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Interact CardioVasc Thorac Surg 2009;9:89-93. doi:10.1510/icvts.2009.202465
© 2009 European Association of Cardio-Thoracic Surgery
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Institutional report - Coronary

Prevention of perioperative atrial fibrillation with betablockers in coronary surgery: betaxolol versus metoprolol{star}

Luminita Iliutaa,*, Ruxandra Christodorescub, Daniela Filpescua, Horatiu Moldovana, Bogdan Radulescua and Rasvan Vasilea

a Department of Cardiac Surgery, Institute for Cardiovascular Diseases ‘C.C. Iliescu’, Bucharest, Romania
b Department of Cardiology, Ascar, The City Hospital, Timisoara, Romania

Received 10 January 2009; received in revised form 18 March 2009; accepted 24 March 2009

{star} Paper was presented as oral presentation at the European Society of Cardiology Congress, ESC Congress 2008, Munich, Germany, 30 August–3 September 2008 on 3rd September 2008 (abstract number 4582).

*Corresponding author. Luminita Iliuta, SOS Fundeni, nr 258, Sector 2, Zip Code 022322, Bucharest, Romania. Tel.: +40722 32 71 83; fax: +4021 317 52 25.

E-mail address: luminitailiuta{at}yahoo.com (L. Iliuta).


   Abstract
Top
 Abstract
1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
In this study, we tried to compare the efficacy and safety of betaxolol vs. metoprolol immediately postoperatively in coronary artery bypass grafting (CABG) patients and to determine whether prophylaxy for atrial fibrillation (AF) with betaxolol could reduce hospitalization and economic costs after cardiac surgery. Our trial was open-label, randomized, multicentric enrolling 1352 coronary surgery patients randomized to receive betaxolol or metoprolol. The primary endpoints were the composites of 30-day mortality, in-hospital AF (safety endpoints), duration of hospitalization and immobilization, quality of life, and the above endpoint plus in-hospital embolic event, bradycardia, gastrointestinal symptoms, sleep disturbances, cold extremities (efficacy plus safety endpoint). At the end of the study the incidence and probability of early postoperative AF with betaxolol was lower than with metoprolol in coronary surgery (P<0.0001). In the two study groups minor side effects were similar and no major complication was reported (P<0.001). Patient compliance was good and the general condition improved due to shortened hospitalization and immobilization with subsequent improvement in the psychological status, less arrhythmias and lack of significant side effects. In conclusion, because of its efficacy and safety, betaxolol was superior to metoprolol for the prevention of the early postoperative AF in coronary surgery.

Key Words: Postoperative atrial fibrillation; Coronary artery bypass grafting; Betablockers


   1. Introduction
Top
 Abstract
 1. Introduction
2. Material and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Atrial fibrillation (AF) is a common arrhythmia following coronary artery bypass grafting (CABG) that is associated with increased morbidity and mortality. Patients who develop postoperative AF are more likely to have perioperative myocardial infarction, congestive heart failure, respiratory failure [1], prolonged hospitalization and intensive care unit stay with increased cost burden.

The true incidence of postoperative AF following CABG is unclear, reported incidence ranges from 10% to 65% [2, 3].

Many randomized trials have evaluated the effectiveness of pharmacological and non-pharmacological interventions in prevention of postoperative AF including betablockers, intravenous amiodarone and override suppression of automatic atrial foci by atrial pacing with modest results. However, a comparison between these three interventions has not been yet reported.

The betablockers used in the studies related to AF incidence in coronary surgery were: acebutolol [4], carvedilol vs. metoprolol [5, 6], timolol [7] and sotalol [8].

Data from large-scale studies using betaxolol given in the perioperative period in coronary artery surgery for the prevention of early postoperative AF are not yet available.

The main objectives of this study were:

  1. To compare the efficacy and safety of betaxolol vs. metoprolol for prevention of early postoperative AF in patients undergoing CABG irrespective of their preoperative estimated risk for atrial arrhythmias.
  2. To determine whether prophylactic betablocker therapy with betaxolol can reduce hospital stay and economic cost after cardiac surgery by reducing the risk of AF.


   2. Material and methods
Top
 Abstract
 1. Introduction
 2. Material and methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
The clinical trial was open-label, randomized, multicentric with open study period, carried out on 1352 patients submitted to CABG with arteries (internal mammary, radial, gastroepiploic) or inverted saphenous veins. Surgical methodology and treatment of the patients were done based on a common standard protocol.

2.1. Eligibility criteria

The study included all patients undergoing CABG in six cardiac surgery clinics in Romania between 1 November 2005 and 1 November 2007.

