Influence of Pulmonary Hypertension on Patients With Idiopathic Pulmonary Fibrosis Awaiting Lung Transplantation

Influence of Pulmonary Hypertension on Patients With Idiopathic Pulmonary Fibrosis Awaiting Lung Transplantation Don Hayes, Jr, MD, MS, Sylvester M. Black, MD, PhD, Joseph D. Tobias, MD, Stephen Kirkby, MD, Heidi M. Mansour, PhD, and Bryan A. Whitson, MD, PhD Departments of Pediatrics, Internal Medicine, Surgery, and Anesthesiology, Ohio State University College of Medicine, and Section of Pulmonary Medicine and Department of Anesthesiology and Pain Medicine, Nationwide Children’s Hospital, Columbus, Ohio; and Skaggs Pharmaceutical Sciences Center, University of Arizona College of Pharmacy, Tucson, Arizona

Background. The influence of varying levels of pulmonary hypertension (PH) on survival in idiopathic pulmonary fibrosis is not well defined. Methods. The United Network for Organ Sharing database was queried from 2005 to 2013 to identify firsttime lung transplant candidates listed for lung transplantation who were tracked from waitlist entry date until death or censoring to determine the influence of PH on patients with advanced lung disease. Using data for right heart catheterization measurements, mild PH was defined as mean pulmonary artery pressure of 25 mm Hg or more, and severe as 35 mm Hg or more. Results. Of 6,657 idiopathic pulmonary fibrosis patients, 6,651 were used for univariate analysis, 6,126 for Kaplan-Meier survival function, 6,013 for multivariate Cox models, and 5,186 (mild PH) and 2,014 (severe PH) for propensity score matching, respectively. Univariate Cox proportional hazards analysis found significant

differences in survival for mild PH (hazard ratio [HR] 1.689, 95% confidence interval [CI]: 1.434 to 1.988, p < 0.001) and severe PH (HR 2.068, 95% CI: 1.715 to 2.493, p < 0.001). Further assessment by multivariate Cox models identified significant risk for death for mild PH (HR 1.433, 95% CI: 1.203 to 1.706, p < 0.001) and severe PH (HR 1.597, 95% CI: 1.308 to 1.949, p < 0.001). Propensity score matching confirmed the risk for death for mild PH (HR 1.530, 95% CI: 1.189 to 1.969, p [ 0.001) and severe PH (HR 2.103, 95% CI: 1.436 to 3.078, p < 0.001). Conclusions. The manifestation of PH, even with mild severity, is associated with significantly increased risk for death among patients with idiopathic pulmonary fibrosis awaiting lung transplantation, so referral should be considered early in the disease course.

diopathic pulmonary fibrosis (IPF) is a fibrotic lung disease of unknown cause characterized by relentless and progressive cough, dyspnea, hypoxemia, and restrictive ventilatory limitation that is often fatal [1–6]. The diagnosis of IPF is exclusionary in the appropriate clinical situation of gas exchange or pulmonary function impairment with evidence of usual interstitial pneumonia. Differences in diagnostic criteria, study population, and study design contribute to the variability of epidemiologic findings of IPF, but experts suggest that both prevalence and incidence of IPF are increasing [1]. The rise of IPF is due to multiple factors including an aging population, increased public awareness, and improved diagnostic capabilities of computed tomography imaging [7]. Pulmonary hypertension (PH) is considered to be an important comorbidity in the IPF population. In retrospective studies, the prevalence of PH in IPF has ranged

between 14% and 84% [8–16]. With this wide variation in prevalence estimates, there is conflicting evidence of the impact of PH on survival in IPF. Some series have reported a higher mortality when PH occurred concurrently in patients with IPF, with the rate proportionate to the PH severity [8, 9], but these findings have not been supported entirely [10]. This research is limited because the majority of the work draws on single-center experiences and the severity of PH is not consistently correlating with the levels of hypoxemia, fibrotic alternations, and respiratory impairment in IPF [9, 17]. To better estimate the prevalence of PH in patients with severe lung disease due to IPF and to substantiate the influence of PH in the IPF population, we sought to evaluate the influence of mean pulmonary artery pressure (PAP) of 25 mm Hg or greater and 35 mm Hg or greater on survival among IPF candidates for lung transplantation (LTx) by using a publically available database in the United States.

