Aortic Valve Replacement or Heart Transplantation in Patients With Aortic Stenosis and Severe Left Ventricular Dysfunction L.S.C. Czer, S. Goland, H.J. Soukiasian, S. Gallagher, M.A. De Robertis, J. Mirocha, R.J. Siegel, R.M. Kass, and A. Trento ABSTRACT Introduction. The decision to perform aortic valve replacement (AVR) or heart transplantation (HTx) for aortic stenosis (AS) with severe left ventricular dysfunction is difficult and may be affected by prior myocardial infarction (MI) and coronary artery disease (CAD). Methods. Patients who underwent AVR from 1988 to 2001 with left ventricular ejection fraction (LVEF) 30% and severe AS (aortic valve area [AVA] 1.0 cm 2 ; n 51) were assessed for operative mortality, late survival, and predictors of outcome, and were compared with HTx. Subsequently, 131 patients with LVEF 35% who underwent AVR for critical AS (AVA 0.8 cm 2 ) were evaluated. Results. In the first 51 patients, 3-year survival was 100% 0% with no CAD, and 45% 10% with CAD (P.05); 3-year survival was 88% 12% with no bypass, 73% 12% with one to two grafts, and 18% 11% with three grafts (P.01). Survival with HTx was 78% at 3 years. In the subsequent analysis of 131 patients, 90-day survivors were followed for a mean 4.6 3.5 years. Advanced age (P.001) was the only predictor of long-term mortality. LVEF improved from 28.5% 5.2% before AVR to 45.4% 13.2% at 1-month postoperatively (P.0001). New York Heart Association (NYHA) class III/IV decreased from 94.2% pre-avr to 12.8% at 1 year (P.0001). Predictors of LVEF recovery were no previous MI (P.007) and higher AS gradient (P.03). Conclusions. In severe AS and LVEF 30% with no concomitant CAD or with CAD requiring one to two bypass grafts, AVR has a survival equal to or exceeding that of HTx. In patients with CAD requiring more than two bypass grafts, survival is significantly reduced, and HTx can be considered. AORTIC STENOSIS (AS) carries a high mortality and is associated with a survival of less than 2 years without operative intervention. 1,2 After aortic valve replacement (AVR), median survivals of 10 years or more have been reported. 3,4 In the presence of left ventricular dysfunction (LVD), survival in patients with AS is reduced after AVR. 1,5 11 Previously published studies suggest that the presence of a prior myocardial infarction (MI) decreases survival after AVR. 1,7 Nevertheless, improvement in left ventricular function may occur after AVR in patients with preoperative LVD and AS. This suggests that myocardial function may be recoverable in some patients after AVR. However, this recovery may be impaired in patients with myocardial infarction prior to AVR. 7 The interaction of preoperative LVD, prior MI, and coronary artery disease (CAD) remains poorly understood in patients requiring AVR for AS. The goal of the present study was to assess the survival after AVR in patients with AS, severe LVD, and no CAD. We also compared the early mortality, late survival, and From the Divisions of Cardiology (L.S.C.C., S.G., S.G., R.J.S.) and Cardiothoracic Surgery (H.J.S., M.A.D.R., R.M.K., A.T.), Cedars-Sinai Heart Institute, and the Section of Biostatistics (J.M.), Cedars-Sinai Medical Center, Los Angeles, California, USA. Address reprint requests to Lawrence S. C. Czer, MD, Medical Director, Heart Transplant Program, Cedars-Sinai Heart Institute, 8700 Beverly Boulevard, Los Angeles, CA. 90048. E-mail: lawrence.czer@cshs.org 0041-1345/13/$ see front matter 2013 by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.transproceed.2012.04.032 360 Park Avenue South, New York, NY 10010-1710 364 Transplantation Proceedings, 45, 364 368 (2013)
AS WITH SEVERE LVD 365 predictors of outcome after AVR in patients with severe AS and LVD, and in the presence or absence of CAD. Finally, we compared survival in the present study with that after heart transplantation during a similar time period. METHODS Study Population The initial portion of the study comprised 51 patients undergoing AVR at Cedars-Sinai Medical Center during the period from 1988 through 2001 with a left ventricular ejection fraction (LVEF) 30% and AS with an aortic valve area (AVA) 1.0 cm 2.A subsequent analysis consisted of 131 consecutive patients through 2005 with LVEF 35% who underwent AVR for critical AS (AVA 0.8 cm 2 ). The study was approved by the Institutional Review Board of Cedars-Sinai Medical Center. Coronary angiography was performed in all patients more than 40 years of age and in selected patients under age 40 who