Assessment of survival benefit after lung transplantation by patient diagnosis

Assessment of Survival Benefit After Lung Transplantation by Patient Diagnosis Susan C. Charman, MSc,a,b Linda D. Sharples, PhD,a,b Keith D. McNeil, FRACP,a and John Wallwork, FRCSa Background: Lung transplantation has become an established procedure for treating patients with endstage lung disease, resulting in broadening criteria for recipient selection. The survival benefit for some patient groups has yet to be established. Methods: We reviewed 653 patients accepted for lung transplantation at our center. Patients were categorized into 6 diagnosis groups: cystic fibrosis (174), obstructive lung disease (163), pulmonary fibrosis (100), Eisenmenger’s syndrome (76), pulmonary hypertension (68), bronchiectasis (51), and other (21). Using Cox regression, we estimated the time at which early operative risk of death fell below pre-operative risk levels (crossover point) and the point at which early high post-operative risk was offset by later low risk (equity point). The relative benefits of single lung vs double lung/heart–lung transplantation were assessed for patients with obstructive lung disease and pulmonary fibrosis. Results: Post-operative risk of death fell below pre-operative risk levels for all diagnosis groups, indicating a survival advantage. The equity point was achieved for all distinct diagnosis groups (except Eisenmenger’s); this survival benefit was significant for patients with obstructive lung disease, cystic fibrosis, and pulmonary hypertension. Single lung vs double lung/ heart–lung comparisons showed no significant difference in survival benefit. Conclusion: All survival benefit patient groups achieve after lung transplantation, with the exception of patients with Eisenmenger’s syndrome, who may have prolonged survival while listed. Differences in survival benefit between single lung and double or heart–lung transplantation are not significant for patients with obstructive lung disease or pulmonary fibrosis. J Heart Lung Transplant 2002;21:226–232.

L

ung transplantation (single lung [SL], double lung [DL] and heart–lung [HL]) is an effective treatment for patients with various endstage lung diseases, both in terms of survival and quality of

From aPapworth Hospital National Health Service (NHS) Trust, Papworth Everard, and bMedical Research Council (MRC) Biostatistics Unit, Institute of Public Health, University Forvie Site, Cambridge, United Kingdom. Submitted May 1, 2001; accepted July 24, 2001. Reprint requests: Susan C. Charman, Research and Development Unit, Papworth Hospital NHS Trust, Papworth Everard, Cambridge CB3 8RE. Telephone: 44-0-1480-364445. Fax: 440-1480-831450. Copyright © 2002 by the International Society for Heart and Lung Transplantation. 1053-2498/02/$–see front matter S1053-2498(01)00352-7

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life.1–3 As surgical techniques and patient management improve, the spectrum of disease considered suitable for transplantation has expanded. The shortage of donor organs continues to remain a major problem and contributes to death while on waiting lists.4,5 Patients with different disease indications have different potential benefits, reflecting varying survival patterns while on the waiting list.6 – 8 Studies of large numbers of patients to evaluate outcomes after lung transplantation are often based on International Society for Heart and Lung Transplantation (ISHLT) Registry data.9,10 Such studies are limited because of the lack of consistency in assessment criteria and in the management of transplant waiting lists. Given the extensive and detailed

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TABLE I Patient characteristics and outcomes Number of Patients

Diagnosis Group (n)

Died Waiting

Removed or Still Waiting

Obstructive lung disease (163) Single lung (92) Double lung (35)/heart–lung Cystic fibrosis (174) Eisenmenger’s syndrome (76) Bronchiectasis (51) Pulmonary fibrosis (100) Single lung (63) Double lung (10)/heart–lung Pulmonary hypertension (68) Other (21) Overall (653)

29 18 11 65 15 15 33 18 15 25 2 184

12 6 6 8 6 10 7 3 4 2 3 48

Transplanted

Mean (SD) Age*

Median (IQR) Days Waiting

122 68 54 101 55 30 60 42 18 41 16 425

51 (7) 53 (6) 48 (8) 25 (7) 32 (9) 46 (8) 49 (12) 52 (11) 41 (11) 37 (10) 41 (12) 39 (14)

120 (45, 320) 90 (45, 295) 165 (38, 356) 216 (82, 397) 552 (249, 1108) 281 (93, 661) 117 (43, 231) 104 (5, 194) 147 (94, 305) 173 (81, 364) 229 (40, 498) 178 (65, 432)

*age (years) at acceptance on to the waiting list. IQR, interquartile range.

information available at this center gained during 15 years of lung transplantation, we investigated the potential survival benefits of lung transplantation and, in particular, the effect of the underlying disease diagnosis on that benefit. In the current climate of donor organ shortage, there is much discussion on how to maximize use of the donor pool and, in particular, how to weigh quality of life gains with expected survival benefits.9,11–13 Therefore, for groups in which SL transplantation is an option, the relative benefit of bilateral compared with unilateral transplantation is also assessed.

