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Outcomes of COPD Lung Transplant Recipients After Lung Volume Reduction Surgery*

November 28, 2004

Study objectives: We sought to assess the outcomes of COPD lung transplant recipients who had previously undergone lung volume reduction surgery (LVRS), and to compare these patients to those COPD lung recipients who had not previously undergone LVRS.

Design: Retrospective analysis of the United Network for Organ Sharing transplant database over the period between October 25, 1999, and December 31, 2002.

Patients: All COPD patients who were listed and underwent transplantation during the time period were analyzed and categorized according to who did and did not have a history of LVRS. The two groups were compared for demographics, severity of illness, and various measures of outcomes after transplantation, including survival.

Results: There were 791 COPD patients who underwent transplantation, of whom 50 had a history of LVRS. The two groups had similar demographics and severity of disease. There was no difference in the need for reoperation, hospital length of stay, or survival between the groups.

Conclusion: A history of LVRS does not impact on outcomes after lung transplantation and should not influence a patient’s candidacy for transplantation. Similarly, a patient’s potential need for lung transplantation should not impact on the decision-making process for undergoing LVRS. (CHEST 2004; 126:1569-1574)

Key words: chronic obstructive lung transplantation; cohort studies; mortality: pneumonectomy; pulmonary disease; pulmonary emphysema; surgery; survival analysis

Abbreviations: LVRS = lung volume reduction surgery; NETT = National Emphysema Treatment Trial; OPTN = Organ Procurement and Transplantation Network; QOL = quality of life; UNOS = United Network for Organ Sharing

COPD is now the fourth-leading cause of death in the United States, with 123,550 deaths reported per annum and an estimated prevalence of 3.1 million.1 Medical therapy and pulmonary rehabilitation are useful palliative measures and can improve a patient’s symptoms and quality of life (QOL); however, they do not alter the natural history of the disease.2 Transplantation is now well established as a viable option for patients who have disease of sufficient severity, are of an appropriate age, and do not have any contraindications. A second surgical option is lung volume reduction surgery (LVRS) or pneumoreduction. This procedure came to the fore in the early 1990s, but, despite numerous reports3-5 attesting to its utility, its role has remained controversial. To address this issue, the National Emphysema Treatment Trial (NETT), cosponsored by Medicare and the National Institutes of Health, was undertaken.6 The results of this landmark study have verified that there is a subgroup of patients who have significant improvements in their lung function, exercise tolerance, and QOL.7 In addition, there also appears to be a smaller subgroup that may derive a significant survival benefit from the procedure.

An unanswered question, however, is what impact the one procedure may have on the outcomes of the other. Specifically, does a history of LVRS impact on the outcomes of COPD patients who ultimately require transplantation? With this as our objective, we performed an analysis of the United Network for Organ Sharing (UNOS)/Organ Procurement and Transplantation Network (OPTN) database to assess the outcomes of COPD lung transplant recipients who had a history of LVRS.

MATERIALS AND METHODS

The cohort in this study included all patients with COPD who were listed with UNOS and had undergone transplantation between October 20, 1999, and December 31, 2002. The start of the cohort corresponds to the date that information regarding pneumoreduction began to be collected by the OPTN. Prior to October 25, 1999, only a history of sternotomy or thoracotomy was collected. While some of these latter patients likely had LVRS, it is unknown which of them did. Therefore, to obtain the most homogeneous cohort possible, we included oly COPD lung transplant recipients who underwent transplantation after October 25, 1999. In order to provide adequate follow-up, the cohort included only those transplants performed on or prior to December 31, 2002.

Comparisons were made between those COPD patients with a history of LVRS who had undergone transplantation and those COPD patients who had undergone transplantation during the same period, but who had not undergone LVRS. Demographic measures, including age sex, race, gender, and type of transplant procedure, were compared for the two groups. They were also compared for disease severitv based on pretransplant pulmonary function test results and pulmonary artety pressures. Their waiting times on the transplant list were contrasted, as was their incidence of pneumothoraces while waiting. Postoperative outcomes were compared for incidence of prolonged graft ischemia, prolonged graft dysfunction, bronchopleural fistulas, the need for reoperation, hospital length of stay, and survival. Comparisons of categoric factors were made using the χ^sup 2^ test or the Fisher exact test. Comparisons of continuous factors were made using the Wilcoxon test. Survival rates were computed using the Kaplan-Meier method and were compared using the log-rank test.

