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Keywords:

  • Cardiac disease in transplant;
  • coronary artery disease;
  • lung transplant;
  • revascularization;
  • surgery—heart, lung, transplant

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure
  9. References

Coronary artery disease (CAD) is not uncommon among lung transplant candidates. Several small, single-center series have suggested that short-term outcomes are acceptable in selected patients who undergo coronary revascularization prior to, or concomitant with, lung transplantation. Our objective was to evaluate perioperative and intermediate-term outcomes in this patient population at our institution. We performed a retrospective, observational cohort analysis of 898 lung transplant recipients between 1997 and 2010. Pediatric, multivisceral, lobar or repeat transplantations were excluded, resulting in 791 patients for comparative analysis, of which 49 (median age 62, 79.6% bilateral transplant) underwent concurrent coronary artery bypass and 38 (median age 64, 63.2% bilateral transplant) received preoperative percutaneous coronary intervention (PCI). Perioperative mortality, overall unadjusted survival and adjusted hazard ratio for cumulative risk of death were similar among both revascularization groups as well as controls. The rate of postoperative major adverse cardiac events was also similar among groups; however, concurrent coronary artery bypass was associated with longer postoperative length of stay, more time in the intensive care unit and more postoperative days requiring ventilator support. These results suggest that patients with CAD need not be excluded from lung transplantation. Preferential consideration should be given to preoperative PCI when feasible.


Abbreviations
AHR

adjusted hazard ratio

BMI

body mass index

CABG

coronary artery bypass grafting

CAD

coronary artery disease

CBP

cardiopulmonary bypass

CI

confidence interval

CMV

cytomegalovirus

FEV1

forced expiratory volume at 1 second

FVC

forced vital capacity

IQR

interquartile range

MI

myocardial infarction

MRI

magnetic resonance imaging

OR

odds ratio

PCI

percutaneous coronary intervention

PO2

partial pressure of oxygen

SRTR

Scientific Registry of Transplant Recipients

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure
  9. References

Coronary artery disease (CAD) is a significant public health concern [1], and its incidence among potential lung transplant recipients is likewise not uncommon. It is estimated that over half of patients with advanced lung disease have occult CAD [2], and the prevalence in lung transplant candidates is expected to increase with higher proportions of elderly patients referred for transplantation [3]. In general, CAD is felt to be a relative contraindication to lung transplantation for several reasons. The limited availability of donor organs mandates strict selection criteria to optimize allocation of this precious resource [4, 5]. In addition, the potential for accelerated atherosclerosis in the setting of chronic immunosuppression and other drug therapy has led to patient exclusion from the lung transplant process [6].

The feasibility of coronary revascularization either by percutaneous coronary intervention (PCI) prior to transplant, or concomitant coronary artery bypass grafting (CABG) at the time of transplant, has previously been described [7-11]. As advances in lung transplantation continue to expand the donor pool [12-14] and improve outcomes in high-risk recipients [15], it is increasingly likely that transplant teams will need to address occult CAD in lung transplant candidates.

At our center, we have performed coronary revascularization either by PCI or CABG on a carefully selected group of lung transplant recipients who do not have other significant comorbidities. Left ventricular function is documented to be normal and each case is reviewed by the lung transplant surgeon to determine the best revascularization strategy. We have previously reported our early experience with this approach [9].

In the current study, we report our expanded experience with coronary revascularization in lung transplant recipients with concomitant CAD, which includes the largest series of simultaneous lung transplant and CABG reported in the literature. Our objective is to analyze intermediate-term outcomes and need for coronary reintervention in this patient population compared with control subjects. We hypothesize that in carefully selected recipients with isolated, discrete, CAD and preserved left ventricular function, lung transplantation and concomitant revascularization can be performed with acceptable outcomes and similar intermediate-term survival to those recipients without CAD.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure
  9. References

The Institutional Review Board of Duke University Medical Center approved this study.

Data source

Our institution maintains an enterprise data warehouse that allows investigators access to administrative, financial and clinical information generated during patient care [16]. This system was used for this study to acquire patient demographic information, preexisting comorbidities at the time of surgery, operative characteristics, postoperative complications and survival information. These data were supplemented, validated and cross-referenced with manual chart review as well as with data obtained from the Duke Database for Cardiovascular Disease [17]. Survival data were cross-referenced with the Social Security Death Index. Additionally, we acquired donor, organ matching and transplant information specific to our institution from the United Network for Organ Sharing. It is our practice that all potential lung transplant patients over the age of 40, or those patients with suspected CAD or a history suggestive of same should undergo coronary catheterization, and this information was used to categorize patients with preexisting CAD at the time of lung transplantation.

