Abstract
Introduction: Prevalence of pulmonary hypertension (PH) and its influence on survival in chronic obstructive pulmonary disease (COPD) are not well studied in the lung allocation score (LAS) era.
Methods: The UNOS database was queried from 2005 to 2013 to identify first-time adult lung transplant candidates with COPD who were tracked from wait list entry date until death or censoring to determine both prevalence and influence of PH. Using right heart catheterization measurements, mild PH was defined as mean pulmonary artery pressure (mPAP) ≥ 25 mmHg and severe ≥ 35 mmHg.
Results: Of 1315 COPD candidates not transplanted, 1243 were used for survival analysis using Cox proportional hazards models, and 1010 (mild PH) and 244 (severe PH) were used for propensity score matching, respectively. A total of 52% (652) of subjects had PH mPAP ≥ 25 mmHg. Univariate analysis revealed significant differences in survival for mild PH (HR = 1.769; 95% CI: 1.331, 2.351; p < 0.001) and severe PH (HR = 3.271; 95% CI: 2.311, 4.630; p < 0.001). Kaplan–Meier survival function demonstrated significant disparities for mild PH (Log-rank test: Chi-square1: 15.87, p < 0.0001) and severe PH (Log-rank test: Chi-square1: 50.13, p < 0.0001). Multivariate Cox models identified significant risk for death for mild PH (HR = 1.987; 95% CI: 1.484, 2.662; p < 0.001) and severe PH (HR = 3.432; 95% CI: 2.410, 4.888; p < 0.001). Propensity score matching confirmed increased mortality hazard associated with mild PH (HR = 2.280; 95% CI: 1.425, 3.649; p = 0.001) and severe PH (HR = 7.000; 95% CI: 2.455, 19.957; p < 0.001).
Conclusions: PH is highly prevalent in advanced COPD and associated with a significantly higher risk for mortality.
Introduction
Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow obstruction that is strongly associated with smoking tobacco and other factors including genetic determinants, lung growth, and environmental stimuli (Citation1). Several comorbidities are recognized in COPD with the more common ones including systemic hypertension, diabetes mellitus, atrial fibrillation, coronary artery disease, cardiac arrhythmias, congestive heart failure, and obstructive sleep apnea (Citation2–Citation4).
Pulmonary hypertension (PH) is a recognized complication in several forms of chronic lung disease, especially COPD (Citation5). The influence of PH on survival in the general COPD population is unknown as right heart catheterization (RHC) is not frequently performed in this patient population. According to the current diagnostic guidelines, PH is classified into five groups: [1] pulmonary arterial hypertension, [2] PH with left heart disease, [3] PH associated with lung diseases and/or hypoxemia, [4] PH owing to chronic thrombotic and/or embolic disease, and [5] miscellaneous (Citation6). Therefore, PH in patients with COPD would be considered Group 3.
With COPD being a common indication for lung transplantation (LTx) (Citation7), these patients undergo RHC as a component of the diagnostic evaluation for candidacy for transplant. Therefore, patients with advanced lung disease awaiting LTx is a patient population that may help address gaps in the medical literature regarding prevalence and influence on survival, especially in advanced stages. In a previous analysis by our group of the United Network for Organ Sharing (UNOS) thoracic database from 1987 to 2012, we demonstrated that an increase in the mean pulmonary artery pressure (mPAP) from the time of wait listing to the time of LTx was associated with poorer survival in patients with COPD after LTx (Citation8). To expand our understanding with regards to both prevalence of PH in COPD and its influence survival in patients before LTx since the implementation of the lung allocation scoring (LAS), we completed a study involving patients who died or were censored on the wait list. Our hypothesis was that PH occurs more commonly as reported and PH significantly increases mortality risk in the COPD population with advanced lung disease in the LAS era.
Methods
Data collection
A retrospective cohort study was performed of adult LTx candidates who were registered in the Organ Procurement and Transplant Network (OPTN) Standard Transplant Analysis and Research (STAR) Database administered by UNOS (Citation9). The study was approved by The Ohio State University Wexner Medical Center Institutional Review Board with a waiver of the need for individual consent (IRB#2012H0306). The UNOS/OPTN thoracic database was queried for all patients with COPD listed from May 2005 to September 2013 since the inception of the LAS. Each first-time LTx candidate listed was tracked until death or censoring prior to LTx.
