Liou TG, Adler FR, Cahill BC, FitzSimmons SC, Huang D, Hibbs JR, Marshall BC. Survival Effect of Lung Transplantation Among Patients With Cystic Fibrosis. JAMA. 2001;286(21):2683-2689. doi:10.1001/jama.286.21.2683
Author Affiliations: Division of Respiratory, Critical Care and Occupational Pulmonary Medicine (Drs Liou, Cahill, and Marshall), Departments of Mathematics and Biology (Dr Adler), Lung Transplantation Program (Dr Cahill), and Intermountain Cystic Fibrosis Center (Drs Liou and Marshall), University of Utah, Salt Lake City; Medical Department, Cystic Fibrosis Foundation, Bethesda, Md (Dr FitzSimmons); Salt Lake Veterans Affairs Medical Center, Salt Lake City, Utah (Dr Marshall); School of Public Health, University of California, Los Angeles (Dr Huang); and the New York State Department of Health, Albany (Dr Hibbs). Dr FitzSimmons is now with FitzSimmons and Associates.
Context Patients with cystic fibrosis (CF) are the second largest group of lung
transplant recipients in the United States. The survival effect of transplantation
on a general CF population has not previously been measured.
Objective To determine the impact of bilateral lung transplantation on survival
in patients with CF.
Design, Setting, and Patients Retrospective observational cohort study of 11 630 CF patients
who did not undergo lung transplantation (controls) and 468 transplant recipients
with CF from 115 CF centers in the United States, 1992-1998. Patients were
stratified into 5 groups based on a 5-year survival prediction model (survival
group 1: <30%; survival group 2: 30 to <50%; survival groups 3-5: 50
Main Outcome Measure Five-year survival from date of transplantation in 1992-1997 in the
transplant group and from January 1, 1993, in the control group.
Results Lung transplantation increased 5-year survival of CF patients in survival
group 1. Survival group 2 had equivocal survival effects, and groups 3-5 had
negative survival effects from transplantation. From 1994-1997, there was
a mean annual prevalence of 238 patients in survival group 1 and mean annual
incidence of 154 patients entering the group, approximately 1.5 times the
number of lung transplantations performed each year in CF patients (mean,
104). Use of the criterion of forced expiratory volume in 1 second of less
than 30% resulted in an equivocal survival benefit and identified 1458 potential
candidates for transplantation in 1993.
Conclusions Cystic fibrosis patients in group 1 have improved 5-year survival after
lung transplantation. The majority of patients with CF have equivocal or negative
survival effects from the procedure. Selection of patients with CF for transplantation
based on group 1 survival predictions maximizes survival benefits to individuals
and may reduce the demand for scarce donor organs.
Cystic fibrosis (CF) is an autosomal recessive, multisystem disease
leading to significant morbidities and early death. Treatments for pancreatic
and pulmonary manifestations have improved median survival in the United States
from less than 6 months to about 32 years in 1998.1
Severe pulmonary disease is the primary cause of mortality in CF, underlying
76.4% of deaths in 1998.1
Multiple medical therapies specifically treat CF-related pulmonary disease.
However, lung transplantation is the most aggressive therapy available for
CF patients with severe pulmonary disease.2- 4
Bilateral lung transplantation, introduced in 1988, is now the most widely
used technique.2 Cystic fibrosis is the second
most common indication for lung transplantation,5
and lung transplantation–related deaths are the second most common cause
of death in CF patients.1 The current demand
for donated lungs exceeds the available supply.6
Approximately 11% of all patients awaiting lung transplantation in 1998 died
prior to receiving an organ.5
Despite the high costs, high risks of morbidity, and unmeasured survival
benefit, a rigorous, prospective clinical trial of lung transplantation has
not been and probably will not ever be performed. A recent estimate of the
survival effect of lung transplantation comparing survival among CF patients
posttransplantation with survival of those on the waiting list is limited
in generalizability because it studied highly selected CF patients.7 Deaths of patients on the wait list may have created
a survivor bias for patients who actually received transplants. Which patients
should be referred, when referrals should be made, and what survival effect
results from transplantation are questions that remain unanswered.
