Lung (2009) 187:383–387 DOI 10.1007/s00408-009-9180-4
COPD
The Lung Allocation Score and Survival in Lung Transplant Candidates with Chronic Obstructive Pulmonary Disease David R. Nunley • Gerene S. Bauldoff • Christopher H. Holloman • Amy Pope-Harman
Received: 1 May 2009 / Accepted: 9 September 2009 / Published online: 6 October 2009 Ó Springer Science+Business Media, LLC 2009
Abstract The Lung Allocation Score (LAS), devised to prioritize candidates awaiting lung transplantation (LTX), is calculated using the predicted duration of survival on the wait list while also considering the recipient’s likelihood of post-transplant survival. This score is generated based, in part, on the severity of the candidate’s comorbid illnesses. The actual relationship between the LAS and survival is unknown. The current study was performed to evaluate the relationship between the LAS and both wait-list survival and post-transplant survival in candidates with COPD. The study was a retrospective analysis of 41 LTX candidates with chronic obstructive pulmonary disease (COPD) as well as a cohort of 17 candidates who survived to receive a graft. The study was conducted at a university hospital transplant center. Thirty-six of 41 candidates survived to transplant. The LAS of these survivors was 32.62 ± 1.06 and was significantly lower than the score of 34.45 ± 1.19 of the nonsurvivors (P \ 0.01). The LAS also exhibited a negative association with survival to transplant (P \ 0.05, b = 1.39). A cohort of 17 LTX recipients was chosen for posttransplant analysis in which 13 survived at least 1 year. In this cohort the LAS did not exhibit significant association with 1-year post-transplant survival (P = 0.58, b = 0.25). As might be anticipated by virtue of its calculation D. R. Nunley (&) A. Pope-Harman The Ohio State University College of Medicine, Columbus, OH, USA e-mail:
[email protected] G. S. Bauldoff The Ohio State University College of Nursing, Columbus, OH, USA C. H. Holloman Department of Statistics, The Ohio State University, Columbus, OH, USA
being based in part on the existence and severity of comorbid conditions, a lower LAS was associated with improved survival to transplantation in LTX candidates with COPD. However, the pretransplant calculation of the LAS was not associated with actual post-transplant survival. Keywords Lung Allocation Score COPD Lung transplantation
Introduction In May 2005, the United Network of Organ Sharing (UNOS) abandoned their lung allograft allocation system, which assigned a rank order to transplant candidates based only on the time they had accrued on a waiting list at a given transplant center, in favor of a strategy that involved the calculation of a Lung Allocation Score (LAS). Rather than assigning priority based on time on the waiting list, the LAS is based on several of the candidate’s physical parameters and comorbidities. The LAS attempts to rank candidates on a scale ranging from 0 to 100 based on the urgency of their need by accounting for the probability that a candidate will (1) survive until he/she receives a suitable organ and (2) survive at least 1 year following transplantation. The implication of this system is that the higher the LAS assigned, the more ill the candidate, and therefore the less time remains to be matched to a suitable organ. Considering that the calculation of LAS is based, in part, on the probability of post-transplant survival, an additional implication of this system is that one might expect to observe a correlation between the LAS and actual posttransplant survival. Since its inception there has been controversy regarding whether the LAS would be useful in achieving the goals of
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correctly identifying those candidates who were more ill and therefore in more immediate need of a transplant while also favoring those with acceptable post-transplant survival. Typically, patients with significant pulmonary dysfunction resulting from diseases such as cystic fibrosis (CF) and idiopathic pulmonary fibrosis (IPF) tend to be more ill and thus generate a higher LAS. While clear indications exist for lung transplantation (LTX) in this group, patients with chronic obstructive pulmonary disease (COPD) experience a slower rate of decline with respect to their physical limitations and pulmonary function and thus tend not to generate such high scores [1]. This has led some experts to express concern that this group of patients may be unfairly disadvantaged under the new system by delaying their opportunity to receive a suitable organ [2]. This controversy is even more charged when one considers the further evidence that recipients with COPD may not derive any survival benefit from LTX [3]. We hypothesize that the LAS does not accurately reflect both the likelihood of pretransplant wait- list survival and at least 1-year post-transplant survival in the COPD population. To address this we retrospectively reviewed our experience with transplant candidates and recipients with respect to the following questions: (1) Is there any association between the assigned LAS and surviving to receive a transplant, and if so, is survival directly or inversely related to an increasing LAS? (2) Is there any association between the pretransplant calculation of the LAS and actual survival time following transplantation?