METHODS This single-center study included 653 patients who were accepted for SL, DL, or HL transplantation between April 1984 and September 1999. Patients were considered for transplantation if they had a life expectancy of 18 to 24 months or if their disease severely impaired their quality of life despite maximal medical therapy. They were assessed for transplantation on the basis of pulmonary function, exercise tolerance, gas exchange criteria, and general health status. Specific indications for transplantation for the different disease groups varied. In general, acceptance criteria were in accordance with those recently recommended by the American Society for Transplant Physicians, American Thoracic Society, European Respiratory Society, and the ISHLT.4 When an organ became available, a suitable recipient was chosen from the waiting list based on ABO blood type and on size (based on total lung capaci-

ty). Between 1986 and 1996, Cytomegalovirus antibody mismatches from positive donor to negative recipient were avoided. With the introduction of oral ganciclovir prophylaxis post-operatively, this was no longer considered necessary. Data were routinely collected for all patients from the time they were accepted for transplantation. We therefore have patient assessment data and ongoing functional measures for monitoring pre-transplant disease progression as well as pre- and post-transplant survival information. Patients listed for a second transplant were not considered twice but recorded as deaths or censored as appropriate. Patients were allocated to 1 of 7 groups according to their pre-transplant underlying lung disease: obstructive lung disease (OLD, n ⫽ 163), cystic fibrosis (CF, n ⫽ 174), Eisenmenger’s syndrome (ES, n ⫽ 76), bronchiectasis, (n ⫽ 51), pulmonary fibrosis (PF, n ⫽ 100), pulmonary hypertension (PH, n ⫽ 68, and other, (n ⫽ 21). The OLD group included 154 patients with emphysema. Table I summarizes the outcomes from listing for each diagnosis group at the time of analysis. The catch-all group “other” (n ⫽ 21) contains a wide range of diseases, and although the group characteristics are included for completeness, a full analysis of this group has little clinical relevance. Kaplan Meier methods were used to compare survival between diagnosis groups for before (with censoring at transplantation) and after transplant. The comparisons at each stage were made using the log-rank statistic adjusted for multiple comparisons.

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The median time on the waiting list is given for each group in Table I. We investigated the effect of diagnosis on survival using Cox regression, with transplantation as a time-dependent covariate. In previous studies,14,15 it has been assumed that the post-transplant mortality risk is constant, but this assumption is not clinically realistic and comparisons are dominated by early post-operative risk. In this study, we have assumed that after transplant, there is a high initial risk relative to continued waiting, followed by exponential decline to a constant risk. Separate models were fitted for each diagnosis group. From each curve, we calculated the time at which the post-operative risk of death relative to the risk while remaining on the waiting list equals 1. This is the time post-transplant when the risk of death while waiting exceeds the risk of death post-operatively. In Figure 1, this “crossover point” is where the curve crosses the straight line corresponding to a relative risk of 1. We also calculated the time when the total survival after transplantation equaled the total survival while remaining on the waiting list. This is the point at which the early post-operative increased risk is offset by the later period of lower risk and therefore the time at which transplantation has an overall survival advantage (equity point). The equity point is the time at which the area between the curve and the straight line (relative risk ⫽ 1) to the left of the crossover point is equal to the area between the curve and the line on the right of the crossover point. If the equity point falls below the lower limit of the 95% confidence interval (CI) of the estimated median posttransplant survival time, then transplantation confers a significant survival benefit. Using the same model with an additional covariate for type of transplant (SL vs DL/HL), the crossover and equity points were also found for the SL and DL/HL recipients in the OLD and PF groups.