Since 1992, patient selection for transplantation has been heavily influenced
by a survival model based on percent predicted forced expiratory volume in
1 second (FEV1%).8 That model suggested
that the 2-year mortality rate approaches or exceeds 50% for CF patients with
an FEV1 less than 30%, and that these patients should be considered
for lung transplantation. However, while this model continues to influence
patient selection for transplantation,9,10
it fails to identify the high-mortality population originally intended.8,11,12
Recent consensus statements suggest the use of FEV1% along
with a number of other clinical factors such as PCO2 and PO2 values, female sex, increasing numbers of hospitalizations, rate of
decline of FEV1%, and increasing cachexia.9,10
Other clinical factors, especially the number of acute exacerbations and poor
nutrition, have been shown to be correlated with survival, but only when combined
with multiple other variables.13
We recently developed and validated a multivariable logistic regression
survivorship model for CF.13 The model includes
multiple clinical features of CF and is generalizable to the majority of CF
patients. It includes most of the consensus criteria for lung transplantation
and quantitatively shows the relative impact of each variable on survival.
Application of the model allows measurement of the impact of lung transplantation
performed in the United States from 1992 through 1997 on CF survival.
We used data from the CF Foundation Patient Registry (CFFPR), which
contains longitudinal data on 27 849 patients at 115 CF care centers,
representing approximately 90% of all CF patients in the United States.1 Reports for each patient, containing a wide range
of clinical data, are submitted annually to the CFFPR. Over 300 pieces of
clinical and socioeconomic data, including survival status and death dates,
are recorded annually. Our application to use registry data was reviewed and
approved by the data access committee at the CF Foundation. Our study was
also reviewed by the institutional review board of the University of Utah.
We received access to a longitudinal database for the years 1986 through 1997
which was later updated with 1998 mortality data.
Patients in the CFFPR who were alive on January 1, 1993, were eligible
for inclusion in the control group if they had survival data through December
31, 1997 and had pulmonary function data. Patients were excluded if they lacked
data needed to calculate a 5-year survival prediction or if they received
any type of solid organ transplant prior to December 31, 1997.
Patients in the CFFPR who received bilateral lung transplantation from
January 1, 1992 through December 31, 1997 without other solid organ transplantation
were eligible for inclusion in the transplant group if they had survival data
through December 31, 1997 or for 5 years following transplantation and had
pretransplantation pulmonary function data. We chose 1992 because it was the
first year in which substantial numbers of bilateral lung transplants were
done in the United States. We included patients through 1997 because overall
posttransplantation survival rates have not changed.5
Including patients from 1992 through 1997 provided a large enough population
for sufficient statistical power. Patients were excluded if they lacked the
additional pretransplantation data needed for 5-year survival predictions.
To ascertain transplantation dates, we requested data from the United Network
for Organ Sharing (UNOS) Web site (http://www.unos.org) for all
patients who received any type of lung transplantation for CF through 1997.
To predict 5-year survival for CF patients, we used a multivariable
logistic regression model, fully described elsewhere.13
This model estimates the likelihood of survival for 5 years from the day of
calculation based on 9 clinically relevant and commonly assessed variables
(Table 1). The model was developed
using data derived from 5810 patients in the 1993 CFFPR with survival data
through 1997 and was validated using data from an additional 5820 patients
from 1993. Approximately 92% of patients older than 5.5 years were included
in the development and validation of the model. Thus the model is generalizable
to CF patients older than 5.5 years who have undergone pulmonary function
testing. Other models derived from small cohorts or highly selected cohorts
may not be so generalizable and may not allow an evaluation of the survival
effect of transplantation on a general population of CF patients.7,8,14,15 The
new model makes predictions that are more accurate than predictions made by
models that include FEV1% or age, sex, and FEV1%,8 and it is easier and more precise to use than older
models that include large, subjective components.16,17
Survival predictions for patients who received lung transplantation
were based on data collected within the 24 months prior to transplantation.
The CFFPR does not include a transplant wait-listing date; however, once listed,
patients wait approximately 2 years for the procedure.5
Many transplant candidates have little data reported to the CFFPR in the last
year prior to transplantation.
Survival predictions for control patients were based on data from 1993.
