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Post-CABG Atrial Fibrillation: What Are the Incidence, Predictors, Treatment, and Long-Term Outcome?

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Predictors, Treatment, and Long-Term Outcome?

C. BLOMSTRÖMLUNDQVIST

Post operative atrial fibrillation (AF) is a common complication of coronary artery bypass surgery (CABG), occurring in 5–40% of patients during the first postoperative week, depending on definitions and methods of detection.

A meta-analysis of controlled randomised trials confirmed that in trials using 24-h Holter ECG monitoring, the incidence of supraventricular arrhythmias was higher with Holter recordings (41.3 %) than in trials with- out (19.9 %) [1]. Despite recent improvements in surgical techniques and postoperative patient care, the incidence of postoperative AF seems to increase, most likely related to the existence of an increasing number of elderly patients with co-morbidities. In the majority of cases postoperative AF is transient and not life-threatening, although it may cause marked sub- jective symptoms, congestive heart failure, hypotension, and ischaemia, requiring pharmacological treatment or electrical cardioversion, resulting in prolonged hospital stay and additional costs in medical care [2].

Stroke is a major adverse event, complicating the immediate outcome of CABG in about 2% of cases. AF was reported to be a major determinant of stroke after CABG, preceding the occurrence of neurological complications in approximately 37% of the patients [3]. Apart from a higher risk of stroke (odds ratio, OR 2.02), postoperative AF was associated with greater in-hospi- tal mortality (OR 1.7) and worse survival (74% versus 87%) at long-term fol- low-up (4–5 years) [2]. In a multivariate analysis it was an independent pre- dictor of long-term mortality [2]. The complexity of distinguishing the intrinsic hazards due to postoperative AF from the risks related to its aetio- logical factors and treatment should, however, be recognised in this retro- spective cohort study.

Department of Cardiology, University Hospital in Uppsala, Uppsala, Sweden

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The mechanisms responsible for postoperative AF are still unclear and are probably multifactorial. Since risk stratification strategies for patients under- going CABG could lead to more targeted preventive or therapeutic interven- tions, large number of trials have aimed at identifying risk factors for the development of postoperative AF. Risk factors associated with AF include advanced age (OR for 10-year increase, 1.75); history of AF (OR 2.11) or chronic obstructive lung disease (OR 1.43); valve surgery (OR 1.74); peripher- al vascular disease (OR 1.54); and postoperative withdrawal of β-blockers (OR 1.91) or angiotensin-converting enzyme inhibitors (OR 1.69) [2, 4].

Among preoperative risk factors, advancing age has a significant associa- tion with the incidence of AF, a relationship that is particularly important as the number of elderly patients considered for CABG steadily increases.

Advanced age was associated with increased levels of circulating norepi- nephrine, which could be related to imbalance in the autonomic nervous sys- tem, previously reported in some but not other studies as an independent risk factor for postoperative AF. Thoracic epidural anaesthesia, aimed at blocking excessive sympathetic activity, was, however, not effective in pre- venting postoperative AF [5].

There is still no consensus as to whether operative clinical and/or elec- trocardiographic characteristics further distinguish patients who would develop postoperative AF. Prolonged P-wave duration consistent with intra- atrial conduction delay, the presence of preoperative supraventricular arrhythmias, and fluctuations in autonomic balance as measured by heart rate variability were identified in some but not other studies as independent risk factors for postoperative AF [6].

Postoperative AF is probably the most important potentially reversible health care expenditure related to CABG. The recognition of the potential benefits of preventing AF after CABG is reflected by the large number of prophylactic strategies reported in the literature. In a meta-analysis includ- ing 42 randomised controlled trials,β-blocking agents, sotalol, and amio- darone significantly reduced the incidence of postoperative AF compared with placebo, and with no marked difference between them [7]. The three drugs each prevented AF with the following odds ratios:β-blockers 0.39, sotalol 0.35, and amiodarone 0.48 [7]. From the analysis of 10 pacing trials, atrial pacing was shown to be effective, with an odds ratio of 0.46 for biatrial pacing [7]. Biatrial pacing significantly reduced length of hospital stay by 1.5 days, but there was no evidence that the stroke rate was lowered. In another meta-analysis of prophylactic anti-arrhythmic therapy (amiodarone, sotalol, procainamide, pacing) for the prevention of postoperative AF, the incidence of AF varied from 8% to 37% in the treatment groups and from 29% to 53%

in the control groups, with a combined overall significant decrease of 0.52 (OR) in the treatment groups [8]. When the studies were combined there was

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1.0 ± 0.2 day overall decrease in length of hospital stay, but no significant effect on the incidence of stroke or mortality. Data on costs, available for five of the six studies that used amiodarone and one of the studies that used pac- ing, showed a combined insignificant decrease in cost [8].