RESULTS

During the study time period, there were 1,922 COPD patients added to the transplant waiting list. Of these, 1,663 patients had not undergone LVRS, 95 patients had a history of LYRS, and the LYRS status of the remaining 164 patients was unknown. There did not appear to be any substantial difference in terms of disposition on the list between the LVRS transplant candidates and their COPD non- LVRS counterparts (Fig 1, 2).

There were a total of 791 transplants performed in COPD patients during the study period. Of these, 50 patients had a history of LVRS (6.3%). Demographic data for the two groups are shown in Table 1. In the non-LVRS group, 22% (162 of 741 patients) had bilateral/double- lung transplants, while in the LVRS group 28% (14 of 50 patients) had bilateral transplants (p = 0.31). Of the LVRS patients, 62% had the procedure prior to being listed for transplant, while 20% underwent the procedure after being listed but prior to transplantation. The remaining 18% were reported to have LVRS both prior to listing, and between listing and undergoing the transplant. There were a total of 31 centers that were responsible for the 50 transplants in the LVRS patients. Of these, 29 performed between one and three of the procedures, while the two centers with the highest volume performed live and six of the lung transplants.

FIGURE 1. Outcomes on the waiting list for adult COPD patients added between October 25, 1999, and December 30, 2002 for the non- LVRS group.

There was no difference in disease severity between the two groups based on their pulmonary function study findings and pulmonary artery pressures at the time of transplantation (Table 2). The LVRS patients appeared to have a slightly longer waiting period (median waiting time, 353 days) compared to that of the non-LVRS group (median waiting time, 211 days; p = 0.014). In the LVRS group, 8% had a history of pneumothorax between listing and transplant vs 1.5% in the non-LVRS group (p = 0.01).

There was no difference in grail ischemic time between groups, with a median of 3.9 h for the non-LVRS patients (interquartile range, 3.0 to 4.8) and 4.0 h for the LVRS patients (interquartile range, 3.0 to 5.1; p = 0.76). Two percent of both groups required posttransplant cardiac reoperation (p = 0.99). Similarly, there was no difference in other surgical procedures required by both groups (non-LVRS patients, 13%; LVRS patients, 12%; p = 0.99). The incidence of posttransplant prolonged graft dysfunction was similar between the two groups (non-LVRS patients, 9%; LVRS patients, 7%; p = 0.8), as was the incidence of posttransplant bronchopleural fistulas (non-LVRS patients, 0.8%; LVRS patients, 0%). There was no significant difference in postoperative length of stay from transplant to hospital discharge between the two groups, with a median stay of 19.7 days for the non-LVRS patients and 18.3 days for the LVRS patients (p = 0.4).

FIGURE 2. Outcomes on the waiting list for adult COPD patients added between October 25, 1999, and December 30, 2002 for the LVRS group.

Table 1-Patient Demographics Stratified by LVRS

Survival times for the two groups of patients are shown via Kaplan-Meier curves in Figure 3. There was no significant difference in survival within 1 month, 3 months, or 1 year (p = 0.5, p = 0.4, and p = 0.4, respectively). The 1-year survival rate of the cohorts was 88.1% for the LVRS patients and 82.4% for the non-LVRS transplant recipients. For an overall comparison of survival for the entire follow-up period, the p value was 0.1, with the LVRS group having a higher survival rate at all time points. There was no significant differences in cause of death between the two groups (p = 0.8), but as there were only six deaths in the LVRS patient group, the sample size may have been too small to draw any definitive conclusions.

Table 2-Physiologic Parameters in the LVRS and Non-LVRS Patients at Transplantation*

FIGURE 3. Posttransplant survival.

