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Ann Thorac Surg 2009;87:1401-1407. doi:10.1016/j.athoracsur.2009.02.062
© 2009 The Society of Thoracic Surgeons
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Paolo Nardi
Antonio Pellegrino
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Original Articles: Adult Cardiac

Long-Term Outcome of Coronary Artery Bypass Grafting in Patients With Left Ventricular Dysfunction

Paolo Nardi, MD, PhDa,*, Antonio Pellegrino, MDa, Antonio Scafuri, MDa, Dionisio Colella, MDb, Carlo Bassano, MDa, Patrizio Polisca, MDa, Luigi Chiariello, MDa

a Department of Cardiac Surgery, Policlinico Tor Vergata, Tor Vergata University of Rome, Rome, Italy
b Department of Anesthesiology, Policlinico Tor Vergata, Tor Vergata University of Rome, Rome, Italy

Accepted for publication February 20, 2009.

* Address correspondence to Dr Nardi, Policlinico Tor Vergata, Tor Vergata University of Rome, Viale Oxford 81, Rome, 00133, Italy (Email: pa.nardi{at}hotmail.it).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
Background: Coronary artery bypass grafting (CABG) is a well-accepted therapeutic strategy for patients with multivessel coronary artery disease and left ventricular dysfunction. The aim of the study was to evaluate long-term results after CABG in patients with preoperative left ventricular ejection fraction (LVEF) of 0.35 or less.

Methods: Data from 302 consecutive patients (mean age, 62 ± 8.7 years) with LVEF of 0.35 or less who had undergone CABG were analyzed. Epinephrine and enoximone with or without norepinephrine were used to increase cardiac index. Intra-aortic balloon pump or left ventricular assist devices, or both, were used in case of postoperative low output syndrome.

Results: Complete revascularization was achieved in 298 of 302 patients (98.7%); internal thoracic artery was used in 294 (97.4%). Operative mortality was 5.3%; independent predictors of operative mortality were emergency CABG (p = 0.005), history of ventricular arrhythmias (p = 0.007), and previous anterior myocardial infarction (p = 0.05). At follow-up, all-cause mortality was 30.8%, and 10-year survival was 63% ± 4%; independent predictors of late all-cause mortality were history of ventricular arrhythmias (p < 0.0001), chronic renal dysfunction (p = 0.0004), and diabetes mellitus (p = 0.04). Cardiac death was 20.4%, and 10-year freedom from cardiac death was 73% ± 3.3%; independent predictors of cardiac death were history of ventricular arrhythmias (p = 0.004), chronic renal dysfunction (p = 0.03), and more than one previous anterior myocardial infarction (p = 0.004). At 80 ± 44 months of follow-up, echocardiography showed significant LVEF improvement (0.43 ± 0.09 versus 0.28 ± 0.06, p < 0.0001). Ten-year freedom from myocardial infarction was 87% ± 3%.

Conclusions: Excellent long-term results after CABG can be expected for patients with LVEF of 0.35 or less. Complete revascularization and internal thoracic artery grafting are associated with high freedom from myocardial infarction. Careful treatment of arrhythmias, diabetes, and renal dysfunction is necessary to improve long-term survival.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 References
 
Coronary artery bypass graft surgery (CABG) in patients with multivessel coronary artery disease and left ventricular dysfunction is associated with improved survival compared with medical treatment [1–4]. In these patients, CABG is reported to be associated with high perioperative mortality [2, 5]. Impaired left ventricular function could lead to perioperative low cardiac output syndrome and high postoperative mortality, and many patients may require inotropic or mechanical support for hours to days after surgery. Advances in surgical techniques, myocardial protection, and perioperative anesthesiology management have led to improved outcomes; therefore, a greater number of patients with advanced left ventricular dysfunction undergo CABG [6, 7]. Although surgical revascularization can be an effective therapy in the short term and midterm, little is known about the long-term follow-up. Late death of these patients may be caused by progression of heart failure, ventricular arrhythmias, and myocardial infarction, but also by other comorbidities such as diabetes mellitus or chronic renal dysfunction.

