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Original Articles: Adult Cardiac

Aortic Valve Replacement for Aortic Stenosis in Patients With Left Ventricular Dysfunction

^a Clinical Research Unit, Division of Cardiothoracic Surgery, Emory University School of Medicine, Atlanta, Georgia
^b Department of Biostatistics, Rollins School of Public Health, Emory University School of Medicine, Atlanta, Georgia

Accepted for publication May 27, 2009.

^_* Address correspondence to Dr Halkos, Division of Cardiothoracic Surgery, Emory University School of Medicine, 550 Peachtree St NE, Emory University Hospital-Midtown, 6th Floor, Medical Office Tower, Atlanta, GA 30308 (Email: mhalkos{at}emory.edu).

Presented at the Poster Session of the Forty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Francisco, CA, Jan 26–28, 2009.

Dr Thourani discloses that he has a financial relationship with Edwards Lifesciences, Medtronic, and St. Jude.

 

	Abstract

Top Abstract Introduction Material and Methods Results Comment References

 
Background: The purpose of this study was to assess the impact of left ventricular dysfunction and other risk factors on short- and mid-term outcomes after aortic valve replacement for aortic stenosis.

Methods: From January 1, 2002, to December 31, 2007, 773 consecutive patients underwent primary aortic valve replacement for aortic stenosis at a single institution; concomitant coronary artery bypass graft surgery (CABG) was performed in 45.4% (351 of 773). Multivariable regression analysis was used to identify predictors of in-hospital mortality, with ejection fraction (EF) as the primary variable of interest. After discharge, survival status was determined using the Social Security Death Index. A Cox proportional hazards regression model was used to identify predictors of mid-term mortality.

Results: On univariable analysis, EF (odds ratio [OR] 0.979, 95% confidence interval [CI]: 0.960 to 0.999, p = 0.044) but not concomitant CABG emerged as a predictor of in-hospital mortality. However, on multivariable analysis, neither EF nor concomitant CABG was associated with increased in-hospital mortality. Multivariable predictors of in-hospital mortality included age, emergent status, and prolonged bypass time. On univariable analysis, mid-term mortality was associated with EF and concomitant CABG (OR 0.979, 95% CI: 0.966 to 0.991, p = 0.001, and OR 1.61, 95% CI: 1.11 to 2.36, p = 0.013, respectively). However, after multivariable adjustment, only EF was associated with mid-term mortality (adjusted OR 0.985, 95% CI: 0.970 to 1.00, p = 0.049). Other multivariable predictors of mid-term mortality included age, dialysis-dependent renal failure, previous stroke, and peripheral vascular disease.

Conclusions: Left ventricular dysfunction, in addition to other patient comorbidities, may negatively impact survival after aortic valve replacement. Careful consideration of the cumulative effect of these multiple risk factors is necessary to optimize patient outcomes.

Aortic valve replacement (AVR) remains the only effective treatment for patients with severe aortic stenosis. Once symptoms of congestive heart failure develop, mean survival is less than 2 years with medical treatment [1]. Compared with patients with normal left ventricular (LV) function, short- and long-term outcomes are worse in the presence of LV dysfunction [2–4]. Importantly, long-term survival in patients with depressed LV function, including those with low transvalvular gradients, is improved with AVR [5–8].

Recent studies investigating outcomes in patients with low-gradient aortic stenosis [6–8] have documented improved hospital survival over the last decade [6]. However, a recent report revealed that although low ejection fraction (EF) occurs in 26% of patients with severe aortic stenosis, fewer than one-third of such patients are ever referred for surgical intervention [8]. Patients presenting with LV dysfunction commonly have contractile reserve and can expect to have some degree of functional recovery after AVR [9]. Furthermore, comorbidities such as advanced age, coronary disease, and hypertension frequently coexist with aortic stenosis and may obscure the etiology of LV dysfunction. In the presence of these comorbidities, the impact of moderate LV dysfunction on short- and mid-term outcomes is not well defined in the current era of surgical therapy.

Therefore, the purpose of this investigation was to examine the impact of LV dysfunction on in-hospital as well as mid-term outcomes. Other patient variables and comorbidities were included in the analysis to represent common presentations in clinical practice and to provide insight into risk stratification of these sometimes highly complex patients.