The 1-year Kaplan-Meier survival rates for the LVRS patients were 91.7% for double-lung recipients (95% confidence interval, 76.0 to 100.0%) and 87% for si\ngle-lung recipients (95% confidence interval, 75.1 to 99.0%). Survival rates for the two groups were not significantly different (p = 0.6), but there is relatively low power to detect a difference due to the small number of transplants in each group.

DISCUSSION

Lung transplantation is generally regarded as a last-resort option for patients with many forms of end-stage lung disease. All other treatment options, both medical and surgical, should be explored before subjecting patients to the inherent risks of transplantation. COPD patients form the largest group of patients in whom lung transplantation is performed.8 For select patients with COPD, LVRS is another surgical option that might be considered prior to lung transplantation.

LVRS gained popularity in the mid-1990s as a potential palliative surgical option for some patients with advanced COPD.3-5 However, since the efficacy of the surgery was thought to be uncertain, Medicare discontinued reimbursing for the procedure, and most private payers followed suit. In a follow-up to this, a large multicenter study, the NETT, was undertaken. From January 1998 until July 2002, 3,777 patients were screened and 1,218 patients were randomized to either LVRS or standard medical care. The outcomes of this landmark study have now been published in two reports.7,9 Aside from the initial high-risk group of patients identified, two independent risk factors (ie, exercise capacity after pulmonary rehabilitation and upper lobe-predominant distribution of disease) were found to be predictive of outcome. Based on these factors, four groups of patients were identified. One group (with low exercise capacity and upper lobe-predominant disease) had the most benefit with improvements in QOL, exercise tolerance, and survival compared to their medically managed counterparts. Two of the groups had more patients (ie, those with upper lobe-predominant disease/high exercise capacity and those with non-upper lobe emphysema/ low exercise capacity) who showed an improvement in their exercise capacity and/or symptoms, but there was no difference in their survival times. The last group constituted by those patients with predominantly non-upper lobe emphysema and a high exercise capacity had a deleterious response with a worse survival compared to their medical treatment counterparts.7

With these groups and their characteristics now identified, it appears likely that there will be a focused resurgence in popularity of the procedure. Some patients who are appropriate lung transplant candidates may also be suitable for LVRS, and it is possible that the need for transplantation might be deferred in such patients, provided that they obtain a successful outcome from LVRS.10-13

The expected duration of benefit from LVRS is yet to be determined. In the NETT, it appeared that most of the benefit was maintained for at least the 2 years of follow-up. In addition, there are reports10,11 attesting to a duration of benefits for as long as 5 years in most patients. However, not all patients maintain the benefit for this long, and once they do deteriorate. LVRS patients might still remain good lung transplant candidates.

The issue that we attempted to address was whether a history of LVRS would have any impact on the postoperative course and prognosis of lung transplant patients. There are theoretic reasons as to why this might be the case. Any surgical instrumentation of the chest cavity results in the subsequent formation of adhesions. This might result in difficulty in removing the native lung during the explant phase of the transplant procedure. The dissection of the adhesions can result in excess bleeding, the need for blood products, hypotension, and hemodynamic instability. Therefore, patients with a history of LVRS may be at a higher operative risk, and this might impact on their short-term prognosis and, hence, on their long-term prognosis. If this were the case, then their potential transplant candidate would need to be addressed at the same time that consideration was being given to LVRS.

For any potential transplant or LVRS candidate to make the appropriate choice, the outcomes that need to be weighed are what their QOL and life expectancy might he with or without the procedure. Furthermore, for LVRS the heterogeneity of response needs to he considered since individual patients might not have a significant improvement. For those patients with COPD, who might be eligible for both LVRS and transplantation, not only does their QOL and life expectancy with LVRS need to be considered, hut also what their life expectancy and course is likely to be posttransplant if they first undergo LVRS and subsequently undergo lung transplantation.