Study population

All lung transplants performed at our institution between January 1997 and November 2010 were included for analysis, with follow-up through November 2012. Pediatric (age ≤18), multivisceral, lobar or repeat transplantations were excluded. The study population was stratified into three groups: (1) patients treated with concomitant CABG (referred to as CABG group); (2) patients treated with preoperative PCI (PCI group) and (3) the remaining contemporary transplant recipients without CAD (control group).

Our methodology for determining appropriate candidates for preoperative PCI versus intraoperative CABG has been previously documented [9]. Briefly, our general policy is to perform a diagnostic cardiac catheterization on all transplant candidates over 40 years of age or with significant risk factors or symptoms requiring such diagnostics. For abnormal results of the catheterization, pharmacological magnetic resonance imaging (MRI) stress test is the preference at our center. Patients with obstructive disease or for whom MRI is contraindicated, electrocardiogram, echocardiography or nuclear stress test may be used. Preoperative percutaneous intervention was pursued after mutual agreement between interventional cardiology and the transplant team for patients with angiographic findings consistent with American College of Cardiology/American Heart Association guidelines for PCI [18]. These lesions are readily accessible, discrete, typically concentric, nonostial, and do not involve major side branches. The type of stent (bare metal vs. drug eluting) is at the discretion of the interventional cardiologist; however, when clinically appropriate our preference is bare metal to avoid prolonged dual anti-platelets therapy. In general, our protocol is to wait 30 days after bare metal stent before listing for transplant and approximately 6 months following drug eluting stent, although exceptions are made if clinically necessary. Patients are not listed while taking clopidogrel. Concurrent CABG is considered an option for recipients with proximal disease and the presence of adequate distal vessels estimated to be more than 1.5 mm in diameter and the absence of diffuse CAD. Our protocol throughout the time period of this study was to maintain these patients on statin therapy unless intolerance occurred, such as sever myositis or elevated liver enzymes. In general, patients with significant CAD on catheterization that was not felt to be fully revascularizeable (either by PCI or concomitant CABG) were excluded from transplant.

Variable definitions

Baseline characteristics

Our data sources included donor, recipient and transplant-related characteristics. The following characteristics and risk factors were available for analysis:

  1. Donor characteristics: Age, diabetes, hypertension, smoking history (>20 pack years ever), cocaine use ever, terminal serum creatinine (mg/dL), body mass index (BMI) kg/m2 and arterial partial pressure of oxygen (PO2) on 100% inspired oxygen.
  2. Recipient characteristics: Age, gender, race/ethnicity, etiology of lung failure (obstructive disease, restrictive disease, cystic fibrosis/immunodeficiency or pulmonary vascular disease), comorbidities (diabetes, hypertension and hypercholesterolemia), serum creatinine at the time of transplant (mg/dL), BMI (kg/m2), requirement for intensive care preoperatively, ventilator dependence at the time of transplant and pulmonary function and hemodynamic metrics (% predicted forced expiratory volume at 1 second [FEV1], % predicted forced vital capacity [FVC], mean pulmonary artery pressure, pulmonary vascular resistance and cardiac index [L/min/m2]).
  3. Transplant characteristics: Type of transplant (single vs. double lung), donor/recipient gender mismatch, donor/recipient race mismatch, human leukocyte antigen mismatch level, donor/recipient cytomegalovirus (CMV) mismatch (defined as donor CMV positive and recipient CMV negative), Lung Allocation Score (available from May 2005), days on the waitlist and total ischemic time (h).
Outcome measures and follow-up

The primary outcome variable was overall survival. Survival information for each patient was ascertained from the date of transplantation until patient death, date of last follow-up or the end of study period (November 30, 2012). Secondary outcome measures included postoperative major adverse cardiac events (defined as 30-day mortality or any of the following occurring prior to discharge or within 30 days if discharged prior to 30 days: myocardial infarction [MI], cardiopulmonary arrest or stroke), postoperative noncardiac adverse events (defined as any of the following occurring prior to discharge or within 30 days if discharged prior to 30 days: deep vein thrombosis, pulmonary embolism, atrial fibrillation, acute renal failure, dialysis, requirement for tracheostomy or requirement for surgical feeding tube placement), postoperative length of stay, postoperative days requiring intensive care, postoperative days requiring ventilator support (available after January 1, 2005) and readmission within 30 days of discharge. Posttransplant PCI during the follow-up period and posttransplant CABG during the follow-up period were also analyzed for time to event.