In a randomised study, amiodarone plus pacing significantly decreased the frequency of AF after open heart surgery, compared with amiodarone alone, pacing alone, and placebo [9]. In the cost-effectiveness analysis, when compared with placebo, the probability of lower cost but higher effect (supe- riority) was 67% for amiodarone, 15% for pacing, and 97% for amiodarone plus pacing [9]. In the multivariate analysis, preoperative β-blockers and amiodarone were negatively associated with hospital costs (P < 0.05). Data suggest that both amiodarone alone and the combination of amiodarone plus pacing are cost-effective compared with placebo.

A meta-analysis of 8 prophylactic pacing trials, with 776 patients enrolled, demonstrated a significant anti-arrhythmic effect of biatrial over- drive and fixed high-rate pacing and overdrive right atrial pacing, with a rel- ative risk reduction of approximately 2.5-fold for new-onset AF at open heart surgery [10]. Another, larger meta-analysis of 58 studies (8565 patients) demonstrated that prophylactic therapies (amiodarone,β-blockers, sotalol, and pacing) favoured treatment for postoperative AF with an odds ratio of 0.43 [11]. A positive result for cost of hospitalisation in favour of treatment was achieved, but the statistic was not significant due to low power and large standard deviations.β-Blockers had the greatest magnitude of effect across 28 trials (4074 patients), with an odds ratio of 0.35. The data for stroke favoured treatment by a non-significant effect size of 0.81. Similarly, a posi- tive indication for length of stay was derived, but it too was not significant, with a weighted mean difference of –0.66.

Hypomagnesaemia is frequently observed after cardiac surgery and is related to the extracorporeal circulation and the use of diuretics In a meta- analysis of 17 trials with 2069 patients, magnesium supplementation reduced the risk of supraventricular arrhythmias (relative risk 0.77) but had no effect on the length of the hospital stay or mortality [12]. Administration of pro- phylactic magnesium reduced the risk of postoperative AF by 29%, although the homogeneity among trials may limit the formulation of definitive con- clusions.

The effect of cardiopulmonary bypass on the incidence of AF after CABG has been addressed in several trials. A meta-analysis of all observational studies comparing cardiac pulmonary bypass (2253 patients) and off-pump techniques (764 patients) in elderly patients demonstrated a significantly lower incidence of postoperative AF (odds ratio 0.70) after off-pump surgery [13]. The results were confirmed in another meta-analysis of 37 randomised trials (3369 patients), in which off-pump CABG significantly decreased AF

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(OR, 0.58) and hospital stay (weighted mean difference, –1.0 days) but with- out affecting 30-day mortality or stroke rate (OR, 0.68) [14]. It should be emphasised, though, that the lower risk profile of patients undergoing off- pump CABG could contribute to a lower AF risk.

Radiofrequency ablation of pulmonary vein triggers has had a remark- able high success rate for non-postoperative AF. Our own data showed that onset of AF after CABG was triggered by premature beats in 72% of patients with postoperative AF, which implies that atrial triggers may be important in the postoperative setting. It is, however, as yet unclear whether a surgical epi- cardial approach would be effective and safe if implemented during routine CABG procedures.

The importance of the parasympathetic nervous system for the initiation of AF is still incompletely understood, although it is thought to play a role in the subsets of patients with paroxysmal non-postoperative AF. Vagal post- ganglionic neurons are located in well-defined anatomic fat pads situated in two posterior epicardial regions around the heart and adjacent structures.

Transvenous radiofrequency (RF) ablation at such sites has resulted in vagal denervation and improved outcome in patients with non-postoperative AF subjected to circumferential pulmonary vein ablation [15]. In animal studies the destruction of an anterior fat pad shown to contain vagal neurons result- ed in decreased susceptibility to AF. The anterior fat pad, located in the aor- topulmonary window, was therefore studied in humans with respect to its role in postoperative AF [16]. The authors’ question was whether its removal, as routinely done during the process of placing the aortic cross-clamp, would decrease subsequent AF [16]. By stimulating the anterior fat pad in patients undergoing CABG, the sinus rate was slowed with no change in PR interval, consistent with innervation of the sinus node but not the atrioven- tricular node [16]. Since enhanced vagal tone is pro-fibrillatory in the atria by shortening refractoriness, the underlying theory was that removal of tis- sue responsible for vagal atrial influences would improve AF outcome. In the randomised study, paradoxically, 37% of patients in whom the interior fat pad was dissected developed postoperative AF compared with 7% in whom the fat pad was preserved [16]. Supportive of these findings is the reported lower incidence of AF after off-pump CABG, during which the anterior fat pad is often preserved [13]. Animal experiments support vagal denervation as an effective anti-arrhythmic strategy, which is consistent with the finding of a lower incidence of AF following vagal denervation during catheter abla- tion procedures. The importance of vagal influences and the role of the car- diac fat pads for developing postoperative AF demand further clinical research to determine the optimal surgical technique.

