Kathryn L. O Keefe, 1 Ahmet Kilic, 1 Amy Pope-Harman, 2 Don Hayes, Jr., 2,3 Stephen Kirkby, 2,3 Robert S. D. Higgins, 1 Bryan A. Whitson 1.

Transcription

1 ArtIcle Changes in Pulmonary Artery Pressure Affect Survival Differently in Lung Transplant Recipients Who Have Pulmonary Hypertension or Chronic Obstructive Pulmonary Disease Kathryn L. O Keefe, 1 Ahmet Kilic, 1 Amy Pope-Harman, 2 Don Hayes, Jr., 2,3 Stephen Kirkby, 2,3 Robert S. D. Higgins, 1 Bryan A. Whitson 1 Abstract Objectives: Pulmonary hypertension and right ventricular dysfunction can complicate lung transplant. Pulmonary artery pressures affect outcome are uncertain during wait list. We evaluated changes in wait list pulmonary artery pressures on survival after lung transplant. Materials and Methods: We queried the United Network for Organ Sharing/Standard Transplant Analysis and Research registry from 1987 to 2012 for all lung transplants. Recipients with unique pulmonary artery pressure measurements upon listing and transplant were included. Mean pulmonary artery pressure was rated as increased (increase > 5 mm Hg), decreased (decrease > 5 mm Hg), or unchanged (variation < 5 mm Hg). Results: There were lung transplants and 1677 recipients were included. Diagnoses demonstrated significant changes in mean pulmonary artery pressure during the listing period (P.0001). In recipients with chronic obstructive pulmonary disease, survival was poorer when mean pulmonary artery pressure was increased than decreased (P.03). In recipients with primary pulmonary hypertension, survival was poorer when mean From the 1 Department of Surgery, Division of Cardiac Surgery; 2 Department of Internal Medicine, Division of Pulmonary, Allergy, and Critical Care & Sleep Medicine, Wexner Medical Center, Ohio State University; and the 3 Nationwide Children s Hospital, Department of Pediatrics, Division of Pulmonary Medicine, Columbus, OH, USA Acknowledgements: The authors have no conflicts of interest. There was no external funding for the research. Corresponding author: Bryan A. Whitson, MD, PhD, Division of Cardiac Surgery, Ohio State University, Wexner Medical Center, N-813 Doan Hall, 410 W. 10th Avenue, Columbus, OH USA Phone: Fax: bryan.whitson@osumc.edu Experimental and Clinical Transplantation (2014) 4: pulmonary artery pressure was decreased than increased (P.02). Proportional hazards analysis showed that increases in mean pulmonary artery pressure independently affected survival (hazard ratio, 0.78; 95% confidence interval, ). Conclusions: Although the mechanism is unknown, an increase in mean pulmonary artery pressure in patients with chronic obstructive pulmonary disease is associated with poorer survival after lung transplant. In contrast, patients with primary pulmonary hypertension with decreased mean pulmonary artery pressure have poorer survival after lung transplant. In patients with primary pulmonary hypertension, changes in pulmonary artery pressure may be a surrogate for a failing right ventricular function. In chronic obstructive pulmonary disease, the change in pressure suggests an undetermined progressive process. Further study of right ventricular function is warranted to determine the effects of changes in pulmonary artery pressure on lung transplant recipients. Key words: Hemodynamics, Idiopathic pulmonary fibrosis, Outcomes, Pulmonary failure Introduction Lung transplant is an effective treatment for patients who have various end-stage lung diseases and may improve quality of life and survival in these patients. However, there is a shortage of donor organs, and transplant recipients have a high frequency of early mortality after surgery. There is a need to identify factors that affect primary graft dysfunction and Copyright Başkent University 2014 Printed in Turkey. All Rights Reserved. DOI: /ect