Methods Sample Chronic obstructive pulmonary disease encompasses many pathologic entities, but because our program is replete with candidates having COPD from smoking-related emphysema and/or chronic bronchitis and because considerable controversy surrounds this group with respect to the new allocation system, these patients were chosen for analysis. Four candidates with a-1-antitrypsin deficiency (but who also had a smoking history) were included in the analysis. All candidates with COPD met the standard criteria for airflow limitation and were listed for transplantation in accordance with standard guidelines [4, 5]. Demographic and clinical information for patient groups is outlined in Table 1. Design and Procedures For candidates evaluated after January 1, 2000, a comprehensive retrospective review was conducted of the data obtained at the time of their listing for transplantation.
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Lung (2009) 187:383–387 Table 1 Demographic and clinical information for patient groups Variable
Range
Mean/count
SD/percent
56.10
±7.32
22/19
54/46%
LTX candidates (n = 41) Age (years)
38-66
Male/female FVC% predicted
19-84%
45.60%
±14.80%
LTOT l/min
0-4
2.05
±0.69
PCO2 mmHg
33–76
49.20
±9.10
PAPm mmHg
12–53
25.83
±7.35
BMI (kg/m2)
16–35
24.02
±4.82
3/38
7/93%
238.05
±96.86
57
±6.11
Diabetes: yes/no 6 MW (m)
53.0-470.9
LTX recipients (n = 17) Age (years) 40-66 Male/female FVC% predicted
19-84%
9/8
53/47%
45.60%
±14.80% ±0.53
LTOT l/min
0-2.5
1.94
PCO2 mmHg
33-76
48.40
±10.70
PAPm mmHg
18-35
25.18
±5.18
BMI (kg/m2)
18-36
24.24
±4.83
1/16
6/94%
266.70
±87.39
Diabetes: yes/no 6 MW (m)
149.0–470.9
SD Standard deviation, FVC% forced vital capacity percent predicted, LTOT long-term oxygen therapy, PCO2 partial pressure carbon dioxide, PAPm mean pulmonary artery pressure, BMI body mass index, 6 MW 6-minute walk distance
Each of these candidates was wait-listed in accordance with the previously used ‘‘time accrued’’ system. While not utilized for determining their position on the waiting list, the accumulated data available at the time of their listing was used to retrospectively calculate the LAS. The LAS was calculated by using the equations to predict ‘‘waiting list survival probability during the next year’’ and ‘‘posttransplant survival probability during the first post-transplant year’’ [6]. Of the COPD candidates assigned a LAS, not all survived to transplant thus creating a scenario that allowed for an evaluation of the score’s potential association with candidate survival. To assess the association of the LAS with 1-year posttransplant survival, a cohort of those COPD candidates who survived to receive grafts was reviewed. The cohort comprised all candidates who received single lung grafts after July 1, 2002, and for whom follow-up data were available. Instead of using all of the candidates who survived to receive a transplant, this cohort was chosen because their data could be standardized against national survival statistics and still permit for the collection of follow-up data for at least 1 year following transplantation. The LTX program at our institution commenced in November 1998 and, as with many new programs, there was an early period where outcomes did not attain national
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Data are expressed as mean (±SD) unless otherwise stated (Table 1). Between study groups, the distributions of continuous data were compared using the Wilcoxon rank sum test. Logistic regression analysis was used to evaluate the association between linear and dichotomous data. Cox proportional hazard model was used to analyze risk changes over time with respect to specified parameters. A P value of less than 0.05 was considered to be significant.
Results During the study period, 41 candidates with COPD were listed for transplantation and thus provided the various groups and cohorts that were analyzed (Fig. 1). Review of the calculated LAS for these 41 candidates revealed that these data were normally distributed. Of these candidates, 36 survived to receive a single lung graft (left = 14, right = 22). No double-lung transplants were performed for COPD during the study interval. The mean (±SD) LAS calculated for those who survived to receive a transplant was 32.62 ± 1.06 and was statistically lower than the mean score of 34.45 ± 1.19 for those five candidates who did not survive to transplant (P \ 0.01) (Fig. 2). Furthermore, in these 41 candidates the LAS exhibited a negative association with respect to wait-list survival to transplant (P \ 0.05, b = -1.39, exp(b) = 0.25, 95% CI = 0.080.75), suggesting that the lower the LAS, the more likely one was to survive to receive a transplant.