The aim of the present study was to evaluate operative outcomes and long-term results, as long as 10 years after CABG, of patients with preoperative severe left ventricular dysfunction expressed by a left ventricular ejection fraction of 0.35 or less. The impact of preoperative and surgical variables on long-term survival, freedom from cardiac death, myocardial infarction, and congestive heart failure was also analyzed.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
From January 1993 to December 2003, at the Cardiac Surgery Division of the Tor Vergata University of Rome, 302 consecutive patients (mean age 62 ± 8.7 years) with multivessel coronary artery disease and left ventricular ejection fraction (LVEF) of 0.35 or less underwent isolated CABG. This population of patients represented 6.6% of the isolated CABG procedures (n = 4,599) performed in the same time at our institution. The study was approved by our local Institutional Review Board, which waived the need for patient consent.

Left ventricular ejection fraction was measured preoperatively in all patients by echocardiography or cardiac catheterization, or both. Mean value of LVEF was 0.28 ± 0.06 (range, 0.10 to 0.35; median value 0.30). Surgical indication for CABG was presence of left main stem stenosis of 50% or greater, triple-vessel coronary artery disease, or double-vessel coronary artery disease with proximal left descending artery stenosis of 70% or greater. Hypokinetic or akinetic areas of myocardium with preserved thickness detected by transthoracic echocardiography were considered as ischemic viable myocardium. The presence of hibernating myocardium was estimated by dobutamine stress test or by thallium-201 rest-redistribution scintigraphy in 185 patients (61%).

Two hundred and twenty-eight of 302 patients (75%) presented with symptoms of angina associated with several grades of dyspnea; 74 patients (25%) had symptoms of dyspnea alone, and 17 of them were in New York Heart Association (NYHA) functional class IV (23%), 32 in class III (43%), and 25 in class II (34%). History of ventricular arrhythmias was present in 21 of 302 patients (7%). Two hundred and sixty-six of 302 patients (88%) had a previous myocardial infarction; 167 of 302 (55%) had a previous anterior myocardial infarction.

Diabetes mellitus was present in 80 patients (26%); chronic renal dysfunction, as defined when preoperative serum creatinine level was higher than 1.4 mg/dL, was present in 27 (9%); chronic obstructive pulmonary disease was present in 35 (11.6%). Emergency CABG, namely, ought to be performed before the beginning of the next working day after coronary angiography, was needed in 87 patients (29%).

Patients requiring coronary surgery reoperation or concomitant procedures (valvular or ablation surgery, left ventricular aneurysmectomy) were excluded from the study.

Surgical and Perioperative Management
The CABG was performed by means of cardiopulmonary bypass, with either intermittent antegrade cold blood cardioplegia (600 mL for the first dose, 400 mL for the others, administered every 20 to 25 minutes), moderate hypothermia (28°C), and topical cooling for 82 patients (27%), and tepid blood cardioplegia and mild hypothermia (34°C) for 220 patients (73%).

At weaning from cardiopulmonary bypass, epinephrine (0.02 to 0.1 {gamma} · kg-1 · min-1) and phosphodiesterase-III inhibitor enoximone (3 to 5 {gamma} · kg-1 · min-1) were used routinely to increase cardiac index perioperatively; infusion of norepinephrine (0.02 to 0.1 {gamma} · kg-1 · min-1) was added when mean arterial pressure was lower than 60 to 70 mm Hg. Intravenous infusion of enoximone, epinephrine, and norepinephrine was gradually reduced and then discontinued within the first 24 postoperative hours. Intra-aortic balloon pumping or left ventricular assist device, or both, was only used for patients who could not be weaned from cardiopulmonary bypass or for those who had postoperative low output syndrome despite the pharmacologic protocol.