This last consideration may be moot since, contrary to our hypothesis, there does not appear to be anv statistical difference in outcomes between patients who have previously undergone LVRS and their non-LVRS counterparts. If there were any significant increased perioperative risk, we would have expected a difference in mortality at 1 month, which was not seen. Further supportive evidence of a lack of increased morbidity in the LVRS group is the similarity in the posttransplant hospital length of stay between the two groups. It also appears that intermediate-term outcomes are no different, with similar survival rates seen at 12 months. The OPTN does not collect any data that reflect the difficulty of surgery, so differences in the explant part of the procedure could not reliably be distinguished between the two groups. For example, it is possible that the LVRS group required longer operations and more blood products. However, even if either of these were the case, it did not impact on other measures of relevance to the patients postoperative course, including graft ischemic times, the incidence of prolonged graft dysfunction, or the need for reoperation. The latter could possibly he construed as a surrogate for episodes of severe pleural hemorrhage and might therefore indicate that even if this group did have more bleeding, it was not sufficient to require a greater number of reexplorations. Whether there were other differences in their operative and perioperative course that were not captured by the UNOS/OPTN database, remains unanswered.

The two groups of patients that formed our cohorts appeared to he very well-matched by demographics and severity of disease. The one difference between the two groups was the apparent increased incidence of pneumothoraces in the LVRS group while listed. This most likely was related to the fact that 38% of the patients underwent LVRS during this waiting period. The other apparent difference was the longer waiting times in the LVRS group. There are a number of possible reasons for this. It is conceivable, for example, that patients in whom the waiting time was expected to be longer were offered LVRS as a temporizing measure. It is also possible that LVRS patients were more likely to be listed earlier since they were being followed closer. A survival advantage for the LVRS patients appears unlikely to have accounted for the difference since the mortality rate on the waiting list for the two groups was similar, as were their physiologic characteristics at the time of transplantation.

One caution in interpreting these results is that the relatively small sample size of the LVRS group does not provide sufficient power to be able to detect small-to-moderate differences in survival or other outcomes. It is also possible that there was a selection bias in the LVRS group. It is likely that this group of patients was highly motivated and otherwise “pristine” transplant candidates. It is similarly conceivable that some less robust patients who might have otherwise been considered reasonable candidates for lung transplantation were excluded from transplantation because of their prior LVRS. There does not appear to have been a center bias to explain our results as 78% of the procedures were performed at 29 different centers, with the two highest volume centers accounting for the remaining 22%.

With the results of our study, it is enticing to attempt placing LVRS and lung transplantation in context with one another. However, one needs to be cognizant that, as a group, appropriate LVRS candidates have milder disease than lung transplant candidates, which limits the ability to do direct comparisons of outcomes between these two procedures. Patients who present for LVRS may be too early in their course to consider transplantation, and, similarly, the conditions of those who present for transplantation may be too far advanced for LVRS to be an option. However, there is a group of patients who at the time of initial presentation may be candidates for either of the two procedures.12 It is also important to be cognizant of the inclusion criteria of the NETT, as only a minority of all COPD patients were included. The characterization of patients into one of the four groups described depends first on them fulfilling the other inclusion criteria of the study. With these and other caveats in mind, then, in those patients with predominantly upper lobe disease and low exercise tolerance, who choose a surgical option for their COPD, we contend that LVRS should be favored. Similarly, we hypothesize that in the group of patients who have a high exercise capacity with predominantly upper lobe disease, if their symptoms are such that surgery is contemplated, then LVRS should be favored since there are improvements in QOL with a mortality rate of only 16.5% at a median follow-up time of 29 months. This survival time is no different from that seen with medical management and compares very favorably with the expected outcomes after lung transplantation.11 In those patients with predominantly non-upper lobe disease and low exercise tolerance, the mortality rates that can be expected from LVRS and transplantation appear equivalent to67% of the LVRS patients surviving a mean time of 29 months vs a 2-year survival rate of 66% in our cohort of non- LVRS lung transplant recipients.7 In these situations, other factors such as the likelihood and degree of improvement in QOL as well as financial considerations should be factored into the decision. In the two high-risk groups of patients identified in the NETT study, the decision between transplantation and LVRS is quite clearly weighted in favor of the former.

