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Original Articles: Adult Cardiac

Survival After Isolated Coronary Artery Bypass Grafting in Patients With Severe Left Ventricular Dysfunction

Cardiac and Thoracic Surgical Unit, Department of Medicine, Flinders Medical Centre and Flinders University, Adelaide, South Australia, Australia

Accepted for publication December 26, 2008.

^_* Address correspondence to Asst Prof Baker, Cardiac and Thoracic Surgical Unit, Level 6, Flinders Private Hospital, Bedford Park, Adelaide, South Australia, 5042, Australia (Email: rob.baker{at}health.sa.gov.au).

	Abstract

Top Abstract Introduction Patients and Methods Results Comment References

 
Background: The number of patients with severe left ventricular dysfunction referred for coronary artery bypass graft surgery (CABG) continues to increase. The aim of this study was to document the long-term survival in this group.

Methods: The 30-day mortality and long-term survival outcome of 162 patients with severely depressed left ventricular ejection fraction (LVEF [30%]) who had consecutive isolated CABG between 1996 and 2005 were compared with 661 patients who had impaired LVEF (31% to 59%) and 1,231 patients with normal LVEF (60%).

Results: The 30-day mortality for patients with severely depressed LVEF was 5.6%. The median survival for deceased patients was 3.4 years (interquartile range, 1.3 to 5.9). The risk of all-cause mortality attributable to severe left ventricular dysfunction was increased twofold compared with having normal LVEF (hazard ratio = 2.28; 95% confidence interval: 1.64 to 3.18; p < 0.001). Among the covariates, older age, emergency surgery, mitral incompetence, smoking history, respiratory disease, diabetes mellitus, cerebrovascular disease, intensive care unit intubation for 24 hours or more, postoperative renal failure, postoperative pleural effusion, and nonuse of left internal mammary artery were detected as significant predictors of increased mortality risk.

Conclusions: The mortality rate among CABG patients with severely depressed LVEF was comparable to that reported in other series. Severe left ventricular dysfunction carried more than a twofold increased mortality risk compared with patients who had an impaired LVEF, adjusted for traditional risk factors. These data suggest that LVEF has an impact on long-term patient survival even after preoperative covariates and postoperative morbidity outcomes are considered.

	Introduction

Top Abstract Introduction Patients and Methods Results Comment References

 
Heart failure (HF) is a worldwide public health problem, as highlighted by the American Heart Association Statistic Committee report in 2006 that revealed more than 5 million people have HF in the United States [1]. More than 1 million patients are hospitalized, and more than 50,000 patients die each year with HF as a primary diagnosis [1]. Coronary artery disease (CAD) is the most common cause of HF and is responsible for between 60% and 68% of HF etiology [2]. In ischemic coronary artery disease (CAD) without valvular lesion, HF is commonly caused by left ventricular systolic dysfunction.

Aggressive medical treatment of patients with severe left ventricular dysfunction (LVD) is unsatisfactory in terms of controlling symptoms and long-term survival, as reported in the Assessment of Treatment with Lisinopril and Survival (ATLAS) trial [3]. The ATLAS investigators reported that there were 717 cardiovascular deaths among 1,596 patients treated with low-dose lisinopril and 666 cardiovascular deaths from among 1,568 patients treated with high-dose lisinopril in patients with mild, moderate or severe HF at a median follow-up of 46 months. Favorable results with CABG in comparison with medical treatment alone make CABG a more attractive clinical option [4, 5]. However, high hospital mortality and morbidity makes CABG a surgical challenge among patients with severe LVD [6]. Previous reports have shown favorable short-term survival among severe LVD patients [7], although the long-term survival outcomes of patients with severe LVD undergoing CABG are not well defined in recent series with modern surgical techniques. In the present study, we compare the short- and long-term survival of patients with severe LVD, as ascertained by left ventricular ejection fraction (LVEF), with that of patients who have impaired and normal LVEF.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Comment References

 
Patients
All patients having isolated CABG with cardiopulmonary bypass (CPB) performed at the Flinders Medical Centre from January 1, 1996, to December 31, 2005, were considered eligible for the study. Patients undergoing concomitant procedures for mitral incompetence or aortic aneurysms were not considered eligible for this study. All data were collected prospectively at the time of operation by resident medical officers and entered into an electronic database. Identification of LVEF was based on either the preoperative echocardiography or cineangiography assessment performed by an independent cardiologist. Patient LVEF was stratified accordingly: severely impaired 30% or less, impaired 31% to 59%, and normal 60% or more.