Data Collection
Ventricular arrhythmias were defined as one or more episodes of nonsustained or sustained ventricular tachycardia. Complete revascularization was defined when each of three major vascular territories subtended by a significant coronary artery stenosis was grafted. Postoperative low output syndrome was defined by a cardiac index value equal to or less than 2.0 L · min-1 · m-2. Operative mortality included death in hospital after operation at anytime or within 30 days after discharge.

The status of every patient was ascertained during a 2-month period. Patients were followed for 80 ± 44 months (range, 53 to 192). Seven patients were lost, and follow-up was 98% complete. Clinical diagnosis of congestive heart failure was made if patients had orthopnea or bilateral basal crepitation on auscultation, bilateral edema of the legs, congested neck veins, and hepatomegaly.

All causes of death, data of echocardiography examinations, and need for hospital readmission for congestive heart failure or cardiac events, permanent pacemaker or automatic internal cardioverter defibrillator implantation, and functional status of the patients were recorded at the outpatient clinic visit or by telephone interview.

Statistical Analysis
Analysis was performed with Stat View 4.5 (Abacus Concepts, Berkeley, CA). Univariate analysis of preoperative and perioperative variables considered as potential risk factors for operative mortality and for postoperative low output syndrome was performed using the Student's t test for continuous data and the {chi}2 or Fisher's exact test for categorical data. Univariate variables with p value of or less than 0.2 were included in a multivariate logistic regression analysis. Twenty-five variables were selected for the univariate and multivariate analyses, as follows: age, sex, previous myocardial infarction, presence of one or more previous myocardial infarctions of the anterior myocardial wall, smoking habit, history of ventricular arrhythmias, comorbid disease (arterial hypertension, diabetes mellitus, chronic renal dysfunction, chronic obstructive pulmonary disease, hyperlipidemia), Canadian Cardiovascular Society (CCS) grade of angina, NYHA functional class, preoperative left ventricular ejection fraction severely depressed (LVEF of 0.20 or less), preoperative left ventricular end-systolic and end-diastolic diameters, systolic pulmonary artery pressure, left ventricular end-diastolic pressure, systolic contractile status (normal = 1, hypokinetic = 2, akinetic = 3) of the myocardial segments (anterior, lateral, posterior, inferior, septum wall), number of diseased coronary artery vessels, presence of a total occlusion of the left anterior descending artery, need for emergency CABG, number of grafts per patient, cardiopulmonary bypass time, and aortic cross-clamp time. Overall survival (not including operative mortality) and freedom from late cardiac death and congestive heart failure were expressed as mean values plus or minus 1 standard deviation, and computed by using the Kaplan-Meier method; the log-rank test was used to compare survival estimates among subgroups, and the Cox proportional hazards methods was used to evaluate the influence of variables on time to death. All other values were expressed as mean plus or minus 1 standard deviation of the mean.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
The mean number of grafts per patient was 3.4 ± 0.8; complete revascularization was achieved in 298 of 302 patients (98.7%). The internal thoracic artery was used in 294 patients (97.4%), and in 285 of them (97%), it was used as a graft for the left anterior descending artery.

Independent Predictors of Operative Mortality and Postoperative Low Output Syndrome
Operative mortality was 5.3% (16 of 302 patients). Baseline and operative characteristics of all patients and risk factors for mortality at the univariate analysis are reported in Tables 1 and 2. Causes of death were heart failure in 8 patients (50%), ventricular arrhythmias in 3 (18.7%), neurologic damage in 3 (18.7%), and acute pulmonary failure in 2 (12.5%). Independent predictors of in-hospital mortality were emergency CABG (odds ratio [OR] 4.9, p = 0.005), history of ventricular arrhythmias (OR 6.3, p = 0.007), previous anterior myocardial infarction (OR 2.4, p = 0.05; Table 3). Postoperatively, low output syndrome occurred in 4.3% of patients (13 of 302); independent predictors of low output syndrome were emergency CABG (OR 4.6, p = 0.05) and LVEF 0.20 or less (OR 11, p = 0.001).