I

Accepted for publication June 1, 2015. Address correspondence to Dr Hayes, Ohio State University, Nationwide Children’s Hospital, 700 Children’s Dr, Columbus, OH 43205; e-mail: [email protected].

Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier

(Ann Thorac Surg 2015;-:-–-) Ó 2015 by The Society of Thoracic Surgeons

The Appendix can be viewed in the online version of this article [http://dx.doi.org/10.1016/j.athoracsur.2015. 06.024] on http://www.annalsthoracicsurgery.org.

0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2015.06.024

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Fig 1. Patient inclusion and exclusion criteria for patients with idiopathic pulmonary fibrosis (IPF) and subsequent univariate analysis, Kaplan-Meier survival curve, multivariate Cox analysis, and propensity score matching. (PH ¼ pulmonary hypertension.)

Material and Methods

Results

Data Collection

Study Population

A retrospective cohort study was performed of lung transplant candidates who were registered in the Organ Procurement and Transplant Network standard transplant analysis and research database administered by the United Network for Organ Sharing [18]. The study was approved by Ohio State University Wexner Medical Center Institutional Review Board (IRB#2012H0306). The United Network for Organ Sharing/Organ Procurement and Transplant Network thoracic database was queried for all patients with IPF listed from May 2005 to September 2013. Each first-time lung transplant candidate was tracked until death or censoring. Lung transplantation, if performed, was considered to be a censoring event.

Figure 1 presents inclusion and exclusion criteria for the current study. Of all 136,498 listed organ transplant candidates, 6,657 were first-time lung transplant candidates diagnosed with IPF. Of this cohort, 4,969 candidates received transplants, 1,038 were censored on the waiting list without undergoing transplantation, and 650 died before receiving a transplant. Among the 1,038 patients who neither died on the waiting list nor received a transplant and were considered censored in this analysis, we identified a plurality (395, 38%) for whom deteriorating condition was cited as a reason for removal from the waiting list. In the group of censored patients, another 271 patients (26%) remained on the waiting list at the most recent date of follow-up in September 2013. The remaining 372 patients (36%) who were considered censored in this analysis were removed from the waitlist for other reasons. A comparison of means and proportions between censored patients and other patients in the study found that censored patients were more likely to be female and less likely to be white, and had on average younger age, lower serum creatinine levels, higher initial supplemental oxygen requirement, and higher 6-mile walk distance (6MWD) scores, as compared with patients who died on the waitlist or received LTx. However, there was no statistically significant difference in mean PAP by censoring status (detailed results available on request). In constructing the analytic sample, further exclusions included zero days at risk after listing, missing PH-related data for Kaplan-Meier survival curve

Statistical Methods All analyses were performed using Stata/MP, version 13.1 (StataCorp, College Station, TX). Survival duration was analyzed from the date of listing until the date of death, transplantation, or censoring. Right-side heart catheterization (RHC) data were entered into the United Network for Organ Sharing dataset, including mean PAP measurements. The current diagnostic standards define PH as a mean PAP of 25 mm Hg or greater [19, 20], so we completed an analysis with mild PH being 25 mm Hg or greater and severe PH being 35 mm Hg or greater. A detailed description of the statistical analysis is outlined in the supplemental statistics material (Appendix).