Anesthetic, Surgical, and Cardiopulmonary Bypass Techniques
Anesthetic technique was standardized for all patients. For induction, midazolam, pancuronium, and fentanyl were used, and maintenance was with isofluorane or sevoflurane, and nitrous oxide or propofol, or both, as required. Before aortic cannulation, heparin was given at a dose of 300 IU/kg to achieve a target activated clotting time of 400 s or longer before commencement of CPB. On completion of all anastomoses and weaning of CPB, protamine was given to return the activating clotting time to preoperative levels.

After median sternotomy, and harvesting of arterial or venous conduit, CPB was instituted using an ascending aortic and either a two-stage right atrial or bicaval cannulation. Cardiopulmonary bypass was performed utilizing roller pumps; the circuit included a hard shell membrane oxygenator, PVC or biopassive tubing (SMARxT; Cobe Cardiovascular, Arvada, CO) and a 40 µm arterial line filter. Routine CPB protocol included nonpulsatile arterial flow rate of 1.8 to 2.4 lpm/m², alpha-stat pH management, gravity venous drainage, and tepid systemic temperature management (30° to 36°C). Myocardial protection was achieved by using intermittent antegrade hyperkalemic tepid blood cardioplegia (30° to 36°C). The initial or induction dose was given for 2 minutes (250 mL/min), then the maintenance dose was given approximately every 20 minutes as required through the grafting procedure. Attempts were made at all procedures to revascularize all vessels deemed operable by the respective surgeons. The heart was arrested, and the target coronary artery was opened; and distal anastomoses between the bypass graft and native coronary artery were performed using 7-0 or 6-0 polypropylene under aortic cross clamping. Proximal anastomoses were performed on beating heart and partial aortic clamping using 6-0 polypropylene. Gradual weaning from bypass started after completion of the proximal anastomoses. At the end of surgery, patients were transferred to the intensive care unit (ICU) and managed according to unit protocol.

Mortality Assessment
The study aim was to assess the 30-day mortality and long-term survival in severe LVD and compare them with the normal and impaired LVEF groups. Survival was ascertained by patient identification within the National Death Index provided to our institution by the Australian Institute of Health and Welfare for use in epidemiologic studies and medical research. National Death Index data provided all-cause mortality until December 31, 2006, and this date was taken as the censor date for patient survival. Eligible patients were operated on or before December 31, 2005, thus enabling a minimum 12-month follow-up on the cohort. Approval was granted by the Clinical Governance Committee of the Flinders Medical Centre to report these findings, waiving the need for patient consent for this study.

Statistical Analysis
Statistical analyses were performed using SPSS version 15.0 (SPSS, Chicago, IL) to compare the LVEF groups on demographic and surgical variables. Continuous data were analyzed with one-way analysis of variance. Categorical data were analyzed using the ² statistic with Fisher's exact test where appropriate.

The primary endpoint of all-cause long-term mortality was analyzed using multivariable Cox proportional hazard modeling. Covariate selection was determined a priori from previous survival research [8, 9, 10]. Covariates adjusted for in multivariable analysis included the categorical variables of female sex, age (quartiles), angina (Canadian Cardiovascular Society [CCS] classification system) class II to IV versus I or none, diabetes mellitus, hypercholesterolemia, hypertension, renal disease, peripheral vascular disease, mitral incompetence, acute myocardial infarction 30 days or less, presence of cerebrovascular disease, tobacco-smoking history, respiratory disease, urgency of surgery (elective as the reference category versus urgent and emergency), use of left internal mammary artery (LIMA), ICU intra-aortic balloon pump (IABP), postoperative pleural effusion, postoperative renal failure, or ICU intubation for 24 hours or longer. Continuous variables adjusted for in multivariable analysis included the total cross-clamping time and the total number of anastomoses. All covariates described above were forced into the final adjusted hazard model in block fashion regardless of significance. The LVEF grouping variable was entered at the second step of the hazard model, with normal set as the reference category. During data screening, there were no outliers that influenced hazard models, and multicollinearity statistics were acceptable as determined by squared multiple correlations less than 0.90 and inspection of correlations between regression coefficients. The proportionality of hazards assumption was checked initially by entering covariates as interactions with time, and also ascertained graphically in final models by examination of the baseline hazards function plot and also the log-minus-log plot of survival function.

