ORIGINAL ARTICLE Pulmonary Hypertension in Cystic Fibrosis with Advanced Lung Disease Don Hayes, Jr.1,2,3, Joseph D. Tobias4,5, Heidi M. Mansour6, Stephen Kirkby1,2,3, Karen S. McCoy1,3, Curt J. Daniels1,2,7, and Bryan A. Whitson8 1
Department of Pediatrics, 2Department of Internal Medicine, 4Department of Anesthesiology, and 8Department of Surgery, The Ohio State University College of Medicine, Columbus, Ohio; 3Section of Pulmonary Medicine, 5Department of Anesthesiology and Pain Medicine, and 7Section of Cardiology, Nationwide Children’s Hospital, Columbus, Ohio; and 6Skaggs Center of Pharmaceutical Sciences, The University of Arizona College of Pharmacy, Tucson, Arizona
Abstract Rationale: The impact of pulmonary hypertension (PH) on survival in cystic fibrosis (CF) remains unclear. Objectives: To determine the influence of PH on survival in the CF population. Methods: The United Network for Organ Sharing database was
queried from 1987 to 2013 to identify first-time lung transplant candidates who were tracked from wait list entry date until death or censoring to determine influence of PH. Using right heart catheterization measurements, mild PH was defined as mean pulmonary artery pressure greater than or equal to 25 mm Hg and severe greater than or equal to 35 mm Hg.
Measurements and Main Results: Of 2,781 CF patients, 2,100
were used for univariate analysis, 764 for Kaplan-Meier survival function, 687 for multivariate Cox models, and 576 and 132 for matching on the propensity of mild PH and severe PH, respectively. Univariate Cox analysis found significant differences in survival for mild PH (hazard ratio [HR], 1.747; 95% confidence interval [CI], 1.387–2.201; P , 0.001) and severe PH (HR, 2.299; 95% CI, 1.639–3.225; P , 0.001). Further assessment by multivariate Cox models identified significant risk for death associated with mild PH (HR, 1.757; 95% CI, 1.367–2.258; P , 0.001) and severe PH (HR,
Cystic fibrosis (CF) is an inherited multisystem disease associated with chronic respiratory infections and the development of bronchiectasis. As the lung disease progresses in CF, patients develop
2.284; 95% CI, 1.596–3.268; P , 0.001). Cox regression stratified on matched pairs of PH cases and control subjects confirmed the risk for death for mild PH (HR, 1.919; 95% CI, 1.290–2.85; P = 0.001) and severe PH (HR, 4.167; 95% CI, 1.709–10.157; P = 0.002). Conclusions: The manifestation of PH is associated with
significantly increased risk for death in CF patients with advanced lung disease. Keywords: advanced lung disease; cystic fibrosis; pulmonary
hypertension; survival
At a Glance Commentary Scientific Knowledge on the Subject: Because of limited research, the influence of pulmonary hypertension in patients with cystic fibrosis is unclear What This Study Adds to the Field: The current study
reveals that pulmonary hypertension significantly reduces survival in patients with cystic fibrosis with advanced lung disease. Earlier diagnosis and interventions need to be considered to determine if they could modify the disease course.
progressive respiratory failure resulting in hypoxemia and hypoventilation (1–3). Subsequently, patients are at risk for developing pulmonary hypertension (PH) and right ventricular dysfunction (4–7).
With no sizeable epidemiologic studies using right heart catheterization (RHC), the gold standard diagnostic test for PH, the prevalence of PH in the general CF population is unknown. Despite limitations,
( Received in original form July 30, 2014; accepted in final form September 13, 2014 ) Author Contributions: Conception and design, acquisition of data, interpretation of data, and drafting of the manuscript, D.H. Interpretation of data and revision of the manuscript, J.D.T., H.M.M., S.K., K.S.M., and C.J.D. Conception and design, interpretation of data, and revision of the manuscript, B.A.W. Correspondence and requests for reprints should be addressed to Don Hayes, Jr., M.D., M.S., The Ohio State University, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205. E-mail: [email protected] Am J Respir Crit Care Med Vol 190, Iss 8, pp 898–905, Oct 15, 2014 Copyright © 2014 by the American Thoracic Society Originally Published in Press as DOI: 10.1164/rccm.201407-1382OC on September 15, 2014 Internet address: www.atsjournals.org
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American Journal of Respiratory and Critical Care Medicine Volume 190 Number 8 | October 15 2014
ORIGINAL ARTICLE several studies have identified that PH occurs frequently in advanced lung disease caused by CF (5–21). A recent study found that 57% (470 of 831) of CF patients had PH before lung transplantation (LTx), but the PH did not significantly alter the risk of death after transplant (7). Because of this gap in the medical literature, we sought to assess the effect of PH on survival in lung transplant candidates with a CF diagnosis by tracking them until death or censoring before LTx using an available database in the United States.
