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Ann Thorac Surg 2003;76:793-799
© 2003 The Society of Thoracic Surgeons


Original article: cardiovascular

Early and midterm clinical outcome in patients with severe left ventricular dysfunction undergoing coronary artery surgery

Raimondo Ascione, MDa, Pradeep Narayan, FRCSa, Chris A. Rogers, PhDa, Kelvin H. H. Lim, FRCSa, Radek Capoun, MDa, Gianni D. Angelini, FRCSa*

a Bristol Heart Institute, Bristol Royal Infirmary, Bristol, United Kingdom

Accepted for publication March 25, 2003.

* Address reprint requests to Prof Angelini, Bristol Heart Institute, Bristol Royal Infirmary, Bristol BS2 8HW, UK
e-mail: g.d.angelini{at}bristol.ac.uk


    Abstract
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 
BACKGROUND: Patients presenting with severe left ventricular (LV) dysfunction undergoing coronary artery surgery are at increased risk of perioperative morbidity and mortality. The present study investigated early and midterm outcomes in a consecutive series of patients with severe LV dysfunction undergoing coronary surgery at our institution.

METHODS: Data on 5,195 consecutive patients undergoing coronary artery bypass grafting (CABG) alone (in-hospital mortality 1.35%) from April 1996 to August 2002 were prospectively recorded in the Patient Analysis and Tracking System. Two hundred and fifty patients (median age 65 years [interquartile range, 57 to 70]) with preoperative left ventricular ejection fraction less than 30% (74 off pump; 29.6%) were identified and early and midterm clinical outcomes analyzed. Propensity scores were used to take account of the imbalance in the distribution of prognostic factors between the on-pump and off-pump groups.

RESULTS: Patients undergoing on-pump surgery were less likely to have current congestive heart failure, insulin-dependent diabetes, a history of hypertension, have had gastrointestinal tract surgery or an ulcer, or unstable angina. They had on average lower Parsonnet scores and New York Heart Association and Canadian Cardiovascular Score ratings. However they were more likely to have more extensive coronary artery heart disease and to require more grafts than those undergoing off-pump surgery. After adjustment for consultant team and propensity scores no differences between groups with regard to in-hospital mortality and morbidity were found. The only in-hospital outcome to show a significant difference after adjustment was the need for intraoperative inotropic support, which was higher in the on-pump group (odds ratio 5.1; 95% confidence interval 2.55 to 10.2; p < 0.001)). The median follow-up times for the on- and off-pump groups were 3.4 years and 1.4 years respectively. Three-year survival was higher with on-pump surgery (87% on-pump versus 73% off-pump) but this difference did not reach statistical significance after adjustment for prognostic variables (hazard ratio 0.54, 95% confidence interval 0.22 to 1.26, p = 0.16).

CONCLUSIONS: In-hospital mortality and morbidity in patients presenting with severe LV dysfunction is low with comparable results with both on- and off-pump coronary artery surgery. Midterm clinical outcome is encouraging and seems to justify surgical revascularization for this high-risk group of patients.


    Introduction
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 
The prevalence of patients presenting with severe left ventricular (LV) dysfunction is increasing together with an increasing profile of comorbidity [1]. Severe LV dysfunction has been reported as an independent predictor of operative mortality in patients undergoing CABG [14]. It also often leads to low cardiac output and a high postoperative morbidity, with many of these patients requiring inotropic or mechanical support and vasopressors for hours to days after surgery [5]. Increasingly patients are being offered a surgical option as opposed to the medical treatment alone, which may have failed to control symptoms or to improve long-term survival in these patients [2]. However the information available on the efficacy of surgery in patients presenting with severe LV dysfunction is often misleading due topoor study design, inadequate sample size, and definition of LV dysfunction. Furthermore differences in patient and operative factors, inadequate myocardial protection, residual ischemia, incomplete revascularization, and suboptimal anastomosis are all potential confounding factors when assessing outcomes.

The present study investigated early and midterm outcome in a consecutive series of patients with severe LV dysfunction undergoing coronary artery surgery at our institution.


