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© 2003 European Association of Cardio-Thoracic Surgery
Preoperative ß-blocker therapy in coronary artery bypass surgery: a propensity score analysis of outcomes
a Department of Cardiothoracic Surgery, The Cardiothoracic Centre-Liverpool, Thomas Drive, Liverpool L14 3PE, UK
* Corresponding author. Tel.: +44-151-293-2397; fax: +44-151-220-8573 Received March 7, 2003; received in revised form June 5, 2003; accepted June 18, 2003
Preoperative ß-blockade in patients undergoing coronary artery bypass grafting (CABG) has recently been shown to be beneficial in improving the early outcomes after surgery. We aimed to quantify the effect of preoperative ß-blockade on outcomes in our own patient population. We performed a retrospective analysis on CABG patients identified from our prospectively collected cardiac surgery database. Logistic regression was used to adjust in-hospital outcomes for differences in patient and disease characteristics. Treatment selection bias was controlled by deriving a propensity score for ß-blocker therapy. Consecutive patients (4381) underwent CABG on cardiopulmonary bypass between 1 April 1997 and 31 March 2002, with 2836 (64.7%) on preoperative ß-blocker therapy. After adjustment with the propensity score, ß-blocker therapy was significantly associated with a reduction in post-operative stroke (adjusted OR 0.59,  ). The incidence of atrial arrhythmia was significantly increased in patients who had received preoperative ß-blockers (adjusted OR 1.21, ). There were no significant differences in operative mortality or other morbidity outcomes. Preoperative ß-blocker therapy significantly reduces the incidence of post-operative cerebrovascular events in patients undergoing on-pump coronary artery bypass surgery.
Key Words: ß-Blockers; Coronary artery bypass grafting; Stroke; Propensity score
ß-Blockers are one of the oldest and most commonly used drugs for the treatment of ischaemic heart disease [1]. Complications that have been traditionally considered as serious problems with ß-blocker therapy, like heart failure, are now reconsidered in light of development of more cardiac selective medications and increasing evidence for long-term benefit of these drugs [2]. The cardio-protective action of ß-blockers in a surgical stress situation like major vascular surgery in patients with ischaemic heart disease has also been well documented in the literature [3]. Prior ß-blocker therapy has also been shown to have a cardio-protective effect in limiting CK-MB release and lower intermediate term mortality rate following percutaneous coronary interventions [4]. Interest has now turned to explore this myocardial protective effect of ß-blockers in coronary artery surgery. Operating on a ß-blocked heart is controversial with concerns arising about the negative inotropic effect of ß-blockers and complications of ß-blockade like bronchospasm [5]. Weightman et al. [6] showed a beneficial effect on in-hospital mortality with a relative risk of 0.4 (95% confidence intervals (CI) 0.2–0.8) for patients on preoperative ß-blockers. A recent publication in JAMA [7] has looked at outcomes after cardiac surgery in a large multi-centre observational study in North America. Their analysis shows that preoperative ß-blockade improved operative survival in all patients who underwent coronary artery surgery except in those with poor left ventricular function (<30%). It has also been shown that these patients also have significantly lower rates of stroke, renal failure, and prolonged ventilation. The aim of this study is to quantify the effect of preoperative ß-blocker therapy continued to the day of surgery on morbidity and mortality following coronary artery bypass grafting (CABG) in our patient population.
2.1. Patient population and data This study consisted of 4381 consecutive patients undergoing CABG performed on cardiopulmonary bypass between 1 April 1997 and 31 March 2002 at the Cardiothoracic Centre-Liverpool. Patients undergoing CABG that was incidental to heart valve repair or replacement, resection of a ventricular aneurysm or other surgical procedure were not included. Patients who received off-pump CABG were also excluded from this study. Definitions and data collection methods are available from http://www.nwheartaudit.nhs.uk. Data were collected prospectively during the patient's admission as part of routine clinical practice and entered onto a cardiac surgery database. The preoperative and operative data collected are shown in Table 1. Post-operative data collected included operative mortality, creatine kinase-MB release, myocardial infarction, re-exploration for bleeding, atrial arrhythmia, stroke, sternal wound infection, renal failure, gastrointestinal complications, duration of mechanical ventilation, intra-aortic balloon pump (IABP) support, and length of intensive care unit (ICU) and post-operative hospital stay.