COPD Transplant Candidates (n=41)
Died on wait list (n=5) Not meeting criteria for analysis (n=19)
Survived to transplant (n=36)
Study Cohort (n=17)
Fig. 1 Study population
P < 0.01
37 36 35 34 33 32 31 30
Statistical Analysis
Survived > 1 year (n=13)
38
LAS
standards. During the first 3.5 years of our program, fewer than 75% of our recipients survived their first post-transplant year, while survival in subsequent years exceeded this benchmark. Therefore, in an effort to control for the potential confounders encountered during this ‘‘start-up’’ period, we selected the cohort after which our program’s 1year post-transplant survival improved to be comparable with national 1-year post-transplant survival rates [7].
Survived < 1 year (n=4)
Died while awaiting transplant (n=5) X=34.45 + 1.19
Survived to transplant (n=36) X=32.62 + 1.06
Fig. 2 LAS and survival to transplant
Of the 36 candidates (from the original 41) who survived the wait list to undergo transplantation, 19 were excluded from post-transplant analysis because their procedures were performed during the ‘‘start-up’’ period of our program and were subject to several potential confounders that may have contributed to a disproportionately high early mortality. An analysis was performed of the remaining 17 COPD candidates who were listed after July 1, 2002, and received a single lung graft. Thirteen of these 17 (77%) survived at least 1 year following transplantation. Analysis using the Cox proportional hazard model, including the right-censored data, failed to demonstrate any significant association of the LAS with post-transplant survival [P = 0.58, b = 0.25, exp(b) = 1.29, 95% CI = 0.53–3.13].
Discussion While LTX has become an increasingly viable option for patients with end-stage lung disease, there has developed a growing disparity between the availability of suitable donor organs and the number of candidates on the waiting list [8]. As waiting times increased, evidence amassed suggesting that a candidate’s ability to survive the waiting period was associated with his/her specific type of lung disease. For example, it is now recognized that transplant candidates with COPD are more likely to survive for longer waiting periods than candidates with IPF [9, 10]. This observation along with the relative scarcity of suitable donor organs has led to the development of the LAS. The previously utilized system of assigning candidate priority based on the waiting time accrued was replaced with this newer strategy that considers not only a candidate’s ability to tolerate waiting for donor organs, but also the probability of post-transplant survival. Unfortunately, almost from its inception there has been controversy surrounding the equity of this new allocation system [2]. One of the early criticisms was that under the
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new system candidates with COPD might be disadvantaged with respect to receiving a transplant because of their relative stability and likelihood of surviving for longer waiting periods. Many believed that the scoring system made it more likely for those with IPF or other lung diseases to preferentially receive a transplant compared to those with COPD. Indeed, to date experience with the new system has suggested that a greater percentage of candidates with IPF receive a lung graft compared with candidates with COPD [1]. Proponents of the new system partially justify this criticism by reminding us that there exist data suggesting that any lung transplant procedure may not necessarily improve survival in patients with COPD [3, 11]. It is for these reasons, together with the fact that COPD patients comprise the largest volume of candidates at our center that we chose to examine how the new allocation system may affect this specific population. The LAS is assigned with a value from 0 to 100, where the greater the assigned value, the higher the priority that is given to receive an available organ. It is calculated from a complicated statistical derivation that attempts to account for the probability of wait-list survival by analyzing the number and severity of comorbid conditions experienced by a given candidate [6]. Thus, a lower LAS should reflect a healthier candidate and one that might be expected to have a better chance of surviving the wait-list period. Conversely, a higher LAS is designed to indicate a more seriously ill candidate who may not have the luxury of an extended waiting period and therefore may be in more immediate need of an available organ. In a retrospective fashion, our pilot investigation attempted to ascertain whether the LAS is indeed useful for estimating the probability of candidate survival until the time of transplant. The data suggest that in our population of COPD candidates, those with a lower LAS had a significantly improved chance of surviving to receive a transplant. This finding may not be surprising since the lower LAS should identify candidates with a lower severity of illness and, therefore might be expected to have a better chance of surviving on the wait list. Thus, the use of the LAS to identify those COPD candidates in more immediate need of a transplant would appear to be justified by accurately stratifying survival potential while awaiting a transplant. There are limited data from other transplant centers with regard to the LAS and wait-list survival, but one study from the University of California-San Francisco has suggested that candidates with COPD (as well as those with CF) experience no increased risk with respect to waitlist mortality [12]. Those same authors further conclude that only those candidates with idiopathic pulmonary hypertension (IPAH) incur an increased risk of wait-list mortality since the implementation of the new allocation system.
