Does the Presence of Preoperative Mild or Moderate Coronary Artery Disease Affect the Outcomes of Lung Transplantation?

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1 Does the Presence of Preoperative Mild or Moderate Coronary Artery Disease Affect the Outcomes of Lung Transplantation? Cliff K. Choong, FRACS, Bryan F. Meyers, MD, Tracey J. Guthrie, BSN, Elbert P. Trulock, MD, G. Alexander Patterson, MD, and Nader Moazami, MD Division of Cardiothoracic Surgery, Department of Surgery, and Division of Pulmonary and Critical Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri Background. Significant coronary artery disease (CAD) is an exclusion criterion for lung transplantation at most centers. However, the impact of preoperative noncritical CAD (single or multivessel mild <30% or moderate 30% to 50% stenosis) on the outcomes of lung transplantation is unknown. Methods. A retrospective review of 268 adult patients who underwent lung transplantation between June 1998 and June 2003 at Barnes-Jewish Hospital, a tertiary care center affiliated with Washington University School of Medicine, was performed. Results. Two hundred ten patients had coronary angiography performed as part of their pretransplantation evaluation. Among these patients, 177 patients had no CAD, and 33 patients (mild, 16; moderate, 17) had noncritical CAD. Patients with noncritical CAD were older (59 versus 55 years, p < 0.001) and had a higher prevalence of diabetes (24% versus 9%, p 0.014) and systemic hypertension (58% versus 36%, p 0.004) than patients without CAD. There was no significant difference in the underlying lung disease, other comorbidities, type of lung transplantation performed, early postoperative complications, and hospital or late mortality between recipients with or without CAD. Among the patients with noncritical CAD, there was no hospital mortality and no late cardiac mortality. Three recipients with preoperative moderate CAD developed late ischemic cardiac events, and revascularization was performed in 2 of these recipients. Long-term survival was similar among recipients with or without preoperative CAD. Conclusions. Preoperative noncritical (mild or moderate) CAD was not associated with increased perioperative morbidity or mortality, and it did not adversely affect short-term or long-term survival. Late ischemic events developed in 18% of the recipients with moderate CAD disease with no effect on mortality. (Ann Thorac Surg 2006;82: ) 2006 by The Society of Thoracic Surgeons Lung transplantation (LT) is a beneficial treatment for appropriately selected patients with end-stage lung disease; improvement in both survival and quality of life have been demonstrated [1, 2]. Because the donor supply is limited, the selection criteria for LT have been relatively strict in an effort to maximize outcomes after LT [3]. Significant coronary artery disease (CAD) has usually been considered a potential risk factor for excess posttransplantation morbidity and mortality, and, consequently, it has been an exclusion criterion for LT at most centers. However, the real impact of preoperative noncritical CAD (single or multivessel mild 30% stenosis or moderate 30% to 50% stenosis) is unknown. The objective of this study is to describe the incidence of mild or moderate CAD in a recent cohort of recipients at our center and to compare the outcomes of recipients with and without CAD. Accepted for publication March 15, Address correspondence to Dr Moazami, Division of Cardiothoracic Surgery, Washington University School of Medicine, Suite 3108, Queeny Tower, One Barnes-Jewish Hospital Plaza, St. Louis, MO 63110; moazamin@msnotes.wustl.edu. Patients and Methods Patients This is a single-center, retrospective report. Between June 1998 and June 2003, 268 adult LT were performed in the Washington University Adult Lung Transplant Program at the Barnes-Jewish Hospital. The specific aim of this study is to evaluate the impact of noncritical CAD (single or multivessel mild 30% stenosis or moderate 30% to 50% stenosis) on LT outcomes. Three patients with significant CAD (single or multivessel 50% stenosis) who underwent concomitant coronary artery bypass grafting (CABG) and LT were excluded from this analysis. Patients who did not have preoperative angiography were also excluded from this analysis. Two hundred ten patients who had coronary angiography performed as part of their pretransplantation evaluation formed the cohort of this study (Table 1). Among these patients, 177 patients had no CAD and 33 patients (mild, 16; moderate, 17) had noncritical CAD. All pulmonary diagnoses of end-stage lung disease are included in this analysis (Table 1). This study was reviewed and approved by the Washington University School of Medicine Human Studies Committee on September 30, Individual consent 2006 by The Society of Thoracic Surgeons /06/$32.