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Ann Thorac Surg 2004;77:1567-1574
© 2004 The Society of Thoracic Surgeons

Original article: cardiovascular

Do off-pump techniques reduce the incidence of postoperative atrial fibrillation in elderly patients undergoing coronary artery bypass grafting?

Thanos Athanasiou, MD, PhDa*, Omer Aziz, MBBSa, Omar Mangoush, FRCSa, Arjuna Weerasinghe, PhD, FRCSa, Sharif Al-Ruzzeh, FRCSa, Sanjay Purkayastha, MBBSa, John Pepper, FRCSa, Mohamed Amrani, FRCSa, Brian Glenville, FRCSa, Roberto Casula, FECTSa

a The National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, Department of Cardiothoracic Surgery, St. Mary's Hospital and Royal Brompton Hospital, London, United Kingdom

Accepted for publication October 16, 2003.

* Address reprint requests to Dr Athanasiou, Cardiothoracic Surgery, 70 St. Olaf's Rd, Fulham, London SW6 7DN, UK
e-mail: tathan5253{at}aol.com


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
BACKGROUND: Atrial fibrillation is the most common postoperative complication in patients undergoing coronary artery bypass grafting (CABG) with advancing age having been shown to have a significant association with its incidence. This study aims to assess whether off-pump coronary artery bypass (OPCAB) reduces the incidence of atrial fibrillation in elderly patients.

METHODS: A meta-analysis of all observational studies reporting a comparison between the two techniques in elderly patients (> 70 years) between 1999–2003 was performed. The primary outcome of interest was the incidence of postoperative atrial fibrillation. The quality of each study was evaluated by examining three items: patient selection, matching of the off-pump and cardiopulmonary bypass patient groups, and assessment of outcome. Meta-regression analysis was undertaken to see the effects of study size and quality on the calculated odds ratio.

RESULTS: Eight studies fulfilled our inclusion criteria, all of which were nonrandomized. In total the studies identified 3017 subjects, of which 764 had off-pump surgery (25%) and 2253 underwent cardiopulmonary bypass (75%). Meta-analysis showed that after off-pump surgery there was a significantly lower incidence of postoperative atrial fibrillation in these patients (odds ratio 0.70, 95% confidence interval [CI] 0.56–0.89). Meta-regression analysis including study characteristics did not show any associations affecting the calculated odds ratio of atrial fibrillation.

CONCLUSIONS: Our study demonstrates a reduced incidence of postoperative atrial fibrillation in an elderly population with off-pump as compared with cardiopulmonary bypass techniques. We appreciate, however, that our statistical analysis uses nonrandomized published data and that the results must be treated with caution. If this finding is confirmed by a large-scale randomized trial, it has significant implications on the operative strategy employed for this patient group.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 References
 
Atrial fibrillation (AF) is the most common postoperative complication in patients undergoing coronary artery bypass grafting (CABG) with the reported incidence being as high as 40% [1]. This is important because it cannot only cause patient discomfort but is also associated with increased postoperative morbidity from thrombo-embolic events and hemodynamic deterioration in patients with left ventricular dysfunction [2]. Advancing age has been shown to have a significant association with the incidence of AF [3], a relationship that is particularly important as the number of elderly patients considered for surgical revascularization steadily increases [4].

The effect of cardiopulmonary bypass (CPB) on the incidence of AF in elderly patients after CABG has not yet been clearly addressed. Although several groups have reported that off-pump coronary artery bypass (OPCAB) appears to improve the postoperative outcome of elderly and high-risk patients [5], it is unclear whether this technique can specifically reduce the incidence of postoperative AF. Studies comparing OPCAB and CPB in the younger patient group report conflicting evidence on the incidence of AF [6, 7]. Beauford and associates recently reported that in octogenarians undergoing multivessel off-pump revascularization, postoperative AF rates remain as high as 43% [8].

Our aim was to compare CPB to OPCAB with regards to the incidence of postoperative AF in elderly patients by performing a meta-analysis of studies comparing the two techniques in this group.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
Study selection
A Medline search was performed on all publications between 1999–2003 reporting elderly patients undergoing CABG and comparing OPCAB and CPB techniques. The following mesh search headings were used: "elderly," "aged 70 and over," "cardiopulmonary bypass," "coronary artery bypass methods," and "atrial fibrillation." The "related articles" function was used to broaden the search and all abstracts, studies, and citations scanned were reviewed.