RESULTS Time spent on the waiting list for each diagnosis group is given in Table I. Patients with ES spent the longest time on the list (median, 552 days) and for the whole cohort, the median waiting time was 178 days. Those groups for which a SL transplant is sometimes an option spent the shortest time on the list (OLD, 120 days; PF, 117 days). Expected survival while awaiting transplant was greatest for patients with ES. There were statistically significant differences in survival at this stage between patients with ES and those with OLD (p ⫽ 0.003), CF (p ⬍ 0.0001), PF (p ⬍ 0.0001), or PH (p ⬍ 0.0001). No

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significant differences between groups in post-transplant survival were found. One-year post-transplant survival (95% CI) was OLD, 73% (65% to 81%); CF, 71% (62% to 80%); ES, 69% (57% to 82%); bronchiectasis, 71% (55% to 87%); PF, 55% (42% to 68%); and PH, 80% (68% to 92%). We also found no significant differences in the survival (pre: and post-transplant) for patients who were accepted for a SL compared with those in the same diagnosis group who had been accepted for a DL or HL (OLD and PF groups only). Median (interquartile range) lung function data for the OLD patients at time of listing were as follows: forced expiratory volume at 1 minute (FEV1), 0.5 liter (0.4 to 0.6 liter), and % predicted FEV1, 15% (12% to 19%). Of the 163 OLD patients, the above data were available for 159 and 158 patients, respectively. Of the 425 patients who received transplant, common causes of death in the first 30 days after transplant (n ⫽ 68) were infections (38%) and donor organ failure (16%). One patient died of acute rejection. Risk profiles for each distinct diagnosis group appear in Figure 1 A to F. All the curves show an initial high risk because of the transplant procedure and immediate post-operative hazards. For all groups, the risk falls below that of continued waiting on the list; i.e., the crossover point is achieved. The earliest crossover point was 16 days post-transplant (bronchiectasis) and the latest was 245 days (ES) (Table II). The time at which the early increase in risk because of transplant is balanced by later survival benefit is given in the third column of Table II and varies from 111 days (PH) to 6,525 days for the ES group. The fact that the crossover point is achieved for the ES group, indicates that a survival benefit is possible. However, in this study, all 34 deaths among the 55 transplanted patients occurred within 4,608 days, and the longest follow-up time for a surviving patient was 4,424 days. In the other groups where the equity point was achieved, it was less than the median post-transplant survival time, but only the OLD, CF, and PH groups reached significance (p ⬍ 0.05). The cumulative survival rates (95% CI) at these equity points were OLD, 73% (65% to 81%); CF, 73% (64% to 82%); bronchiectasis, 59% (41% to 77%); PF, 56% (43% to 69%); and PH, 83% (71% to 95%). Table II also shows the crossover and equity points for SL and DL/HL recipients for the OLD and PF groups. There was no significant difference in the survival benefit incurred for DL/HL recipients compared with SL recipients in these groups (p ⫽ 0.38 for the

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FIGURE 1 Risk profiles for each of the 6 distinct diagnosis groups: (A) obstructive lung

disease, (B) cystic fibrosis, (C) Eisenmenger’s syndrome, (D) bronchiectasis, (E) pulmonary fibrosis, (F) pulmonary hypertension.

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TABLE II Crossover points, equity points, and post-transplant survival for each distinct diagnosis group

Diagnosis Group (n)

Crossover Point* (days)

Equity Point† (days)

Post-transplant Survival (days) Median (95% CI)

Cumulative Survival (%) at Equity Point (95% CI)

Obstructive lung disease (163) Single lung (92) Double lung (35)/heart–lung Cystic fibrosis (174) Eisenmenger’s syndrome (76) Bronchiectasis (51) Pulmonary fibrosis (100) Single lung (63) Double lung (35)/heart–lung Pulmonary hypertension (68)

104 99 110 59 245 16 104 107 104 39

369 317 448 260 6525 1022 342 332 393 111

1777 (1183, 2371) 1777 (970, 2584) 1801 (829, 2773) 1984 (1230, 2738) 1811 (1542, 2080) 1847 (688, 3006) 931 (98, 1764) 449 (0, 1287) 1121 (0, 3024) 1371 (740, 2002)

73 (65, 81) 79 (69, 88) 64 (50, 77) 73 (64, 82) 0 59 (41, 77) 56 (43, 69) 53 (37, 69) 56 (33, 79) 83 (71, 95)

*Time risk of death post-transplant falls below that of continued waiting. †Time total survival after transplant is equal to survival while remaining on the waiting list.