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  		Table 1 Preoperative Characteristics
 

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  		Table 3 Multivariable Predictors of Operative Mortality
 
Independent Predictors of Long-Term and Event-Free Survival
At 5 and 10 years, survival was 80% ± 2.5% and 63% ± 4%, respectively (Fig 1); and freedom from cardiac death was 85% ± 2.2% and 73% ± 3.3% (Fig 2), respectively. Freedom from onset of and worsening of congestive heart failure was 92% ± 1.7% and 74% ± 4.2%, respectively. Eighty-six of 279 patients (30.8%) surviving at operation with completed follow-up (not including 7 patients lost) died. Causes of late death were cardiac events in 57 patients (66.3% [sudden death n = 13, acute myocardial infarction n = 17, congestive heart failure n = 27]), malignancy in 15 (17.4%), stroke in 6 (6.9%), renal failure in 4 (4.7%), pulmonary insufficiency in 2 (2.3%), and unknown in 2 (2.3%).


Figure 1
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  		Fig 1. Survival during follow-up of 80 ± 44 months after coronary artery bypass graft surgery in patients with left ventricular ejection fraction of 0.35 or less.

 

Figure 2
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  		Fig 2. Freedom from cardiac death during follow-up of 80 ± 44 months after coronary artery bypass graft surgery in patients with left ventricular ejection fraction of 0.35 or less.

 
On multivariate analysis, independent predictors of overall late mortality were preoperative history of ventricular arrhythmias (p < 0.0001), chronic renal dysfunction (p = 0.0004), diabetes mellitus (p = 0.04; Figs 3 to 5). Go Go Independent predictors of late cardiac mortality were preoperative history of ventricular arrhythmias (p = 0.004), more than one previous myocardial infarction of the anterior wall (p = 0.004), and chronic renal dysfunction (p = 0.03).


Figure 3
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  		Fig 3. Survival after coronary artery bypass graft surgery in patients with (n = 16) and without (n = 270) preoperative history of ventricular arrhythmias (log-rank test).

 

Figure 4
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  		Fig 4. Survival after coronary artery bypass graft surgery in patients with (n = 21) and without (n = 265) chronic renal dysfunction (log-rank test).

 

Figure 5
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  		Fig 5. Survival after coronary artery bypass graft surgery in patients with (n = 76) and without (n = 210) diabetes mellitus (log-rank test).

 
Although diabetes mellitus was significantly associated with a higher all-causes late mortality, it was not recognized as a predictor of late cardiac-related death (p = 0.08).

Thirty-seven patients, 27 of whom died, were affected by congestive heart failure. The only predictor of onset or worsening of congestive heart failure was the presence of more than one myocardial infarction of the anterior wall (p = 0.02).

Of note, LVEF 0.20 or less was not an independent predictor either of late mortality, or of cardiac death, or of worsening of congestive heart failure status. Freedom from cardiac death at 5 and 10 years in patients with LVEF 0.20 or less was similar to that of patients with LVEF higher than 0.20 (79% ± 6.2% and 73% ± 7.2% versus 86% ± 2.3% and 73% ± 4%, respectively; p = 0.4; Fig 6).


Figure 6
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  		Fig 6. Freedom from cardiac death after coronary artery bypass graft surgery in patients with (n = 47) and without (n = 239) left ventricular ejection fraction of 0.20 or less (log-rank test). (NS = not significant.)

 
Functional and Clinical Status of the Patients
At 80 ± 44 months of follow-up, echocardiography showed significant improvement of LVEF: 0.43 ± 0.09 versus 0.35 ± 0.09 immediately after CABG (p < 0.0001) and 0.28 ± 0.06 preoperatively (p < 0.0001); CCS anginal class improved from 2.7 ± 1.1 preoperatively to 1.1 ± 0.4 (p < 0.0001), and NYHA functional class improved from 1.9 ± 1.1 preoperatively to 1.7 ± 0.9, although with a minor statistical relevance (p = 0.03). Five- and 10-year freedom from myocardial infarction was 96% ± 2% and 87% ± 3%, respectively. Permanent pacemaker or automatic internal cardioverter defibrillator implantation was recorded in 16 patients.