	Material and Methods

Top Abstract Introduction Material and Methods Results Comment References

 
In this retrospective cohort study, the Society of Thoracic Surgeons (STS) Adult Cardiac Database was queried for all consecutive patients undergoing primary AVR between January 1, 2002, to December 31, 2007, within the Emory Healthcare hospitals. The study was approved by the Institutional Review Board of Emory University in compliance with the Health Insurance Portability and Accountability Act (HIPAA) regulations and the Declaration of Helsinki. The Institutional Review Board waived the need for individual patient consent.

Demographic and Preoperative Data
Patients were excluded from this study if they required concomitant mitral valve, tricuspid valve, aortic surgery, or redosternotomy, or if the main indication for AVR was aortic insufficiency. Within the study period, 791 patients underwent primary AVR for aortic stenosis. For 18 patients (2.3%), EF was either missing or not determined; these patients were excluded from further analysis. All data for consecutive patients were prospectively entered into a computerized cardiac surgical database and retrospectively reviewed. Before analysis, preoperative and intraoperative variables, including EF, were identified and harvested utilizing the data fields and definitions of the STS National Adult Cardiac Database (available at: www.sts.org/documents/pdf/AdultCVDataSpecifications2.61.pdf). Preoperative characteristics are listed in Table 1. Cardiac catheterization was performed in all patients over the age of 40 years or in younger patients with risk factors for coronary artery disease. Operative characteristics are summarized in Table 2. Preoperatively, EF was determined using echocardiography in 368 patients (47.6%), angiography in 354 patients (45.8%), or with another method in 51 patients (6.6%). Left ventricular ejection fraction was determined by visual estimation. This method of assessing EF has been employed and validated in several studies [5, 10].

Surgical Technique
Surgical intervention was left to the discretion of the referring cardiologist and cardiac surgeon. Conventional cardiopulmonary bypass was performed utilizing roller head pumps, membrane oxygenators, cardiotomy suction, arterial filters, cold antegrade and retrograde blood cardioplegia, and moderate systemic hypothermia (32° to 34°C). Induction was achieved with 1 L cold antegrade blood cardioplegia followed by continuous retrograde cardioplegia. Intermittent doses of antegrade cardioplegia were delivered selectively according to surgeon discretion. When proximal anastomoses were required, they were constructed before removal of the aortic clamp.

Outcomes
The primary outcomes of interest were in-hospital and mid-term mortality. Survival data after hospital discharge was obtained using the Social Security Death Index, which is a public use national database of death records extracted from the United States Social Security Administration's Death Master File Extract. The sensitivity of the Social Security Death Index (92.2%) is comparable to that of the National Death Index among American-born persons (87% to 98%) [11]. For each patient that died before the cutoff date of March 30, 2007, a mortality date was provided, allowing construction of Kaplan-Meier curves and product-limit estimates of survival time to estimate mid-term survival. The cause of death was not readily available; thus, mid-term mortality in this context was all-cause mortality.

Statistical Methods
The effects of LV dysfunction, assessed by EF as a continuous variable, as well as other comorbidites, were analyzed using univariable and multivariable statistical methods. The effect of EF on in-hospital mortality was evaluated using a multiple logistic regression model adjusting for age, perfusion time, cross-clamp time, and presence of any of the following: renal failure, renal failure requiring dialysis, New York Heart Association functional class III-IV heart failure, previous myocardial infarction, emergent status, chronic lung disease, previous stroke, diabetes mellitus, hypertension, peripheral vascular disease, valve implant size of 19 mm or 21 mm, concomitant coronary artery bypass, and implantation of a mechanical prosthesis. The impact of each of these covariates on mortality was also assessed. The adjusted hazard ratio (HR) associated for each unit increase in EF was computed along with a 95% confidence interval. The adjusted odds ratios (AOR) for other variables were calculated along with 95% confidence intervals (CI).

The effect of EF on mid-term survival was evaluated using a Cox proportional hazards model adjusting for the same variables used for the in-hospital mortality analysis. The adjusted HR associated for each unit increase in EF was computed along with a 95% confidence interval. The assumption of proportional hazards was verified for each covariate by determining that the Schoenfeld residuals associated with each covariate was not correlated with ranked failure time.