All organ transplant candidates N = 136,498 Exclude cases if transplant performed and if diagnosis not cystic fibrosis Cases listed with cystic fibrosis N = 2781
Exclude cases with identical waiting list entry and exit dates
Cases for univariate analysis N = 2100
Exclude cases with missing PH-related data
Cases for Kaplan-Meier survival curve N = 764
Methods
Exclude cases with missing covariate data
Cases for multivariate Cox analysis N = 687
Data Collection
We retrospectively evaluated data from lung transplant candidates who were registered in the Organ Procurement and Transplant Network (OPTN) Standard Transplant Analysis and Research Database administered by United Network for Organ Sharing (UNOS) since 1987 (22). 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 CF listed from January 1, 1987 to September 6, 2013. Each first-time lung transplant candidate who did not receive LTx was tracked until death or censoring. RHC data were entered into the UNOS dataset including mean pulmonary
Exclude unmatched cases of pulmonary hypertension
Cases for propensity score matching N = 576 ( 25 mmHg) N = 132 ( 35 mmHg) Figure 1. Patient inclusion and exclusion criteria for patients with cystic fibrosis and subsequent univariate analysis, Kaplan-Meier survival curve, multivariate Cox analysis, and propensity score matching. PH = pulmonary hypertension.
artery pressure (PAP) measurements. In our analysis, we used two mean PAP cutoffs at greater than or equal to 25 mm Hg for mild PH and at greater than or equal to 35 mm Hg for severe PH to assess if there were differences in survival based on severity of PH. These cutoff parameters were chosen arbitrarily because there are no published severity guidelines for PH caused by hypoxemia and lung disease with
previous reports (1, 23) describing 25–35 mm Hg as modest PH. Statistical Methods
All analyses were performed using Stata/ MP, version 13.0 (StataCorp LP, College Station, TX). All values are expressed as means 6 SD for continuous measures, and numbers and percentages for categorical variables. For all analyses, a P value less
Table 1. Patient Characteristics with PH Cutoff of Mean Pulmonary Artery Pressure Greater Than or Equal to 25 mm Hg
Variable Male Race White Black Other Age, yr Creatinine, mg/dl Body mass index FEV1 ,% pred FVC, % pred 6MWD, ft
All (n = 2,781)* N (%) Mean (SD)
PH (n = 465) N (%) Mean (SD)
No PH (n = 434) N (%) Mean (SD)
P Value t Test Chi-Square
1,260 (45.31%) — 2,573 (92.52%) 50 (1.80%) 158 (5.68%) — —
— — — — — 26.21 (10.33) 0.71 (0.38)
219 (47.10%) — 432 (92.90%) 11 (2.37%) 22 (4.73%) — —
— — — — — 30.50 (10.26) 0.68 (0.25)
198 (45.62%) — 415 (95.62%) 5 (1.15%) 14 (3.23%) — —
— — — — — 30.91 (10.51) 0.78 (0.46)
— — — — — 0.549 ,0.001
—
18.91 (3.59)
—
19.56 (3.38)
—
19.47 (2.96)
0.663
—
—
26.48 (12.18)
—
24.73 (10.50)
—
28.51 (9.50)
,0.001
—
—
43.26 (15.48)
—
40.72 (14.52)
—
48.30 (13.62)
,0.001
—
—
978.42 (611.31)
—
1023.75 (631.27)
—
1111.92 (536.85)
0.481
—
0.658 0.192 — — — — —
Definition of abbreviations: 6MWD = 6-minute-walk distance; PH = pulmonary hypertension. *A total of 899 cases have data on PH.