Data extraction
Two reviewers (A.T. and A.R.S), independently extracted the following data from each study: first author, year of publication, study population characteristics, study design (prospective, retrospective, or other), inclusion and exclusion criteria, number of subjects operated on with each technique, quality of study, and conversion rate from OPCAB to CPB. Meta-analysis was performed in line with recommendations for reporting meta-analyses of observational studies in epidemiology.

The quality of each study was evaluated by examining three items: patient selection, matching of OPCAB and CPB patient groups, and assessment of outcome using a modified Newcastle–Ottawa scale [9] (Table 1). Studies were rated on an ordinal star scoring scale with higher scores representing studies of higher quality. Using this system a study could be awarded a maximum of one star for each numbered item within the selection and exposure categories and a maximum of four stars could be given for the comparability of the two groups. The quality of each study was graded as either level 1 (0–5 stars) or level 2 (6–9 stars).


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  		Table 1. Checklist for Quality Assessment and Scoring of Nonrandomized Studies

 
In comparing the two groups we focused on variables that have been previously identified as independent predictors of AF particularly age, sex, hypertension, diabetes, ejection fraction, chronic obstructive pulmonary disease, and advanced coronary artery disease (left main stem, three vessel disease, reoperation) [10]. The distribution of these variables between OPCAB and CPB groups is presented in Table 2.


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  		Table 2. Distribution of Risk Factors for Atrial Fibrillation Between OPCAB and CPB Groups (Hypertension, Reoperation, Diabetes, Sex, Ejection Fraction, Chronic Obstructive Pulmonary Disease [COPD] and Left Main Stem or Three Vessel Disease)

 
Inclusion and exclusion criteria
In order to enter our analysis, studies had to include the following:
  1. Compare OPCAB with CPB in an elderly patient group (age > 70 years).
  2. Contain a previously unreported patient group (if patient material was reported more than once we chose the most recent article).
  3. Be based at single institutions.

Studies were excluded from our analysis if they included any of the following:

  1. The surgical technique (whether OPCAB or CPB) could not be defined.
  2. The development of AF with both techniques was not reported or it was impossible to calculate this from the published results.
  3. They displayed a zero for the outcome of interest in both OPCAB and CPB groups.

Outcome of interest and definitions
OPCAB and CPB were compared with development of postoperative AF being the only outcome of interest. This outcome was identified in the studies selected wherever the term "atrial fibrillation" was used. Other types of supraventricular or ventricular arrhythmias were excluded from our analysis. It is important to note that the studies identified in this meta-analysis reported "new onset" postoperative AF and thus by definition excluded patients with preexisting AF. Also different studies may have varying definitions of AF (intermittent or persistent), the type and duration of monitoring of the patient, and protocols for prophylaxis (the use of ß-blockers). It was not the interest of our study to differentiate between these differing practices. Finally the role of magnesium supplementation in patients undergoing cardiac surgery has been described for both OPCAB and CPB techniques [11]. The studies included in our meta-analysis did not mention the use of magnesium replacement and thus this information was not included in our study.

Statistical analysis
This was carried out using the odds ratio (OR) as the summary statistic. This ratio represents the odds of an adverse event occurring in the treatment (OPCAB) group compared with the reference (CPB) group. An OR of less than one favors the treatment group and the point estimate of the odds ratio is considered statistically significant at the p less than 0.05 level if the 95% confidence interval (CI) does not include the value one. Aggregation of the overall rates of the outcomes of interest was performed with the Mantel–Haenszel {chi}2 test [12]. Yates correction was used for those studies that contained a zero in one cell for the number of events of interest in one of the two groups. These "zero cells" create problems with the computation of ratio measure and its standard error of the treatment effect. This can be resolved by adding the value 0.5 in each cell of the 2 x 2 table for the study in question and if there are no events for both OPCAB and CPB groups the study should be discarded from the meta-analysis.

In this study we used both fixed and random effect models. In a fixed effect model it is assumed that the treatment effect in each study is the same. In a random effect model, however, it is assumed that there is variation between studies and the calculated OR has a more conservative value. In surgical research meta-analysis using the random effect model is preferable. This is because patients that are operated on in different centers have varying risk profiles and selection criteria for each surgical technique [13].