2 284 Kathryn L. O Keefe et al/experimental and Clinical Transplantation (2014) 4: Exp Clin Transplant long-term survival in transplant recipients. Pulmonary hypertension is associated with an increased risk of primary graft dysfunction and death. 1-3 Previous studies that evaluated pulmonary hypertension in recipients have focused primarily on the increase in pulmonary artery pressure (PAP) and the effect of increased PAP on the development of primary graft dysfunction. The purpose of the present study was to assess the effect of changes in waiting list PAP measurements on survival in lung transplant recipients. Materials and Methods We accessed the United Network for Organ Sharing (UNOS)/Standard Transplant Analysis and Research (STAR) Database. 4 This database, maintained by the United States Department of Health & Human Services, contains information about donor characteristics, recipient characteristics before and after transplant, and outcomes from 1987 to the present after solid-organ transplants. Data are entered when a patient is added to the wait list and when the patient undergoes transplant. The data were extracted by individual centers and submitted as aggregate data to the Organ Procurement and Transplantation Network (OPTN), United States Scientific Registry of Transplant Recipients (SRTR), which collates and administers the data. The present study was a retrospective review of the UNOS/STAR registry and was approved by the Institutional Review Board at Ohio State University with a waiver of need for individual consent. We assessed data about all lung transplant recipients who received a lung transplant between 1987 and 2012 in the United States aged 18 years. We limited the analysis to single and bilateral deceased-donor, first-time lung transplant recipients. Patients having revision transplant were excluded. We evaluated PAP measurements when patients were placed on the waiting listed and underwent a lung transplant. Recipients included in the analysis had unique PAP measurements when added to the wait listing and when undergoing a transplant. A change in mean PAP (mpap) was defined as mpap upon being added to the waiting list minus mpap at transplant: mpap change = mpap listing mpap transplant. The mpap was rated as increased (increase > 5 mm Hg), decreased (decrease > 5 mm Hg), or unchanged (variation < 5 mm Hg). Recipients who had no PAP values recorded or had identical measurements at listing and transplant were excluded. Statistical analyses Data were analyzed with statistical software (SAS for Windows version 9.4, SAS Institute Inc., Cary, NC, USA). Results were reported as mean ± standard deviation. Data were analyzed with chi-square test for between-group comparisons. Survival comparisons to evaluate unadjusted all-cause mortality were made with the Kaplan-Meier method. Cox proportional hazards regression model was used to adjust for covariates associated with survival and adjust the survival analysis for potentially confounding patient factors. 5-9 Statistical significance was defined by P.05. Results Study cohort A total of lung transplants were performed between 1987 and 2012 during the study period. There were 1677 recipients who had complete, unique mpap data and satisfied the inclusion criteria according to the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) flow diagram (Figure 1). 10 Figure 1. Strengthening Reporting of Observational Studies in Epidemiology (STROBE) Flow Diagram of Study Patients Who Were Included and Excluded From the Study Pulmonary artery pressure changes and indications for transplant The most frequent indications for lung transplant were chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) (Table 1). The mpap increased in 555 recipients (33%), decreased in 385 recipients (23%), and was unchanged in 737 recipients (44%) (Table 2). Each diagnosis was

3 Kathryn L. O Keefe et al/experimental and Clinical Transplantation (2014) 4: associated with significant changes in mpap while on the waiting list (Table 2). table 1. Indications for Lung Transplant For Patients in the United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research (STAR) Database* Indication Entire Included in Database Present Study Chronic obstructive pulmonary disease 7690 (35) 616 (37) Idiopathic pulmonary fibrosis 5596 (26) 464 (28) Primary pulmonary hypertension 795 (4) 109 (7) Cystic fibrosis 2893 (13) 89 (5) Alpha-1 antitrypsin deficiency 1376 (6) 76 (5) Sarcoidosis 646 (3) 64 (4) Revision transplant 0 (0) 0 (0) Other 2889 (13) 259 (15) Total (100) 1677 (100) *Data reported as number (%). table 2. Changes in Mean Pulmonary Artery Pressure From Wait-Listing to Lung Transplant in Study Patients* Mean Pulmonary Artery Pressure Diagnosis Decreased Unchanged Increased Total P Chronic obstructive pulmonary disease 161 (26) 292 (47) 163 (27) Idiopathic pulmonary