Forced vital capacity (FVC) recorded 0 to 30 days before listing. PAP ¼ pulmonary artery pressure;

6MWD ¼ 6-minute walk distance.

c

Forced expiratory volume in 1 second (FEV1) recorded at time of listing. b

In all, 6,132 cases have data on pulmonary hypertension. a

0.046 <0.001 . . . . . . . . . . . . . . . . <0.001 0.784 <0.001 <0.001 0.340 <0.001 <0.001 <0.001 . . . . . 59.76 (8.74) 0.88 (0.53) 27.04 (4.00) 4.11 (3.96) 51.44 (16.37) 45.28 (15.36) 841.75 (509.02) 18.67 (3.96) 2,112 (66.27) . 2,598 (81.52) 151 (4.74) 438 (13.74) . . . . . . . . 2,022 (68.66) . 2,285 (77.59) 313 (10.63) 347 (11.78) . . . . . . . . 4,475 (67.22) . 5,296 (79.56) 505 (7.59) 856 (12.86) . . . . . . . .

. . . . . 59.00 (9.56) 0.88 (0.44) 27.43 (4.06) 4.94 (4.63) 50.98 (16.58) 47.04 (17.49) 754.02 (504.80) 25.93 (10.27)

. . . . . 58.67 (9.38) 0.89 (0.33) 27.95 (3.97) 5.81 (5.00) 50.31 (16.34) 49.28 (19.12) 667.17 (472.88) 33.80 (9.13)

Mean (SD) n (%) Mean (SD) n (%) Mean (SD) n (%)

No Pulmonary Hypertension (n ¼ 3,187)

t test

p Value

Male Race White Black Other Age, years Creatinine, mg/dL Body mass index Supplemental oxygen, L FEV1, % predictedb FVC, % predictedc 6MWD, feet Mean PAP

Among patients with data on PH, 1 case was missing data on BMI and 112 cases were missing data on supplemental oxygen requirement at listing. These cases were excluded from the multivariate Cox models. All covariates shown in Table 2 were included in the

Variable

Multivariate Survival Analysis

Pulmonary Hypertension (n ¼ 2,945)

In all, 6,651 patients was included in the univariate Cox models and 6,126 patients in the Kaplan-Meier survival function. Both mild and severe PH were associated with significantly increased risk of death. Analysis for mean PAP of 25 mm Hg or more (as compared with mean PAP less than 25 mm Hg) identified a hazard ratio (HR) of 1.689 (95% confidence interval [CI]: 1.434 to 1.988, p < 0.001; Table 2, Fig 2), whereas mean PAP of 35 mm Hg or greater (as compared with mean PAP less than 35 mm Hg) demonstrated HR of 2.068 (95% CI: 1.715 to 2.493, p < 0.001; Table 2, Fig 3). Analysis of continuous mean PAP likewise found a positive association between higher mean PAP and mortality hazard (HR 1.028, 95% CI: 1.022 to 1.035, p < 0.001; Table 2). Covariates that significantly reduced the risk for death included higher BMI, higher FEV1, higher FVC, and longer 6MWD; whereas male sex was associated with significantly higher risk for death. A nonlinear relationship between BMI and the logarithm of the mortality hazard was considered by modeling the latter as a quadratic function of BMI (ie, including both linear and quadratic BMI terms in the Cox proportional hazards model). The quadratic term was not statistically significant, meaning that a linear relationship between BMI and log mortality hazard could not be rejected. Therefore, continuous BMI was modeled linearly here and in the following analyses.

Alla (n ¼ 6,657)

Univariate and Kaplan-Meier Survival Analysis

Table 1. Patient Characteristics With Pulmonary Hypertension Threshold of Mean Pulmonary Artery Pressure 25 mm Hg or Greater

analysis, missing covariate data for multivariate survival analysis, and PH cases with no suitable non-PH matches as well as non-PH controls not used in the propensity score matching process. Table 1 and Supplemental Table 1 summarize the patient characteristics of the cohort used for the analysis with respective division by mean PAP thresholds of 25 mm Hg or greater and 35 mm Hg or greater. Gender was significantly different when comparing PH and non-PH groups (Table 1), with PH cases more likely to be male. Using either severity threshold, patients without PH were significantly older, more likely to be white, and receiving a greater quantity of supplemental oxygen at the time of listing. The group without PH (using either threshold) had significantly greater mean 6MWD. There were no significant differences in forced expiratory volume in 1 second (FEV1) across either PH threshold, although data on this variable were not collected after 2006. Mean forced vital capacity (FVC) was higher in the PH group compared with the group without PH using either mean PAP threshold. Mean creatinine was significantly higher in patients with mild PH but not significantly different across the higher PH threshold. Using either PH threshold, body mass index (BMI) was significantly higher in patients with PH.