In the tabulation of our results (Fig 1), squares indicate point estimates of treatment effect (OR) with the size of the square representing the weight attributed to each study and 95% confidence interval (CI) indicated by horizontal bars. The diamond represents the summary OR from the pooled studies with 95% CI.



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  		Fig 1. Meta-analysis of atrial fibrillation comparing off-pump coronary artery bypass (OPCAB) versus cardiopulmonary bypass (CPB) in the elderly. (CI = confidence intervals; n = number of patients with postoperative atrial fibrillation; N = total number of patients in each of the two groups compared; OR = odds ratio.)

 
Analysis was conducted by using the statistical software SPSS version 10.0 for Windows (SPSS Inc., Chicago, IL), Intercooled Stata version 7.0 for Windows (Stata Corporation, College Station, TX), Review Manager version 4.2 (The Cochrane Collaboration, Software Update, Oxford, England), and the PS software version 2.1.25 (© 1997 WD DuPont and WD Plummer) for power analysis calculations.

The strategies we employed to quantitatively assess heterogeneity were statistical tests (reanalyzing data with two different statistical approaches using a random and a fixed effect model), graphical exploration (using funnel plots to evaluate publication bias), and sensitivity analysis (by subgroup analysis and by meta-regression). We also calculated the following parameters: absolute risk reduction (ARR) which is the difference in the incidence of AF between OPCAB and CPB groups and number needed to treat (NNT) which is the number of patients who must be treated (in this case to be operated by using OPCAB technique) in order to prevent one event of atrial fibrillation (NNT = 1/ARR) [14].

We performed a subgroup analysis taking into consideration the quality of the studies and used meta-regression analysis to evaluate any associations between treatment effect (odds ratio of AF) and study characteristics (study size and quality). The model of meta-regression analysis we used has been previously described [15, 16]. The dependent variable in this regression was the log odds ratio (logOR) (calculated using the random effect model) and the independent variables were the size of the study and the quality score (an index of the comparability between OPCAB and CPB groups). We calculated the within-study variance and used the restricted maximum-likelihood to estimate the variance between studies.

Sample size considerations
The incidence of AF in CPB patients (Fig 1) ranged from 14%–53%, allowing us to calculate an average AF rate of 28%. In order to rule out a 20% relative risk reduction (from 28%–23%) with a 5% significance level and 80% power a traditional randomized controlled trial with 3:1 ratio (CPB:OPCAB) would require 3,324 patients in total (2493 in the CPB group and 831 patients in the OPCAB group).


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 References
 
Selected studies
Using the previously mentioned criteria ten studies comparing OPCAB and CPB in the elderly were identified [17–26]. Of these, eight noted the incidence postoperative AF and were thus included in our study [17–24]. These were all nonrandomized retrospective studies dating from 1999–2002 and contained 3,017 subjects, of which 764 underwent OPCAB (25%) and 2,253 underwent CPB (75%) (Table 3). The criteria used to assess study quality and the subsequent scores are shown Table 1 and Table 4 respectively.


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  		Table 3. List of Studies Comparing OPCAB With CPB in Elderly Patients

 

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  		Table 4. Assessment of Quality of Studies

 
On review of the data extraction there was 100% agreement between the two reviewers and the agreement on quality score of the individual studies was very high (weighted {kappa} = 0.94). Six out of eight studies were ranked at level 2 [18–23] with two studies at level 1 [17, 24]. Conversion rate from OPCAB to CPB was reported in four out of eight studies (range 0%–3%). The term "elderly" was used for those more than 70 in six studies and above 80 in two studies (Table 3). In three out of the eight studies the OPCAB group had higher mean age in comparison to the CPB group [17, 19, 20].

Apart from two cases [19, 20] the majority of studies showed that the completeness of revascularization (mean number of distal anastomoses) was significantly higher in the CPB group than in comparison to the OPCAB group. Looking at the postoperative complication data comparing OPCAB versus CPB (Table 5), only one study demonstrated a higher incidence of reexploration for bleeding/tamponade in the OPCAB group [20]. Two studies showed a higher incidence of pulmonary complications in this group as well as an increased use of inotropic agents [20, 23]. The use of intraaortic balloon pumping was less frequent in the OPCAB group.