fibrosis 74 (16) 205 (44) 185 (40) Primary pulmonary hypertension 38 (35) 39 (36) 32 (29) Cystic fibrosis 15 (17) 45 (51) 29 (33) Alpha-1 antitrypsin deficiency 12 (16) 41 (54) 23 (30) Sarcoidosis 14 (22) 21 (33) 29 (45) Other 71 (27) 94 (36) 94 (36) Total (%) 385 (23) 737 (44) 555 (33) 1677 (100) *Data reported as number (%). Pulmonary artery pressure and survival after transplant Kaplan-Meier analysis showed that an increase in mpap was associated with poorer survival in patients who had lung transplant because of COPD. This was significant compared with COPD patients who had a decrease in mpap while on the waiting list (P.03) (Figure 2). When patients who had unchanged mpap were removed from the analysis, significantly lower survival also was demonstrated in COPD patients who had an increase in mpap (P.01) (Figure 2). Patients who had lung transplant because of PPH and who had decreased mpap while on the waiting list had lower survival than patients who had increased mpap (P.02) (Figure 3). When patients who had unchanged mpap were removed from the analysis, there was significantly lower survival in PPH patients who had decreased mpap (P.02) (Figure 3). There were no significant survival differences noted with other diagnoses such as IPF (Figure 4). In multivariate Cox proportional hazards analysis model, several variables independently affected overall survival including increased mpap, recipient race other than white or African-American, African- American donor race, donor age, waiting list time, and recipient age (Table 3). African-American donor race, donor age, waiting list time, and recipient age were factors that had a negative effect Figure 2. Relation Between Changes in Mean Pulmonary Artery Pressure (mpap) From Wait Listing to Surgery and Survival After Lung Transplant in Recipients Who Had Chronic Obstructive Pulmonary Disease P =.0298 P =.0095 (A) Changes in mpap (increased, unchanged, and decreased) had a significant effect on survival. (B) The effect of increases and decreases alone were increased when patients who had unchanged mpap were removed from the analysis. Analysis was by log-rank test with the number at risk over time in the Table below the x axis.

4 286 Kathryn L. O Keefe et al/experimental and Clinical Transplantation (2014) 4: Exp Clin Transplant Figure 3. Relation Between Changes in Mean Pulmonary Artery Pressure (mpap) From Wait Listing to Surgery and Survival After Lung Transplant in Recipients Who Had Primary Pulmonary Hypertension (PPH) P =.0134 P =.014 (A) Changes in mpap (increased, unchanged, and decreased) had a significant effect on survival. (B) The effect of increases and decreases alone were increased when patients who had unchanged mpap were removed from the analysis. Analysis was by log-rank test with the number at risk over time in the Table below the x axis. Figure 4. Relation Between Changes in Mean Pulmonary Artery Pressure (mpap) From Wait Listing to Surgery and Survival After Lung Transplant in Recipients Who Had Idiopathic Pulmonary Fibrosis P =.89 Changes in mpap (increased, unchanged, and decreased) did not affect survival. Analysis was by log-rank test with the number at risk over time in the Table below the x axis. on overall long-term survival of transplant recipients. Increased mpap and recipient race other than white or African-American positively affected overall long-term survival. Diagnosis, recipient sex, donor sex, single- vs bilateral-lung transplant, ischemic time, prostacyclin use, and inhaled nitric oxide use had no effect on overall survival in this model (Table 3). table 3. Proportional Hazards Analysis Associated With Survival After Lung Transplant* Covariate P Hazard Ratio 95% Confidence Interval Mean pulmonary artery pressure Unchanged Decreased NS Increased Diagnosis Sarcoidosis Alpha-1 antitrypsin deficiency NS Cystic fibrosis NS Chronic obstructive pulmonary disease NS Idiopathic pulmonary fibrosis NS Pulmonary hypertension NS Other NS Recipient race White African-American NS Other Recipient sex Male Female NS Donor race White African-American Other NS Donor sex Male Female NS Transplant type Single-lung transplant Bilateral-lung transplant NS Increasing donor age Increasing waiting list time Increasing recipient age Increasing ischemic time NS Prostacyclin use NS Inhaled nitric oxide use NS *N = 1677 patients. NS, not significant (P >.05)

