Lung transplantation has become a feasible option. Bronchiolitis Obliterans Syndrome and Additional Costs of Lung Transplantation*

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1 Bronchiolitis Obliterans Syndrome and Additional Costs of Lung Transplantation* Jan W. K. van den Berg, MD, PhD; Petra J. van Enckevort, PhD; Elisabeth M. TenVergert, PhD; Dirkje S. Postma, MD, PhD; Wim van der Bij, MD, PhD; and Gerard H. Koëter, MD, PhD Study objectives: The influence of bronchiolitis obliterans syndrome (BOS) on costs after lung transplantation was investigated by comparing the costs of patients with and without this condition. Design: Follow-up costs were prospectively investigated in a medical technology assessment of the Dutch Lung Transplant Program, in relation to the development of the BOS. First, average follow-up costs per week per patient were compared between patients who did or did not develop BOS. Second, in the BOS group, these costs were compared before and after the onset of BOS. Setting: Dutch Lung Transplant Program, University Hospital of Groningen. Results: Data on 53 patients (37 patients without BOS and 16 with BOS) who underwent transplantation between November 1990 and April 1995 were available. The average follow-up time of these 53 patients was 1.5 years. The follow-up costs amounted to an average (in Dutch guilders [Dfl]) of 1,774/wk for non-bos patients, compared to 3,072/wk for BOS patients ( 73%; p 0.002; one Dfl 50 cents US currency). This difference in costs was largely accounted for by an increase in used health-care resources, in particular hospitalization and medication. For the BOS patients, the average costs per week before and after the onset of BOS were 1,941 Dfl and 2,422 Dfl, respectively. Conclusion: BOS is associated with substantial extra costs. These findings reemphasize the need to focus efforts on prevention of BOS to enhance the cost-effectiveness of lung transplantation. (CHEST 2000; 118: ) Key words: bronchiolitis obliterans; cost analysis; lung transplantation Abbreviations: BOS bronchiolitis obliterans syndrome; Dfl Dutch guilders; UHG University Hospital of Groningen *From the Department of Pulmonology (Drs. van den Berg, Postma, van der Bij, and Koëter) and Office for Medical Technology Assessment (Drs. van Enckevort and TenVergert), University Hospital, Groningen, the Netherlands. Manuscript received December 15, 1999; revision accepted July 10, Correspondence to: Jan W. K. van den Berg, MD, PhD, Department of Pulmonology, Isala Clinics, PO Box , 8000 GM Zwolle, the Netherlands; j.w.k.van.den.berg@isala.nl Lung transplantation has become a feasible option in the treatment of end-stage pulmonary parenchymal or vascular diseases. However, the costeffectiveness of lung transplantation compares unfavorably to that of other solid-organ transplants. 1 In part, this may be explained by a lower survival advantage of lung transplantation. 1 One of the main determinants of survival after lung transplantation is the development of chronic transplant dysfunction, the so-called bronchiolitis obliterans syndrome (BOS). 2,3 BOS is characterized by a slowly progressive decline in the FEV 1 and is also associated with increased morbidity. 4 Furthermore, we have recently demonstrated 5 that lung transplant patients with BOS experience a lower health-related quality of life compared to recipients without BOS. In addition to a lower survival advantage, the costs of follow-up after transplantation are higher for lung transplantation compared to heart or liver transplantation. 1 It is not fully disclosed which factors contribute to the higher costs of follow-up after lung transplantation. The aim of the present study was to assess the contribution of chronic transplant dysfunction to the higher costs of follow-up of lung transplantation. Those costs were calculated in patients who underwent transplantation between 1990 and 1995, ie, before the introduction of the newer immunosuppressive drugs, thus allowing for a fair comparison under standard triple immunosuppression Clinical Investigations