OLD group and p ⫽ 0.54 for the PF group). However, in this single-center study, the number in each sub-group was low, with limited power to detect significant differences. In this case, registry data are more likely to be sensitive to any such sub-group survival differences. The risk of death after transplantation relative to continued waiting at 1, 6, and 12 months, is given in Table III for each distinct diagnosis group, and by procedure (SL or DL/HL) for the OLD and PF groups. In this latter analysis, 1 month after transplant, in both disease groups, the risk of death relative to continued waiting is higher for DL/HL recipients than for SL recipients. However, the profiles differ later. In the OLD group, both SL and DL/HL recipients have a similar relative risk of around 0.6 at 6 months, but thereafter the relative risk for DL/HL starts to drift lower than that for SL. That is, DL/HL recipients

have superior survival after 6 months, conditional on surviving the early post-transplant period. In the PF group, the relative risks are not so close at 6 months and drift even further at 12 months. This indicates that it took longer for the SL recipients to achieve the overall survival benefit.

DISCUSSION The results reported here suggest a survival benefit for all the distinct diagnosis groups, except for patients with ES. With the exception of this group, the risk of death after transplantation relative to the risk while remaining on the waiting list falls below 1 within 15 weeks. However, the time when risk of death on the waiting list equals risk of death after transplantation varies considerably, ranging between 111 days and 34 months. Hosenpud et al9 conducted a similar analysis on

TABLE III Relative risk of death at 1, 6, and 12 months post-transplant Risk of Death after Transplant Relative to That of Continued Waiting At Diagnosis Group (n)

1 Month

6 Months

12 Months

Obstructive lung disease (163) Single lung (92) Double lung (35)/Heart–lung Cystic fibrosis (174) Eisenmenger’s syndrome (76) Bronchiectasis (51) Pulmonary fibrosis (100) Single lung (63) Double lung (10)/heart–lung Pulmonary hypertension (68)

2.77 2.25 3.52 2.42 13.18 0.62 2.23 1.96 2.88 1.18

0.55 0.58 0.54 0.21 1.26 0.58 0.65 0.71 0.57 0.37

0.32 0.38 0.29 0.15 0.85 0.58 0.46 0.54 0.36 0.34

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registry data, comparing the survival benefits for CF, PF, and emphysema patients. Their study included more patients (n ⫽ 2,419) and covered a shorter period (1992–1994). They found the crossover point for CF patients (n ⫽ 664) was 26 days and the time to overall survival benefit was 182 days, both earlier than our findings of 59 and 260 days, respectively. For their PF group (n ⫽ 481), the results were similar. They found the crossover point at 83 days and the equity point at 350 days, compared with ours of 104 and 342, respectively. However, they found that for emphysema patients, the crossover point was not achieved in their 2-year follow-up period. The OLD group in our study included 154 patients with emphysema, 4 with asthma, and 5 with (nontransplant) obliterative bronchiolitis. We have shown here that they do achieve survival benefit even with a longer follow-up period. Because this is a single-center study, assessment methods and acceptance criteria are likely to be more uniform than with registry data; therefore, we can be confident of homogeneity at least within diagnosis groups. For the patients with ES, the median time on the waiting list was 552 days for the whole group, 552 days for patients who underwent transplantation, and 341 days for those who died while waiting. This confirms previous findings at this center,7 which concluded that this group waits longer than others as a result of the natural history of its disease. For these patients, acceptance to the waiting list is based much more on quality of life than on survival. As has been demonstrated, the improvement in quality of life for this and other groups is a persuasive argument for their continued listing.3 Double lung transplants give better results than SL transplants in terms of lung function tests and exercise tolerance.16,17 However, much uncertainty remains about relative survival rates. ISHLT Registry data18 showed no significant differences in post-transplant survival, comparing SL with bilateral/DL transplantation. In contrast, DL transplantation had a survival advantage (p ⫽ 0.003) in the report 1 year later.19 Sundaresan et al16 compared the outcomes of 50 SL recipients and 69 DL recipients who had emphysema. They found no significant differences in 90-day mortality or in 5-year actuarial survival. They did find improvements in FEV., and exercise tolerance was significantly better in the DL group. In a review of SL (n ⫽ 99) and DL (n ⫽ 24) transplantation at this center, Herrera et al17 found that the DL recipients had significantly greater pulmonary function with similar survival. The results in this study show that both SL and

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DL/HL recipients in the OLD and PF groups achieve survival benefit. In both groups, those patients receiving DL/HL took longer to achieve the overall survival benefit than those receiving SL. The differences in overall survival benefit between procedures (SL vs DL/HL) were not significant. However, when groups are sub-divided in this way, the numbers in each sub-group and the power to detect clinically significant differences are low. In a larger study, the differences seen in relative risk may be statistically significant.