5 Kathryn L. O Keefe et al/experimental and Clinical Transplantation (2014) 4: Statistically significant differences were observed between the waiting list times for patients with increased, decreased, and unchanged mpap (P.01); patients who had increased mpap had the longest mean time on the waiting list (increased mpap, 546 ± 619 d [555 patients]; decreased mpap, 422 ± 467 d [385 patients]; unchanged mpap, 492 ± 619 d [737 patients]). The patient groups differed significantly in mean mpap (increased mpap, 11 ± 5 mm Hg; decreased mpap, -10 ± 5 mm Hg; unchanged mpap, 0 ± 3 mm Hg; P.01). Discussion The present analysis of the UNOS/STAR database showed that changes in waiting list mpap were associated with differences in survival in lung transplant recipients who had COPD or PPH. recipient pulmonary artery pressure and primary graft dysfunction An effort has been made to accurately identify risk factors in either donors or recipients that contribute to primary graft dysfunction. Primary graft dysfunction is the main cause of early morbidity and mortality after lung transplant and correlates with reduced long-term survival. 3 Multiple studies have demonstrated the presence of recipient pulmonary arterial hypertension as a risk factor for developing primary graft dysfunction, increased 90-day mortality, and decreased overall survival. 1,2,10,11 These studies include large registry and multicenter cohort studies. Increases in PAP by 10 mm Hg significantly increase the risk of developing primary graft dysfunction in some cohorts, as reported in a multicenter study of 1255 patients. 10 We used a change in mpap of 5 mm Hg to evaluate survival changes because of several recent studies that evaluated the effect of elevated preoperative mpap on transplant recipient survival and/or the development of primary graft dysfunction. A multicenter cohort study of patients who had IPF showed that an increase in mpap of 8.9 mm Hg was a risk factor for primary graft dysfunction, with an odds ratio of 1.64 for every 10 mm Hg increase in mpap. 13 Another cohort study of patients who had IPF confirmed that increased mpap was a risk factor for increased 90-day mortality after transplant, and mpap 35 mm Hg caused a 1.5-fold increase in early mortality. 12 Changes in relative mortality risk were seen with incremental changes in mpap as low as 5 mm Hg. Therefore, the cutoff of increased mpap 5 mm Hg was justified in the present study because of the previously reported data. effect of pulmonary artery pressure on survival after transplant There are conflicting opinions about whether primary and secondary pulmonary hypertension may be associated with poorer transplant outcomes. 12,13 In a previous study, secondary pulmonary hypertension in patients who had parenchymal lung disease did not preclude successful allograft function, and there was no relation between elevated PAP and poorer longterm survival. 13 Long-term survival after transplant in patients who had COPD was unaffected by the presence or absence of pre-existing, secondary pulmonary hypertension. 14 However, other studies showed that primary and secondary pulmonary hypertension may be associated with decreased survival after transplant. 2,15 The effect of pulmonary hypertension on survival after transplant is well established In recipients who have COPD, elevated mpap has a significant decrease on survival. In 409 recipients who had COPD, pulmonary hypertension was present in 36% COPD recipients, and hypoxemia and hypercapnia affected the mpap. Elevated mpap directly, adversely affected survival in the COPD patients. 14 In the present study, 26% of COPD patients had an increase in mpap, and the increase in mpap negatively affected survival after transplant. Elevation in PAP and depressed right ventricular parameters correlate with poor survival in patients who have IPF. 17 However, the change in mpap in the IPF patients in the present study did not affect survival, possibly because of the small IPF sample size with complete data. Patients who have IPF may have a baseline degree of fibrosis and pulmonary hypertension, and any substantive increase in mpap may precipitate an acute or terminal exacerbation that may necessitate emergency transplant or cause death. Although elevated PAP is associated with poor long-term survival, little information is available about the effect of changing PAP on the development of primary graft dysfunction or recipient survival after transplant. The present data suggest that the presence or absence of pulmonary hypertension