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Table 2. Univariate Survival Analysis (n ¼ 6,651) Variable Pulmonary hypertension thresholds Mean PAP 25 mm Hg Mean PAP 35 mm Hg Mean PAP, continuous Male Race White Black Other Age, years Creatinine, mg/dL Body mass index Supplemental oxygen, L FEV1, % predicted FVC, % predicted 6MWD, feet a

n

HR

95% CI

p Value

6,126 6,126 6,126 6,651 6,651

1.689 2.068 1.028 1.228

(1.434–1.988) (1.715–2.493) (1.022–1.035) (1.046–1.441)

<0.001 <0.001 <0.001 0.012

Ref 0.886 1.138 0.997 1.041 0.976 1.189 0.989 0.972 0.9989

(0.668–1.175) (0.925–1.400) (0.989–1.004) (0.931–1.164) (0.958–0.993) (1.174–1.204) (0.978–0.999) (0.965–0.980) (0.9985–0.9992)

0.401 0.221 0.400 0.482 0.007 <0.001 0.029 <0.001 <0.001

a

6,651 6,651 6,650 6,513 864 3,024 885

Each threshold represents a dichotomous measure with all patients below threshold constituting the reference group.

CI ¼ confidence interval; monary artery pressure;

FEV1 ¼ forced expiratory volume in 1 second; FVC ¼ forced vital capacity; Ref ¼ reference; 6MWD ¼ 6-minute walk distance.

HR ¼ hazard ratio;

PAP ¼ pul-

multivariate models, except for FEV1 and 6MWD, which ceased to be collected after 2006 and 2008, respectively, as well as FVC. In all, 6,013 patients were included in the multivariate Cox models, which are illustrated in Table 3. Cox proportional hazards model found that both mild PH (HR 1.433, 95% CI: 1.203 to 1.706, p < 0.001) and severe PH (HR 1.597, 95% CI: 1.308, 1.949, p < 0.001) were associated with significant risk for death. Likewise, a continuous measure of mean PAP was

positively associated with increased mortality hazard (HR 1.017, 95% CI: 1.010 to 1.025, p < 0.001). Male sex was associated with a significantly higher risk for death, whereas higher BMI was associated with lower mortality hazard. The addition of FVC assessed 0 to 30 days before listing as a covariate reduced the sample size of the multivariate models to 2,757, but did not change the findings of significant association between PH and increased mortality hazard (Supplemental Table 2).

Fig 2. Kaplan-Meier survival functions comparing pulmonary hypertension (blue line) and no pulmonary hypertension (red line) in patients with idiopathic pulmonary fibrosis using mean pulmonary artery pressure 25 mm Hg or greater as the threshold (n ¼ 6,126; log rank test c2 [df ¼ 1] 40.44, p < 0.001).

Fig 3. Kaplan-Meier survival functions comparing pulmonary hypertension (blue line) and no pulmonary hypertension (red line) in patients with idiopathic pulmonary fibrosis using mean pulmonary artery pressure 35 mm Hg or greater as the threshold (n ¼ 6,126; log rank test c2 [df ¼ 1] 60.62, p < 0.001).