The data available from the UNOS Registry included mPAP measurements from right heart catheterization (RHC) procedures for candidates listed. The current diagnostic standard to diagnose PH is a mPAP ≥25 mmHg on RHC (Citation10,Citation11), so we used that as the threshold for mild PH. Additionally, a mPAP threshold of 35 mmHg was used for severe PH due to recent evidence that pulmonary vascular lesions from explanted lungs of COPD patients correlated with idiopathic pulmonary arterial hypertension histologically when mPAP was ≥35 mmHg in the COPD cohort (Citation12).
Statistical methods
All analyses were performed using Stata/MP, version 13.1 (College Station, TX: StataCorp LP). All values were expressed as means ± standard deviation (SD) for continuous measures, and numbers and percentages for categorical variables. For all analyses, a p value < 0.05 was considered statistically significant. For evaluation of mean differences between baseline characteristics for patients with and without PH, we used unpaired t-tests for continuous measures and Chi-square tests for dichotomous measures.
The date of entry for patients who were enrolled from May 2005 onward was used as the starting point for survival duration. Survival duration was analyzed from the date of listing until the date of death or censoring before LTx. Survival was first estimated using univariate analysis and Kaplan–Meier survival models with log-rank tests for comparison of curves between COPD patients with and without PH. A Cox proportional hazards model was used to adjust for covariates, including gender, race, age, creatinine, and body mass index (BMI). Covariates of interest for which >50% of the sample had missing data were analyzed using univariate Cox proportional hazards models only, and were not included in multivariate models. These covariates included forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and 6-minute walk distance (6MWD).
Propensity score matching was completed to confirm risk with a comparison of each patient with PH to the most similar patient without PH at the time of listing. The propensity of exceeding the PH threshold at the time of listing was calculated as a logit function of the covariates included in the multivariate Cox analysis. Each patient with PH at the time of listing was matched to one patient without PH at the time of listing with the most similar propensity score, without replacement. Therefore, some patients without PH were not used creating the matched pair sample. To ensure that PH patients were not matched to excessively dissimilar non-PH controls, matching was performed only when the difference in the logit of the propensity score was equal or less than 0.2 standard deviations within each pair. Therefore, some patients with PH could not be included in the matched pairs sample because they did not have adequately similar non-PH counterparts in the sample. Cox proportional hazards regression stratified on the matched pairs was used to estimate a hazard ratio (HR) of PH in COPD prior to LTx.
Results
Study population
Of all 136,498 listed organ transplant candidates, 1,315 cases had COPD that were first-time candidates listed for LTx but were not transplanted during the study period (Figure ). Of this COPD cohort, 71 adult cases were excluded from the analysis with missing mPAP measurements. One case was excluded from survival analysis due to having zero days at risk between listing and death or censoring. In the propensity analysis of mild PH, 87 patients without PH were not used in the process of matching each patient with PH to one patient without PH, whereas no adequately similar matches could be found for 146 patients with PH, leading to 233 total patients being excluded from the sample. In the propensity analysis of severe PH, 999 patients without PH were not used in the matching process.
Figure 1. Patient inclusion and exclusion criteria for the cohort of patients with COPD (chronic obstructive pulmonary disease).
Table and Table summarize patient characteristics in the entire sample and with comparisons between PH and non-PH groups, using mPAP thresholds of ≥25 and ≥35 mmHg, respectively. Using mPAP ≥25 mmHg as the diagnostic criterion, 52% (652/1244) of the COPD patients would meet criteria for PH. In comparison, 9.8% (122/1244) of COPD patients had mPAP ≥ 35 mmHg.