6 288 Kathryn L. O Keefe et al/experimental and Clinical Transplantation (2014) 4: Exp Clin Transplant alone may not affect a patient s outcome. The UNOS database provided an opportunity to evaluate changes in waiting list hemodynamic parameters by evaluating the database entries at wait-listing and transplant. We demonstrated changes in long-term survival based on the analysis of PAP measurements at those 2 times. The present analysis depended on transplant centers measuring and documenting hemodynamic data with separate candidacy and transplant entries in the registry database. The study cohort included a higher percentage of patients who had PPH (109 of 1677 patients [7%]) than the UNOS registry database (795 of patients [4%]), possibly because of the more rigorous measurements of mpap performed at transplant centers in patients with PPH. Patients who had COPD and an elevation in waiting list mpap had a decrease in long-term survival. We postulate that in this group of patients undergoing transplant, an increase in mean PAP may be caused by worsening pulmonary hypertension and/or intrinsic lung disease that may decrease overall survival. In the present study, patients who had PPH and a decrease in waiting list mpap also had significantly decreased long-term survival. Moderate-to-severe right ventricular dysfunction may negatively affect outcomes after lung transplant. 21 It is possible that in the PPH patient population, decreased mpap may be a marker for a failing right ventricle, which may affect survival after transplant. Strengths and limitations For this analysis, we used national data from an administrative database of lung transplant recipients (the UNOS/STAR registry). The study was a retrospective review of the registry data and has limitations inherent with observational studies such as selection and recorder bias. The UNOS/STAR registry contained transplant data only from the United States. The study also was limited by incomplete datasets; many patients from the total transplant registry were excluded because of a lack of unique PAP measurements recorded in the database. There may be the possibility that datasets were inaccurately entered. Although lung transplant for end-stage lung disease is a common procedure, there is a wide range of center volume and practice patterns across the country. Variations between centers in patient care during waiting list time, transplant surgical technique, and postoperative care were not evaluated in this study. Furthermore, there may have been bias in the measurement of mpap at transplant because this measurement may be altered by variations in right ventricular function and volume status. The UNOS/STAR registry and the current listing process may be limited by the absence of an objective measurement of right ventricular function. The PAP and right ventricular function have been correlated using newer electrocardiogram-gated computed tomography and magnetic resonance imaging techniques. 19 These correlations may enable the determination of right ventricular ejection fraction in addition to left ventricular ejection fraction and provide a real-time, noninvasive evaluation of changes in the pulmonary artery system and right ventricular ejection fraction. Determination of right ventricular ejection fraction may enable a more accurate prediction of survival after lung transplant. 19 Despite these limitations, the present study demonstrates significant survival differences in patients undergoing lung transplant. The inclusion and exclusion criteria were precise. The analysis was adjusted to account for potential confounders of the data. We had a large multicenter cohort from the largest registry of transplant patients currently available. The population-based data may reflect the practice and patterns of care across the United States and may be an accurate reflection of the outcomes of these patients. Conclusions The present analysis of the UNOS registry showed that changes in mpap during the waiting list period may affect survival outcomes in patients undergoing lung transplant. In patients who had COPD, an increase in mpap was associated with decreased survival, possibly because of worsening of intrinsic lung disease during the waiting list time. In patients who had PPH, a decrease in mpap caused decreased survival, which may have been caused by the development of right ventricular failure. The present study highlights the importance of obtaining hemodynamic data for lung transplant recipients throughout the time on the waiting list. Further evaluation of changes in waiting list mpap data, and analysis and inclusion of data about recipient