2 Materials and Methods In 1991, a technology assessment study of the Dutch Lung Transplant Program at the University Hospital of Groningen (UHG) was initiated by the Dutch National Health Insurance Board. From November 1990 until April 1995, data were gathered on all patients entering the Dutch Lung Transplant Program. The aim of the technology assessment was to provide information on costs, clinical effectiveness, quality of life, demand for lung transplantation, and supply of donors. 6 In the present study, data pertaining to the costs of transplant recipients entering the outpatient follow-up phase were analyzed. Patients All patients who survived 60 days after transplantation were considered at risk for developing BOS and were included in the study. The costs of their outpatient follow-up phase were studied. BOS BOS was diagnosed according to the criteria of the International Society for Heart and Lung Transplantation. 7 A diagnosis of BOS was based on a decline of the FEV 1 to 80% of a baseline value, or on the histologic evidence of obliterative bronchiolitis in biopsies. All patients were seen frequently at the outpatient clinic. On all visits to the outpatient clinic and twice a week when patients were admitted to the hospital, spirometry was recorded, allowing for an accurate diagnosis of BOS. Immunosuppression All patients received standard triple immunosuppression, consisting of cyclosporin A (aiming at initial postoperative plasma trough levels of 400 g/l, tapering to a maintenance level of 150 g/l [high-performance liquid chromatography] from 3 weeks postoperatively onwards), and azathioprine, 1- to 3-mg/kg maintenance dose. Intraoperatively, methylprednisolone, 1,000 mg, was administered, followed by three doses of 125 mg on the first postoperative day. Subsequently, oral prednisolone, 1 mg/kg/d, was initiated and subsequently reduced to an initial maintenance dose of 15 mg/d. Rabbit antithymocyte globulin was administered during the first postoperative week as immunosuppression induction. Acute rejection was treated with a 3-day course of methylprednisolone, 500 to 1,000 mg/d, followed by oral prednisolone, tapering the dose over several days. In cases of persistent rejection or when BOS was diagnosed, cytolytic therapy with rabbit antithymocyte globulin was commenced. following items: work (paid and unpaid); hospitalizations and outpatient visits in hospitals other than the UHG, hospitalizations in nursing homes; location of the hospitals and nursing homes (to assess traveling costs); home help; use of medication, medical tools (eg, wheelchair), clothes, and special food. Unit prices within the UHG were largely based on information from the financial administration of the hospital. For instance, the costs of one day of hospitalization in the intensive care and normal care departments were based on detailed information on costs of staff, materials, accommodation, cleaning, food, laundry, and overhead for those departments. Unit prices outside the hospital were based on external information sources. 9 Production losses were estimated on the basis of the friction costs method of Koopmanschap et al, 10 using a friction period of 3 months. To assess the influence of BOS on costs of follow-up, the total costs of follow-up divided by the number of weeks in follow-up were compared for both groups. Additionally, in patients developing BOS, the costs per week of follow-up were compared prior to and after the onset of BOS. Statistical Analysis The costs did not display a normal distribution. Hence, differences in costs between patients with and without BOS were tested by the Mann-Whitney U test. Differences in costs before and after development of BOS were analyzed with the Wilcoxon signed rank test. A p 0.05 was considered statistically significant. Results Of the 57 patients who underwent transplantation between November 1990 and April 1995, 53 patients survived 60 days after transplantation and entered the outpatient follow-up phase. Sixteen patients developed BOS during the study period. Patient characteristics are specified in Table 1. Table 2 presents the average costs of the outpatient follow-up phase expressed in Dutch guilders (Dfl) per patient per week for each category. The total costs per week of follow-up were statistically significantly higher in patients developing BOS, compared to patients without BOS ( 1,298 Dfl; p 0.002). An increase in costs that was incurred within the UHG was largely responsible for the difference ( 1,161 Dfl; p 0.001). The increase in Costs All costs related to the lung transplant procedure were calculated per patient per week of follow-up, from the moment of discharge after the transplant procedure until death or the end of the study period. The costs consisted of health-care costs (hospitalization, outpatient visits, medication, professional home help); patient and family costs (traveling expenses, medical tools, special diets, nonprofessional home help); and production losses (paid or unpaid work). If possible, full resource costs were estimated (base year 1992) for BOS and non-bos patients. 