Study design and statistical analysis

We performed a retrospective, observational cohort analysis of lung transplant recipients subject to inclusion/exclusion criteria and grouping as described above. Baseline characteristics were described using medians and interquartile range (IQR) for continuous variables and proportions (frequency, percentage) for discrete variables. Comparisons for continuous and ordered categorical variables were made using Kruskal–Wallis tests and unordered categorical variables were compared using the Pearson chi-square or Fisher's exact test, as appropriate.

Unadjusted patient survival rates were estimated using the product-limit (Kaplan–Meier) method and compared between groups by the log-rank test [19]. Kaplan–Meier methods and log-rank testing were also used to examine time to postoperative revascularization and to determine differences between groups.

Characteristics associated with 30-day postoperative mortality were analyzed using univariate logistic regression (note that the number of events [n = 29] prevented multivariable analysis of this outcome measure). Characteristics included in this analysis were era of transplant (either before or after year 2000 as defined by the International Society of Heart and Lung Transplantation [20]), type of transplant (single vs. double lung) and risk factors as indicated based on the Scientific Registry of Transplant Recipients (SRTR) lung transplant postoperative risk model [21, 22], which included donor age (separately analyzed over/under 50 years), donor BMI, donor history of diabetes, recipient age (separately analyzed over/under 45 years), gender, race, etiology of lung failure, intensive care requirement preoperatively (yes/no), ventilator requirement preoperatively (yes/no) and ischemic time (note that not all variables in the risk model were included due to our sample size). Odds ratio (OR) and 95% confidence interval (CI) were calculated as measures of strength of association and precision, respectively.

Multivariable Cox's proportional hazards modeling [23] was used to assess the simultaneous effect of treatment group on risk of patient death, while adjusting for characteristics and risk factors described above. Hazard ratio and 95% CI were calculated as measures of strength of association and precision, respectively. The proportionality assumption was verified by assessment of Schoenfeld residual plots [24]. Multivariable logistic regression modeling was used to assess the effect of treatment group on the risk of postoperative cardiac and noncardiac adverse events, again while adjusting for covariates as described above with OR and 95% CI calculated as measures of strength of association and precision, respectively.

Statistical analyses were performed using SAS Version 9.3 (SAS Institute, Inc., Cary, NC), JMP Version 10.0 (SAS Institute, Inc.) and R version 2.15.1 (R Core Team [2012]. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0, Available at: http://www.R-project.org/). For all comparisons, p-values ≤ 0.05 were considered statistically significant.

Subgroup analysis

A subset analysis was performed in the group undergoing concomitant CABG to compare patients age ≥65 years to those under age 65. Unadjusted survival for the CABG group and controls were estimated using the Kaplan–Meier method and compared using the log-rank test as described above. The cause of death for both the younger and older cohort in the CABG group were reported.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure
  9. References

Study population

A total of 898 lung transplants were performed at our institution between January 1997 and November 2010. Of these, 25 pediatric recipients and 74 recipients of a multi-organ, en-bloc, lobar or repeat transplant were excluded (see Figure 1 for study inclusion algorithm). Eight patients had a history of CABG prior to lung transplant and were excluded. The limited numbers of this category precluded comparative analyses; however, this population is described. The resulting study population included 791 lung transplant recipients for comparative analysis (=898-25-74-8), of which 49 received a concurrent CABG (median follow-up 2.7 years), 38 received preoperative PCI (median follow-up 3.0 years) and 704 were controls with no evidence of preexisting CAD (median follow-up 3.9 years). The proportion of patients in the CABG and PCI groups by year of transplant in 5-year increments is shown in Figure 2. This indicates an increase in the proportion of patients undergoing these procedures, with PCI increasing from 2.8% in the early years of the study (1997–2000) to 6.0% in later years (2006–2010) and CABG increasing from 4.0% in the early years of the study to 8.3% in later years. Median follow-up for the entire study population was 3.7 years (mean 4.4 years).

image

Figure 1. Study inclusion algorithm. CABG, coronary artery bypass grafting.

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image

Figure 2. Proportion of recipients with coronary revascularization by year of transplant. CABG, group undergoing concurrent coronary artery bypass grafting; PCI, group with preoperative percutaneous coronary intervention.

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The eight patients who received a CABG procedure before the time of lung transplant had a median age of 63 years (range 58–66), all had white ethnicity and one was female. All had restrictive lung disease with the exception of one with obstructive disease. The median time between CABG and transplant was 3.8 years (mean 5.4 years) ranging from approximately 1.5 to 20 years. None of the prior CABG procedures were performed at our institution. Two patients received a single lung transplant with the remaining six receiving bilateral transplant. Three of the eight patients were still alive at the last follow-up with survival times of 2.0, 3.9 and 7.9 years. Of the five deaths, one died at 4.4 years from infection (Pseudomonas pneumonia), one at 1.8 years from complications of hepatitis C, one at 361 days from unknown causes, one at 154 days from graft failure and one died postoperative day 1 from bleeding complications.