7 Kathryn L. O Keefe et al/experimental and Clinical Transplantation (2014) 4: ventricular function, may clarify the causes of survival differences noted in this study. s 1. Christie JD, Kotloff RM, Pochettino A, et al. Clinical risk factors for primary graft failure following lung transplantation. Chest. 2003;124(4): Whitson BA, Nath DS, Johnson AC, et al. Risk factors for primary graft dysfunction after lung transplantation. J Thorac Cardiovasc Surg. 2006;131(1): Whitson BA, Prekker ME, Herrington CS, et al. Primary graft dysfunction and long-term pulmonary function after lung transplantation. J Heart Lung Transplant. 2007;26(10): Organ Procurement and Transplantation Network. Standard Transplant Analysis and Research Database. U.S. Department of Health & Human Services, Health Resources and Services Administration Web site. about/optndatabase.asp. Accessed January 23, Allen JG, Kilic A, Weiss ES, et al. Should patients 60 years and older undergo bridge to transplantation with continuous-flow left ventricular assist devices? Ann Thorac Surg. 2012;94(6): Groth SS, Virnig BA, Whitson BA, et al. Determination of the minimum number of lymph nodes to examine to maximize survival in patients with esophageal carcinoma: data from the Surveillance Epidemiology and End Results database. J Thorac Cardiovasc Surg. 2010;139(3): Kilic A, Merlo CA, Conte JV, Shah AS. Lung transplantation in patients 70 years old or older: have outcomes changed after implementation of the lung allocation score? J Thorac Cardiovasc Surg. 2012;144(5): Whitson BA, Groth SS, Andrade RS, Habermann EB, Maddaus MA, D'Cunha J. T1/T2 non-small-cell lung cancer treated by lobectomy: does tumor anatomic location matter? J Surg Res. 2012;177(2): Whitson BA, Groth SS, Andrade RS, Maddaus MA, Habermann EB, D'Cunha J. Survival after lobectomy versus segmentectomy for stage I non-small cell lung cancer: a population-based analysis. Ann Thorac Surg. 2011;92(6): Diamond JM, Lee JC, Kawut SM, et al. Clinical risk factors for primary graft dysfunction after lung transplantation. Am J Respir Crit Care Med. 2013;187(5): Whelan TP, Dunitz JM, Kelly RF, et al. Effect of preoperative pulmonary artery pressure on early survival after lung transplantation for idiopathic pulmonary fibrosis. J Heart Lung Transplant. 2005;24(9): Barr ML, Kawut SM, Whelan TP, et al. Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part IV: recipientrelated risk factors and markers. J Heart Lung Transplant. 2005;24(10): Huerd SS, Hodges TN, Grover FL, et al. Secondary pulmonary hypertension does not adversely affect outcome after single lung transplantation. J Thorac Cardiovasc Surg. 2000;119(3): Andersen KH, Iversen M, Kjaergaard J, et al. Prevalence, predictors, and survival in pulmonary hypertension related to end-stage chronic obstructive pulmonary disease. J Heart Lung Transplant. 2012;31(4): Kuntz CL, Hadjiliadis D, Ahya VN, et al. Risk factors for early primary graft dysfunction after lung transplantation: a registry study. Clin Transplant. 2009;23(6): Long J, Russo MJ, Muller C, Vigneswaran WT. Surgical treatment of pulmonary hypertension: lung transplantation. Pulm Circ. 2011;1(3): Rivera-Lebron BN, Forfia PR, Kreider M, Lee JC, Holmes JH, Kawut SM. Echocardiographic and hemodynamic predictors of mortality in idiopathic pulmonary fibrosis. Chest. 2013;144(2): Venuta F, Tonelli AR, Anile M, et al. Pulmonary hypertension is associated with higher mortality in cystic fibrosis patients awaiting lung transplantation. J Cardiovasc Surg (Torino). 2012;53(6): Selimovic N, Andersson B, Bech-Hanssen O, Lomsky M, Riise GC, Rundqvist B. Right ventricular ejection fraction during exercise as a predictor of mortality in patients awaiting lung transplantation: a cohort study. BMJ Open. 2013;3(4). pii: e doi: / bmjopen