiedades antiinflamatorias, incluyendo inhibidores de la reductasa HMG-CoA o corticoesteroides, podría probar ser beneficioso. Se requieren más estudios con terapias nuevas para poder establecer estrategias preventivas.

CONCLUSIONES:La evidencia disponible apoya el continuar los bloqueadores β-adrenérgicos preoperatorios así como amiodarona, sotalol y magnesio de manera preventiva. Otras terapias, principalmente atacando la inflamación, están bajo investigación y podrían representar estrategias adicionales.

Giselle Rivera-Miranda

RÉSUMÉ

OBJECTIF:Revoir la documentation scientifique traitant des stratégies permettant de prévenir la survenue de la fibrillation auriculaire suivant une chirurgie cardiothoracique.

REVUE DE LITTÉRATURE:Les articles traitant de l’étiologie, des facteurs de risque et de stratégies préventives ont été identifiés via une recherche MEDLINE (1966–mars 2007) à l’aide des mots-clés suivants: fibrillation auriculaire, chirurgie cardiothoracique, chirurgie cardiaque, étiologie, neurohormonale, sympathique, volume, liquide, inflammation, facteurs de risque, opération, stimulation cardiaque, bloquants bêta-adrénergiques, amiodarone, sotalol, bloquants des canaux calciques, magnésium, inhibiteurs de l’HMG-CoA réductase, statines, acides gras, acides gras polyinsaturés, stéroïdes et anti-inflammatoires non

stéroïdiens. Les articles retenus ont été les études cliniques, de langue anglaise ayant un pointage Jadad supérieur à 3. Les bibliographies d’articles ont également été consultées.

RÉSUMÉ:La fibrillation auriculaire post-chirurgie cardiothoracique survient habituellement au jour 2 ou 3 post-opératoire avec une incidence variant entre 20 et 50%. Les différentes théories permettant d’expliquer la survenue de la fibrillation auriculaire incluent l’activation neurohormonale, la surcharge volémique et l’inflammation. Les études ayant évalué les traitements non-pharmacologiques ont montré que le maintien du tissu graisseux épicardique antérieur ne constitue pas une stratégie de prévention efficace. Toutefois, la stimulation cardiaque bi-auriculaire, notamment en combinaison avec l’amiodarone, est une stratégie de prévention efficace. Le retrait des β-bloquants en pré-opératoire augmente le risque de fibrillation auriculaire. Par conséquent, les β-bloquants devraient donc être poursuivis en post-opératoire. Des données probantes supportent l’utilisation de l’amiodarone, du sotalol et du magnésium en combinaison avec les β-bloquants. Puisque la plupart de ces interventions agissent en atténuant l’activation neurohormonale, les effets indésirables du type hypotension et bradycardie sont à craindre. L’ajout de médicaments avec propriétés anti-inflammatoires tels que les inhibiteurs de l’HMG-CoA réductase et les corticostéroïdes pourrait s’avérer utile. D’autres études évaluant de nouvelles thérapies en association avec les stratégies préventives reconnues seront nécessaires.

CONCLUSIONS:Les données disponibles actuellement recommandent la poursuite des β-bloquants en pré-opératoire de même que l’utilisation prophylactique d’amiodarone, de sotalol ou de magnésium. D’autres traitements, ciblant principalement l’inflammation, sont actuellement en investigation et pourraient constituer des stratégies de prévention supplémentaires.

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