In the CABG group, 32 incisions were via a clamshell approach, 14 via sternotomy and three via posteriolateral thoracotomy with 39 of 49 patients undergoing bilateral transplant. Surgical revascularization was performed prior to lung transplantation, with appropriate time allowance being communicated to the organ recovery team to minimize ischemia time. Choice of graft was directed by surgeon preference; however, in cases where left-system revascularization was to be performed, an arterial graft was chosen when possible (left in situ internal mammary artery or free mammary graft). Mammary arterial graft was used in 31 of 49 cases. One graft was used for 22 recipients, two grafts for 11 recipients, three grafts for 13 recipients and four grafts for three recipients. Our preferred operative approach is to avoid the use of cardiopulmonary bypass (CPB) support for both coronary artery revascularization and the lung implantation; however, CPB was required in 23 (46.9%) of cases. CPB requirement was typically due to hemodynamic or ventilator compromise as well as positioning of the heart to access target vessels.

Of the 38 patients receiving a preoperative PCI, five (13%) were remote (4–7 years before transplant) and not directly related to the pretransplant evaluation. Treatment for the remaining 33 patients was directly related to pretransplant management. Of these, 24 patients (73%) received bare metal stents versus nine (27%) with drug eluting stents. Coronary artery distributions intervened upon were as follows: 16 patients (48%) right coronary artery; 10 (30%) left anterior descending; four (12%) left circumflex and three (9%) involving both the left anterior descending and left circumflex distributions. The median time between PCI and transplant was 73 days (mean 133 days) ranging from eight to 773 days.

Baseline characteristics

The median donor age for the CABG group was 30 years (IQR 21–41) with a median BMI of 24.4 kg/m2 (IQR 21.4–29.3) and a median PO2 on 100% inspired oxygen of 437 mmHg (IQR 396–502). When compared to both the PCI group and the control group, there were no significant differences in baseline donor characteristics (p ≥ 0.18 for all) (Table 1).

Table 1. Donor, recipient and transplant characteristics
CharacteristicConcomitant CABG (n = 49)Comparison groups (each compared against the CABG group)
Pre-op PCI (n = 38)p-ValueControls (n = 704)p-Value
  • CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention; BMI, body mass index; PO2, arterial partial pressure of oxygen; CF, cystic fibrosis; FEV1, forced expiratory volume at 1 second (%); FVC, forced vital capacity.

  • Median (interquartile range) for continuous variables. N (%) for categorical variables. If data are missing for >5% of the study population, the denominator is give for categorical variables and “n” given for continuous variables. Comparison using Wilcoxon signed-rank test for continuous variables and Pearson chi-square or Fisher's exact test for categorical variables.

  • 1

    n CABG = 46; n PCI = 36; n controls = 580.

  • 2

    n CABG = 33; n PCI = 25; n controls = 335.

  • 3

    n CABG = 42; n PCI = 33; n controls = 618.

  • *

    Indicates statistical significance.

Donor characteristics
Donor age30 (21, 41)28 (22, 47)0.48832 (21, 47)0.180
Donor BMI (kg/m2)24.4 (21.4, 29.3)23.8 (21.6, 27.1)0.75223.7 (21.1, 26.9)0.192
PO2 on 100% inspired oxygen (mmHg)437 (396, 502)1427 (359, 492)0.416450 (368, 512)0.969
Recipient characteristics
Age62 (56, 65)64 (60, 68)0.037*55 (42, 62)<0.001*
Female gender1 (2.0%)5 (13.2%)0.082324 (46.0%)<0.001*
White ethnicity46 (93.9%)37 (97.4%)0.629620 (88.1%)0.352
Etiology of lung failure0.684<0.001*
Obstructive16 (32.7%)14 (36.8%)304 (43.2%)
Pulmonary vascular0 (0.0%)0 (0.0%)28 (4.0%)
CF or immunodeficiency0 (0.0%)0 (0.0%)119 (16.9%)
Restrictive33 (67.4%)24 (63.2%)252 (35.9%)
Comorbidities8 (16.7%)5 (13.2%)76 (10.8%)
Diabetes9 (18.4%)4 (10.5%)0.30985 (12.1%)0.198
Hypertension17 (34.7%)19 (50.0%)0.151152 (21.6%)0.034*
Hypercholesterolemia6 (12.2%)9 (23.7%)0.16142 (6.0%)0.082
BMI (kg/m2) at transplant26.5 (23.0, 28.3)26.2 (22.8, 28.1)0.86423.3 (20.2, 26.3)<0.001*
Intensive care preoperatively3 (6.1%)0 (0.0%)0.25322 (3.1%)0.218
Requiring ventilator at transplant3 (6.1%)0 (0.0%)0.25332 (4.6%)0.492
Pulmonary function
FEV1, % predicted41 (20, 56)42 (23, 56)0.67125 (18, 43)0.012*
FVC, % predicted52 (41, 60)52 (43, 69)0.37246 (36, 59)0.113
FEV/FVC0.97 (0.39, 1.09)0.97 (0.38, 1.03)0.7770.63 (0.38, 1.00)0.080
Transplant characteristics
Bilateral transplant39 (79.6%)24 (63.2%)0.089596 (84.7%)0.345
Lung allocation score44.4 (36.8, 62.2)249.1 (35.9, 70.9)0.48540.3 (34.7, 48.2)0.035*
Days on waitlist12 (5, 45)12 (3, 77)0.86470 (13, 260)<0.001*
Ischemic time (h)7.3 (6.2, 9.6)35.3 (4.5, 7.0)<0.001*6.2 (5.2, 7.3)<0.001*