Table 1. Patient characteristics with pulmonary hypertension threshold of mean pulmonary artery pressure ≥ 25 mmHg
Table 2. Patient characteristics with pulmonary hypertension threshold of mean pulmonary artery pressure ≥ 35 mmHg
Comparing PH to non-PH groups in the mPAP ≥ 25 mmHg analysis (Table ), the PH group included a higher proportion of men and had higher average BMI and higher average FVC. Comparing PH to non-PH groups in the mPAP ≥35 mmHg analysis (Table ) the PH group had a higher proportion of men, as in the mild PH analysis, and exhibited significant differences in racial composition compared to the non-PH group, with the latter including a higher proportion of White patients and a lower proportion of Black patients. BMI was significantly higher in the PH group, with either mPAP cutoff, there were no significant differences by PH diagnosis status for age, creatinine, FEV1, or 6MWD.
Univariate and Kaplan-Meier survival analysis
A total of 1243 patients were included in the univariate Cox models and the Kaplan-Meier survival function, respectively. Both mild and severe PH was associated with significantly increased risk of death. Analysis for mPAP ≥25 mmHg identified HR = 1.769; 95% CI: 1.331, 2.351; p < 0.001, while mean PAP ≥35 mmHg demonstrated HR = 3.271; 95% CI: 2.311, 4.630, p < 0.001 (Table ). Higher BMI, higher FVC, and longer 6MWD were associated with significantly lower mortality hazard in univariate models, although sample sizes for analyses of FVC and 6MWD were highly limited due to missing data (Table ). Kaplan–Meier survival function confirmed survival differences between mild and severe PH (Figure and Figure ).
Table 3. Univariate survival analysis (N = 1243)
Figure 2. Kaplan–Meier survival functions comparing pulmonary hypertension and no pulmonary hypertension in patients with chronic obstructive pulmonary disease using mean pulmonary artery pressure ≥25 mmHg as the threshold (N = 1243), Log-rank test: Chi-square (df = 1): 15.87, p < 0.0001. PH = pulmonary hypertension.
Figure 3. Kaplan-Meier survival functions comparing pulmonary hypertension and no pulmonary hypertension in patients with chronic obstructive pulmonary disease using mean pulmonary artery pressure ≥35 mmHg as the threshold (N = 1243), Log-rank test: Chi-square (df = 1): 50.13, p < 0.0001. PH = pulmonary hypertension.
Multivariate survival analysis
A total of 1243 patients were included in the multivariate Cox models, which are illustrated in Table and Table . Both mild PH (HR = 1.987; 95% CI: 1.484, 2.662; p < 0.001) and severe PH (HR = 3.432; 95% CI: 2.410, 4.888; p < 0.001) were associated with significant risk for death. In the adjusted models, higher BMI significantly reduced mortality hazard with the other covariates not reaching statistical significance.
Table 4. Multivariate survival analysis with mean pulmonary artery pressure ≥25 mmHg as the pulmonary hypertension threshold (N = 1243)
Table 5. Multivariate survival analysis with mean pulmonary artery pressure ≥35 mmHg as the pulmonary hypertension threshold (N = 1243)
Propensity score matching
Propensity score matching was performed to match each patient with PH to one non-PH patient with the most similar propensity of having PH at the time of listing. All covariates from Table and Table were used to calculate the propensity score for mild and severe PH, respectively. Stratified survival analysis was performed on the sample of matched pairs. A total of 1010 patients were used for the mPAP ≥25 analysis and 244 for the mPAP ≥35 analysis. A significant risk of death was confirmed in both PH severity groups: mild PH (HR = 2.280; 95% CI: 1.425, 3.649; p = 0.001) and severe PH (HR = 7.000; 95% CI: 2.455, 19.957; p < 0.001).
Discussion
Research investigating the prevalence and clinical outcomes associated with PH in COPD is not vigorous. Although there is published literature on the impact of PH in advanced COPD (Citation13–Citation15), no study to date has examined this effect on this patient population in the LAS era. This current study analyzes a contemporary cohort of patients with COPD with a higher risk for mortality associated with COPD as compared to Cuttica et al. (Citation13), who used the UNOS thoracic database for their analysis from 1997 to 2006.
The diagnosis of PH in the general COPD population is commonly delayed due to symptomatic overlap between progressing lung disease and PH and the invasiveness of RHC, which is the gold standard diagnostic modality. Based on our experience, PH is commonly not recognized in COPD until patients are referred for LTx, so the current study took advantage of a multi-institutional database with RHC data for COPD patients listed for LTx in the United States.