The technique of myocardial protection varied according to operator preference. Although blood cardioplegia was the favoured choice, cold crystalloid cardioplegia and intermittent cross-clamp and fibrillation were also used by some surgeons. Mammary artery, saphenous vein, and radial arteries were the predominant conduits used. Operative mortality was defined as death within 30 days of surgery, whether in or out of hospital, or death in-hospital regardless of length of hospital stay. Gastrointestinal complications were defined in accord with the Society for Cardiothoracic Surgeons of Great Britain and Ireland (http://www.scts.org.uk). Other morbidity definitions have been previously published [8]. 2.2. Statistical methods Due to the non-normality of continuous variables, results are shown as median with 25th and 75th percentiles. Categorical variables are shown as a percentage with 95% CI. Comparisons were made with Wilcoxon rank sum tests and Chi-square tests as appropriate. The European System for Cardiac Operative Risk Evaluation (EuroSCORE) was derived to assess differences in patient case mix between study groups. Standard statistical tests were used to calculate odds ratios with 95% CI. Logistic regression was used to assess the effect of ß-blocker therapy on each outcome (expressed as odds ratio (OR), which approximates relative risk) after adjusting for differences in patient and disease characteristics (treatment selection bias).Treatment selection bias was controlled for by constructing a propensity score [9]. The propensity score was the probability that a patient would receive preoperative ß-blocker, and was constructed from the variables listed in Table 1 (C statistic=0.71). Once the propensity score is constructed for each patient, there are three ways of using the score for comparisons: matching, stratification, and multivariable adjustment. We have decided to use multivariable adjustment because matching would have reduced the study size and stratification can be difficult to interpret. The propensity score is then included along with the comparison variable (ß-blocker or non-ß-blocker) in a multivariable analyses of outcome producing adjusted OR as shown in Table 3. The propensity score adjusts for the treatment selection bias, which is evident in Table 1, between one group versus another (e.g. cerebrovascular disease and congestive cardiac failure). Using a propensity score as the sole means for adjusting outcomes was preferable due to the low number of events in our study and provides better adjustment for those factors driving treatment selection; the overall effect is more complete risk adjustment [9]. In all cases a p value <0.05 was considered significant. All statistical analyses were performed retrospectively with SAS for Windows Version 8.2.
3.1. Patient characteristics Overall, 2836 (64.7% (95% CI 63.3–66.1)) patients received preoperative ß-blocker therapy, while 1545 (35.3% (95% CI 33.8–36.7)) patients did not receive preoperative ß-blocker therapy. Table 1 lists patient and disease characteristics based on preoperative use of ß-blocker. 3.2. Outcomes The median post-operative length of stay, in survivors, for patients who received preoperative ß-blocker therapy was 7 days (25th and 75th percentiles: 6–9) compared to 8 days (25th and 75th percentiles: 7–10) for the non-ß-blocker patients . In-hospital outcomes with preoperative ß-blocker therapy are shown in Table 2 (crude) and Table 3 (adjusted for the propensity score).
Preoperative ß-blocker therapy was associated with a significant 35% reduction in operative mortality in the univariate analysis  , however, after risk adjustment this difference disappeared (adjusted OR 0.93,  ).
ß-Blocker was associated with post-operative atrial arrhythmia in the univariate analysis, just failing to reach statistical significance
The incidence of post-operative stroke was significantly lower in patients receiving preoperative ß-blocker therapy in both the univariate and multivariate analyses (adjusted OR 0.57,
4.1. Patient characteristics This study aimed to examine the effect of preoperative ß-blocker therapy in a single institution in the North West of England, which serves a population of 2.8 million with a high prevalence of ischaemic heart disease (>3%) and high mortality attributed to it (standardised mortality ratio for catchment area=141). In this study 65% of patients with ischaemic heart disease are initiated on ß-blocker therapy. This figure is similar to the ß-blocker therapy rate in North America [7]. The most common reason for not initiating ß-blocker therapy is the presence of co-morbid conditions like diabetes mellitus, obstructive airways disease, congestive cardiac failure, peripheral vascular disease, cerebrovascular disease, and renal dysfunction. With recent improvements and proven benefits of ß-blockade in patients with ischaemic heart disease there is potential room for improvement in this patient population. 