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg CHOONG ET AL 2006;82: CORONARY ARTERY DISEASE AND LUNG TRANSPLANTATION 1039 Table 1. Pretransplant Demographic Information Variable No CAD (n 177) CAD (n 33) p Value Age (y) (IQR: ) 59.4 (IQR: ) Sex (male) 81 (45.8%) 23 (69.7%) Diagnosis Emphysema 136 (76.8%) 28 (84.8%) Cystic fibrosis 5 (2.8%) 0 Pulmonary vascular disease 8 (4.5%) 0 Other pulmonary disease 28 (15.8%) 5 (15.2%) Comorbidities Diabetes 15 (8.5%) 8 (24.2%) Systemic HTN 64 (36.2%) 19 (57.6%) Arrhythmia 11 (6.2%) 4 (12.1%) Hyperlipidemia 31 (17.5%) 9 (27.3%) Myocardial infarction 5 (2.8%) CAD coronary artery disease; HTN hypertension; IQR interquartile range. was not obtained as this was waived by the institutional review board. Pretransplant Evaluation and Perioperative Management Cardiac catheterization to assess ventricular function was routinely performed on all patients as part of their evaluation for LT. Coronary angiography was also performed if the patient was aged 45 years or older. Coronary angiography was performed in patients younger than 45 years of age if one or more cardiac risk factors, such as hypertension, diabetes, hypercholesterolemia, smoker, or personal or family history of CAD, was present. Patients with significant CAD, defined as single or multiple coronary arteries with more than 50% stenosis, were in general excluded from LT unless the CAD was discrete, the ventricular function was normal, and there was suitable coronary artery anatomy for revascularization. As previously mentioned, 3 patients with significant CAD who underwent concomitant CABG and LT were excluded from this analysis. The surgical techniques of LT have been well described elsewhere [4, 5].In general, bilateral LT is the preferred procedure. The LT is routinely performed without cardiopulmonary support unless the patient has significant pulmonary hypertension or develops hemodynamic instability during the LT. When indicated, cardiopulmonary bypass is performed through standard aortic and right atrial cannulation. Normothermia is maintained. In cases in which there is suggestion of elevated right ventricular pressures, a separate vent is placed through the pulmonary artery to assure right ventricular decompression. Routine postoperative management has been discussed elsewhere [6].In general, the management has been consistent over time and has depended on triple-drug immunosuppression (typically prednisone, cyclosporine, and azathioprine) with routine scheduled surveillance bronchoscopy to guide the maintenance immunosuppression. Statistics Descriptive statistics were expressed as mean standard deviation unless otherwise specified. Categorical data were expressed as counts and proportions. Comparisons were done with paired, two-tailed Student s t tests for means of normally distributed continuous variables and the Wilcoxon s rank-sum tests for skewed data. 2 or Fisher s exact tests were used to analyze differences among the categorical data. Kaplan Meier estimate was used to depict survival. All data analysis was performed using SPSS (SPSS 11.0 for Windows: SPSS Inc, Chicago, IL). Results Pretransplant Data Preoperative coronary angiography was performed in 210 (78%) of the 268 LT recipients (Table 1). Noncritical CAD was found in 33 (16%) of these patients, in which 16 had mild (single or multivessel 30% stenosis) and 17 had moderate (30% to 50% stenosis) CAD. Single-vessel, double-vessel, and triple-vessel CAD disease was present in 10, 5, and 1 patient with mild CAD and 9, 4, and 4 patients with moderate CAD, respectively. Among these 33 patients, CAD involved the left main stem in 24%, the left anterior descending artery in 73%, the circumflex system in 21%, and the right coronary artery in 42% of the cases. More than 80% of the patients with noncritical CAD had a pulmonary diagnosis of emphysema (Table 1). The other diagnoses in patients with noncritical CAD were idiopathic pulmonary fibrosis in 4 patients and sarcoidosis in the other patient. Patients with preoperative CAD were older and had a higher prevalence of male sex, diabetes, and systemic hypertension than patients without CAD (Table 1). There were no significant differences in the other comorbidities between the patients with and without CAD (Table 1).