2.2. Non-eligibility criteria

  1. Second and third degree atrioventricular block.
  2. Known hypersensitivity to BB.
  3. Conditions associated with increased risk for bradycardia (vagal predominance, sick sinus syndrome).
  4. Heart failure NYHA class >II.
  5. Cardiogenic shock, perioperative myocardial infarction or low cardiac output.
  6. Bradycardia (HR<50 beats/min).
  7. Severe COPD or pulmonary impairment.
  8. Consented participation in another clinical trial.
  9. Failure to comply with the hospital protocol or absence to follow-up.

Study drop-out criteria included the occurrence of adverse events (severe bradycardia, skin reactions, gastrointestinal symptoms, cold extremities).

The study protocol was approved by the institute Management and Ethics Committee. All patients included in the trial gave written informed consent for participation in this study.

2.3. Study protocol (Fig. 1)

After inclusion in the study, patients were randomized to receive:
  1. Group A: 674 patients with betaxolol postoperative 20 mg once daily.
  2. Group B: 678 patients with metoprolol postoperative 200 mg in two equal doses daily.


Figure 1
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  		Fig. 1. Treatment protocol phases.

 
The treatment was given for two days preoperatively and not less than 10 days postoperatively.

The percentage of the patients which did not require the change of the drug was 17.66% in group A and 67.55% in group B, metoprolol being more used in coronary artery diseased patients because of the existing trials.

The mean age, gender, number of grafts per patient, the type of the grafts (arterial or venous) and the mean left ventricular ejection fraction, left atrial dimensions (diameters and area) and risk score for atrial arrhythmias were similar in the two groups (P<0.0001).

The patients undergoing ventricular remodeling for aneurysms and CABG were not taken in our study.

Clinical and laboratory parameters were initially assessed, at baseline, every day during the first 10 days postoperatively, in day 15 and at the end of the treatment (day 30 postoperatively). Patients with short in-hospital evolution were evaluated ambulatory. The clinical measurements included: NYHA class for heart failure, ventricular rhythm, patient compliance and clinical status. Laboratory parameters included: the usual blood tests (platelet count, hemoglobin, hematocrit, aminotransferases, LDH, biochemistry), electrocardiogram (with the evaluation of rhythm and frequency), 24 h ECG Holter monitoring and echocardiographic measurements of the left ventricular dimensions, systolic and diastolic performance, left atrium dimensions and compliance [9]. Cardiac rhythm was continuously monitored until discharge from intensive care unit. During further hospital stay, subsequent ECG tests and a 24-h ECG Holter monitoring was carried out prior to discharge.

Follow-up time points were in day 15 and in day 30 after surgery and consisted of physical examination and a 15-min interview, repeated ECG test, echocardiography and a 24-h ECG Holter monitoring.

Early episodes of decompensated heart failure were diagnosed based on clinical criteria and through thoracic and transesophageal echocardiography. The presence of bradycardia or atrioventricular block, second or third degree, was diagnosed using clinical evaluation, electrocardiogram and Holter monitoring. The general condition was assessed by using the Short Form Health Survey questionnaire with 36 questions (The SF-36).

2.4. Primary endpoints of the study

The primary endpoints were the composites of 30-day mortality, in-hospital occurrence of AF (safety endpoints), total hospital stay and immobilization (measured in days), intensive care unit length of stay and cost, quality of life, and the above endpoint plus in-hospital embolic events, bradycardia, gastrointestinal symptoms, sleep disturbances, cold extremities (efficacy plus safety endpoint).

2.5. Statistical methods

No sample size assumptions have been made for this trial. For the primary endpoints Kaplan–Meier curves were constructed and log-rank tests were done. For each endpoint, a two-sided 95% CI was also calculated and an overall {chi}2-test, comparing the two treatment groups was done [10]. Also, we performed simple and multivariate, linear and logistic regression analysis and we calculated relative risks and correlation coefficients.


   3. Results
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
A total of 1400 patients were enrolled of whom 1352 received study medication.

We excluded postoperatively 48 patients from the study (28 from betaxolol group and 20 from metoprolol group) for different reasons (25 patients who failed to comply with the hospital protocol or absented to follow-up visits, two patients with severe bradycardia <30 bpm, 12 patients with pericardial effusion needed re-intervention, nine patients with early postoperative myocardial infarction and re-operated in <5 days).

The baseline characteristics were similar in the two groups (Table 1).


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  		Table 1 Baseline characteristics of study patients (n=1352)

 
The essential inclusion criteria were similar in the two treatment groups (P<0.0001).

The percentage of patients with previous episodes of AF was similar in the two groups (17.80% in group A and 17.85% in group B). There was a high number of patients with known or newly diagnosed diabetes mellitus in both groups (about 41%), compared with other studies on CABG patients.

In-hospital concomitant medication is listed in Table 2.