    Material and methods
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 
Patient selection
All data were collected prospectively at the time of operation and entered into the Patient Activity Tracking System (PATS) database (Dendrite Systems, London, UK), which is maintained routinely in our institution to document cardiac surgical activity. All patients with poor LV function based on a recorded ejection fraction (EF) less than 30% undergoing CABG alone between April 1, 1996, and August 31, 2002, were analyzed. During the study period surgeons in our institution began to carry out off-pump coronary artery bypass (OPCAB) surgery and have used this new technique with increasing frequency and on a wider range of patients as they have gained more experience. All CABG patients irrespective of whether they underwent conventional CABG or OPCAB were considered. Allocation to on- and off-pump surgery was on the basis of the preference and expertise of the surgeons carrying out the operations and also, during the early part of data collection when experience with off-pump techniques was limited, on coronary anatomy and number of grafts required. The decision about which method to use was taken after opening the chest, when the anatomy of the coronary vessels could be explored.

Identification of poor LV function was based on either the preoperative echocardiography or cineangiography assessment performed by an independent cardiologist. Patients with a myocardial infarction (MI) in the 24 hours before surgery, patients having emergency/salvage procedures, and patients with insufficient data to determine eligibility were excluded.

Anesthetic and surgical techniques
Anesthetic technique was standardized for all patients and has been previously reported [6]. Briefly, this consisted of intravenous anesthesia with propofol infusion at 3 mg · kg-1 · h-1 combined with remifentanil infusion at 0.5 to 1 µg · kg-1 · min-1. Neuromuscular blockade was achieved by 0.1 to 0.15 mg/kg pancuronium bromide or vecuronium and the lungs ventilated to normocapnia with air and oxygen (45% to 50%) without positive end-expiratory pressure (PEEP). In the on-pump group heparin was given at a dose of 300 iu/kg to achieve a target activated clotting time (ACT) of 480 seconds or above before commencement of cardiopulmonary bypass (CPB). In the off-pump group heparin (100 iu/kg) was administered before the start of the first anastomosis to achieve an ACT of 250 to 350 seconds. On completion of all anastomoses protamine was given to reverse the effect of heparin and return the ACT to preoperative levels. For patients undergoing on-pump CABG, CPB was instituted using ascending aortic cannulation and two-stage venous cannulation of the right atrium. Nonpulsatile flow was used and flow rates throughout bypass were 2.4 L · m-2 · min-1. Systemic temperature was kept between 34°C and 36°C. Myocardial protection was achieved by using intermittent anterograde hyperkalemic warm blood cardioplegia [6].

For patients undergoing off-pump CABG the target vessel was exposed and snared above the anastomotic site using a 4-0 Prolene (Ethicon, Somerville, NJ) suture with a soft plastic snugger. The coronary artery was then opened, an intracoronary shunt was used, and the anastomosis performed using a pressure stabilizer [7].

Postoperative management
At the end of surgery patients were transferred to the intensive care unit (ICU) and managed according to unit protocol [68]. The lungs were ventilated with 60% oxygen using volume-controlled ventilation and a tidal volume of 10 mL/kg with 5 cm H2O of PEEP. Forced air warming was used until a stable nasopharyngeal temperature of 37°C had been reached. Patients were extubated as soon as they met the following criteria: hemodynamic stability, no excessive bleeding (< 80 mL/h), normothermia, and consciousness with pain control. Fluid management postoperatively consisted of 5% dextrose infused at 1 mL · kg-1 · h-1, with additional colloid or blood to maintain normovolemia and hematocrit more than 24%. Potassium and magnesium deficiencies were promptly treated as necessary to mantain electrolyte balance within the normal range.