   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
Twenty-five years ago, two major studies, the Coronary Artery Surgery Study and the Veterans Administration Study, comparing CABG to medical therapy had demonstrated improved survival with CABG for patients with mild to more severe degrees of left ventricular systolic dysfunction [1, 2, 4]. Although for this patient population, CABG remains an optimal therapeutic approach, it is associated with a higher operative risk as compared with that for patients with normal LVEF [6, 8]. Older publications reported a high operative mortality for patients with impaired left ventricular function [2, 5, 8, 9], whereas more recent studies show only a modest increase of risk as compared with patients who have normal or near-normal left ventricular systolic function [7, 10-13]. Although several contemporary studies addressed primarily predictors of operative (in-hospital and 30-day) mortality and medium-term outcome, the predictors of long-term outcome as well as the symptomatic benefits of CABG during a long period of follow-up are poorly investigated. The main findings of our study were that the in-hospital mortality rate was 5.3% and the late mortality rate was 31% (15-year follow-up, 98% complete). The LVEF evaluated as continuous mean value or as discrete variable (LVEF 0.20 or less, and more than 0.20 to 0.35 or less) was not an independent risk factor either of operative mortality or of late survival or event-free survival. The most powerful predictors of reduced survival were preoperative history of ventricular arrhythmias and comorbidities such as diabetes mellitus and chronic renal dysfunction. More than one previous anterior myocardial infarction also predicted a higher late cardiac mortality rate [11].

In-Hospital Results
The 5.3% operative mortality reported in our study was similar to the mortality rate reported in more recent studies [7, 10-14]. The perioperative pharmacologic treatment with enoximone and epinephrine, inducing an increase of cardiac index [15, 16], may have been effective as the perioperative use of intra-aortic balloon pump in reducing the incidence of postoperative low output syndrome, thus lowering the surgical risk. In fact, the low incidence of low output syndrome (4.3%) compared favorably with that observed among high-risk patients, for whom the operative mortality rate with the use of preoperative intra-aortic balloon pump was 5.7% to 13% [17-19].

Although severely depressed LVEF has been identified as an independent risk factor for early mortality [2, 8, 11], in our study, LVEF of 0.35 or less was not shown by multivariate analysis to be an independent risk factor (p = 0.315). Our findings are in accordance with those of recent studies suggesting that severely depressed left ventricular function per se was not a predictor of mortality. Davierwala and colleagues [20], analyzing the impact of low LVEF in patients undergoing CABG during three periods, from 1990 to 2001, showed that the impact of low LVEF on early mortality declined across the study, so that low LVEF was no longer an independent predictor in the last period of their study. These data support the hypothesis that the evolution of operative and perioperative management has significantly improved outcomes for these high-risk patients.

Nevertheless, in our experience, patients with severe left ventricular dysfunction requiring emergency CABG, or patients with preoperative anterior myocardial infarction or ventricular arrhythmias related to a more severe degree of left ventricular remodeling of the ischemic cardiomyopathy (namely, major extension of scarring, progressive dilatation, larger akinetic areas) still present a high risk of operative mortality. These patients may benefit from more aggressive management with the preoperative insertion of an intra-aortic balloon pump.

Ten-Year Follow-Up Results
Late survival and cardiac event-free survival after CABG among patients with LVEF of 0.35 or less in most studies are estimated at a midterm follow-up. Three-year survival reported by previous studies ranges from 80% to 83% [6, 10, 21, 22], 5-year survival from 63% to 77.7% [2, 6, 11, 12, 21, 23, 24], and 7-year survival from 63% to 72% [3, 6]. Late survival of 80% at 5 years of follow-up in our study compared favorably with these previous studies; moreover, we have observed at a follow-up of more than 10 years that CABG in patients with LVEF 0.35 or less provided excellent results, offering a high probability of survival (greater than 60%) and high freedom from cardiac death (greater than 75%) and congestive heart failure (greater than 70%).