Data were complete for all covariates and outcomes of interest. The data were analyzed using SAS 9.2 (SAS Institute, Cary, NC). Group comparisons for categorical and continuous variables were made using ² tests and two-sample t tests, respectively. Unadjusted long-term survival group comparisons were made with a log-rank test. All tests were evaluated at the 0.05 alpha level.

	Results

Top Abstract Introduction Material and Methods Results Comment References

 
Preoperative/Operative Characteristics
Patient preoperative characteristics were summarized by surgery type (AVR alone versus AVR plus CABG) and for the entire cohort (Table 1). Operative characteristics were similarly stratified and also computed for the entire patient cohort (Table 2).

In-Hospital Mortality
Overall in-hospital mortality for the entire cohort was 6.6%: in-hospital mortality for AVR patients was 5.7%; in-hospital mortality for AVR plus CABG patients was 7.7%, but the two groups were not statistically different (p = 0.26). Patients with an EF of 40% or less had a higher incidence of in-hospital mortality compared with patients with EF of more than 40% (13 of 119 [10.9%] versus 38 of 654 [5.8%], p = 0.039). In the 36 patients with EF of 25% or less, only 1 patient suffered an in-hospital death. Patients with EF between 25% and 40% accounted for the majority of in-hospital mortality (12 of 83, 14.5%).

On univariable analysis, ejection fraction emerged as a significant predictor of in-hospital mortality (OR 0.979, 95% CI: 0.960 to 0.999, p = 0.044). This corresponds to a 2.1% decrease in hospital mortality for each unit increase in EF. Other univariable predictors of in-hospital mortality included patient age (OR 1.037, 95% CI: 1.009 to 1.065, p = 0.01, for each year of age), preoperative renal failure (OR 3.22, 95% CI: 1.48 to 7.04, p = 0.003), preoperative renal failure requiring dialysis (OR 3.16, 95% CI: 1.15 to 8.67, p = 0.025), New York Heart Association Class III–IV heart failure (OR 2.30, 95% CI: 1.28 to 4.11, p = 0.005), previous myocardial infarction (OR 2.44, 95% CI: 1.33 to 4.46, p = 0.004), emergent status (OR 12.2, 95% CI: 3.17 to 47.0, p < 0.001), peripheral vascular disease (OR 2.75, 95% CI: 1.40 to 5.37, p = 0.003), cardiopulmonary bypass time in minutes (OR 1.014, 95% CI: 1.008 to 1.020, p < 0.001), and cross-clamp time (OR 1.011, 95% CI: 1.002 to 1.021, p = 0.019). Importantly, concomitant CABG was not associated with an increased risk of in-hospital mortality on univariable analysis (OR 1.38, 95% CI: 0.78 to 2.44, p = 0.27).

On multivariable analysis, EF did not emerge as a predictor of in-hospital mortality (AOR 0.994, 95% CI: 0.970 to 1.019, p = 0.63). Multivariable predictors of in-hospital mortality included patient age, emergent status, and cardiopulmonary bypass time (Table 3).

View larger version (12K): [in this window] [in a new window]   Fig 1. Kaplan-Meier survival estimates of all patients according aortic valve replacement (AVR) alone (solid line) versus AVR plus coronary artery bypass graft surgery (CABG [dashed line]), p = 0.012.

View larger version (10K): [in this window] [in a new window]   Fig 2. Kaplan-Meier survival estimates of all patients according to ejection fraction of 40% or less (solid line) versus more than 40% (dashed line), p = 0.001.

After multivariable adjustment with all covariates, ejection fraction (AOR 0.985, 95% CI: 0.970 to 1.00, p = 0.049) remained a significant predictor of mid-term mortality. This corresponds to a 1.5% decrease in mid-term mortality for each unit increase in EF. Other variables associated with an increase in mid-term mortality included age, peripheral vascular disease, previous stroke, and dialysis-dependent renal failure (Table 4).

	Comment

Top Abstract Introduction Material and Methods Results Comment References

In this study, patients with LV dysfunction had significantly higher in-hospital mortality, which is comparable to other studies in patients with LV dysfunction [4, 6, 12–14]. However, after multivariable adjustment, reduced EF no longer remained a significant predictor of in-hospital mortality. This suggests that other patient comorbidities or variables negatively impact hospital survival in addition to and even possibly more than LV dysfunction. Although several series have evaluated patients with severe LV dysfunction and low transvalvular gradients [5, 7, 9, 12, 15], few have evaluated the impact of specific comorbidities that are often present in these patients [8, 14].