When compared to controls, the CABG group demonstrated significantly a higher age (median 62 years [IQR 56–65] vs. median 55 years [IQR 42–62], p < 0.001), a higher proportion of male gender (98% vs. 46%, p < 0.001), a higher proportion with restrictive lung disease (67.4% vs. 35.9%, p < 0.001) and a higher FEV1% predicted (41% [IQR 20–56%] vs. 25% [IQR 18–43%], p = 0.012) (Table 1). The CABG group had a lower age compared to patients with PCI preoperatively (median age PCI group 64 [IQR 60–68], p = 0.037); however, other baseline recipient characteristics were similar.

The amount of time on the waitlist for the CABG group was similar to the PCI group (median 12 days [IQR 5–45] vs. median 12 days [IQR 3–77], p = 0.86) and significantly lower than controls (control group 70 days [IQR 13–260], p < 0.001) (Table 1). Total ischemic time for recipients of a concurrent CABG was significantly higher than the PCI group and controls (median CABG group 7.3 h [IQR 6.2–9.6] vs. 5.3 h for the PCI group [IQR 4.5–7.0] and median 6.2 h for controls [IQR 5.2–7.3], p < 0.001 for both).

Primary endpoint: mortality

There was no significant difference between groups in overall unadjusted survival (p ≥ 0.36 for all comparisons, Figure 3) or univariate comparison of 30-day mortality (OR for CABG vs. controls 1.99, 95% CI 0.03–2.44, p = 0.46; CABG vs. PCI p = 0.28 [no events in PCI groups precludes OR calculation]) (Table 2). Using multivariable Cox proportional hazard modeling, survival was also similar (adjusted hazard ratio [AHR] for CABG vs. controls 1.15, 95% CI 0.76–1.76, p = 0.51; CABG vs. PCI AHR 1.45, 95% CI 0.79–2.66, p = 0.23) (Table 2).

image

Figure 3. Unadjusted Kaplan–Meier survival curves. CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention.

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Table 2. Perioperative and overall mortality analysis
CharacteristicsUnivariate logistic regression analysis for 30-day mortalityMultivariable Cox proportional hazard for cumulative risk of death
Odds ratio95% Confidence intervalp-ValueOdds ratio95% Confidence intervalp-Value
  • CABG, coronary artery bypass grafting; LTX, lung transplant; PCI, percutaneous coronary intervention; CF, cystic fibrosis.

  • *

    Statistical significance.

Combined CABG/LTX (ref = pre-op PCI)(No events for pre-op PCI)0.2821.450.79–2.660.231
Combined CABG/LTX (ref = controls)1.990.03–2.440.4581.150.76–1.760.508
Era of transplant 1995–1999 (ref = 2000+)3.401.52–7.300.004*1.451.07–1.960.015*
Single lung transplant (ref = bilateral)0.790.23–2.090.6631.110.80–1.540.531
Donor characteristics
Age <50 years (ratios per 5-year increase)0.890.73–1.060.1871.000.95–1.050.955
Age ≥50 years (ratios per 5-year increase)1.320.36–3.960.6371.231.03–1.460.022*
Recipient characteristics
Age <45 years (ratios per 5-year increase)1.020.70–1.500.9050.900.77–1.040.157
Age ≥45 years (ratios per 5-year increase)0.690.47–0.980.040*1.101.00–1.220.051
Etiology of lung failure (ref = obstructive)
Pulmonary vascular9.843.07–29.93<0.001*1.440.85–2.470.177
CF or immunodeficiency1.580.48–4.680.4290.830.52–1.310.417
Restrictive1.080.42–2.810.8671.200.95–1.520.126
Ischemic time (ratios per incremental hour)0.990.78–1.240.9241.010.95–1.080.670