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  		Table 2 Concomitant medication during hospitalization in study patients (n=1328)

 
The primary efficacy and efficacy plus safety endpoints and their individual components in the treatment groups are shown in Table 3.


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  		Table 3 Frequency of composite and single endpoints at hospital discharge and at day 30

 
The combined efficacy and safety outcome in the metoprolol group of 210/678 patients (30.97%) was similar to that estimated before the beginning of the trial (31%). Because postoperative AF is associated with increased morbidity and mortality and longer, more expensive hospital stays [9], we combined endpoints such as death at 30 days, in-hospital AF and hospitalization duration >15 days. Betaxolol was superior to metoprolol in respect to the combined efficacy and safety for prevention of AF after CABG (Table 4). The composite efficacy and safety endpoint in the metoprolol group (30.97%) was bigger than betaxolol group (20.92%), showing the superiority of betaxolol after CABG for prevention of AF.


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  		Table 4 Relative risks and 95% CIs for primary efficacy composite endpoint in the two groups

 
Kaplan–Meier curves generated for primary endpoints showed a superior efficacy and safety in betaxolol group (Fig. 2). Log-rank tests were highly significant immediately after the treatment started. Betaxolol curve started to separate from metoprolol curve and the difference was evident after 48 h. For the primary efficacy endpoint, event rates were 2.97% for betaxolol group and, respectively, 3.1% for metoprolol group (P<0.0001). For the primary efficacy plus safety endpoint, the rates were 14.98% for betaxolol group and, respectively, 24.48% for metoprolol group (P=0.02).


Figure 2
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  		Fig. 2. Betaxolol vs. Metoprolol Kaplan–Meier curves for primary efficacy plus safety endpoint.

 
In-hospital AF occurred less frequently in patients treated with betaxolol than in those treated with metoprolol (12.02% vs. 21.39%, P<0.001). The associated relative risk showed a higher protective value for the appearance of postoperative AF in CABG patients treated with betaxolol compared with metoprolol (0.56 vs. 1.78).

The rates of in-hospital death were also lower in the betaxolol group (2.97%) than in metoprolol group (3.1%).

The general condition was considerably better in the betaxolol group. The mean duration of hospitalization in the betaxolol group was 10.5±4.3 days and 14.5±5.8 days in the metoprolol group. Hospitalization >15 days was found in 9.94% of the patients from betaxolol group and in 13.27% of the patients from metoprolol group. Most of the patients with hospitalization duration >15 days had AF unconverted in sinus rhythm, left ventricular systolic dysfunction, postoperative mediastinitis or deep sternal wound infection. The mean immobilization interval during the immediate postoperative period in group A vs. group B was 1.52±3 days vs. 2.5±2.8 days, respectively. The percentage of patients with immobilization interval >3 days was smaller in betaxolol group compared with metoprolol group (5.19% vs. 8.26%).

The non-cardiac side effects of betablocker therapy and the incidence among the study patients are summarized in Table 5. The incidence of worsening heart failure under betablocker treatment, severe bradycardia and atrioventricular block second and third degree is given in Table 6.


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  		Table 5 In-hospital rates of non-cardiovascular side effects

 

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  		Table 6 Rate of in-hospital bradycardia, atrioventricular block and worsening heart failure

 
The incidence of early postoperative AF was smaller in betaxolol group compared with metoprolol group.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
AF is a common complication after cardiac surgery that is associated with increased morbidity, mortality and prolonged hospitalization. Despite the effectiveness in reducing the episodes of AF by the betablocker therapy, the clinical trials so far have shown no improvement in reduction of hospitalization or stroke [10, 11].

Data from a few small studies have suggested that beta-blockers reduce the risk of developing AF after heart surgery [4, 7, 12]. Unfortunately, in some of these trials, patients assigned to placebo who had previously been on beta-blockade probably suffered from betablocker withdrawal, thus biasing the results against placebo.

A small number of clinical trials using BB in coronary surgery have been published [5, 6]. Patients who have used preoperative betablockers that are withdrawn after surgery seem to be at particularly high risk of AF. Reinstitution of betablockers after surgery has been associated with a reduction of postoperative AF in most clinical trials.

Betablocker prophylaxis is more effective when initiated preoperatively rather than postoperatively [13, 14].

The almost 10% reduction in the incidence of postoperative AF in patients with betaxolol is more than reduction previously reported in smaller studies with other betablockers compared with metoprolol [4, 7, 12]. Thus, this study suggests that prophylactic betablocker therapy with betaxolol is useful.

In summary, betablockers represent the simplest and most cost-effective prophylactic treatment of postoperative AF and are easy to use in a patient population that requires betablockers for other purposes as well. Betablockers should be used as first-line medication to prevent postoperative AF [9, 14].