The most important findings of the current study include the high prevalence of PH in advanced COPD and the significant mortality risk associated with PH in the patient population listed for LTx. In advanced COPD, recent studies have demonstrated a prevalence of PH closer to 38%; however, some of this research involves diagnostic evaluation by transthoracic echocardiography (TTE) (Citation16,Citation17). The limitations of TTE estimating mPAP and diagnosing PH have been described, especially in the setting of lung disease (Citation18,Citation19). Using the diagnostic threshold of mPAP ≥25 mmHg, we found that PH occurred at a higher rate of 52% (652/1244), so clinicians should not underestimate PH in the setting of advanced COPD.
When diagnosed in COPD, PH is typically mild-to-moderate in severity with preserved cardiac output, but this may worsen with progression of lung disease and hypoxemia (Citation20). In a recent study of 101 COPD patients who were consecutively diagnosed with PH by RHC, Hurdman et al. (Citation21) reported that 58% (59/101) had severe PH (mPAP ≥40 mmHg) with 1-year and 3-year survival rates for severe PH of 70% and 33% compared to 83% and 55% COPD patients with less severe PH, respectively (Citation21). The results of the current study demonstrate slightly higher survival rates at both PH severity levels as compared to the cohort in the Hurdman et al. (Citation21) study. Differences between the studies include different mPAP threshold for severe PH, while both studies used mPAP ≥25 mmHg as the PH diagnostic threshold.
Despite evolving research investigating PH in various lung diseases, little evidence exists on a causal relationship of PH in COPD. Although hypoxemia can be corrected by supplemental oxygen therapy in COPD, severe PH can still persist, so there is likely several factors involved in the pathobiology of PH in this patient population (Citation22,Citation23). In a study of 70 COPD patients where pulmonary vascular lesions from explanted lungs after LTx were analyzed, histological severity of PH was more prevalent when the mPAP was ≥35 mmHg (Citation12). These investigators reported that acidosis, dynamic pulmonary hyperinflation, parenchymal destruction, pulmonary vascular remodeling, endothelial dysfunction and inflammation were mechanisms involved in the development of PH in COPD that are interdependent and modulated by genetic factors (Citation12).
In the unadjusted models of the current study, several significant covariates were identified that support the current medical literature (Citation24–Citation32), including higher pulmonary function (as measured by FVC) and longer 6MWD associated with a lower risk for death. The single covariate in the adjusted models found to be significant was higher BMI being associated with lower mortality risk, which is consistent with the current medical literature (Citation33–Citation35) that shows lower BMI is a variable influencing mortality in COPD.
The current study has limitations due to the retrospective collection of data from a large database with missing data and where there is risk for data entry errors and the potential for not including confounding variables. Despite its limitations, the current study draws results from a large, multi-institutional registry database of LTx recipients and thus reduces potential biases observed in single-institution observational studies.
In conclusion, the current study demonstrates a high prevalence of PH in COPD in the LAS era and establishes that PH in COPD is clinically relevant due to significant mortality risk in this patient population. Importantly, our results validate the need for RHC in this patient population. Although systematic screening for PH in COPD should be considered even before referral for LTx, routine RHC is not feasible for every patient diagnosed with COPD. Further research is needed to identify optimal screening methods for PH in this patient population using non-invasive technology, possibly expanded TTE and/or cardiac magnetic resonance imaging, to establish well-defined indications for RHC in COPD.
Declaration of Interest Statement
The authors report no conflicts of interest and have no relevant disclosures. No funding was required to complete this work. Responsibilities as follows: Don Hayes, Jr.: Conception and design, acquisition of data, interpretation of data, drafting of the manuscript; Sylvester M. Black: Conception and design, interpretation of data, revision of the manuscript; Joseph D. Tobias: Interpretation of data, revision of the manuscript;
Heidi M. Mansour: Interpretation of data, revision of the manuscript; and, Bryan A. Whitson: Conception and design, interpretation of data, revision of the manuscript.
The authors report no conflicts of interest and have no relevant disclosures regarding this manuscript.
Acknowledgments
The authors would like to acknowledge Dmitry Tumin for his statistical expertise in the data analysis.
Color versions for one or more of the figures in the article can be found online at www.tandfonline.com/icop.
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