In summary, it appears that a history of LVRS does not impact negatively on patients’ subsequent post-transplant course and, hence, on their candidacy for transplantation. If patients are deemed to be suitable LVRS candidates, there is no evidence to suggest that the possibility of transplantation in the future should impact on this decision. Indeed, based on the NETT results and other reports,12-14 LVRS may help to defer the need for transplantation in some patients.

* From the Inova Heart and Lung Transplant Center (Drs. Nathan, Ahmad, Burton, and Barnett), Falls Church; and the United Network for Organ Sharing (Dr. Edwards), Richmond, VA.

REFERENCES

1 US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute. Morbidity and mortality: chart-book on cardiovascular, lung, and blood diseases, 1998. Available at: http:/ /www.nhlbi.nih.gov/resources/docs/cht-book.htm. Accessed October 14, 2004

2 Rennard SI, Farmer SG. COPD in 2001. Chest 2002; 121: 113s- 115s

3 Cooper JD, Trulock EP, Triantafillou AN, et al. Bilateral pneumonectomy (volume reduction) for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg 1995; 109:106-119

4 Cooper JD, Patterson GA, Sundaresan RS, et al. Results of 150 consecutive bilateral lung volume reduction procedures in patients with severe emphysema. J Thorac Cardiovasc Surg 1996; 112:1319-1330

5 McKenna RJ, Brenner M, Fischel RJ, et al. Should lung volume reduction for emphysema be unilateral or bilateral? J Thorac Cardiovasc Surg 1996; 112:1331-1339

6 Ciccone AM, Meyers BF, Guthrie TJ et al. Long-term outcome of bilateral lung volume reduction in 250 consecutive patients with emphysema. J Thorac Cardiovasc Surg 2003; 125:513-525

7 National Emphysema Treatment Trial Research Group. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med 2003; 348:2059-2073

8 Trulock EP, Edwards LB, Taylor DO, et al. The Registry of the International Society for Heart and Lung Transplantation: twentieth official adult lung and heart-lung transplant report; 2003. J Heart Lung Transplant 2003; 22:625-635

9 National Emphysema Treatment Trial Research Group. Patients at high risk of death after lung-volume-reduction surgery. N Engl J Med 2001; 345:1075-1083

10 Gelb AF, McKenna RJ, Brenner M, et al. Lung function 4 years after lung volume reduction surgery for emphysema. Chest 1999; 116:1608-1615

11 Yusen RD, Lefrak SS, Gierda DS, et al. A prospective evaluation of lung volume reduction surgery in 200 consecutive patients. Chest 2003; 123:1026-1037

12 Meyers BF, Yusen RD, Guthrie TJ, et al. Outcome of bilateral lung volume reduction in patients with emphysema potentially eligible for lung transplantation. J Thorac Cardiovasc Surg 2001; 122:10-17

13 Bavaria JE, Pochettino A, Kotloff RM, et al. Effect of volume reduction on lung transplant timing and selection for chronic obstructive pulmonary disease. J Thorac Cardiovasc Surg 1998; 115:9- 18

14 Zenati M, Keenan RJ, Landreneau RJ, et al. Lung reduction as bridge to lung transplantation in pulmonary emphysema. Ann Thorac Surg 1995; 59:1581-1583

Steven D. Nathan, MD, FCCP; Leah B. Edwards, PhD; Scott D. Barnett, PhD; Shahzad Ahmad, MD; and Nelson A. Burton, MD

Manuscript received December 4, 2003; revision accepted June 21, 2004.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Steven D. Nathan, MD, FCCP, Medical Director, Lung Transplant Program, Inova Heart and Lung Transplant Center, Inova Fairfax Hospital, 3300 Gallows Rd, Falls Church, VA 22042; e- mail: steven.nathan@inova.com

Copyright American College of Chest Physicians Nov 2004




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