Secondary endpoints

Perioperative adverse cardiac events and adverse noncardiac events are demonstrated in Table 3. There were no significant differences in postoperative events comparing CABG and PCI groups. Compared to controls, the CABG group had a higher rate of postoperative MI (6.1% vs. 1.3%, p = 0.009), atrial fibrillation (46.9% vs. 30.0%, p = 0.013), surgical feeding tube placement (51% vs. 33%, p = 0.010) and tracheostomy (34.7% vs. 16.3%, p = 0.001) (Table 3). However, upon multivariable logistic regression analysis adjusting for risk factors and potential confounders, treatment group was not predictive of postoperative adverse cardiac or noncardiac events (p ≥ 0.24 for all comparisons, Table 4).

Table 3. Summary of secondary outcome measures
CharacteristicsConcomitant CABG (n = 49)Comparison groups (each compared against the CABG group)
Pre-op PCI (n = 38)p-ValueControls (n = 704)p-Value
  • Median (interquartile range) for continuous variables. N (%) for categorical variables. Comparison using Wilcoxon signed-rank test for continuous variables and Pearson chi-Square test for categorical variables. CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention.

  • 1

    Ventilator data available after January 1, 2005, n CABG = 33; n PCI = 26; n controls = 354.

  • 2

    See Figure 3 for time-to-event statistical comparison between groups of the proportion of patients requiring revascularization.

  • 3

    Two patients in the control group separately received both a PCI and CABG postoperatively.

  • *

    Statistical significance.

Perioperative adverse cardiac events
30-day mortality1 (2.0%)0 (0.0%)0.37628 (4.0%)0.496
Myocardial infarction3 (6.1%)3 (7.9%)0.7469 (1.3%)0.009*
Stroke3 (6.1%)1 (2.6%)0.44122 (3.1%)0.258
Cardiopulmonary arrest3 (6.1%)2 (5.3%)0.86431 (4.4%)0.575
Any above cardiac event8 (16.3%)5 (13.2%)0.68174 (10.5%)0.206
Perioperative adverse noncardiac events
Deep vein thrombosis1 (2.0%)2 (5.3%)0.4146 (0.9%)0.402
Pulmonary embolism0 (0.0%)2 (5.3%)0.10425 (3.6%)0.180
Post-op atrial fibrillation23 (46.9%)17 (44.7%)0.838211 (30.0%)0.013*
Acute renal failure11 (22.5%)7 (18.4%)0.64689 (12.6%)0.051
Dialysis requirement2 (4.1%)3 (7.9%)0.44947 (6.7%)0.477
Surgical feeding tube placement25 (51.0%)15 (39.5%)0.283232 (33.0%)0.010*
Tracheostomy17 (34.7%)7 (18.4%)0.092115 (16.3%)0.001*
Any above noncardiac event36 (73.5%)25 (65.8%)0.438390 (55.4%)0.014*
Postoperative length of stay18 (14, 47)11 (7, 28)0.001*13 (9, 23)<0.001*
Postoperative intensive care days6 (3, 27)3 (2, 10)0.014*3 (2, 9)0.005*
Post-op days requiring ventilator support3 (1, 21)11 (1, 4)0.018*1 (1, 4)<0.001*
Readmission with 30-days of discharge24 (49.0%)18 (47.4%)0.881308 (43.8%)0.476
Postoperative coronary revascularization
PCI5 (10.2%)24 (10.5%)10 (1.4%)
CABG0 (0.0%)2,31 (2.6%)4 (0.6%)
Table 4. Postoperative cardiac and noncardiac adverse events
CharacteristicsMultivariable logistic regression for adverse cardiac events1Multivariable logistic regression for adverse noncardiac events
Odds ratio95% Confidence intervalp-ValueOdds ratio95% Confidence intervalp-Value
  • CABG, coronary artery bypass grafting; LTX, lung transplant; PCI, percutaneous coronary intervention; CF, cystic fibrosis.

  • 1

    Logistic regression for adverse cardiac events adjusted only for era of transplant and recipient characteristics due number of events (n = 87).

  • *

    Statistical significance.