Patients undergoing AVR can be categorized according to several hemodynamic factors. Patients with reduced LV function may be able to generate elevated mean gradients with dobutamine stress testing [16]. Accordingly, those with low-gradient aortic stenosis and low EF are often categorized according to the presence or absence of contractile reserve. There is also a growing recognition that patients may present with low transvalvular gradients despite preserved LV function [8, 17]. It is evident from these studies that among patients with reduced LV function, those with low transvalvular gradients [4, 5, 8, 12] and absence of contractile reserve have the highest perioperative mortality [9]. However, patients in these studies showed significant long-term survival benefit compared with those treated medically.

In this study, depressed LV function was not a significant predictor of in-hospital mortality after multivariable analysis. Although several univariable predictors of mortality were identified including renal failure, previous myocardial infarction, and heart failure functional class, the only multivariable predictors identified were advanced age, emergent status, and prolonged cardiopulmonary bypass time. Therefore, other patient variables need to be considered in addition to LV function to provide adequate risk assessment in these patients.

Mid-term survival was significantly reduced in patients with depressed LV function. After multivariable adjustment, reduced EF remained a predictor for reduced mid-term survival when analyzed as a continuous variable. However, assessment of other risk factors in addition to LV function warrants careful consideration. Specifically, advanced age, preoperative renal failure requiring dialysis, previous stroke, and peripheral vascular disease emerged as independent multivariable predictors of mid-term mortality in this study. In this study, concomitant CABG did not adversely affect in-hospital or mid-term mortality on multivariable analysis. In a study by Powell and colleagues [14], patients with LV dysfunction and a history of prior myocardial infarction had significantly worse outcomes compared with those with previous infarction and preserved LV function, although previous infarction did not emerge as a significant predictor of mortality in our study. These data imply that LV dysfunction in conjunction with other well-known risk factors can adversely affect survival after AVR. This finding emphasizes the importance of a careful clinical preoperative assessment of patients before considering AVR.

Despite these results, improved long-term survival after AVR can be expected in virtually all categories of patients with depressed LV function compared with medical management alone. Pai and associates [8] documented a significant survival advantage in patients treated with AVR versus medical therapy. Furthermore, they concluded that valve area instead of transvalvular gradient was the more important measure of severity of aortic stenosis. Quere and colleagues [9] showed that even among patients without contractile reserve, LV functional recovery can be anticipated in many patients undergoing AVR. Even patients with low-gradient severe stenosis with preserved EF have a significant improvement in 5-year survival with AVR versus medical therapy [8, 17]. Although 5-year survival (by Kaplan Meier estimates) was significantly less in patients with an EF of 40% or less (61.9% versus 76.3%), these outcomes are far better than those in medically-treated patients with severe aortic stenosis in recent studies [5, 7, 8].

The current study was limited by its retrospective nature and the selection bias inherent in all database analyses. Specifically, only patients who were referred for and underwent AVR were evaluated. Therefore, patients deemed too high risk for surgery, either by their referring cardiologist or cardiac surgeon, were not included in this analysis. Furthermore, the etiology of LV dysfunction was not defined nor was mean gradient calculated in all patients. Patients with low gradients despite preserved EF, a group known to have lower operative and long-term survival, were not identified in this study. In addition, left ventricular dimensions were not available. However, the reported in-hospital and mid-term survival rates for patients with EF of more than 40% argues against this having a significant impact on our outcomes. It is clear that patients with severe LV dysfunction can have acceptable short- and mid-term outcomes if appropriate consideration is given to multiple patient comorbidities, and not LV function alone. Furthermore, with the advent of transfemoral and transapical approaches to treat aortic stenosis in patients with high-risk profiles, improvement in survival and quality of life can be expected, even for patients with severely depressed LV function.

	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): Michael E. Halkos Edward P. Chen Eric L. Sarin Vinod H. Thourani Omar M. Lattouf Cullen D. Morris Thomas Vassiliades William A. Cooper Robert A. Guyton John D. Puskas Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Halkos, M. E. Articles by Puskas, J. D. Search for Related Content PubMed PubMed Citation Articles by Halkos, M. E. Articles by Puskas, J. D. Related Collections Coronary disease Valve disease