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  		Table 5. Postoperative Respiratory Complications, Reexploration for Bleeding, Inotropic Support/Low Cardiac Output/Intraaortic Balloon Pump Use, and Completeness of Revascularization—OPCAB Versus CPB in the Elderly Patients

 
Meta-analysis
Two out of the eight studies showed a statistically significant difference between the two groups in the incidence of AF [18, 20]. This was 22% (168/764) in the OPCAB group versus 28% (641/2253) in the CPB group. Using the random effect model we calculated an OR of 0.70 with 95% CI 0.56–0.89 and a {chi}2 of heterogeneity of 8.17 (p = 0.32). This suggests a significant reduction in the incidence of AF in the OPCAB group (Fig 1). Using a fixed effect model, the OR was calculated to be 0.69, 95% CI of 0.56–0.86 with identical heterogeneity.

Sensitivity analysis results
We did not identify any significant differences in the OR and heterogeneity for the outcome of interest when comparing random or fixed effect models.

The plot in Figure 2 resembles a symmetrical inverted funnel (95% CI) inside which are all studies included in our meta-analysis. This is a scatter plot of the treatment effects estimated from individual studies on the horizontal axis (OR) against a measure of study size on the vertical axis (SE[logOR]). The name "funnel plot" is based on the fact that the precision in the estimation of the underlying treatment effect will increase as the sample size of the component studies increases [27]. All the studies were inside the 95% CI and no asymmetry was identified.



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  		Fig 2. Funnel plot showing the association between standard error of log odds ratio [SE (log OR)] and odds ratio as it was calculated by the fixed effect model.

 
Subgroup analysis showed that when we excluded studies of lower quality (< 6 stars) the OR for incidence of AF changed to 0.62, 95% (CI of 0.48–0.82), with a heterogeneity of 5.34 (p = 0.38). Meta-regression analysis including study characteristics did not show any associations affecting the calculated OR of AF (Table 6).


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  		Table 6. Metaregression Analysis Between Treatment Effect (Odds Ratio of Atrial Fibrillation) and Study Characteristics

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
Our meta-analysis shows a reduction in the incidence of postoperative AF in an elderly population with OPCAB as compared with CPB techniques. It is important to note, however, that because our statistical analysis uses nonrandomized published data the results must be treated with caution. Although every effort was made to ensure that these were accurate it was impossible to quantify the potential biases of the studies and adjust for inadequate study design. Meta-analysis is most effective when looking at randomized studies but in this case only observational studies were available [28].

Despite this we believe that we have revealed an important link between CPB and the incidence of postoperative AF in the elderly. As shown in Figure 2, the maximum value of the OR favoring the treatment (OPCAB) group was 0.89 (within 95% CI) meaning a relative risk reduction of at least 10%. For the studies included in our analysis the average incidence of AF in elderly CPB patients was 28%. Therefore a 10% reduction in this would translate to an incidence of AF with OPCAB of 25%. The calculated absolute risk reduction would be 3% with OPCAB meaning the numbers needed to treat would be 33. This number would be less in patients at high-risk of AF (age > 70 years, hypertensive, chronic obstructive pulmonary disease [COPD], diabetes, left ventricular dysfunction, and advanced coronary artery disease).

The exact etiology of AF from cellular or electrophysiological perspectives is not yet clear. Reentry phenomena in the atrial wall are thought to play a prominent role and these include varying refractory periods in parts of the atrial wall, different points of reentry, rapid firing foci, and "triggers" such as premature atrial contractions [29]. These electrophysiologic phenomena may be precipitated by physiologic (ischemia, hypoxia, or increased sympathetic activation) or anatomical mechanisms (loss of nodal fibers, fibrous or adipose tissue accumulation in the sino-atrial node, atrial enlargement, and atrial wall fibrosis) related to age or hypertension [30]. Pre-, intra-, and postoperative factors predisposing to AF in patients undergoing cardiac surgery have already been identified [2, 31–33], although the role of CPB in the generation of this arrhythmia is unclear [34]. There are randomized studies in the literature comparing OPCAB with CPB with regards to postoperative AF but in all of these the average age of the studied population is less than 70 years of age and even between them there is conflicting evidence that avoidance of CPB decreases the incidence of postoperative AF [35, 36]. Only one study reported a very significant reduction in the incidence of AF (OR of 0.34 with 95% CI of 0.23–0.51, p < 0.0001) in the OPCAB group [35].