4.1. Limitations of the study

It is important to point out that about 80% of patients were on preoperative betablocker therapy and it was not stopped before the randomization. The practice in our hospital was to routinely continue preoperative betablocker therapy without any pause and changing the active principle depending on the study group. It should be noted also that about 40% of the patients with previous episodes of AF were prior to the inclusion in the study on anti-arrhythmic agents such as amiodarone or sotalol. These limitations would induce a possible underestimation of some relationships.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Conclusions
References
 

  1. Betaxolol has shown increased efficacy over metoprolol in the postoperative prevention of AF in patients undergoing coronary surgery.
  2. The incidence of early postoperative AF was smaller in the betaxolol group compared with the metoprolol group with no major side effects reported in either of the two groups.
  3. Patient compliance was good, and the general condition was improved due to shortened hospital stay, shortened immobilization time during the immediate postoperative period with subsequent improvement in the psychological status and lack of significant side effects.
  4. Betaxolol should be regarded as an attractive pharmacological strategy for the prophylaxis of atrial arrhythmias after CABG.


   References
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

  1. Adam E, Saltman MD. New-onset postoperative atrial fibrillation: a riddle wrapped in a mystery inside an enigma. J Thorac Cardiovasc Surg 2004;127:311–313.[Free Full Text]
  2. Cox JL. A perspective of postoperative atrial fibrillation in cardiac operations. Ann Thorac Surg 1993;56:405–409.[Medline]
  3. Taylor G, Malik S, Colliver J. Usefulness of atrial fibrillation as a predictor of stroke after isolated coronary artery bypass grafting. Am J Cardiol 1987;60:905–907.[CrossRef][Medline]
  4. Daudon P, Corcos T, Gandjbakhch I, Levasseur JP, Cabrol A, Cabrol C. Prevention of atrial fibrillation or flutter by acebutolol after coronary bypass grafting. Am J Cardiol 1986;58:933–936.[CrossRef][Medline]
  5. Kamei M, Morita S, Hayashi Y, Kanmura Y, Kuro M. Carvedilol versus metoprolol for the prevention of atrial fibrillation after off-pump coronary bypass surgery: rationale and design of the carvedilol or metoprolol post-revascularization atrial fibrillation controlled trial (COMPACT). Cardiovasc Drugs Ther 2006;20:219–227.[CrossRef][Medline]
  6. Celik T, Iyisoy A, Jata B, Celik M, Gunay C, Isik E. Betablockers for the prevention of atrial fibrillation after coronary artery bypass surgery: carvedilol versus metoprolol. Int J Cardiol Feb 14, 2008. [Epub ahead of print].
  7. White HD, Antman EM, Glynn MA, Collins JJ, Con LH, Shemin RJ, Friedman PL. Efficacy and safety of timolol for prevention of supraventricular tachyarrhythmias after coronary artery bypass surgery. Circulation 1984;70:479–484.[Abstract/Free Full Text]
  8. Gomes JA, Ip J, Santoni-Rugiu F, Mehta D, Ergin A, Lansman S, Pe E, Newhouse TT, Chao S. Oral d, sotalol reduces the incidence of postoperative atrial fibrillation in coronary artery bypass surgery patients: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 1999;34:334–339.[Abstract/Free Full Text]
  9. Maisel WH, Rawn J, Stevenson WG. Atrial fibrillation after cardiac surgery. Ann Intern Med 2001;135:1061–1073.[Abstract/Free Full Text]
  10. Mathew JP, Parks R, Savino JS, Friedman AS, Koch C, Mangano DT, Browner WS. Atrial fibrillation following coronary artery bypass graft surgery: predictors, outcomes and resources utilization. Multicentric Study of Perioperative Ischemia Research Group. J Am Med Assoc 1996;276:300–306.[Abstract/Free Full Text]
  11. Mathew JP, Fontes ML, Tudor IC, Ramsay J, Duke P, Mazer CD, Barash PG, Hsu PH, Mangano DT. A multicentric risk index for atrial fibrillation after cardiac surgery. J Am Med Assoc 2004;291:1720–1729.[Abstract/Free Full Text]
  12. Connolly SJ. The Beta Blocker Length of Stay Study (BLOSS) Trial. J Am Coll Cardiol 2000;36:313–314.
  13. Aranki SF, Shaw DP, Adams DH, Rizzo RJ, Couper GS, Vander Vliet M, Colins JJ, Cohn LH, Burstin HR. Predictors of atrial fibrillation after coronary artery surgery. Current trends and impact on hospital resources. Circulation 1996;94:390–397.[Abstract/Free Full Text]
  14. 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.[Abstract/Free Full Text]




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