Of note, LVEF evaluated as a continuous mean value or as a discrete variable (0.20 or less, and more than 0.20 to 0.35 or less) was not an independent risk factor, either of late mortality for all causes or of late cardiac death (Fig 6). On the contrary, comorbidities such as diabetes mellitus and chronic renal dysfunction were two powerful predictors of reduced survival, and chronic renal dysfunction was also a predictor of late cardiac death. Chronic renal dysfunction is a well-recognized risk factor for death after CABG [22, 25]. Dries and colleagues [26], analyzing the data of the Studies of Left Ventricular Dysfunction Trial, found that the adequacy of renal function represents a primary determinant of compensation in patients with heart failure and of reduction of all-cause mortality. Hillis and colleagues [22], in a cohort of 379 patients with LVEF 0.35 or less who underwent CABG during a 4-year period, found renal dysfunction with serum creatinine level of 1.5 mg/dL or greater as the strongest independent predictor of mortality during a midterm follow-up.

Diabetes mellitus was independently associated with increased mortality among patients with ischemic cardiomyopathy, as reported by Domanski and colleagues [27], because of the close relationship between diabetes and acceleration of myocardial dysfunction in patients with ischemic heart failure. Of a total of 5,259 patients undergoing CABG in the United Kingdom, Rajakaruna and colleagues [28] identified diabetes mellitus as an independent predictor of 5-year mortality and of lower 5-year cardiac-related event-free survival. Further work should be required to assess which measures are to be used to preserve renal function and to control better blood glucose level after performing CABG in this population of patients, considering that in our study, survival was importantly affected by these variables (Figs 4 and 5).

In our experience, preoperative ventricular arrhythmias, as reported by other investigators [5, 23], were an important predictive factor of operative and late mortality. In particular 13 (23%) of 57 cardiac deaths were caused by sudden death (probably due to this risk factor), and 10-year survival and freedom from cardiac death for patients with a history of ventricular arrhythmias was 42% ± 13% and 55% ± 14%, respectively, compared with 74% ± 3% and 74% ± 3.6% for patients without this risk factor. Holmes and the CASS investigators [29] showed that CABG surgery compared with medical therapy had a greater beneficial effect at 5 years in reducing sudden death among patients with three-vessel disease and history of congestive heart failure. However, recent evidence given by the Multicenter Automatic Defibrillator Implantation Trial II indicates that patients with previous myocardial infarction and LVEF less than 0.30 show a better survival at 20 months when an automatic internal cardioverter defibrillator is implanted [30]. Adjunctive implantation of the automatic defibrillator in association with or immediately after CABG may lead to further improvement in long-term survival for this group of patients.

We observed during a long-term follow-up period, high values of survival rate, cardiac event-free survival, and freedom from myocardial infarction. Left ventricular ejection fraction and functional CCS and NYHA status at follow-up were significantly improved in most of patients as compared with preoperative data. The significant improvement of CCS class at follow-up and high values of freedom from myocardial infarction at 5 and 10 years (96% and 87%, respectively), are likely to be related to a revascularization technique, aimed at being as complete as possible, using the internal thoracic artery to the left anterior descending artery in most patients, as routinely performed at our center. The high rate of freedom from myocardial infarction may explain, at least in part, a 10-year low rate of cardiac death.

In conclusion, excellent results after CABG can be expected for patients with LVEF of 0.35 or less, with acceptable operative mortality and good long-term results. All patients with graftable coronary artery disease and poor left ventricular function may greatly benefit from surgery. Using contemporary perioperative surgical and anesthesiology techniques, LVEF of 0.35 or less should not be considered an independent risk factor. Renal disease, diabetes mellitus, and ventricular arrhythmias are strong predictors of worse outcomes. Careful postoperative treatment of these subsets of patients may be essential to improve their long-term outcome.


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  		Table 2 Echocardiographic, Angiographic, and Operative Characteristics
 

   References
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 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 
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