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a Division of Cardiac Surgery, Department of Surgery, The Johns Hopkins Medical Institution, Baltimore, Maryland
b Division of Pulmonary and Critical Care Medicine, Department of Medicine, The Johns Hopkins Medical Institution, Baltimore, Maryland
Accepted for publication June 4, 2009.
* Address correspondence to Dr Shah, Division of Cardiac Surgery, The Johns Hopkins Hospital, Blalock 618, 600 N Wolfe St, Baltimore, MD 21287 (Email: ashah29{at}jhmi.edu).
Presented at the Forty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Francisco, CA, Jan 26–28, 2009.
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Abstract |
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Methods: We retrospectively reviewed United Network for Organ Sharing data to identify 1,256 lung transplant (LTx) recipients with IPF between 2005 and 2007. Risk of 30-day, 90-day, and 1-year mortality for SLT versus BLT was examined across levels of the lung allocation score (LAS [both continuous with incorporation of interaction terms and categorized by LAS quartiles]). Multivariable analysis was conducted through Cox proportional hazards regression.
Results: Lung allocation score quartiles were as follows: quartile 1, 29.8 to 37.8, n = 315; quartile 2, 37.9 to 42.4, n = 313; quartile 3, 42.5 to 51.9, n = 314; and quartile 4, 52.0 to 94.1, n = 314. Overall, 21.1% more patients received BLT in the highest LAS quartile (59.5%) than in the lowest LAS quartile (38.4%, p < 0.05). In patients at highest risk, BLT was associated with a 14.4% decrease in mortality at 1 year after LTx. This survival benefit was confirmed on univariate analysis (hazard ratio 1.90 [95% confidence interval: 1.16 to 3.13], p = 0.01) and multivariable analysis (hazard ratio 2.09 [95% confidence interval: 1.07 to 4.10], p = 0.03) as well as in sensitivity analyses incorporating pulmonary hypertension and maximizing follow-up. There were no differences in the risk of death with SLT at 30 or 90 days after LTx in any quartile on unadjusted or multivariable adjusted analysis.
Conclusions: We provide an initial examination of survival by procedure type and LAS score for LTx recipients with IPF. Bilateral LTx appears to offer advantages over SLT for high-risk patients.
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Introduction |
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Although studies examining this issue have been valuable, institutional practices still vary. There is a legitimate concern that BLT is not the optimal use of a limited resource. Moreover, with only 510 adult IPF patients receiving LTx in the United States in 2007, it is difficult for any single LTx center to accrue sufficient patient numbers to fully address this issue.
The LAS prioritizes patients based on the difference between posttransplant 1-year survival and pretransplant urgency. Although not initially designed for this purpose, the LAS can identify patients at high risk for death on the waitlist [6] and may provide a means for risk stratification in IPF. Furthermore, survival differences relating to SLT versus BLT may differ across levels of LAS. We utilized UNOS data to examine an open cohort of IPF patients receiving LTx, after implementation of the LAS system, to examine whether BLT improves short-term mortality for patients with IPF, and whether there are levels of clinical acuity over the range of LAS scores at which BLT may be more favorable for minimizing short-term mortality. We hypothesize that high-risk patients (namely, those having increased LAS scores) will have improved short-term survival with the use of BLT.
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Material and Methods |
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TopAbstractIntroductionMaterial and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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Study Design and Outcome Measures
We retrospectively examined a cohort of adult (more than 17 years old) first-time LTx recipients with a primary diagnosis of pulmonary fibrosis (coded as IPF or other causes) receiving either SLT or BLT (patients receiving heart-lung transplantation were excluded) from May 2005 to December 2007 (Fig 2). This interval corresponds with implementation of the LAS system in the United States. The outcome of interest was all-cause mortality at 1 year after transplant. We also examined the incidence of mortality at 30 and 90 days after LTx. The primary exposure was transplantation type (SLT versus BLT). The analysis examined whether differences in 1-year mortality occurred with SLT versus BLT over the range of LAS scores in the cohort.