were at increased risk for coronary atherosclerosis. CAD was defined as luminal diameter narrowing of 50% or more in at least one coronary artery. Extent of CAD was classified according to the number of affected major coronary vessel distributions (one, two, or three) and the presence or absence of left main stenosis. The LVEF was calculated by the area-length method from the right anterior oblique left ventricular cineangiogram. In the Doppler echocardiographic studies, LVEF was calculated using a single plane or biplane method. Aortic valve area was calculated using the continuity equation or from direct planimetry of the aortic valve. Surgical Techniques Cardiopulmonary bypass was performed with a membrane oxygenator. Myocardial preservation consisted of moderate systemic hypothermia (20 C to 28 C), topical cooling with electrolyte solution (Normosol), and intermittent antegrade and retrograde multidose potassium cardioplegia (St Thomas Hospital; Plegisol, Abbott Laboratories, Chicago, III, USA; or modified blood solution) infused at 4 C. The native aortic valve was replaced with a bioprosthesis (Hancock, Carpentier-Edwards) or a mechanical valve (St Jude Medical). Concomitant coronary artery bypass grafting was performed with saphenous vein, the internal thoracic artery, or the radial artery. When coronary artery bypass grafting was performed with the saphenous vein, the distal anastomoses were performed first, followed by valve excision and replacement, and then the proximal anastomoses. of variance techniques. Categorical variables were compared by the chi-square test or Fisher exact test. Actuarial survival was constructed by the life-table method, with all patients included at the initiation of the analysis. All comparisons with P.05 were considered significant. RESULTS A total of 51 patients comprised the initial portion of the study. Of the 51 patients, 15 (29.4%) had a prior history of MI, 43 (84.3%) had coronary artery disease (CAD), and 39 (76.5%) had coronary artery bypass surgery (CABG); four patients had unbypassed CAD. The average age was 76 12 years; 36 (71%) were male; the mean LVEF was 25% 5%; the average AVA was 0.66 0.15 cm 2 ; and the mean ischemic time was 121 32 minutes. Of the 43 patients with CAD, 4 (7.8%) had single vessel, 22 (43.1%) had double vessel, and 17 (33.3%) had triple vessel or left main disease. Of the 51 patients in the initial study, there were 31 patients who survived (60.8%). Survivors and nonsurvivors were similar in age (75 10 versus 78 15 years), gender (68% versus 75% male), ejection fraction (26% 4% versus 25% 5%), AVA (0.66 0.16 versus 0.66 0.13 cm 2 ), etiology of valvular disease (90% versus 80% calcific aortic stenosis), and ischemic time (119 34 versus 125 29 minutes). Prior MI was present in 6 (19%) of survivors and in 9 (47%) of nonsurvivors (P.06, Fisher exact test). Presence of CAD and CABG The presence or absence of CAD had a significant impact on survival (Fig 1). Early (30-day) mortality was 0% and 3-year survival was 100% in patients without CAD, compared with an early mortality of 7% and a 3-year survival of 45% 10% in patients with CAD (P.05). In patients with CAD and a prior MI (Fig 2), early mortality was 14% and 3-year survival was 38% 16%, whereas in patients Postoperative Follow-up All hospital survivors have been contacted yearly by telephone interview or mailed questionnaire. Deaths were classified as early (within 30 days of operation) or late (more than 30 days postoperatively). When interim events or hospitalization occurred, the hospital records and patients physicians were contacted for additional documentation. Statistical Methods Tabular data are summarized by the mean and standard deviation for continuous variables and by percentages for categorical variables. Comparisons of continuous variables between two groups were made with the unpaired Student t test or the nonparametric Mann-Whitney U test. Comparisons of continuous variables among three groups were done with parametric or nonparametric analysis Fig 1. Survival after aortic valve replacement by presence or absence of coronary artery disease (CAD). The solid line depicts the survival of patients with CAD, and the dashed line represents those with no CAD. In the box inset are the survivals ( SE or standard error) at 30 days and 1 and 3 years. Numbers below figure indicate patients at risk during follow-up. There was a significant difference in survival by presence or absence of CAD (P.05 by log-rank statistic).