HAYES ET AL PULMONARY HYPERTENSION WITH IPF

0.179 0.205 0.132 0.406 0.010 <0.001

Results from survival analysis using the entire sample were confirmed using one-to-one propensity score matching with a total of 5,186 candidates for the mean PAP 25 mm Hg or greater threshold (ie, 2,593 PH cases matched to 2,593 non-PH controls) and 2,014 candidates for the mean PAP 35 mm Hg or greater threshold. The covariates from Table 3 were included in the models of PH propensity, with the exception of supplemental oxygen, which may have been a therapy for PH rather than a predictor of this condition. A significant increase in mortality hazard was confirmed for both PH thresholds using Cox proportional hazards models stratified on the matched pairs: mild PH (HR 1.530, 95% CI: 1.189 to 1.969, p ¼ 0.001) and severe PH (HR 2.103, 95% CI: 1.436 to 3.078, p < 0.001).

PH ¼ pulmonary hypertension. PAP ¼ pulmonary artery pressure; HR ¼ hazard ratio; CI ¼ confidence interval;

Each threshold represents a dichotomous measure, with all patients below threshold constituting the reference (Ref) group.

Comment

a

(0.607–1.129) (0.919–1.451) (0.997–1.016) (0.943–1.166) (0.956–0.996) (1.612–1.194) Ref 0.828 1.155 1.007 1.048 0.976 1.178 (0.617–1.144) (0.930–1.468) (0.998–1.017) (0.946–1.168) (0.951–0.991) (1.163–1.195) Ref 0.840 1.168 1.007 1.051 0.971 1.179

0.270 0.182 0.146 0.353 0.005 <0.001

(1.024–1.464) 1.224

5

Propensity Score Matching

1.103) 1.457) 1.017) 1.165) 0.994) 1.193) (0.592, (0.922, (0.998, (0.940, (0.954, (1.160, Ref 0.808 1.159 1.007 1.047 0.974 1.176 0.232 0.218 0.159 0.384 0.017 <0.001

<0.001 0.029 (1.010, 1.025) (1.021, 1.459) 1.017 1.220 0.032 (1.017–1.453) 1.215

<0.001 (1.308–1.949) 1.597 <0.001 (1.203–1.706)

PH thresholds Mean PAP  25 mm Hg Mean PAP  35 mm Hg Mean PAP, continuous Male Race White Black Other Age, years Creatinine, mg/dL Body mass index Supplemental oxygen, L

1.433

0.027

95% CI 95% CI 95% CI HR a

Variable

Model 1

Table 3. Multivariate Survival Analysis (n ¼ 6,013)

p Value

HR

Model 2

p Value

HR

Model 3

p Value

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Because the majority of the current published literature is drawn from single-center experiences, there is wide variability in estimates of the prevalence of PH in the IPF population. This study is the largest to date investigating PH in advanced IPF lung disease. Our most important findings are the high prevalence of PH in IPF and the significantly increased risk of death associated with PH in IPF patients awaiting LTx. Despite discoveries in the pathophysiology of PH and advancements in its treatment, there is lack of rigorous study of PH in advanced lung diseases. Often patients with IPF are not diagnosed with PH until the evaluation process for LTx when a RHC is performed. Despite the complication rate of RHC at experienced centers being low [21], less invasive testing with transthoracic echocardiography is frequently used to fill the diagnostic gap to provide estimation of right-side pressures. However, transthoracic echocardiography requires a tricuspid regurgitation jet velocity, with underestimation of pressures in patients with high PAP and overestimation of PAP in patients without significant elevation in the setting of lung disease [22, 23]. Alveolar hypoxemia, respiratory acidosis [24], and hypercapnia [25] are major factors in the pathophysiology of PH associated with advanced lung disease. With the degree of hypoxemia, fibrosis, and ventilatory impairment not always correlating with PH severity [9, 17], there are likely separate but concomitant pathophysiologic processes occurring in IPF leading to PH. There exists emerging research on molecular mechanisms of PH in IPF, including research with genetic elements. Compared with PH in chronic obstructive pulmonary disease, a differential gene expression pattern was present in pulmonary artery profiles, including several genes involved in retinol metabolism and extracellular matrix receptor interaction that enable discrimination of vascular remodeling in PH between chronic obstructive pulmonary disease and IPF [26]. In comparison with idiopathic pulmonary arterial hypertension, PH in IPF was characterized by distinct gene expression signatures, implying