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The Cox model was constructed predicting the risk of mortality at 1 year. Covariates of interest with p values less than 0.2 (exploratory level only) were incorporated into the Cox model in a forward and backward stepwise fashion using the likelihood ratio test and Akaike's information criterion in a nested model approach to determine which covariates increased the explanatory power of the model. The initial risk-adjusted model incorporated the following covariates with potential for confounding: age, insurance type, recipient race, donor race, ICU before transplantation, and mean annual institutional volume as a continuous variable.
Added to this model was recipient LAS (continuous and centered at 30), procedure type (SLT versus BLT), and the interaction term examining the relationship between SLT versus BLT and LAS on mortality. Inclusion of this interaction term was based on visual inspection of the Lowess smooth plot of Martingale residuals generated by fitting a null Cox model (no covariates) predicting the risk of 1-year mortality. The technique per the method of Grambsch and colleagues [7] utilizes Martingale residuals (observed minus expected failures as predicted by the model) to determine functional forms of covariates. In a null model (no covariates), the Martingale residuals represent the probability of mortality and provide a clue as to the nature of covariate relationships in survival analysis (Fig 3). The final Cox proportional hazards model (model A) was examined initially for the entire cohort. In addition, quartiles of LAS score were generated, permitting a stratified analysis. Patients in LAS quartile 4 were defined as "high risk" for the purpose of this analysis.
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Sensitivity Analysis
Two separate sensitivity analyses were performed. First, to account for the substantial risk of confounding relating to pulmonary hypertension, a new model was created (model B) incorporating those covariates included in model A along with mean pulmonary artery pressure. This variable was not included in the initial model owing to its presence in the LAS score. To maximize follow-up time, a second sensitivity analysis was conducted (model C) using only patients transplanted during the first year of the LAS system, May 1, 2005, to April 30, 2006 (median follow-up, 23.5 months; interquartile range [IQR], 14.1 to 25.6). Finally, multivariable regression was conducted by restricting the cohort to various LAS point cutoffs (in multiples of 10). The hazard ratios (HR) for these comparisons were plotted to assess the overall trend in the hazard for mortality with increasing LAS.
Descriptive Statistics
Descriptive univariate analysis comparing patients among LAS quartiles was conducted through one-way analysis of variance (ANOVA) for continuous variables and the 
2 test for categorical variables. Post-hoc comparisons were performed utilizing the Tukey-Kramer method (continuous variables) or bivariate logistic regression (categorical variables). Cumulative survival was estimated utilizing the Kaplan-Meier method focused on time intervals with adequate follow-up. The log-rank test was used to compare survival estimates by group.
For all analyses, a p value of less than 0.05 (two-tailed) was considered significant. Means are presented with standard deviations, medians with IQR, and all HR with 95% confidence intervals. Statistical analyses were performed with the aid of STATA software (version 9.2 Special Edition; StataCorp LP, College Station, TX).
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Results |
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TopAbstractIntroductionMaterial and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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The median LAS was 47.9 points (IQR, 37.8 to 52.0). All patients in the study population had a recorded LAS. Stratification by LAS quartile revealed the following ranges: LAS quartile 1, 29.8 to 37.8, n = 315; quartile 2, 37.9 to 42.4, n = 313; quartile 3, 42.5 to 51.9, n = 314; and quartile 4, 52.0 to 94.1, n = 314.
Baseline Characteristics
There were distinct differences in baseline characteristics among patients across the range of LAS (Table 1). As expected, patients with low LAS (quartile 1) were younger, with lower oxygen requirements and greater 6-minute walking distances. Of patients in the highest LAS quartile, 11.8% were receiving mechanical ventilation before LTx. Furthermore, pulmonary artery pressures (both mean and systolic) were lower with decreasing LAS (p < 0.001 for each).
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LAS, Survival, and Interaction With Procedure Type
When examining the entire IPF cohort, patients in the highest LAS quartile had 7.1% lower cumulative survival at 1 year when compared with patients in quartiles 1 to 3 (p = 0.02; Fig 3). On visual inspection of Martingale residuals over LAS, the risk of 1-year mortality with SLT diverged from that of BLT as LAS scores increased, indicating a necessity to examine interaction in the model (Fig 4).