The class I recommendations for prevention and management of postop- erative AF are: (1) an oral β-blocker for prevention, and (2) atrioventricular

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nodal blocking agents for rate control [17]. Class IIa recommendations are:

(1) prophylactic sotalol or amiodarone for patients at increased risk of developing postoperative AF; (2) electrical or pharmacological cardioversion to restore sinus rhythm, as recommended for non-surgical patients; (3) attempt at maintenance of sinus rhythm by administration of anti-arrhyth- mic medications if there is recurrent or refractory postoperative AF, as rec- ommended for patients with coronary artery disease who develop AF; and (4) anti-thrombotic medication, as recommended for non-surgical patients.

References

1. Andrews T, Reimold S, Berlin J et al (1991) Prevention of supraventricular arrhyth- mias after coronary artery bypass surgery. A meta-analysis of randomized control trials. Circulation 84(5 Suppl):III236–III244

2. Villareal R, Hariharan R, Liu B et al (2004) Postoperative atrial fibrillation and mortality after coronary artery bypass surgery. J Am Coll Cardiol 43:742–748 3. Lahtinen J, Biancari F, Salmela E et al (2004) Postoperative atrial fibrillation is a

major cause of stroke after on-pump coronary artery bypass surgery. Ann Thorac Surg 77:1241

4. Mathew JP, Fontes ML, Tudor IC et al (2004) A multicenter risk index for atrial fibrillation after cardiac surgery. JAMA 291:1720–1729

5. Jidéus L, Joachimsson P-O, Stridsberg M et al (2001) Thoracic epidural anaesthesia does not influence the occurrence of postoperative sustained atrial fibrillation.

Ann Thorac Surg 72:65–71

6. Jidéus L, Blomström P, Nilsson L et al (2000) Tachyarrhythmias and triggering fac- tors for atrial fibrillation after coronary artery bypass operations. Ann Thorac Surg 69:1064–1069

7. Crystal E, Connolly SJ, Sleik K et al (2002) Interventions on prevention of postope- rative atrial fibrillation in patients undergoing heart surgery a meta-analysis.

Circulation 106:75–80

8. Zimmer J, Pezzullo J, Choucair W et al (2003) Meta-analysis of antiarrhythmic the- rapy in the prevention of postoperative atrial fibrillation and the effect on hospital length of stay, costs, cerebrovascular accidents, and mortality in patients under- going cardiac surgery. Am J Cardiol 91:1137–1140

9. Reddy P, Kalus J, Caron M et al (2004) Economic analysis of intravenous plus oral amiodarone, atrial septal pacing, and both strategies to prevent atrial fibrillation after open heart surgery. Pharmacotherapy 24:1013–1019

10. Daoud EG, Snow R, Hummel JD et al (2003) Temporary atrial epicardial pacing as prophylaxis against atrial fibrillation after heart surgery: a meta-analysis. J Cardiovasc Electrophysiol 14:127–132

11. Crystal E, Garfinkle MS, Connolly SS et al (2004) Interventions for preventing post- operative atrial fibrillation in patients undergoing heart surgery. Cochrane Database Syst Rev CD003611

12. Shiga T, Wajima Z, Inoue T et al (2004) Magnesium prophylaxis for arrhythmias after cardiac surgery: a meta-analysis of randomized controlled trials. Am J Med 117:325–333

13. Athanasiou T, Aziz O, Mangoush O et al (2004) Do off-pump techniques reduce the

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incidence of postoperative atrial fibrillation in elderly patients undergoing coro- nary artery bypass grafting? Ann Thorac Surg 77:1567–1574

14. Cheng D, Bainbridge D, Martin J et al (2005) Does off-pump coronary artery bypass reduce mortality, morbidity, and resource utilization when compared with conventional coronary artery bypass? A meta-analysis of randomized trials.

Anesthesiology 102:188–203

15. Pappone C, Santinelli V, Manguso F et al (2004) Pulmonary vein denervation enhances long-term benefit after circumferential ablation for paroxysmal atrial fibrillation. Circulation 109:327–334

16. Cumming J, Gill I, Akhrass R et al (2004) Preservation of the anterior fat pad para- doxically decreases the incidence of postoperative atrial fibrillation in humans. J Am Coll Cardiol 43:994–1000

17. Fuster V, Ryden LE, Asinger RW et al (2001) ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (committee to develop guidelines for the management of patients with atrial fibrillation) developed in collaboration with the North American Society of Pacing and Electrophysiology. Eur Heart J 22:1852–1923

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