The 30-day mortality and 12-month mortality endpoints were analyzed utilizing logistic regression employing the normal LVEF group as the reference category. The 30-day mortality analysis was performed without adjustment as there were too few endpoints to include covariates without impacting on the model's validity. The number of endpoints at 12 months was also low and, therefore, to reduce overfitting of our model, each a priori selected covariate described above was subjected to univariable logistic regression and those variables with p value less than 0.05 from the Wald statistic were included in the multivariable model for 12-month mortality. The number of potential covariates and 12-month survival endpoints was not sufficient to accommodate a less stringent p value criterion for inclusion into the multivariable logistic regression models without overfitting.

	Results

Top Abstract Introduction Patients and Methods Results Comment References

 
Demographic Data and Preoperative Characteristics
From among 2,255 patients who underwent isolated CABG from 1996 to 2005, 2,054 patients were included in this study. The 201 patients not analyzed in this study were missing either documented LVEF or more than 10 clinical variables. There were 1,231 patients (59.9%) who had a normal LVEF, 661 (32.2%) who had an impaired LVEF, and 162 (7.9%) who had severely impaired LVEF.

There were significant differences in preoperative comorbidity between the LVEF groups, and these descriptive comparisons are shown in Table 1. Specifically, in comparison with patients who had an impaired or normal LVEF, patients who had a severely depressed LVEF were older, had emergency or urgent surgery, presented with statistically significant differences in CCS class IV angina, congestive heart failure symptoms, mitral incompetence, peripheral vascular disease, and diabetes mellitus (all p < 0.01). Patients with severe LVD received significantly fewer LIMA grafts, required more cardiac support with IABP, had a greater proportion of hemodynamic instability, and were more likely to have ICU intubation time longer than 24 hours and longer length of hospital stay (all p < 0.01). The impaired LVEF groups had a greater proportion of acute myocardial infarction less than 30 days and generally received more anastomoses compared with the normal LVEF group.

Twelve-month survival was 98%, 97%, and 88% for the normal, impaired, and severe LVEF groups, respectively. In logistic regression analysis for 12-month mortality, the covariates retained in the final adjusted model were ICU intubation long than 24 hours, urgency of surgery, nonuse of LIMA, postoperative pleural effusion, acute myocardial infarction less than 30 days, and use of IABP; results are shown in Table 2. After adjustment for the effects of these covariates, severe LVD was not associated with an increased odds for 12-month mortality (OR 2.25, 95% CI: 0.90 to 5.63; p = 0.40), as was the case for having a moderately impaired LVEF (OR 0.92, 95% CI: 0.39 to 2.16; p = 0.85). Among the covariates, use of IABP was associated with more than fourfold increased odds for 12-month mortality, and a twofold odds was attributable to the nonuse of LIMA, as shown in Table 2.

View larger version (13K): [in this window] [in a new window]   Fig 1. Kaplan-Meier actuarial survival curves for all-cause mortality in left ventricular ejection fraction (LVEF) groups comparing normal LVEF of 61% or greater (dashed line), impaired LVEF from 31% to 59% (solid line), and severe LVEF of 30% or less (broken line).

	Comment

Top Abstract Introduction Patients and Methods Results Comment References

 
In this observational study, the main findings were that severe LVD was associated with a significantly increased risk of all-cause mortality at 30 days and in the long term, with the latter analysis adjusted for covariates. The prevalence of severe LVD in this study was 7.9%, in keeping with the quoted rates in the literature including a large registry of more than 100,000 patients undergoing CABG in the United Kingdom that reported a consistent rate of 6% to 7% over a 6-year period [11]. This is in contrast to higher rates of severe LVD (14.8% and 18%) reported elsewhere [6, 22], which may in part be explained by different definitions of severe LVD that range from LVEF less than 35%, 30% or 20% [6, 9, 24, 26].

There are few reports in the literature regarding the clinical importance of severe LVD on long-term survival among patients undergoing isolated CABG, and there is indeed a dearth of studies comparing these patients to others who have an impaired or normal LVEF. In this study, the actuarial survival for severe LVD was 88%, 69%, and 48% at 1, 5, and 10 years, respectively. Patients with severe LVD undergoing isolated CABG had a significantly poorer long-term survival when compared with patients who had normal left ventricular function. This finding was comparable to other recent CABG studies, as Appoo and coworkers [24] reported 84.7% and 77% survival at 3 and 5 years, respectively, in a series of 430 patients with severe LVD undergoing CABG. Also, Lee and coworkers [18] reported survival of 87.7%, 80.9%, and 44.4% for 1, 5, and 10 years, respectively, among 120 CABG patients with severe LVD. The report of Bouchart and coworkers [19] showed that survival was 84%, 70%, and 50% at 2, 5, and 7 years, respectively, in 141 CABG patients with LVEF less than 0.30%. The survival comparison of severe LVD patients treated with CABG relative to those treated medically is favorable. For example, in the ATLAS trial [12] that compared high- and low-dose lisinopril for 3,164 patients with ischemic cardiomyopathy, overall mortality was 43.7% at 41.2 months' mean follow-up. Also, a randomized trial of spirolactone for 1,663 patients with ejection fraction less than 35% reported a 35% mortality rate at 24 months compared with a 46% mortality rate for the placebo group [13]. Together, these findings suggest that although the prognosis after CABG among patients who have severe LVD is generally poor (compared with patients who have normal LVEF), undergoing CABG for these patients is associated with better survival than that reported for medically managed patients [12, 13]. This finding underlines the point that severe LVD alone should not be used as a criterion to exclude this group from CABG surgery in anticipation of poor surgical prognosis, as suggested 3 decades ago [17].