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Cumulative Survival in the Stratified Sample
The effect modification observed on the initial exploratory model allowed stratification by LAS quartiles. For patients in LAS quartiles 2 and 4, BLT was associated with a significant increase in survival at 1 year after LTx (88.1% versus 74.2%, p = 0.009 in quartile 2; and 79.7% versus 65.3%, p = 0.03 in quartile 4; Table 3). Single lung transplantation was associated with a 6% improvement in cumulative survival at 90 days in the lowest LAS quartile (LAS 29.8 to 37.8). No differences in unadjusted Kaplan-Meier cumulative survival percentages were observed at any other time point (30 or 90 days after LTx). Comparison of patients in quartile 4 (high risk) with those in quartiles 1 to 3 (low risk) showed that high-risk patients had improved cumulative survival at 1 year with BLT (Fig 5). Overall, the lowest cumulative survival at 1 year of follow-up was 65.3% for high-risk patients receiving SLT (Table 3). The incidence rate for death in this group was 42.5 deaths per 100 person-years. The lowest cumulative incidence for death was in quartile 2, for patients receiving BLT, with a cumulative incidence of 12.6 deaths per 100 person-years.
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Multivariable Analysis Over Ranges of LAS
Examination of the hazard of 1-year mortality by 10-point LAS cutoffs revealed a general trend toward increasing hazard for death with increasing LAS. The risk of death became significant (95% confidence intervals not overlapping 1) when patients with LAS score of 50 or greater were evaluated in the model (Fig 6).
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Comment |
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As expected, patients with high LAS were of high preoperative clinical acuity, with higher rates of mechanical ventilation and ICU care, shorter 6-minute walking distances, and greater oxygen requirements at baseline. Importantly, LAS score was inversely correlated with waitlist times, indicating that organs were allocated in accordance with patient LAS. Notably, high-risk patients received BLT at a rate 21% higher than did patients in the lowest risk group. This trend indicates that LTx surgeons are already performing BLT with increased frequency for high-risk IPF patients . Of note, mean institutional volume did not vary with LAS quartile, indicating that high-acuity patients did not receive BLT simply because they were treated at high-volume centers.
Importantly, SLT only increased the risk of cumulative mortality at 1 year after LTx (by 14.4%) in the highest risk LAS quartile. Within this high-risk quartile, the risk of SLT continued to increase with increasing lung allocation scores. The approximate doubling of the risk of 1-year mortality with SLT for high-risk patients was consistently observed on univariate analysis, in the risk-adjusted model incorporating key covariates, and in two separate sensitivity analyses. The inclusion of mean pulmonary artery pressure (model B) provided evidence that the effect was not simply due to improvement in survival for patients with pulmonary hypertension receiving BLT.
For patients at lowest risk (those in quartile 1), SLT appeared to reduce the risk of 1-year death. This effect was significant on unadjusted analysis as well as in models B and C, and trended toward significance in model A. These data support SLT for IPF patients of very low risk.
A further important finding of the study was that cumulative survival at 30 days was not different between BLT and SLT in either risk group. Single lung transplantation has been advocated because of associated improvement in short-term mortality in IPF patients. However, in this study, SLT did not lead to improvement in early postoperative survival at any level of LAS.
BLT Versus SLT in IPF Patients
Idiopathic pulmonary fibrosis is a debilitating chronic lung disease with a typical transition to severe respiratory failure. It is now well established that survival is improved for IPF patients in respiratory failure who receive LTx [8]. The high acuity of these patients, however, underscores the importance of identifying the optimal surgical treatment to improve both short- and long-term survival.
Traditionally, SLT has been viewed as the appropriate technique for IPF patients undergoing LTx. The primary reason has been a reluctance to pursue a more complex procedure with longer ischemic times. Furthermore, it has been thought that high-acuity IPF patients would be less tolerant of the longer operative times associated with BLT. A large multi-institutional study affirming the use of SLT in IPF patients was conducted by Meyer and colleagues [1]. Utilizing UNOS data, the authors reported 821 patients with pulmonary fibrosis undergoing LTx. The primary findings of the study were that patients aged less than 60 years with pulmonary fibrosis derived short- and long-term survival benefits from SLT. The cohort examined underwent transplantation from 1994 to 2000. Similarly, Whelan and colleagues [9] observed that BLT was a risk factor for 90-day mortality among IPF patients undergoing LTx. Finally, a small study by Meyers and coworkers [2], examining 45 IPF patients, failed to show a difference in short-term survival with BLT versus SLT.