4.2. Outcomes We found a significantly lower operative mortality when using preoperative ß-blocker therapy, in the univariate analyses, which was also shown by Ferguson et al. [7]. However, after adjusting for differences in patient characteristics, we could not find a 30-day survival advantage in our patient population. This different finding can be explained by the differences in case-mix, as well as by the several limitations associated with a large multi-centre observational study including wide variation in practice and a voluntary unvalidated database [7].After adjusting for differences in patient characteristics, such as cerebrovascular disease and congestive cardiac failure through the use of the propensity score, ß-blocker therapy was also found not to be associated with myocardial infarction, CK-MB release, renal failure, gastrointestinal complications, re-exploration for bleeding, sternal wound infection, duration of mechanical ventilation, IABP support, and ICU and post-operative length of stay. The literature reports a wide variation (5–40%) in the incidence of atrial arrhythmias [10]. The evidence on whether atrial arrhythmias are more or less common in patients on preoperative ß-blockers is inconclusive. In this study, the incidence of atrial fibrillation is higher in patients on preoperative ß-blockade therapy. Increased myocardial irritability after cardiac surgery and the proven causal relationship between elevated nor-epinephrine levels with the incidence of atrial fibrillation coupled with the practice of not initiating ß-blocker therapy unless clinically indicated, are all possible reasons for the increased atrial fibrillation rate seen in this study. Several studies have shown that initiation of ß-blocker therapy perioperatively, on a routine basis, reduces the incidence of atrial fibrillation in patients undergoing coronary artery surgery [11,12]. We have shown that stroke is significantly lower in patients on preoperative ß-blocker therapy, even after risk adjustment with the propensity score [9]. It is important to note that the propensity score included known risk factors for stroke such as age, peripheral vascular disease, cerebrovascular disease, and duration of cardiopulmonary bypass. Amory et al. and Grigore et al. [10,12] have also demonstrated this in their studies. Amory et al. [10] discussed in detail the pathophysiology of this effect. ß-Blockers are known to have a high lipid solubility and hence cross the blood–brain barrier with ease. They reduce ischaemia by shifting the oxygen–haemoglobin dissociation curve to the right resulting in increased oxygen dissociation to brain tissues [7]. Circulating catecholamine levels during cardiac surgery have been studied using animal models [13] and in paediatric cardiac surgery [14]. These studies show that the continuous exposure to increased circulating catecholamines result in desensitisation and a reduction in the density of ß-adrenoreceptors. It also leads to an abnormal cerebral vasoconstrictor response to epinephrine and nor-epinephrine which is mediated by ß-adrenogergic receptors and compounding cerebral ischaemia. Amory et al. [10] have postulated that ß-blockade prevents this reversal and partially explains the beneficial neuroprotective action. Other postulated mechanisms are membrane stabilisation and local anaesthetic effects of ß-blockers, properties that have proven neuroprotective effects [7]. We have previously shown that cardiopulmonary bypass is a risk factor for increased cerebrovascular events [15]. ß-Blockers may reduce this risk when coronary artery bypass surgery is performed on cardiopulmonary bypass.
There are some limitations to this study, the most important being the retrospective, observational, and non-randomised nature. We have attempted to correct this by risk adjusting our study groups for differences in patient characteristics with a propensity score. However, propensity score adjustment is no substitute for a properly designed randomised control trial. The retrospective nature of the study cannot account for the unknown variables affecting the outcome that are not correlated strongly with measured variables. On the other hand, retrospective comparisons with propensity score adjustment are more versatile and may be more widely acceptable than randomised control trials [9]. We also did not collect details of dosage and duration of treatment nor the type of ß-blocker used. Obviously with varied specificity and potency, this might be a potential variable influencing outcome.
Preoperative ß-blocker therapy continued to the date of intervention is significantly associated with a reduction in the incidence of stroke following coronary artery surgery performed on cardiopulmonary bypass. Operative mortality is not associated with preoperative ß-blocker therapy. Surprisingly, this study shows that preoperative ß-blocker therapy is associated with an increased incidence of atrial fibrillation in the early post-operative period. There is good evidence to suggest that this risk could be reduced by continuing ß-blocker therapy in the post-operative period.