Additional predictions among nontransplanted patients for 1994 through 1997
were based on data gathered during each of those years.
Nine variables were included in the model (Table 1). Raw spirometry measurements of FEV1 were normalized
to FEV1% using regression formulae from the third National Health
and Nutrition Evaluation Survey.18 The sex,
weight, and age of each patient were used to determine the appropriate median
weight-for-age,19 and z
score was calculated using approximation methods.20,21
Binary variables were assigned a value of 1 if present and 0 if absent pretransplant
in the transplant group in 1993 for the control group, or in another year
of interest for nontransplanted patients. The number of acute pulmonary exacerbations
were counted up to a maximum of 5 per year. Additional exacerbations do not
further decrease predicted survival.13 For
patients receiving transplants, we used the number of acute exacerbations
during the calendar year prior to the year of transplantation. S-plus version
3.4 (Mathsoft Inc, Cambridge, Mass) was used for all analyses.
Our model produces survival predictions for the day of calculation.13 We calculated the 5-year conditional probability
of survival for each control patient on January 1, 1993 and for each transplant
recipient on the day of transplantation. We stratified patients into 5 groups
according to 5-year predicted survival: group 1, <30%; group 2, 30% to
<50%; group 3, 50% to <70%; group 4, 70% to <90%; and group 5, 90%
to <100%. Within each survival stratum, we used Kaplan-Meier survival analysis
to examine the effect of lung transplantation during the 5-year follow-up
period (log-rank test).
Because current practice in the selection of lung transplantation candidates
is influenced by FEV1%,8- 10
we performed a parallel analysis of the survival benefit of lung transplantation
using that parameter alone. We stratified the patients into 2 groups (FEV1 ≤30% and FEV1 >30%) and used Kaplan-Meier survival analysis
to examine the effect of lung transplantation during 5 years of follow-up.
We assessed our methods for potential bias. Data for transplanted patients
were gathered within 24 months prior to transplantation rather than during
12 months as for controls. We compared 5-year survival predictions made on
the basis of data gathered less than 12 months prior to transplant to predictions
made based on older data. To assess survival effect due to such bias, we repeated
Kaplan-Meier survival analysis using only transplant patients with data within
the final pretransplant year.
We estimated bias from including wait list deaths but not wait list
survival in the analysis of control patients. Kaplan-Meier analysis was repeated
to elucidate any change in survival effect of lung transplantation.
Finally, there was a subtle bias introduced because development and
validation of the predictive model excluded patients who received solid organ
transplantation.13 Patients chosen for transplantation
who survive the wait list period and receive a transplant prove themselves
to be more likely to survive than patients who die while on the wait list.
This bias might increase the apparent survival benefit of lung transplantation.
We compared the effect of using the FEV1% criterion vs the
validated model for selecting candidates for lung transplantation from the
1993 CFFPR. We calculated 5-year predicted survival for all nontransplanted
patients for each year from 1994 through 1997 to discover how many patients
might be chosen for lung transplantation after stratification into survival
groups using the validated survival model.
The CFFPR contains 1993 data for 19 156 patients. Of these, 6470
were ineligible for inclusion in the control group: 730 patients received
solid organ transplantation of some type before the end of 1997, 54 belonged
to racial or ethnic groups for whom FEV1% standards do not exist,
and 5686 lacked FEV1 measurements. Of the latter, 4190 were younger
than 5.5 years, a group for whom FEV1 cannot be measured by standard
techniques. Out of 12 686 patients eligible, we excluded 1056 who lacked
data for microbiology, pancreatic sufficiency, diabetes, or acute exacerbation.
The remaining 11 630 patients were the control group for this study (Table 2).
In the CFFPR, 692 patients received bilateral lung transplantation without
other organ transplantation from 1992 through 1997. We excluded 145 patients
for lack of pulmonary function data at any time before lung transplantation
and an additional 15 without pulmonary function data within 2 years prior
to transplantation. One patient was excluded for lack of standards to calculate
FEV1% for the patient's ethnicity and race. We excluded 12 patients
for lack of acute exacerbation data and an additional 49 patients for lack
of microbiology reports, pancreatic sufficiency status, or weight information.