Combined CABG/LTX (ref = pre-op PCI)1.230.36–4.180.7401.120.42–3.000.816
Combined CABG/LTX (ref = controls)1.670.71–3.880.2381.310.64–2.680.455
Era of transplant 1995–1999 (ref = 2000+)1.730.92–3.280.0910.600.36–1.020.058
Single lung transplant (ref = bilateral)0.570.26–1.240.1550.730.42–1.260.253
Donor characteristics
Age <50 years (ratios per 5-year increase)1.010.90–1.140.8291.081.00–1.170.056
Age ≥50 years (ratios per 5-year increase)1.200.79–1.830.4021.110.82–1.500.498
Recipient characteristics
Age <45 years (ratios per 5-year increase)1.250.89–1.750.1991.230.99–1.530.057
Age ≥45 years (ratios per 5-year increase)0.970.79–1.180.7331.261.09–1.460.002*
Etiology of lung failure (ref = obstructive)
Pulmonary vascular8.113.02–21.79<0.001*3.361.31–8.630.012*
CF or immunodeficiency2.991.07–8.390.037*1.310.67–2.570.434
Restrictive2.151.21–3.790.009*1.641.14–2.350.008*
Ischemic time (ratios per incremental hour)1.151.01–1.320.035*1.161.04–1.280.006*

Postoperatively, the CABG group had longer length of stay, more intensive care days and more days on the ventilator (Table 3). The number of patients who subsequently went on to receive either a PCI or CABG after lung transplantation is provided in Table 3 with Kaplan–Meier estimates in Figure 4. The rate of postoperative revascularization was equivalent in the CABG and PCI groups (p = 0.99); however, both groups had significantly higher rates of revascularization compared with controls (p < 0.001 for both comparisons). In total, five patients in the CABG group required postoperative percutaneous intervention. One of these five patients had received an arterial graft, which was a free internal mammary conduit as part of four-graft revascularization for that individual. This patient suffered an MI approximately 1 month after surgery and was found to have occlusion of all four grafts, requiring emergent PCI and intra-aortic balloon pump therapy. The patient survived this event and was discharged from the hospital in stable condition on postoperative day 74; however, the patient died approximately 2 months later (cause of death unknown). Two patients received stenting to a native vessel with patient vein grafts, one at 3 years posttransplant and one at 5 years. One patient was noted to have occlusion of three vein grafts approximately 6 months after the index operation. Successful PCI was performed and the patient lived an additional 5 years. One patient presented with an MI approximately 1 year after CABG and was found to have occlusion of their saphenous vein graft. This was successfully stented via PCI and the patient was still alive at 5-year follow-up.

image

Figure 4. Rate of postoperative coronary revascularization (PCI or CABG). CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention. *Statistical significance.

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Subgroup analysis

Of the 49 patients who underwent concurrent CABG, 35 were under age 65 and 14 were age 65 or older. Survival comparison of this group stratified by age over/under 65 juxtaposed to controls is shown in Figure 5. In the CABG group, there was a trend toward better survival in those under age 65; however, the small numbers in the sample precluded statistical comparison. There was no significant difference in unadjusted survival for the control group stratified by age over/under 65 (p = 0.18). The most common cause of death in the CABG group younger cohort was graft failure (n = 8, 44%) followed by infection (n = 7, 39%) with one death from malignancy, one from heart failure and one unknown cause of death. In the older cohort, the most common cause of death was also graft failure (n = 4, 50%) with one death from infection, one from malignancy and two with unknown cause of death.

image

Figure 5. Survival analysis in the CABG group, stratified by over/under age 65. CABG, coronary artery bypass grafting.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure
  9. References

Concomitant CAD in patients evaluated for lung transplantation is not uncommon given the longer life expectancy for the general population and shared risk factors in the pathogenesis of end-stage lung disease and CAD, such as tobacco use. The current analysis comparing combined lung transplant and CABG to preoperative PCI and controls without CAD demonstrates equivalent survival as well as similar odds of cardiac or noncardiac adverse postoperative events; however, CABG recipients required longer intensive care unit stay, hospital stay and ventilator support. Rates of additional revascularization procedures after transplant were also similar between CABG and PCI groups. Importantly, subgroup analysis of patients over/under age 65 in the CABG group demonstrated shorter survival in the older cohort, though the small numbers for this sample precluded statistical comparison.