ICVTS on-line discussion Author: Dr. Paulo Roberto Evora, Head of the Endothelium Function Laboratory at the Surgical Research Division and Medical Surgeon, Riberião Preto School of Medicine - University of São Paulo and Ribeirão Preto Heart and Lung Specialized Center (CECORP), Department of Surgery and Anatomy, Rua Rui Barbosa, 367, Apt 15, Ribeirão Preto, SP, Brazil Date: 29-Jul-2003 Message: Atrial fibrillation and coronary artery bypass surgery (CABG) and beta-blockers are protagonists of a never-ending story. Dr. Adam E. Saltman wrote a brilliant chapter of this story in recent editorial published in The Journal of Thoracic and Cardiovascular Surgery [1]. In this editorial Dr. Saltman points that despite the astonishing advances that have been made in cardiac surgery over the past 40 years, new-onset atrial fibrillation remains its most common complication. Long thought a nuisance, it has now been clearly shown to increase length of stay, intensive care unit utilization, morbidity, and even long-term mortality. It occurs in anywhere from 15% to 40% of patients and little progress has been made in our understanding, prevention, or treatment of it. He discussed about the growing number of papers about the amiodarone efficacy to treat atrial fibrillation in the milieu of CABG and conclude that until more convincing evidence emerges, the routine administration of beta- blockers remains standard prophylaxis for perioperative atrial fibrillation. Amiodarone should be reserved for those patients in whom beta-blockade would be contraindicated or who poorly tolerate the drug, such as those with poor ventricular function, congestive heart failure, severe lung disease, thyroid disease, or allergy. In the eighties we analyzed 186 patients submitted to coronary artery bypass and reported a incidence of atrial fibrillation of 6.04% (11 cases). The male sex was dominant (81.2%) with ages varying from 49 to 73 (mean 54.58) years. The preoperative incidence of diabetes, smoking and systemic hypertension were, respectively, 18.2%, 54.51% and 36.4%. The mean number of vessels bypassed was 2.42±1.19 and the left circumflex artery was involved in 81.20% of these cases. Cardiopulmonary bypass time was 100±39.6 min and ischemic arrest time of 79.6±37.7 min. Single double stage cannulae for venous drainage were used in 45.5% of the patients and ventricular fibrillation and cardiac overdistention occurred in 63.60% immediately after CPB. Atrial fibrillation presented around 1.66±2.17 days in the postoperative period and 45.5% of the patients had more than one distinct episode of the arrhythmia. Treatment constituted of cardioversion in 25%, atenolol oral in 18.75% and digitalis associated to quinidine in 56.25%. These numbers permitted us to suggest that some of the above factors may contribute to the genesis of arrhythmias, such as single double stage cannulation for venous drainage, inadequate myocardial protection, overdistention and cardiac fibrillation and, mainly, the presence of proximal circumflex artery obstructions responsible for atrial ischemia before and during surgery [2]. After this study, we designed a prospective study, including, coronary artery disease and valve heart disease, and the favorable results (unpublished data), we adopted the use of 50 mg of atenolol for all our patients in the night before surgery. If the patient was in use of beta-blockers we keep prescribing it, and it was our routine. In this paper Srinivasan et al. present one result against all clinical and pharmacological evidences: the incidence of atrial arrhythmia significantly increased in patients who had received preoperative beta-blockers. The authors pointed to study limitations, the most important being the retrospective, observational, and non-randomized natures, beside the capital limitation of the study that did not collect details of dosage and duration of treatment nor the type of beta-blocker used. This data have to be emphasizing as a possible cause of the apparent paradoxal increased atrial arrhythmias in the beta-blocker group of patients. Another important data to explain this increased incidence is the beta-blocker withdrawn. Anesthesiologists and the intensive care team have to be attempt for this pharmacological phenomenon. Since we adopted the preoperative beta-blocker therapy, the beta-blockade must be continuous through the perioperative time, including its use in the operating room and during the early postoperative time. Many times when the patient presents atrial fibrillation the ICU team starts high doses of amiodarone, but small doses of injectable metropolol recover the sinus rhythm. Also, we frequently use atenolol diluted in water by sublingual via. Atenolol is hydrosoluble and its use by the sublingual via should avoid the first-pass liver metabolism. References [1]Saltman AE. Is it time to choose amiodarone for postoperative atrial fibrillation? J Thorac Cardiovasc Surg. 2003;125(6):1202–3. [2]Sgarbieri RN, de Freitas JN, Evora PR, Brasil JC, Ribeiro PJ, Otaviano AG, Bongiovanni HL, Menardi AC, Ferez MA. Postoperative atrial fibrillation in myocardial revascularization. Arq Bras Cardiol. 1989;52(1):19–22.
We would like to acknowledge the co-operation given to us by all the Consultant Cardiac Surgeons at the Cardiothoracic Centre-Liverpool: Mr JAC Chalmers, Mr WC Dihmis, Mr BM Fabri, Ms EM Griffiths, Mr N Mediratta, Mr RD Page, Mr DM Pullan, Mr A Rashid, and Mr WI Weir. We would also like to thank Janet Deane, who maintains the quality and ensures completeness of data collected in our Cardiac Surgery Registry. doi:10.1016/S1569-9293(03)00132-4
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Abstract
1. Introduction
. After adjustment for the propensity score, ß-blockers were significantly associated with an increase in post-operative atrial arrhythmia (adjusted OR 1.21,