Recently, many centers have begun to utilize BLT extensively in LTx [3, 5, 10, 11]. Potential therapeutic benefits of BLT include a reduction in alveolar damage during reperfusion, improved pulmonary compliance and mechanics, and the avoidance of native lung pathology [4, 10]. In a study from our institution utilizing multi-institutional UNOS records, BLT led to equivalent long-term survival when compared with SLT for patients aged more than 60 years [5]. Mason and coworkers [4] reviewed 82 patients with IPF undergoing LTx at a single institution and found a significant reduction in survival for patients receiving SLT after adjustment for potential confounders. The conclusion from this study, that BLT may improve survival for IPF patients, highlights a growing acceptance of BLT for patients with IPF.
From the current literature, there exists no definitive recommendation regarding BLT versus SLT in patients with IPF. Much of this ambiguity may be due to inability to identify high-risk subsets within the small patient samples in single centers. Our current study builds on the growing literature examining this issue and takes an important next step by specifically examining IPF patients stratified by risk in a modern cohort using multi-institutional data. In contrast to UNOS data presented by Meyer and colleagues [1], our study fails to show any differences in survival between BLT and SLT for younger patients. This point may be indicative of the increased experience with BLT since the year 2000. By risk-stratifying the cohort, the data clearly suggest an improvement in 1-year survival with BLT for high-risk patients only. Low-risk patients appeared to derive benefit from SLT, but that was not manifested by an improvement in short-term survival (30 days), which was not affected by lung transplant type in either risk set. We believe that this study provides important guidelines to aid clinicians in LTx for IPF patients.
Resource Utilization
The issue of single versus double LTx expands beyond that of survival alone. Definitive recommendation for BLT must be undertaken with caution, given shortages of donor organs in the United States. Although this study did not specifically address organ utilization, focusing instead on those patients who survived to receive transplantation, there was substantial improvement in 1-year survival with BLT for high-risk IPF patients. Further investigation utilizing UNOS data must be performed to address issues in organ utilization; however, increased experience with BLT nationwide highlights its place as an appropriate treatment for high-risk IPF patients.
Limitations
Our study is limited by its retrospective nature and lack of control of all potential confounders. The UNOS dataset provides limited follow-up and in some cases missing data, and assessment of important variables beyond survival, such as quality of life, are limited. As others have examined IPF patients in the pre-LAS era, it was our intention to focus the analysis only on patients who received LTx after implementation of the LAS. Thus, our sample size of 1,256 patients (although large when compared with single-center studies) is perhaps more limited than if we had utilized the entire UNOS dataset. Because of this, detailed subgroup analysis (for example, examining patients over age 65 in the high-risk cohort) yielded statistical power too low for definitive conclusions. We attempted to control for this by incorporating covariates of interest into our multivariable models. However, we acknowledge that there may be important confounders unaccounted for in this analysis. Finally, we cannot confirm that errors in coding do not exist, although we have made the assumption that these in general are random and unlikely to bias the results.
In conclusion, in this analysis, we have provided important data, likely to aid physicians in determining whether bilateral or single LTx is appropriate for patients with IPF based on LAS. The LAS predicts survival at 1 year after LTx. High-risk IPF patients (as assessed by LAS) have significantly improved survival with BLT at 1 year after transplant when compared with patients receiving SLT. Patients of very low risk derive benefit from SLT. Technique does not affect 30-day survival in any risk set. These data strongly suggest consideration of BLT for high-risk patients with IPF.
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Discussion |
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TopAbstractIntroductionMaterial and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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The simple interpretation would suggest that we perform only double-lung transplants in IPF recipients with an LAS greater than 52. However, this suggests an even greater reliance on an imperfect tool, the LAS system, as opposed to sound clinical and ethical judgment. Although, when it was introduced, the LAS was supposed to fall as the patient's likelihood of posttransplant survival diminished, that does not occur. The 70-year-old recipient awaiting transplant on a ventilator in renal failure who is malnourished and bedbound will have an extremely high priority despite grim hopes for a positive outcome. In practice, as we drift from utility toward futility, the LAS does not fall. Is it better to give two lungs to an older, highly sick IPF recipient as opposed to the young cystic fibrosis patient with a predicted 5-year survival of 70% to 80%? As that question hangs in the air, high-acuity, older IPF recipients continue to repopulate the tops of waitlists around the country. I have three questions for you.