Clinical data collection, monitoring, and definitions
Data characterizing perioperative clinical outcomes were entered prospectively into the PATS database. Perioperative MI, ST-segment changes, pacing, arrhythmias, and inotropic requirement were recorded and defined as previously reported [6]. Pulmonary complications included chest infection, ventilation failure, reintubation, and tracheostomy. Postoperative blood loss was defined as total chest tube drainage [9]. Neurologic complications included permanent and transient stroke [10]. Renal complications included acute renal failure as defined by the requirement of hemodialysis. Infective complications were defined by positive culture and requiring antibiotic therapy [6].

Patient survival
Deaths after hospital discharge were identified from mortality data provided by the National Health Service Strategic Tracing Service (NSTS). All patients in this study were successfully matched to the NSTS database.

Statistical analysis
Propensity scores
Propensity scores, which estimate the probability of having on- versus off-pump surgery, were used to take account of the imbalance in the distribution of prognostic factors between the two groups. Multiple logistic regression using all known characteristics of the study cohort was used to estimate the propensity scores. Fractional polynomials were used to determine the functional form for continuous variables. Jack-knifed estimates of the regression coefficients were used to calculate the propensity score for each patient.

Missing data
When estimating propensity scores missing values were imputed. For categorical variables the most prevalent category was assumed and for continuous variables the median value was used. When comparing outcomes, patients with missing data were omitted.

Analysis
Baseline characteristics were compared using the {chi}2 or Fisher’s exact test (categorical variables) or the Wilcoxon rank sum test (continuous variables). Logit(propensity score) and the interaction between logit (propensity score) and on-pump versus off-pump (where statistically significant at the 5% level) were included as covariates in the adjusted analyses comparing baseline characteristics between the on- and off-pump groups. Comparing outcomes after surgery two analyses were carried out. The first was adjusted for consultant team (four levels) only, and the second adjusted for consultant team and logit(propensity score). Logit(propensity score) was fitted as a continuous variable throughout. Where possible residual confounding was suggested, as indicated by a statistically significant regression coefficient for logit(propensity score), adjustment for Parsonnet score was also applied. Outcomes with fewer than five events were not subjected to statistical analysis.

Multiple linear regression was used to compare continuous variables. Model assumptions were assessed graphically and where untenable transformations of the data were explored. Binary variables were compared using logistic regression and model adequacy was assessed using the Hosmer-Lemeshow goodness-of-fit test. Ordered categorical variables were compared using a proportional odds model. An approximate likelihood ratio test was used to assess the validity of the proportional odds assumption and if untenable the variable was analyzed using multinomial logistic regression. Multicategory variables with no natural ordering were also analyzed using multinomial logistic regression. Where no significant lack of fit was indicated (using a likelihood ratio test) a constrained model with common regression estimates for on-pump versus off-pump and for logit(propensity score) across the categories was used. Time to event variables were analyzed using Cox proportional hazards regression. Patients for whom the event had not occurred were treated as censored observations. Postoperative survival was also censored at 3 years. The proportional hazards assumption was assessed graphically and using the "stphtest" command in Stata. If untenable, a stratified analysis was used. All analyses were carried out using Stata (Stata Corporation, College Station, TX). Results are reported with 95% confidence intervals (95% CI). No correction has been made for multiple comparisons but our interpretation of the findings takes into account both the consistency and magnitude of the associations as well as their statistical significance.


    Results
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 
From a database of 7,339 cases, 5,195 patients underwent CABG alone, 251 of whom were eligible for this study. One eligible patient with missing data for 10 prognostic variables was excluded. Of the 250 patients analyzed, 74 received off-pump surgery and 176, on-pump surgery. The proportion receiving off-pump surgery increased steadily over the study period from 2 of 47 (4%) in 1996–97 to 22 of 49 (45%) in 2001–02. Patients were under the care of one of four consultant teams. Use of off-pump surgery varied significantly between these teams (range, 4% to 68%; p < 0.001) but for all teams the proportion receiving off-pump surgery increased over time.