Two patients were excluded for lack of a transplantation date. The remaining
468 patients were included in the transplantation group. Characteristics of
control and transplant patients within each survival stratum were well matched
Comparison of the Kaplan-Meier survivorship curves of 468 CF patients
who underwent lung transplantation from 1992 through 1997 to survivorship
curves of control patients demonstrated that survival effects of lung transplantation
were specific for each survival group (Figure
1).22 For group 1 patients, lung
transplantation was associated with slightly decreased survivorship during
the first 6 months after the procedure, but a survival advantage for transplanted
patients was evident by 2 years and increased with time (Figure 1, A). Patients in group 2 had an equivocal survival effect
5 years after transplantation but a survival disadvantage for the first 3
posttransplantation years (Figure 1,
B). Patients in groups 3 through 5 had a statistically significant decrease
in 5-year survival due to lung transplantation (Figure 1, C-E).
Kaplan-Meier analysis of survival for patients chosen using FEV1% as the only criterion for lung transplantation showed that the FEV1 less than 30% transplant group had a disadvantage for 3 years following
transplantation and equivocal benefit in the fourth and fifth years following
transplantation (Figure 1, F).
We made approximately half of the survival predictions for lung transplantation
recipients based on data collected before the 12 months prior to transplantation.
This could create a bias that decreases positive survival effects of transplantation
if patients move into lower survival groups while on the waiting list. Comparison
of predictions made based on data collected before and after this 1-year mark
demonstrated no decrease in predicted survival (P
= .17 by Kolmogorov-Smirnov test23). Kaplan-Meier
survival analysis using only the transplant patients with data collected within
the 12 months before transplantation showed the same results as our main analysis.
Patients selected for transplantation who die while on the waiting list
are not identified in the CFFPR. These deaths would be counted in the control
group while years of life on the waiting list by eventual transplant recipients
were excluded. This could create a bias that increases the apparent survival
benefit of transplantation by artifactually decreasing the survival of control
group patients. We stratified 316 patients in the 1993 CFFPR transplanted
after January 1, 1993, with the never-transplanted control patients and censored
them at the time of transplantation. At transplant, these patients were placed
in the appropriate transplant survival groups. Comparison of Kaplan-Meier
analysis of these groups of patients to our primary analysis showed that this
bias results in a maximum 4% underestimate of survival among the control groups
for groups 1 and 2, less than 2% for group 3, and less than 1% for groups
4 and 5 (data not shown). No change in benefit or harm from lung transplantation
resulted from this bias. For patients in group 2, the length of time of survival
disadvantage was extended by 3 or 4 months, which reinforces the result that
lung transplantation had equivocal survival effects for this group.
The potential underestimate of survival for patients who survive the
waiting list and receive lung transplantation is smaller than the biases just
discussed. No change in benefit or harm results for recipients of lung transplantation.
Use of the FEV1 less than 30% criterion identified 1458 CF
patients in 1993 as potential transplant recipients. For these patients, 5-year
predicted survival ranged from 6% to 94%. Patients with an FEV1
greater than 30% had survival predictions ranging from 13% to greater than
99%. FEV1 ranged below and above 30% for patients in all survival
groups (Table 3).
Survival benefit from transplantation occurred only in survival group
1. We identified 309 patients in the 1993 CFFPR in this group. There were
17 784 nontransplanted patients in the 1994 through 1997 CFFPR. After
calculation of 5-year survival predictions, we found that the mean number
of patients entering group 1 status each year was 154, approximately 1.5 times
the number of lung transplants performed each year for CF (Table 4).
We used a validated multivariable logistic regression model to quantify
the survivorship benefits of lung transplantation for CF. Our analysis indicates
that CF patients most likely to benefit from transplantation had a predicted
5-year survival of less than 30%. For this group, transplantation markedly
improved 5-year survival. There was equivocal survival benefit for patients
with 30% to 50% predicted survival. For the patients with predicted survival
of 50% or more, transplantation reduced survival.
Current practice considers patients for referral for lung transplantation
using a number of criteria, including FEV1 less than 30%.8- 10 However, our survival
curves demonstrated that the survival benefit is equivocal when patients are
selected by the FEV1 less than 30% criterion. This criterion was
originally proposed because it seemed to select patients with a less than
50% 2-year survival.8 It was hypothesized that
patients with low predicted survival have the greatest potential survival
benefit from lung transplantation. Using a validated survival model of CF,
we have demonstrated the truth of that original hypothesis.