First, do you think the LAS works well and appropriately prioritizes the ill IPF recipient over others? If not, then caution should be exercised in applying your findings since they will serve to amplify current allocation trends.
Second, assuming the LAS is only a surrogate for clinical variables that actually determine the need for double as opposed to single lung transplant, do you have any insights into which variables we should use to make that decision?
And finally, as UNOS looks to incorporate 3-year posttransplant outcomes into the LAS, and with 3-year data available on at least some of the patients in your study, do you have any longer-term survival data to demonstrate whether these trends seen at 1 year will persist? Clearly, 1-year date is not sufficient to assess the overall survival benefit, and at least 3-year and, preferably, 5-year data are required. Again, congratulations on a well-conducted study, a fine presentation, and an excellent manuscript.
DR WEISS: Thank you very much, Dr Mulligan, for your comments and critique of our manuscript and study. I certainly agree with you that this is clearly a controversial issue, and it is difficult to know where to place priorities in terms of single versus double lung allocation in the post-LAS era. Your initial comment points perhaps to a more ethical than scientific question and is certainly difficult to address from our current study. I think that it falls upon clinicians to appropriately list patients with meaningful chances of survival. I would add that the frail 70-year-old with IPF on a ventilator that you mentioned would not be listed for lung transplantation at our institution.
Whether or not the LAS works well is a difficult question to answer. Certainly the LAS score predicts mortality. Our groups has shown in previous work that the LAS score predicts short-term mortality in an incremental fashion. Does it appropriately allocate organs? That question cannot be answered from the current study. We did not examine waitlist data to ascertain whether the LAS has an impact in preventing mortality on the waitlist.
There have been a multitude of studies that have looked at predictors of short-term and cumulative mortality in lung transplantation. I believe that the best predictor is a combination of several different variables. Certainly ischemic time is important, age is certainly important, as well as the other variables that are identified in the LAS scoring system, such as pulmonary artery pressures and 6-minute walking distance. Do we have long-term data? Unfortunately, no, we don't. The LAS system has only been in place since May of 2005, so it is difficult to comment on long-term trends since its implementation. This is something that we will continue to accrue as we move forward with the LAS system, and will certainly be the subject of future investigation.
DR JOSHUA ROBERT SONETT (New York, NY): We have looked at the UNOS data and showed that a high LAS score and a low-volume center increases the mortality. So in terms of your data and looking at this, for those that had deaths, was there any correlation for a high- and low-volume center, and could that have skewed the overall results of the data?
DR WEISS: Thank you, Dr Sonett, for the question. I absolutely agree with you that institutional volume plays a substantial role in influencing mortality in lung transplantation. We are presenting a paper later in this meeting that directly addresses that issue. In the current study, we attempted to control for confounding related to volume by adjusting for institutional volume in the analysis.
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Acknowledgments |
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TopAbstractIntroductionMaterial and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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References |
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TopAbstractIntroductionMaterial and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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This article has been cited by other articles:
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  N. C. De Oliveira, S. Osaki, J. Maloney, R. D. Cornwell, and K. C. Meyer Lung transplant for interstitial lung disease: outcomes for single versus bilateral lung transplantation Interact CardioVasc Thorac Surg, December 16, 2011; (2011) ivr085v1. [Abstract] [Full Text] [PDF]
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 T. J. George, G. J. Arnaoutakis, and A. S. Shah Lung Transplant in Idiopathic Pulmonary Fibrosis Arch Surg, October 1, 2011; 146(10): 1204 - 1209. [Abstract] [Full Text] [PDF]
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 S. D. Force, P. Kilgo, D. C. Neujahr, A. Pelaez, A. Pickens, F. G. Fernandez, D. L. Miller, and C. Lawrence Bilateral Lung Transplantation Offers Better Long-Term Survival, Compared With Single-Lung Transplantation, for Younger Patients With Idiopathic Pulmonary Fibrosis Ann. Thorac. Surg., January 1, 2011; 91(1): 244 - 249. [Abstract] [Full Text] [PDF]
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