3 1040 CHOONG ET AL Ann Thorac Surg CORONARY ARTERY DISEASE AND LUNG TRANSPLANTATION 2006;82: Table 2. Intraoperative and Early Postoperative Outcomes Variable No CAD (n 177) CAD (n 33) p Value Type of transplant performed Bilateral 159 (89.8%) 30 (90.9%) Single 18 (10.2%) 3 (9.1%) Required CPB support 27 (15.3%) 9 (27.3%) Required ECMO support 5 (2.8%) Perioperative complications CVA 6 (3.4%) 3 (9.1%) Dysrhythmia 70 (39.5%) 19 (57.6%) Myocardial infarction 9 (5.1%) 3 (9.1%) Cardiac arrest 7 (4.0%) 1 (3.0%) Respiratory arrest 19 (10.7%) 5 (15.2%) Reoperation 42 (23.7%) 6 (18.2%) Length of mechanical ventilation (days) 1 (IQR: 1 2) 1 (IQR: 1 4) Length of stay in ICU (days) 2 (IQR: 2 5) 2 (IQR: 2 5) Length of stay in hospital (days) 13 (IQR: 10 19) 13 (IQR: 11 17) Early graft dysfunction 44 (24.9%) 10 (30.3%) Hospital mortality 13 (7.3%) Status at follow-up (expired) 50 (28.2%) 9 (27.3%) CAD coronary artery disease; CPB cardiopulmonary bypass; CVA cerebrovascular accident; ECMO extracorporeal membrane oxygenation; ICU intensive care unit; IQR interquartile range. Transplant Data Bilateral LT was the most common type of procedure performed (Table 2). Among the patients with noncritical CAD, single LT was performed in 2 patients with idiopathic pulmonary fibrosis and in a patient with sarcoidosis. There was no significant difference in the requirement of cardiopulmonary bypass between recipients with or without CAD (Table 2). Cardiopulmonary bypass was used in 15% of the LT patients without CAD, and in about a quarter of the cases for patients with CAD. Posttransplant Data The early outcomes of LT recipients are shown in Table 2. There were no differences in the incidence of cardiac and noncardiac complications after LT between patients with and without CAD. Although cardiac dysrhythmia was more prevalent in patients with CAD, the difference was not statistically significant. Survival There was no hospital death among the patients with preoperative noncritical CAD (Table 2). There were 13 (7%) hospital mortalities among the patients without CAD. The causes of hospital deaths were profound central nervous system events in 5, graft failure in 2, surgical complications in 2, multiorgan failure in 3, and cardiac event in 1 patient. At a mean follow-up of years (median, 2.7 years; interquartile range, 1.4 to 3.8), late mortality occurred in 21% of the recipients without preoperative CAD and 27% of the recipients with noncritical preoperative CAD (mild, 25%; moderate, 29%; Table 3). The causes of late deaths are shown in Table 3. No deaths were attributed to cardiac disease among the recipients with preoperative noncritical CAD. The longterm survival between patients with and without CAD was similar (Fig 1). The Kaplan Meier survival for patients without CAD was 85%, 75%, and 55%, and for Table 3. Causes of Late Deaths Variable No CAD (n 177) Noncritical CAD (n 33) p Value No. of late deaths 37 (21%) 9 (27%) Cause of death (n 46) OB 11 (30%) 6 (67%) Graft or respiratory failure 10 (27%) 0 Infection 5 (13%) 1 (11%) Pulmonary infection 3 (8%) 2 (22%) Cardiac 1 (3%) 0 CNS event 1 (3%) 0 Multiorgan failure 5 (13%) 0 Other 1 (3%) 0 CAD coronary artery disease; CNS central nervous system; OB bronchiolitis obliterans syndrome.

4 Ann Thorac Surg CHOONG ET AL 2006;82: CORONARY ARTERY DISEASE AND LUNG TRANSPLANTATION 1041 occurred as a result of end-stage congestive heart failure secondary to idiopathic cardiomyopathy. Figure 1. Kaplan Meier survival after lung transplant stratified by the presence (solid line) or absence (dashed line) of preoperative coronary artery disease (CAD). patients with noncritical CAD, 94%, 64%, and 64% at 1, 3, and 5 years, respectively. Subset analysis dividing the patients into three groups of no CAD, mild CAD, and moderate CAD did not show any significant statistical difference among the three groups in terms of perioperative complications or short-term and long-term outcomes. Cardiac Complications and Interventions The incidence of cardiac and noncardiac complications was similar between patients with and without CAD (Tables 2, 3). Among the recipients with preoperative CAD, late cardiac complications developed in 3 patients, all of whom had preoperative moderate CAD (Table 4). There was no hospital or late mortality as a result of cardiac complication among the recipients with preoperative noncritical CAD. Among the recipients without preoperative CAD, 2 patients experienced nonischemic cardiac complications and died as a result. One patient had undergone a previous open repair of congenital cardiac defects as a child. During LT, there was profound bleeding owing to significant adhesions, cardiac arrhythmia, and inability to wean from cardiopulmonary bypass that led to his death. In the other patient, late death Comment Lung transplantation is now an accepted form of treatment for many end-stage lung diseases. After the report of the first clinically successful LT in 1983, the number of LTs and LT centers has increased substantially. Between 1985 and 2001, 14,586 LTs had been performed and registered with the International Society of Heart and Lung Transplantation. Numerous studies have reported the improvements in pulmonary function, exercise performance, and quality of life after LT [1, 2, 7, 8]. The survival of LT recipients has also improved as a result of improved patient selection, perioperative care, surgical techniques, and immunosuppression regimens [2, 6 8]. Many patients with end-stage lung disease who are referred for LT have a history of smoking, and almost half of all pulmonary transplants are performed in patients 50 years of age and older [8]. These patients often have other associated common cardiac risk factors such as male sex, hypertension, diabetes, hypercholesterolemia, family