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distinct pathophysiologic mechanisms [27]. Distinct gene signatures were found when comparing IPF with and without PH, as PH was associated with an increased expression of genes, gene sets, and networks related to myofibroblast proliferation and vascular remodeling, whereas the lack of PH was associated with heightened expression of proinflammatory genes [28]. In 16 patients with IPF (8 with PH), vascular proliferation and aberrant apoptosis pathways were activated, thus likely contributing to pulmonary vascular remodeling [29]. Endothelial-derived factors and environmental influences appear to be contributing factors to PH in IPF. In a prospective cohort study of 52 adults with IPF, endothelin-1, a potent vasoconstrictor produced by vascular endothelial cells important in both fibrosis and vascular remodeling, was associated with higher PAP [30]. Compared with controls, tetrahydrobiopterin, the cofactor of nitric oxide synthase, was found to be downregulated in IPF patients with PH [31]. In a study of 55 IPF patients and 41 controls, molecular analysis was used to detect viral genomes in lung tissue, with a higher frequency of viruses found in IPF patients with herpes viruses only detected [32]. Interestingly, the cases of IPF with herpes viruses had significantly higher mean PAP, poorer performance in the 6MWD test, and higher frequency of primary graft dysfunction after LTx [32]. Based on the current medical literature, the etiology of PH in IPF is multifactorial. The current study found that PH significantly influences survival in patients with IPF, even when considering a threshold for mild PH. The HRs identified in each analysis were comparable between the two PH severity thresholds, suggesting that an earlier diagnosis of PH (ie, at the lower threshold) may be more beneficial. Furthermore, the HRs associated with PH were higher when adjusting for BMI than in the unadjusted models, as BMI appears to be protective in IPF [33], but IPF patients with PH tend to have higher BMI than IPF patients without PH. These findings add to the debate whether PH needs to be diagnosed earlier in IPF. A small number of studies have reported methods for screening for PH [34, 35], but there are varying opinions concerning PH screening in the IPF patient population [36]. Regarding invasive diagnostic testing, Kimura and associates [16] used stepwise, multivariate Cox proportional analysis of 101 consecutive IPF patients who underwent RHC to find that a mean PAP was an independent determinant of survival, with a mean PAP greater than 20 mm Hg being the threshold for higher risk for mortality. In addition to IPF patients with severe disease, these investigators found that patients with mild to moderate disease should be under evaluation for PH, and mean PAP may be a better survival predictor than pulmonary function [16]. Because there are limited resources regarding widespread RHC in the entire IPF population, noninvasive imaging techniques will be important as screening modalities. For noninvasive testing, cardiac magnetic resonance imaging is evolving as a valuable tool in assessing and predicting clinical outcomes related to PH and right ventricular

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function [37] and could prove useful in the IPF patient population. The current study is limited by the retrospective collection of data. Key variables such as mean PAP may have been measured inaccurately or inconsistently across centers; the confounding effect of therapies administered to patients with PH while awaiting LTx is not observable; and some important confounders, such as measures of pulmonary function, were discontinued early in the period covered by this study. Despite its limitations, our study draws results from a large, multiinstitutional registry database of transplant recipients and thereby reduces potential biases observed in single-institution observational studies. In conclusion, the current study found PH to be a common comorbidity in IPF patients and to be associated with a significant increase in mortality hazard for patients awaiting LTx. Both mild and severe elevations in mean PAP in the IPF patient population are clinically relevant and warrant further scrutiny. Although systematic screening for PH in IPF would be beneficial, routine RHC for this patient population is not feasible, so further research is needed to identify optimal screening modalities. These findings support yet another reason for early referral for LTx in the IPF patient population. The authors would like to acknowledge Dmitry Tumin for his statistical expertise in the data analysis.

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