366 CZER, GOLAND, SOUKIASIAN ET AL Table 1. Clinical Characteristics of 90-day Survivors and Nonsurvivors Variable Died 90 d (n 21) 90-d Survivors (n 110) P Value* Fig 2. Survival after aortic valve replacement by previous myocardial infarction (MI). The solid line depicts the survival of patients with coronary artery disease (CAD) and no prior MI, the dashed line represents those with no CAD, and the dotted line represents patients with CAD and prior MI. In the box inset are the survivals ( standard error [SE] at 30 days and 1 and 3 years. Numbers below figure indicate patients at risk during follow-up. There was a significant difference in survival according to the presence or absence of prior MI (P.05 by log-rank statistic). *One patient with previous MI had no CAD. with CAD but no prior MI, early mortality was 4% and 3-year survival was 48% 13% (P.085). Thus, the presence or absence of CAD provided better discrimination in survival than prior MI. When the number of bypass grafts was examined, there was a significant difference in survival (Fig 3). With no bypass grafts (including four patients with unbypassed CAD), early mortality was 0% and 3-year survival was 88% 12%. With one or two bypass grafts, early mortality Fig 3. Survival after aortic valve replacement by number of total distal anastomoses (CABG, coronary artery bypass grafts). The solid line depicts the survival of patients with one to two distal anastomoses, the dashed line represents patients with no CABG grafts, and the dotted line represents those with three to four distal anastomoses. In the box inset are the survivals ( standard error [SE]) at 30 days and 1 and 3 years. Numbers below figure indicate patients at risk during follow-up. There was a significant difference in survival according to the number of distal CABG anastomoses (P.001 by log-rank statistic). Age (y) 77.6 9.9 77.3 9.4.9 Age 70 y 81.0% 79.1%.99 Male 91% 72%.1 CAD 100% 83%.04 MI 52% 26%.04 CABG 91% 71%.1 DM 29% 29%.9 HTN 57% 54%.8 Nonelective surgery 67% 31%.003 Creat 1.5 37% 29%.6 Mean AVA (cm 2 ) 0.63 0.12 0.61 0.14.7 Mean AS grad (mm Hg) 31.2 12.9 33.9 10.9.4 AS grad 35 (mm Hg) 65% 55%.6 EF (%) 26.4 5.19 28.9 5.4.06 EF 25% 52% 30%.08 EOA index 0.97 0.14 0.91 0.10.06 CAD, coronary artery disease; MI, myocardial infarction; CABG, coronary artery bypass graft surgery; DM, diabetes mellitus; HTN, hypertension; creat, creatinine; AVA, aortic valve area; AS, aortic stenosis; EF, ejection fraction; EOA, effective orifice area. was 5% and 3-year survival was 73% 12%. With three or more bypass grafts, early mortality was 10% and 3-year survival was 18% 11%. The differences in survival were highly significant (P.001). When entered into a Cox regression analysis, only the number of bypass grafts was a significant predictor of overall survival. No variable was predictive of early mortality. Comparison with Heart Transplantation During the same time period and at the same institution, early mortality after heart transplantation was 4% and 3-year survival was 78%. Continuing Study In a subsequent analysis, 131 patients through 2005 with LVEF 35% who underwent AVR for critical AS (AVA 0.8 cm 2 ) were evaluated for early and late survival and predictors of outcome (Table 1). The patients were separated into survivors ( 90 days) and nonsurvivors ( 90 days). The survivors (n 110) and nonsurvivors (n 21) were similar in age (77.3 9.4 versus 77.6 9.9), gender (72% versus 91% male), mean AVA (0.61 0.14 cm 2 versus 0.63 0.12 cm 2 ), while ejection fraction showed a trend toward significance (28.9% 5.4% versus 26.4% 5.2%; P.06). The nonsurvivors had significantly increased occurrence of prior of MI (26% versus 52%; P.04) and CAD (83% versus 100%; P.04). Of the 90-day survivors (n 110) who were followed for a mean of 4.6 3.5 years, age was the only predictor of long-term mortality (relative risk [RR] 1.06, confidence interval [CI] 1.02 1.09; P.001). Among the 90-day survivors, LVEF improved from 28.5% 5.2% prior to