Preoperative characteristics of the cohort are shown in Table 1. Patients undergoing on-pump surgery were less likely to have current congestive heart failure, insulin-dependent diabetes, a history of hypertension, gastrointestinal tract surgery or an ulcer, or unstable angina (on heparin or nitrates infusion). They had on average lower Parsonnet scores and New York Heart Association (NYHA) and Canadian Cardiovascular Score (CCS) ratings. However they were more likely to have more extensive coronary heart disease and to require more grafts than those undergoing off-pump surgery. The mean number of grafts was 2.91 (SD 0.77) and 2.35 (SD 0.69) in the on-pump and off-pump groups respectively (p < 0.001).


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Table 1. Baseline Characteristics

 
After adjustment for the propensity score no significant differences in baseline characteristics between the on- and off-pump groups were found (Table 1), indicating that the propensity model had successfully served to remove the imbalance in distribution of a number of prognostic factors.

Outcomes after surgery are reported in Table 2 and compared between the two groups in Table 3. The overall incidence of in-hospital mortality and of perioperative MI was 4.0% (95% CI 1.9% to 7.3%). There were five in-hospital deaths in each group (3% and 7% in the on-pump and off-pump groups respectively). Myocardial infarction occurred in 7 (4%) on-pump and 3 (4%) off-pump patients, and 21 (12%) on-pump and 11 (15%) off-pump patients needed an IABP after surgery. The need for intraoperative inotropic support was significantly greater for on-pump patients (p < 0.001), being twice that for the off-pump group (81% required support in the on-pump group compared with 41% in the off-pump group). The incidence of postoperative arrhythmias and of chest infection was slightly higher in the on-pump group (postoperative arrhythmias 27% on-pump, 23% off-pump; chest infection 9% on-pump, 5% off-pump) but not significantly so (p = 0.70 and p = 0.84 respectively). The occurrence of acute renal failure requiring dialysis and permanent stroke was similar in the two groups (5% and 1% respectively in both groups). Chest tube drainage and transfusion requirement of blood, platelets, and fresh frozen plasma did not differ significantly between the groups (p = 0.66 [drainage], p = 0.19 [blood], p = 0.38 [platelets], and p = 0.95 [fresh frozen plasma]), although all were slightly reduced in the off-pump group. The only in-hospital outcome to show a statistically significant difference was inotropic use, which after adjustment for prognostic variables remained significantly lower with off-pump surgery (odds ratio 5.1, 95% CI 2.55 to 10.2).


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Table 2. Outcomes After Surgery

 

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Table 3. Effect Sizes (On-Pump Versus Off-Pump)

 
The median postoperative follow-up times for the on- and off-pump groups were 3.4 years and 1.4 years respectively, which reflects the pattern of use of the two surgical techniques over time. There were 50 deaths in total, 39 occurred after 30 days and 16 deaths occurred more than 3 years after surgery. Three-year postoperative survival was higher with on-pump surgery (87% on-pump versus 73% off-pump) but this did not reach statistical significance after adjustment for prognostic variables (p = 0.16; Fig 1).



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Fig 1. Actuarial survival, adjusted for consultant team and logit (propensity score). Solid line = off pump; dashed line = on pump.

 

    Comment
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 
The growing need to perform coronary revascularization in patients with severely impaired LV function is the result of increasing number of patients presenting with end-stage ischemic cardiomyopathy, the reduced possibility of performing heart transplantation owing to donor shortage, and the unquestionable point of the right of cure.

For patients with congestive heart failure, mortality is directly related to the severity of ventricular systolic function [11], the extent of viability in hypocontractile myocardium [12], and the chosen form of treatment, as suggested by published registry studies and randomized trials [13]. Anguita and coworkers [14] reported a 1-year survival of 54% in medically treated patients with severe congestive heart failure secondary to ischemic cardiomyopathy. This, despite the important improvements in drug therapy to treat ischemic congestive heart failure including the use of diuretics, angiotensin-converting enzyme inhibitors, and more recently ß-blockers. In similar patients on the waiting list for heart transplantation, 1-year survival was only 46% and an EF less than 25% was identified as an independent predictor of death [15].