Few studies have reported the independent predictors of long-term survival among severe LVD CABG patients. In this series, older age, emergency surgery, mitral incompetence, smoking, respiratory disease, diabetes, cerebrovascular disease, postoperative renal failure, pleural effusion, revascularization without use of LIMA, and prolonged intubation were identified as independent risk factors for an increased mortality risk. Among previous LVEF studies, Shapira and coworkers [20] identified female sex, renal failure, postoperative respiratory complications, and presence of grade I/II mitral regurgitation as independent predictors of midterm mortality. Hillis and coworkers [25] from the Mayo Clinic also identified age and renal dysfunction as independent predictors of long-term mortality. Filsoufi and coworkers [22] reported reoperation, peripheral vascular disease, female sex, and congestive symptoms as independent predictors of long-term survival in a group of patients with LVEF less than 30%.

The 30-day mortality rate for patients with severe LVD was 5.6%. Despite a significantly increased risk of mortality attributable to severe LVD in this study, the results compare favorably with other reports of isolated medical treatment in this group. Although the 30-day mortality rate was higher for the severe LVD group compared with the group who had normal LVEF undergoing CABG (5.6% versus 1.1%), this is consistent with recent reports of mortality rates ranging from 4% to 15% [9, 14, 15, 18–20]. These results could be considered a marked improvement from earlier reports indicating a prohibitive operative mortality in the range of 15% to 20% [16, 17].

With regard to short-term mortality, severe LVD was a significant independent predictor in early unadjusted mortality, and this finding is consistent with the results reported by Bouchart and coworkers [19], and Wang and associates [21]. However, the lack of association between severe LVD and 12-month mortality contrasts the findings of Filsoufi and coworkers [22]. A potential methodologic explanation for these discrepancies may be that the present 12-month results are adjusted for covariates in on-pump CABG, whereas Filsoufi and coworkers [22] reported unadjusted 12-month results among both off-pump and on-pump CABG patients according to severity of LVD. Our study further identified important covariates that predicted early mortality for patients undergoing CABG, including the nonuse of LIMA and IABP support, which were associated with more than twofold odds for early mortality. The data reported by Filsouf and coworkers [22], and Topkara and associates [6] also identified depressed LVEF function and IABP support as independent predictors of mortality. Furthermore, Topkara and coworkers [6], and Islamoglu and coworkers [23] identified additional risk factors for early mortality such as older age, female sex, hepatic failure, renal failure, emergency surgery, and cross-clamp time longer than 60 minutes. However, in the present study, these risk factors were not significantly associated with 12-month mortality, and it is possible that the sample size was not large enough to identify some of these factors, given their low prevalence within the sample.

This study was a retrospective and observational study and therefore, the conclusions drawn should be considered according to these constraints. This report has focused on postoperative mortality, morbidity, and long-term survival, and has not assessed whether improvement in postoperative left ventricular function influenced mortality. Furthermore, no attempt was made to delineate the role of LVD in cardiac deaths or other clinically relevant endpoints such as quality of life. The findings of this study are unique in terms of identification of predictors of early and late survival in patients with severe LVD compared with patients who had normal LVEF function.

The mortality rate among CABG patients with severely depressed LVEF was comparable to that reported in previous series. Severe left ventricular dysfunction carried more than a twofold increased mortality risk compared with patients who had impaired LVEF, adjusted for traditional risk factors. These data suggest that LVEF has an impact on long-term patient survival even after preoperative covariates and postoperative morbidity outcomes are considered.

	References

Top Abstract Introduction Patients and Methods Results Comment References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Robert A. Baker John L. Knight Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ahmed, W. A. Articles by Knight, J. L. Search for Related Content PubMed PubMed Citation Articles by Ahmed, W. A. Articles by Knight, J. L. Related Collections Coronary disease