8 Volume data (ie, quantities of resources used) within the UHG were largely obtained from the detailed hospital accounting system and from case report forms. Volume data outside the UHG were gathered by questionnaires completed by the recipients at 1 month, 4 months, and 7 months posttransplantation and every 6 months thereafter. Information was requested about the Characteristics Table 1 Patient Characteristics Patients Not Developing BOS (n 37) Patients Developing BOS (n 16) Age, yr (mean SD) Female gender, % Diagnosis, No. (%) Emphysema 18 (48) 3 (19) Cystic fibrosis 8 (22) 6 (37) Pulmonary hypertension 5 (14) 3 (19) Pulmonary fibrosis 3 (8) 3 (19) Bronchiectasis 3 (8) 1 (6) CHEST / 118 / 6/ DECEMBER,

3 Table 2 Comparison of Costs in BOS and Non-BOS* Variables Patients Not Developing BOS (n 37) Patients Developing BOS (n 16) BOS/Non-BOS (%) p Value Health-care costs within UHG 1,016 (727) 2,177 (1,734) 1,161 (114) Hospitalizations 316 (154) 1,070 (633) 754 (239) Outpatient visits 35 (32) 35 (36) Physician services 215 (193) 210 (229) 5 (2) 0.81 Medication 119 (60) 352 (268) 233 (196) Radiology 41 (27) 53 (43) 13 (32) Laboratory services 281 (253) 444 (467) 163 (58) Health-care costs outside UHG 566 (522) 614 (548) 48 (9) 0.87 Patient and family costs 102 (76) 94 (85) 8 (8) 0.61 Production losses 90 (58) 187 (115) 97 (108) Total costs 1,774 (1,478) 3,072 (2,885) 1,298 (73) *Data are expressed as average costs in Dfl per week per patient (medians) unless otherwise indicated. One Dfl is equal to 50 cents US currency at the time of the study. Mann-Whitney test. days hospitalized accounted for almost three fourths of the extra costs. On average, patients developing BOS spent 1.9 d/wk in the hospital, compared to 0.6 d/wk in patients who did not develop BOS (p 0.001). The rise in costs associated with medication was also considerable ( 233 Dfl; p 0.001). No statistically significant differences could be found for the costs associated with medical services, outpatient visits, health-care costs outside the UHG, or for the family and patient costs. Patients developing BOS experienced higher costs of production losses ( 97 Dfl; p 0.048). When comparing the costs within patients with BOS, ie, before and after the onset of BOS, the costs per week of follow-up are higher after onset of BOS compared to before onset (Table 3). The differences, however, were not statistically significant, with the exception of a decrease in costs associated with outpatient visits and a reduction in patient and family costs. Also, after onset of BOS, patients spent more days per week in the hospital, although this difference failed to reach statistical significance as well (1.7 d/wk prior to BOS vs 2.3 d/wk after onset of BOS; p 0.4). Discussion More than 15 years ago, Burke et al 11 reported a syndrome of irreversible severe air flow obstruction and typical histologic features of obliterative bronchiolitis in several heart-lung recipients. Today, BOS remains a major impediment to long-term success after heart or lung transplantation. In the present study, for the first time, it was demonstrated that BOS is associated with considerable extra costs. This may not be surprising, as BOS is associated with increased morbidity, mainly by superimposed infections. 4 However, this study clearly depicts the extent and the distribution of the extra costs. The bulk of the extra costs was caused by an increase in days spent in the hospital; obviously, Table 3 Comparison of Costs Before and After Onset of BOS* Variables Before BOS (n 16) After BOS (n 16) Before/After BOS (%) p Value Health-care costs within UHG 1,941 (1,801) 2,422 (1,675) 481 (25) 0.47 Hospitalizations 748 (647) 1,324 (612) 576 (77) 0.3 Outpatient visits 59 (48) 26 (23) 33 (56) Physician services 220 (197) 187 (186) 33 (15) 0.8 Medication 292 (286) 419 (222) 127 (43) 0.35 Radiology 62 (54) 50 (43) 12 (19) Laboratory services 547 (490) 399 (423) 148 (27) 0.1 Health-care costs outside UHG 621 (586) 625 (623) 4 (1) 0.47 Patient and family costs 124 (120) 75 (75) 49 (40) Production losses 148 (121) 183 (86) 35 (24) 0.98 Total costs 2,833 (2,822) 3,305 (2,807) 472 (17) 0.44 *Data are expressed as average costs in Dfl per week per patient (medians) unless otherwise indicated. See Table 2 legend for definition. Wilcoxon signed rank test Clinical Investigations