CONCLUSION These data confirm that transplantation confers a significant survival benefit for patients with CF and PH, conditional on surviving the early post-operative period. For the first time, we have shown that patients with emphysema also achieve a significant benefit from transplantation in terms of survival. When compared with SL transplantation, DL or HL transplantation does not significantly differ in terms of survival benefit for patients with OLD or PF, but differential quality of life remains an issue. REFERENCES 1. Trigt PV, Davis DD, Shaeffer GS, et al. Survival benefits of heart and lung transplantation. Ann Surg 1996;223:576 – 84. 2. Chaparro C, Scavuzzo M, Winton T, Keshavjee S, Kesten S. Status of lung transplant recipients surviving beyond five years. J Heart Lung Transplant 1997;16:511– 6. 3. Caine N, Sharples L, Dennis C, Higebottam TW, Wallwork J. Measurement of health-related quality of life before and after heart-lung transplantation. J Heart Lung Transplant 1996;15:1047–58. 4. American Thoracic Society. International guidelines for the selection of lung transplant candidates. Am J Respir Crit Care Med 1998;158:335–9. 5. UKTSSA. 1998 The Eighth Annual Report of the Special Health Authority. 6. Yeatman M, McNeil K, Smith JA, et al. Lung transplantation in patients with systemic diseases: an eleven-year experience at Papworth Hospital. J Heart Lung Transplant 1996;15:144–9. 7. Sharples L, Belcher C, Dennis C, Higenbottam T, Wallwork J. Who waits longest for heart and lung transplantation? J Heart Lung Transplant 1994;13:282–91. 8. D’Armini A, Callegari G, Vitulo P, et al. Risk factors for early death in patients awaiting heart-lung or lung transplantation. Transplantation 1998;66:123–7. 9. Hosenpud JD, Bennett LE, Berkley MK, Edwards EB, Novick R. Effect of diagnosis group on survival benefit of lung transplantation for end-stage lung disease. Lancet 1998; 351:24 –7. 10. Meester JD, Smits JMA, Persijn GG, Haverich A. Lung transplant waiting list: differential outcome of type of endstage lung disease, one year after registration. J Heart Lung Transplant 1999;18:563–71. 11. Dark JH. Priorities for lung transplantation (Commentary). Lancet 1998;351:4 –5.

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12. Gross CR, Raghu G. The cost of lung transplantation and the quality of life post-transplant. Clin Chest Med 1997;18:391– 403. 13. Ramsey SD, Patrick DL, Albert RK, Larson EB, Wood DE, Raghu G. The cost-effectiveness of lung transplantation; a pilot study. Chest 1995;108:1594 –1601. 14. Geertsma A, TenVergert EM, Bonsel GJ, de Boer WJ, van der Bij W. Does lung transplantation prolong life? A comparison of survival with and without transplantation. J Heart Lung Transplant 1998;17:511– 6. 15. Sharples L, Hathaway T, Dennis C, Caine N, Higenbottam T, Wallwork J. Prognosis of patients with cystic fibrosis awaiting heart and lung transplantation. J Heart Lung Transplant 1993;12:669 –74.

The Journal of Heart and Lung Transplantation February 2002 16. Sundaresen RS, Shiraishi Y, Manley J, Lynch J, Cooper JD, Patterson GA. Single or bilateral lung transplantation for emphysema? J Thorac Cardiovasc Surg 1996;112:1485–94. 17. Herrera JM, McNeil K, Wells F, Wallwork J. Lung transplantation at the Papworth Hospital: nine years experience (Abstract). Arch Bronchoneumol 1999;35:64 –70. 18. Hosenpud JD, Bennett LE, Berkeley MK, Fiol B, Boucek MM, Novick RJ. The Registry of the International Society for Heart and Lung Transplantation: fifteenth official report—1998. J Heart Lung Transplant 1998;17:656 – 68. 19. Hosenpud JD, Bennett LE, Berkeley MK, Fiol B, Boucek MM, Novick RJ. The Registry of the International Society for Heart and Lung Transplantation: sixteenth official report—1999. J Heart Lung Transplant 1999;18:611–26.