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In addition to the number and severity of comorbid conditions and the likelihood of surviving on the wait list, the LAS is also calculated based on the probability of posttransplant survival. If accurate, it might be expected that the LAS would have some association or correlation with actual post-transplant survival. One might expect that a higher LAS would indicate a more severely compromised candidate at the time of transplant and therefore translate to a worse post-transplant survival time. Conversely, it could be argued that those with a higher LAS might exhibit improved post-transplant survival by more quickly receiving their graft before experiencing further deterioration of their health as a consequence of their native lung disease. Larger LTX programs are just now acquiring enough experience under the new allocation system to discuss their observations with respect to post-transplant survival. In a report from Johns Hopkins University, 1-year post-transplant survival was significantly worse for all recipients with higher pretransplant LAS [13]. This finding was most pronounced in the group of recipients with IPF who, the authors concluded, tended to preferentially receive a greater number of available grafts compared to before the new allocation scheme was implemented. All do not share this view. The experience from the University of Washington in Seattle suggests that despite a relative increase in the number of transplants performed for IPF, when age and diagnosis are controlled, neither wait list nor post-transplant survival time is affected by the LAS [14]. Other centers have confirmed the University of Washington’s observations noting no significant difference in posttransplant survival for those with CF, COPD, IPF, or IPAH since the new allocation system has been in effect [12]. Some programs have observed that those with increased pretransplant LAS experienced a post-transplant increase in the prevalence of high-grade primary graft dysfunction, increased time on the ventilator, increased length of stay in the ICU, and reduced 6-month graft survival [15]. Conversely, others have so far observed no such increase in these major post-transplant complications [16]. Our data collected from COPD candidates likewise suggests no correlation with improved post-transplant survival, but neither does it correlate with a worse post-transplant outcome. Of course, there exist potential sources of error in our pilot investigation that warrant consideration. In addition to using the experience of a single transplant center, one potential error that clearly is deserving of comment is the timing of the data collection used for the LAS calculation. Since its implementation, the LAS has been calculated at the time a candidate is listed for transplantation, but it can be recalculated as new data become available. If a candidate’s health status is changing, this recalculation allows
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for assignment of a different LAS and thus a potential change in the candidate’s position on the waiting list. For our pilot investigation, only data acquired at the time of listing was utilized in our retrospective calculation of the LAS and no recalculation was performed. We cannot exclude the possibility that if the LAS had been recalculated as the candidate’s health changed, the adjusted scores might have proven to better correlate with post-transplant outcomes. While our investigation revealed a statistically significant association between the LAS and survival to transplant, we were unable to demonstrate any association with post-transplant survival. It is therefore possible that our study may be not be sufficiently powered to demonstrate any association between the LAS and post-transplant survival given that such an association indeed exists. A post hoc analysis using a Monte Carlo approach demonstrated that an analysis with at least 90 participants would be required to obtain 80% power and minimize the potential of a type II error. Therefore, this pilot investigation may suggest that there is no association between the LAS and post-transplant survival but it can make no definitive conclusion regarding this relationship. While the LAS is calculated with attention to multiple variables of a candidate’s health, it is possible that other potential confounders exist that may have obscured our ability to detect any associations between the LAS and survival time. Such factors not accounted for in the calculation of the LAS that could influence post-transplant survival may include items such as post-transplant allograft rejection, infectious and surgical complications, and other organ dysfunction. Unfortunately, a larger patient sample would be necessary for us to perform the needed multivariate analysis in order to identify such variables. In summary, in a sample of LTX candidates with COPD, as expected, a lower LAS is associated with improved survival to transplant. However, even though the LAS is also calculated in part on the probability of surviving at least 1-year following transplant, no association with posttransplant survival was observed. The results of this pilot investigation require confirmation using a prospective design and larger sample size as well as additional evaluation in other populations with end-stage lung disease.
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