The overall incidence of in-hospital mortality and of perioperative MI in our series was 4%. This incidence compares favorably with that of other studies in the literature, which report mortality rates ranging from 4.7% to 15% [3, 4, 6, 16, 17]. Hausmann and coworkers [16] in a series of 514 patients with EF ranging from 10% to 30% reported an overall operative mortality of 7.1%, which rose to 11.3% in patients with a history of more than two previous MIs. In a recent series of 141 patients with poor LV function Bouchart and colleagues [3] reported a similar in-hospital mortality of 7%.

Although not statistically significant the in-hospital mortality was slightly higher in the off-pump group of our series. However significantly more patients in this group presented with a history of congestive heart failure and of unstable angina requiring intravenous heparin or nitrates. Nevertheless the in-hospital mortality rate of our off-pump group compares favorably with those of other off-pump series reported in the literature. Tugtekin and associates [18] and Arom and associates [19] reported an in-hospital mortality of 6.5% and of 4.4% in a series of 31 and 45 patients respectively, in patients presenting with a baseline EF less than 30%. A mortality rate of 2.7% is reported by Moshkovitz and associates [20] in a series of 75 patients. However their definition of poor LV function was a baseline EF of 35% or less.

The only statistically significant difference between the two groups was the inotropic requirement, which was higher in the on-pump group. This outcome is an indirect confirmation of the efficacy of OPCAB surgery in minimizing intraoperative cardiac injury as demonstrated previously by our group [21] and others [2223].

There is very little in the literature on midterm clinical outcome of patients with severe LV dysfunction undergoing coronary surgery. The overall actuarial survival of our series was 90% (95% CI 85% to 93%) and 84% (95% CI 78% to 89%) at 1 and 3 years respectively. The late survival was not affected by the surgical technique with a 1- and 3-years survival of 92% versus 85% and 87% versus 73% in the on- and off-pump groups respectively. This remains encouraging in view of the high incidence of baseline congestive heart failure, an independent predictor of early and late mortality [24], which was particularly high in the off-pump group. This result compares favorably with other reports on conventional surgical revascularization [3, 16], on medical treatment alone, and on patients on the waiting list for transplantation [14, 15]. El Alderman and associates [2] reported the late survival of 420 medically treated and 231 surgically treated patients who had severe LV dysfunction manifested by an EF below 36%. The operative mortality of the surgical group was 6.9%. The 5-year survival was 43% with medical treatment versus 63% with surgery. There is little in the literature on midterm clinical outcome of patients presenting with poor LV function undergoing OPCAB surgery. Moshkovitz and associates [20] reported a 1- and 4-year survival of 96% and 73% respectively. However their definition of poor LV function was based on a less restricted definition (EF <35%) when compared with our series. Differences in clinical outcome might also be determined by the presence of comorbidities rather than LV dysfunction itself. However these were very common in our series.

There are several limitations to highlight in the present study. First is the lack of a randomized design. However the data collection was prospective in our series and none of the health care staff was aware during the period of the study that the comparison was going to be made. Furthermore as described above (see Methods), strict local guidelines are used to make decisions about perioperative patient care management and these guidelines were applied carefully throughout the period of the study and would have minimized the opportunity for bias.

Another limitation of the present study is that EF alone might be not considered a complete method of defining the overall LV function and that might lead to important baseline differences between series using this methodology. Simultaneous data on actual functional capacity of the LV including history of CHF and pharmacologic requirement might provide a more comprehensive evaluation.

Our study lacks data on the extent of viable myocardium. Pagley and associates [12] showed that the viability index was a significantly predictor of 3-year cardiac-related event-free survival after bypass surgery and that this was independent of age, EF, and number of diseased coronary vessels.

A further limitation is that although our series is one of the largest in the surgical literature the study sample remains small and hence the power to detect significant differences between the two groups is low.

In conclusion the results of our series show relatively low in-hospital mortality and morbidity rates associated with either on-pump or off-pump coronary artery surgery in patients with severe LV dysfunction. Midterm clinical outcome compares favorably with that reported in the literature and seems to justify surgical treatment for this high-risk group of patients.


    References
 Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

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