Our results contribute to an increasing body of literature demonstrating acceptable outcomes with combined lung transplant and CABG in selected recipients. Early reports in 2001–2003 demonstrated feasibility of concurrent CABG both on and off pump; however, the sample size in these series precluded definitive conclusions [9, 25, 26]. More recently, Sherman et al [27] reported their experience with 27 patients undergoing either CABG or PCI prior to transplant. They found similar results compared with controls, including hospital length of stay, complication rates, need for reintervention and survival at a mean follow-up of 3 years. Our results support equivalent survival and adverse events in risk-adjusted analysis of recipients with concurrent CABG; however, these patients required substantially more hospital resources including longer intensive care unit and hospital length of stay as well as days requiring mechanical ventilation. Despite equivalent survival, this more tenuous postoperative course is concerning, and therefore in accordance with these results, our current practice is to preferentially perform preoperative PCI with bare metal stents if technically feasible (exceptions may include left main disease and inability to tolerate anti-platelet therapy). The current guidelines by American College of Cardiology Foundation and the American Heart Association provide a Class 1 recommendation for CABG to improve survival in patients with significance stenosis of the left main coronary artery; however, they do note that PCI may be a reasonable alternative in selected patients [28]. Randomized control trials to evaluate this topic are few. The prospective randomized trial titled “Study of Unprotected Left Main Stenting Versus Bypass Surgery” (LE MANS Study NCT00375063) suggested that PCI may have favorable early outcomes in comparison with CABG; however, each treatment group was limited to approximately 50 patients and long-term data are not yet available [29]. In a randomized trial comparing CABG versus PCI for 1800 patients (SYNTAX trial NCT00114972), a prespecified subgroup analysis of 705 patients with left main disease demonstrated comparable safety and efficacy at 1 year; however, the authors noted the need for longer follow-up to confirm these findings [30]. As the data evaluating PCI for left main disease continue to evolve with the accumulation of long-term follow-up, moving forward this may prove to be a reasonable treatment option in the lung transplant population.

The use of an arterial graft when performing concomitant lung transplant and CABG has been debated [25, 27]. The rationale for the use of vein graft is the expectation that the median survival of a lung transplant recipient is generally reported to be in the order of 6 years while in the general cardiac literature vein grafts have been found to be durable for at least that length of time [31]. Although we chose an individual approach for each patient, our preference is to use the mammary graft when possible and we have found it to be technically feasible regardless of the surgical approach (sternotomy, thoracotomy and clamshell). Although the number of patients in our CABG series requiring reintervention is small, it is interesting to note that with the exception of a single patient who suffered a variety of postoperative complications, none of the patients with arterial grafts required reintervention. In contrast, the remaining four patients who did require an intervention demonstrated failure of their vein conduit.

Lung transplant is increasingly performed in elderly recipients [32], and accordingly, CAD is more likely to be encountered in this population. Our results demonstrate the numerically decreased survival in concurrent CABG recipients over age 65. The limited sample size precludes statistical comparison or definitive comments on survival differences in this cohort; however, this is nonetheless a concerning finding. The reasons for lower survival in the older cohort are not entirely clear. Contributing factors may include the increased technical demands of concomitant CABG, longer operative and ischemic times and decreased maximal graft performance. Age-related comorbidities such as atherosclerotic disease and impaired renal reserve may also play a role. Given these concerns, we currently do not offer concomitant CABG to patients over age 65 and recommend exercising caution with concomitant coronary revascularization in this population.

It is important to note that shorter waitlist times were observed in the CABG and PCI groups (median 12 days for both) compared with controls (median 70 days). The most frequent diagnosis for the CABG and PCI groups was pulmonary fibrosis (67% and 63%, respectively) compared to 36% of patients in the control group with this diagnosis (the most common diagnosis for controls was obstructive disease at 43%). The CABG and PCI groups were also significantly older (median age 62 and 64 years, respectively) compared with controls (median age 55 years). These factors likely contribute to the shorter waitlist time observed in the CABG and PCI groups. Additionally, patients with concomitant CAD demonstrated higher rates of functional status requiring assistance (data not shown), which is also factored into the Lung Allocation Score.

There are inherent limitations to this study, which should be considered when interpreting these results. This is a retrospective review, and therefore unmeasured confounders may exist. Patients excluded from transplant due to cardiac evaluation are not tracked in our system and therefore unavailable for analysis. Outcome measures do not include qualitative metrics, such as quality of life. Additionally, our follow-up is limited to intermediate-term (2.7-year median follow-up time for the CABG group) and long-term follow-up data (≥5 years) are currently unavailable.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure
  9. References

Acceptable candidates for lung transplantation need not be excluded due to CAD as revascularization prior to, or concomitant with, lung transplantation can be performed with comparable outcomes to contemporary controls. Caution should be used in offering concurrent CABG to recipients over age 65. Given the more difficult postoperative course in patients undergoing concomitant CABG with longer postoperative length of stay, more time in the intensive care unit and more postoperative days requiring ventilator support, preferential consideration should be given to preoperative PCI with bare metal stents when feasible.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure
  9. References

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. Disclosure
  9. References
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