Unfortunately, the survival model based on FEV1% may not
apply to CF populations outside of the original center where it was developed,11,12 and it does not validate in the large
CFFPR.13 The FEV1% criterion fails
to select the originally intended group of patients. In our study, use of
FEV1% alone selected a group of patients for lung transplantation
that had a wide range of 5-year survival predictions. This variability resulted
from the exclusion of other clinically relevant factors and makes estimates
of the true survival benefit of transplantation difficult. Our analysis suggested
that use of the FEV1% criterion leads to an equivocal survival
benefit for this heterogeneous group.
Using FEV1% as the primary criterion for lung transplantation
is fraught with potential difficulties. Requiring an FEV1 less
than 30% for lung transplantation might have excluded many patients in group
1 who had improved posttransplant survival. Conversely, a majority of transplanted
patients in groups 2 through 4 who had equivocal or negative survival effects
due to transplantation had an FEV1 less than 30%. These patients
had few of the negative factors identified in our model13
that determined 5-year survival.
When applied to patients in the 1993 CFFPR, the FEV1 less
than 30% criterion identified 1458 patients as potential transplant recipients.
Such an approach virtually guarantees that the waiting list for organs will
continue to grow. Patients in group 1 who have an FEV1 greater
than 30% would die without qualifying for transplantation. Many other patients
in group 1 would likely die while on the waiting list for lung transplantation.
Some have proposed that deaths on the waiting list would be reduced by referring
patients with higher FEV1% for transplantation (FEV1
<50%).24 This strategy would lengthen the
waiting list by identifying several thousand additional candidates with CF
for lung transplantation (data not shown) and lead to increased risk to patients
with low predicted survivorship.
The additional criteria proposed in recent consensus statements about
lung transplantation in CF are not quantified.9,10
The lack of specific guidelines makes application of these criteria difficult,
and rigorous assessment of impact on survival impossible.
In contrast, we show that use of our model13
to determine group 1 status and identify transplantation candidates conferred
greatly improved 5-year survival for recipients of the procedure. All other
patients had an equivocal or negative survival effect from transplantation.
This conclusion is unaffected after considering several biases that might
have changed our results.
Furthermore, the number of patients entering group 1 survival status
from 1994 to 1997 was approximately 1.5 times the number of transplants done
per year in patients followed by the CFFPR. Use of group 1 status as a transplantation
selection criterion may reduce the lung transplant waiting list among CF patients.
There are several limitations of this study. Retrospective studies may
be as powerful as prospective studies if biases are adequately addressed.25,26 We have identified and accounted
for a number of likely biases,26,27
but we are unable to completely exclude bias in patient selection for transplantation
that may have an effect on survival outcome. Such unknown biases may or may
not favor transplantation. A major source of bias in our study is the average
2-year interval between the decision to perform transplantation and actual
transplantation. We have shown that these biases tend to decrease the apparent
survival of nontransplanted controls and might increase the apparent survival
benefit of lung transplantation. Although these biases exist, they do not
change the results of our analysis. Should a rigorous randomized controlled
study of transplantation be done, the waiting period between randomization
and actual transplantation could introduce the opposite bias.28
The survival benefit of lung transplantation might be minimized or eliminated
because of the waiting list period.
Finally, a study of survival does not directly address health-related
quality of life. Standardized methods to evaluate quality of life in patients
with CF have not existed until recently, and validation is incomplete.29 We observed, however, that patients with CF in groups
4 or 5 had few of the health limitations that decrease quality of life, whereas
patients in groups 1 or 2 had most if not all of the clinical features of
CF that physically make life more difficult. By better defining survival effects,
our work may provide an objective background for patients and their physicians
to assess the quality of life surrounding transplantation.30
Our study demonstrates that lung transplantation improved survival only
for the minority of CF patients who had a 5-year predicted survival of less
than 30%. In light of our analyses, we urge a revision of lung transplantation
selection criteria to maximize survival among the most severely ill CF patients.