AS WITH SEVERE LVD 367 AVR to 45.4% 13.2% at 1 month post-avr (P.0001). New York Heart Association class III/IV decreased from 94.2% prior to AVR to 12.8% at 1 year (P.0001). Patients with LVEF 40% had better survival than those with LVEF 40% (P.0002). Predictors of LVEF recovery were no previous MI (RR 4.6 for prior MI, CI 1.3 16.4; P.007) and a higher AS gradient (RR 2.0 for a 10-mm Hg increase, CI 1.1 3.8; P.03). DISCUSSION In patients with AS, LVD may be caused by decreased myocardial contractility due to myocardial fibrosis and loss of myofibril function secondary to myocardial infarction and/or superimposed myocardial hypertrophy. 5,12 Patients with a low transvalvular gradient, severe AS, and severe LV dysfunction who underwent AVR had significantly improved survival compared with unoperated patients. 13,14 Improvement of left ventricular function after AVR in patients with a previously low ejection fraction suggests that myocardial systolic function is recoverable in some patients. 1,10,11,15,16 This may be due to the unloading of the ventricle by the replacement of the aortic valve. Improvement in ventricular function (or the lack thereof) may be reflected in the survival after AVR. However, recovery in left ventricular function would most likely be impaired by prior MI or by the presence of CAD. CAD is a frequent finding in patients with AS who require valve replacement. 3,4 The presence of CAD increases early mortality and reduces long-term survival after aortic valve replacement. 3 A decreased ejection fraction also reduces long-term survival after AVR. 3 In the present study of patients with AS and severely impaired left ventricular function (ejection fraction 30%), the presence or absence of CAD was found to have a significant impact on survival (Fig 1). Of note, the subset of patients with AS having severe LVD (ejection fraction 30%) and no evidence of CAD had no early mortality and a 100% 3-year survival. These patients clearly benefit from AVR, despite the low preoperative ejection fraction. The presence or absence of CAD was a better discriminator of survival than was the presence or absence of prior MI (Fig 2). In patients with CAD, although the presence of prior MI conferred a higher early mortality and a lower 3-year survival than the absence of a prior MI, the effect was trending toward significance (P.085). Overall, the presence of CAD had a marked detrimental effect, with an early mortality of 7% and a 3-year survival of 45% 10%. CABG improves survival and reduces late death after AVR without increasing early mortality. 3 Thus, concomitant bypass grafting is typically performed when CAD is present in patients with AS who require valve replacement. In the present study of patients with AS and severely reduced left ventricular function, 3-year survival was 88% 12% with no CABG (including four patients with unbypassed CAD), compared with 73% 12% with one or two grafts, and 18% with three or more grafts (P.001). The requirement for three or more bypass grafts may represent an overwhelming ischemic burden in patients with severely reduced preoperative ejection fraction. The latter patients may be candidates for heart transplantation. In the continuing study, we found that there was a higher percentage of patients with CAD and a prior MI, and a trend toward a lower preoperative ejection fraction, in patients who did not survive 90 days postoperatively. This suggests that a low EF, and instances of CAD and MI prior to AVR increase mortality after AVR. In the 90-day survivors (n 110), age was the only predictor of long-term mortality. LVEF improved from 28.5% 5.2% pre-avr to 45.4% 13.2% at 1 month. The NYHA class III/IV decreased from 94.2% pre-avr to 12.8% at 1 year. Patients with LVEF 40% had better survival than those with LVEF 40%. This suggests that AVR in this high-risk elderly population was beneficial in the majority of patients in terms of improvement of functional class and left ventricular function once they survived 90 days post-avr. 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