4 patients were admitted to the hospital more often for obtaining a diagnosis or undergoing treatment, either directed at the allograft dysfunction or at associated infections. The latter is reflected in the increased costs of medication. As only cyclosporine, azathioprine, and prednisolone were available for standard immunosuppressive therapy at the time of the study, the results are not biased by conversions to a different scheme of maintenance immunosuppressive drugs. The average number of days per week spent in the hospital may be high when compared to the results of a study by Ramsey et al. 12 This may be explained by the fact that the follow-up protocol (with the exception of visits to the outpatient clinic) was performed on an inpatient basis in our hospital at the time of the study. A possible confounding factor is the comparison of two potentially different groups of patients, or a different length of follow-up of two groups. As can be seen in Table 1, the patients developing BOS differ slightly from those who do not with respect to underlying diagnosis. To the best of our knowledge, however, patient characteristics have not been reported as risk factors for development of BOS. The average length of follow-up per patient was comparable in the two groups (492 days in the patients without BOS, and 559 days in those developing BOS). Although the costs per week of follow-up were higher after onset of BOS, the difference did not achieve statistical significance, which may be due to the fact that the number of patients developing BOS was small. Furthermore, we found that the costs started to increase gradually, even before a diagnosis of BOS was made. This probably reflects the impact of reported risk factors for BOS, ie, an increased number and severity of rejection episodes 13,14 and possibly cytomegalovirus disease. 14 BOS is rarely responsive to medical treatment. 15 Stabilization of the decline in pulmonary function can be achieved sometimes through augmented immunosuppression. 16 Recently, several new immunosuppressive drugs have been introduced for use in lung transplantation. 17 Results from studies with tacrolimus suggest that the prevalence of BOS is significantly lower in patients treated with tacrolimus, compared to patients treated with cyclosporine. 18 Tacrolimus has also been used with some success as rescue therapy for BOS in two small, uncontrolled studies. 19,20 Preliminary experience with the use of mycophenolate mofetil in lung transplantation suggests that mycophenolate mofetil is superior to azathioprine in reducing the incidence of BOS. 21 In many countries, however, these drugs have not been licensed yet for use in lung transplantation. In general, these newer immunosuppresive drugs are more expensive than the old ones. Concerns for additional costs to lung transplantation, already one of the most expensive medical interventions available, may have prevented the drug regulatory agencies from licensing these drugs. If these newer drugs, however, are effective in lowering the incidence of BOS, or postponing its onset, such a restrictive, penny-wise approach may be eventually disadvantageous, both to lung transplant recipients and to the overall costs of a lung transplant program. In conclusion, our results show that the development of BOS adds considerably to the costs of lung transplantation. This, in conjunction with a reduced life expectancy associated with BOS, markedly reduces the cost-effectiveness of lung transplantation. Our data stress the need to focus efforts on prevention of BOS to enhance cost-effectiveness of lung transplantation or, at the least, to improve the quality of life of these patients. 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