In the elderly, several mechanisms directly related to the CPB technique may be responsible for the increased incidence of AF when compared with OPCAB:

  1. Ischemia with OPCAB is regional whereas with CBP it is global. This has a detrimental effect on atrial myocardium resulting in generation of arrhythmias.
  2. Left ventricular segmental wall motion and blood supply to the subendocardium and interventricular septum has been found to be better in patients undergoing OPCAB compared with CPB [37]. This is important in patients with poor left ventricular function or those undergoing acute myocardial infarction, as atrial dilatation may occur increasing the risk of AF.
  3. Myocardial injury (higher release of CK MB and troponin I) is more common in the CPB group than in the OPCAB group especially in the first 2 postoperative days as has been shown in elderly patients.
  4. During OPCAB there is less manipulation of the right atrium, as there is no need for a purse string suture and no insertion of atrial venous cannulas.
  5. CPB can result in more inflammation than OPCAB as a result of complement activation, neutrophils, induction of adhesion molecules, release of cytokines, and endothelial activation [38]. This can have a temporary postoperative effect on both respiratory (abnormal gas exchange) and renal function (fluid and electrolyte balance) resulting in atrial irritability. These effects may be less reversible in elderly cardiac patients who often have preexisting renal, respiratory, and neurologic disease.

It is also possible that the reduced incidence of AF in the elderly undergoing OPCAB as compared with CPB is related to the systemic effects of the techniques (Table 5). First, most of the studies included in our analysis showed that postoperative hypotension was less frequent in the OPCAB group resulting in a reduced requirement for inotropic support and intraaortic balloon pumping. Both postoperative hypotension and inotropic support are themselves arrhythmogenic resulting in cellular hypoxia and increased sympathetic activation respectively. Note that in two of the studies in our meta-analysis where more inotropic support was required in the OPCAB group, AF incidence was lower [18, 20].

Second, the reexploration rates for bleeding or tamponade were lower in the OPCAB as compared with the CPB group. Significant blood loss after cardiac surgery is associated with pericardial and pleural collections which can predispose to the generation of AF either as a result of direct pressure on the right atrium or secondary to respiratory dysfunction [39].

Third, there were significantly fewer grafts performed with the OPCAB group compared with the CPB group in most of the studies. It is not yet certain whether higher risk groups of patients, such as the elderly, would benefit more from multivessel as opposed to a limited target vessel revascularization strategy [40]. The balance between the risk of serious postoperative morbidity due to comprehensive grafting was made possible by CPB and the benefit achieved from complete revascularization of a target vessel, as in OPCAB surgery, needs to be found in the elderly patient undergoing CABG.

Our study suggests that OPCAB, a less invasive procedure than CPB, might reduce the incidence of postoperative AF in elderly patients undergoing surgical myocardial revascularization. The limitation of our meta-analysis is that all the studies included were nonrandomized. Our results strongly support a large-scale multicenter randomized trial comparing OPCAB with CPB. If indeed this finding is confirmed it may change the operative strategy employed for this patient group.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

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Biomarker Profile in Off-Pump and On-Pump Coronary Artery Bypass Grafting Surgery in Low-Risk Patients
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S. G Raja and G. D Dreyfus
Current Status of Off-pump Coronary Artery Bypass Surgery
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 Eur. J. Cardiothorac. Surg.Home page
T. Athanasiou, A. Chow, C. Rao, O. Aziz, F. Siannis, A. Ali, A. Darzi, and F. Wells
Preservation of the mitral valve apparatus: evidence synthesis and critical reappraisal of surgical techniques
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T. Athanasiou, C. Jones, R. Jin, G. L. Grunkemeier, and D. N. Ross
Homograft Implantation Techniques in the Aortic Position: To Preserve or Replace the Aortic Root?
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S Purkayastha, T Athanasiou, V Malinovski, P Tekkis, R Foale, R Casula, B Glenville, and A Darzi
Does clopidogrel affect outcome after coronary artery bypass grafting? A meta-analysis.
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D. N. Wijeysundera, W. S. Beattie, G. Djaiani, V. Rao, M. A. Borger, K. Karkouti, and R. J. Cusimano
Off-Pump Coronary Artery Surgery for Reducing Mortality and Morbidity: Meta-Analysis of Randomized and Observational Studies
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 Clin Med ResHome page
J. Pepper
Controversies in Off-pump Coronary Artery Surgery
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S. G. Raja, A. A. Behranwala, and J. Dunning
Does off-pump coronary artery surgery reduce the incidence of postoperative atrial fibrillation?
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 Eur. J. Cardiothorac. Surg.Home page
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