history of CAD, and age. It is therefore not surprising that a significant incidence of CAD is found in this population [9, 10]. Coronary artery disease has been documented in up to 17% of patients referred for LT [9, 11]. Most centers including ours have continued to perform coronary angiography as part of preoperative assessment for CAD [12, 13]. This approach is not unreasonable given the absence of a reliable clinical and noninvasive assessment for significant CAD. The finding of significant CAD is considered a contraindication to LT in most centers [9, 14]. Despite this exclusion criterion, the International Lung Transplant Registry reported 5% perioperative mortality in LT recipients owing to myocardial infarcts and 3% unexplained sudden deaths where CAD could be a contributor [15]. In our center, patient selection criteria for LT candidates have remained strict so as to minimize the risks for eligible recipients and to derive the most benefit from available donor allografts. As such, our center has in general considered significant CAD as a contraindication to LT unless the CAD is discrete, the ventricular function is normal, and the coronary anatomy Table 4. Late Cardiac Events ID Pretransplant Angiography Event Time From Transplant Intervention 1 LMA 30% 40%, CX 20%, distal CX 50% 2 40% 50% proximal portion of the 1st diagonal branch of LAD Non-Q wave MI 2 months Cardiac catheterization revealed no significant CAD and stress test negative. MI 5 months Cardiac catheterization revealed critical stenosis in LAD. Stent placed. 3 LMA 35%, LAD 35% 50% Angina 3 years Cardiac catheterization revealed 3-vessel disease plus 50% LMA stenosis that was thought to be critical and requiring revascularization. CABG 3 performed. CABG coronary artery bypass grafting; CAD coronary artery disease; CX circumflex artery; LAD left anterior descending coronary artery; LMA left main coronary artery; MI myocardial infarction.

5 1042 CHOONG ET AL Ann Thorac Surg CORONARY ARTERY DISEASE AND LUNG TRANSPLANTATION 2006;82: is suitable for revascularization [16]. The presence of noncritical (mild or moderate) CAD is, however, not an exclusion criteria for LT in most centers. Our past and present policies have been to offer suitable LT candidates with mild or moderate CAD without other disqualifying comorbidities an LT. There has been no published report in the literature that has studied this group of patients in terms of the incidence of CAD and the short-term and long-term outcomes after LT. Our study has found that 16% of our transplant recipients who had preoperative angiography had either mild or moderate CAD at the time of their evaluation. The presence of noncritical CAD was not associated with any significant increase in postoperative complications. The short-term and long-term survival of the transplant recipients with preoperative noncritical CAD was similar to recipients without preoperative CAD. The only significant finding was that in the group of patients with preoperative moderate CAD, 3 (18%) of the patients subsequently developed an ischemic event and 2 patients required coronary revascularization. Some centers have offered LT to highly selected patients with significant CAD. These patients have no other disqualifying comorbidities except significant CAD, favorable coronary anatomy, and preserved left ventricular function [11, 12, 17]. Patel and coauthors [12] reported a series of 18 patients who had significant preoperative CAD ( 50% stenoses) who underwent LT. Six patients underwent a staged elective percutaneous transluminal coronary angioplasty (stent) before LT. Five of these patients had interventions for significant CAD involving one vessel. Twelve other patients had combined CABG and LT. Nine of these patients had single-vessel CABG, 1 patient had double-vessel CABG, and the remaining patients had triple-vessel CABG. The patients did not have any relevant ischemic abnormality by postoperative electrocardiography, and there was no hospital mortality. All of the patients were discharged from the hospital, and the addition of CABG did not adversely change the length of operative time or hospital stay. Snell and coauthors [11] also reported their experience in 5 patients. Two patients underwent percutaneous transluminal coronary angioplasty (stent) before their transplant procedure, and 3 patients had concomitant CABG and LT. There were 2 deaths among the patients secondary to acute rejection in 1 and cytomegalovirus infection in the other patient. Our group had also previously reported 4 patients who had concomitant CABG and LT without any hospital mortality [16]. These reports do highlight that in very highly selected patients with significant CAD and no other contraindication, coronary revascularization and LT can be performed either as a staged or concomitant procedure. There are several limitations in this report. It is a retrospective single-center review and has inherent limitations associated with all retrospective studies. The LT patients are also highly selected in accordance to our selection protocol. As a result, there may have been a selection bias as the study does not include recipients and experience from other centers. We also have a small sample size, and our analysis is at risk of a type 2 error. It is possible that important differences exist but we do not have sufficient sample size to show it to be significant. It is likely that a multicenter (data registry) study would overcome some of these limitations. In conclusion, the presence of preoperative mild or moderate CAD does not result in increased perioperative morbidity or mortality, or significantly affect the shortterm or long-term survival in comparison to recipients without CAD. 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