Hayes, Tobias, Mansour, et al.: Pulmonary Hypertension in CF
899
ORIGINAL ARTICLE Table 2. Patient Characteristics with PH Cutoff of Mean Pulmonary Artery Pressure Greater Than or Equal to 35 mm Hg
Variable Male Race White Black Other Age, yr Creatinine, mg/dl Body mass index FEV1, % pred FVC, % pred 6MWD, ft
All (n = 2,781)* N (%) Mean (SD)
PH (n = 97) N (%) Mean (SD)
No PH (n = 802) N (%) Mean (SD)
P Value t Test Chi-Square
1,260 (45.31%) — 2,573 (92.52%) 50 (1.80%) 158 (5.68%) — —
— — — — — 26.21 (10.33) 0.71 (0.38)
47 (48.45%) — 88 (90.72%) 4 (4.12%) 5 (5.15%) — —
— — — — — 30.99 (11.67) 0.65 (0.23)
370 (46.13%) — 759 (94.64%) 12 (1.50%) 31 (3.87%) — —
— — — — — 30.66 (10.22) 0.74 (0.38)
— — — — — 0.771 0.052
0.665 0.145 — — — — —
—
18.91 (3.59)
—
20.17 (4.16)
—
19.43 (3.04)
0.032
—
—
26.48 (12.18)
—
23.90 (12.73)
—
26.96 (9.80)
0.044
—
—
43.26 (15.48)
—
34.72 (13.35)
—
45.69 (14.28)
,0.001
—
—
978.42 (611.31)
—
1141.00 (602.75)
—
1062.97 (580.34)
0.691
—
Definition of abbreviations: 6MWD = 6-minute-walk distance; PH = pulmonary hypertension. *A total of 899 cases have data on PH.
than 0.05 was considered statistically significant. For evaluation of mean differences in baseline characteristics between patients with and without PH, we used unpaired t tests for continuous measures and chi-square tests for dichotomous measures. The date of entry into the transplant registry for patients who entered the registry January 1, 1987 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. Survival was first estimated using univariate analysis and Kaplan-Meier survival models with log-rank tests for comparison of curves between patients with and without PH. A Cox proportional hazards model was used to adjust for potential confounders, which included sex, race, age, creatinine, and body mass index (BMI) at the time of listing, with exclusion of pulmonary function testing measures from this multivariate analysis because of missing data. Propensity score matching was completed to confirm risk. The propensity of PH in patients with CF awaiting LTx was calculated as a logit function of the covariates included in the multivariate Cox analysis. Nearest-neighbor matching without replacement was performed between patients with PH and patients without PH. Patients with PH outside the region of common support were not eligible to be matched. Each remaining patient with PH was matched to one patient without 900
PH having the most similar logit of the propensity score, and not having been previously matched to a different patient with PH. A caliper with a width equal to 0.2 standard deviations of the logit of the propensity score was used to ensure that patients with PH were not matched to excessively dissimilar patients without PH. Because patients with PH accounted for a minority of cases in the analytic sample, some patients without PH were not matched to a patient with PH, and therefore were not included in the analysis of matched pairs. Cox proportional hazards regression stratified on the matched pairs was used to estimate a hazard ratio (HR) of PH in CF before LTx.
Results Study Population
Figure 1 presents inclusion and exclusion criteria for our study. Of all 136,498 listed organ transplant candidates, 2,781 had a diagnosis of CF and were first-time lung transplant candidates who did not undergo LTx. Further exclusions included identical waiting list entry and exit dates for univariate analysis, missing PH-related data for Kaplan-Meier survival curve analysis, missing covariate data for multivariate survival analysis, and unmatched cases of PH for propensity score matching. Tables 1 and 2 summarize the patient characteristics of the respective cohorts
Table 3. Univariate Survival Analysis with Mean Pulmonary Artery Pressure Greater Than or Equal to 25 mm Hg as the Pulmonary Hypertension Cutoff (n = 764) Variable Pulmonary hypertension Male Race White Black Other Age, yr Creatinine, mg/dl Body mass index FEV1, % pred FVC, % pred 6MWD, ft
N
HR
95% CI
P Value
764 2,100 2,100
1.747 0.943
(1.387–2.201) (0.822–1.082)
,0.001 0.403
ref. 1.227 1.263 1.002 0.744 0.950 0.971 0.977 0.9995
(0.795–1.894) (0.962–1.657) (0.996–1.009) (0.568–0.974) (0.929–0.972) (0.964–0.978) (0.972–0.982) (0.9992–0.9998)
0.355 0.093 0.488 0.032 ,0.001 ,0.001 ,0.001 0.001
2,100 1,549 1,961 1,379 1,370 222
Definition of abbreviations: 6MWD = 6-minute-walk distance; CI = confidence interval; HR = hazard ratio.
American Journal of Respiratory and Critical Care Medicine Volume 190 Number 8 | October 15 2014
ORIGINAL ARTICLE used for the analysis with mean PAP cutoffs of greater than or equal to 25 and greater than or equal to 35 mm Hg. In both severity groups, FEV1 and FVC were significantly lower in patients with PH. In the group with mild PH, creatinine was significantly lower in patients with PH, but that was not the case in patients with severe PH. In the group with severe PH, BMI was significantly higher in patients with PH, but that did not occur using the mild PH cutoff. Otherwise, there were no significant differences comparing patients with and without PH for both severity classifications.
1.00
No PH PH
Survival Probability
0.80
0.60
0.40
0.20 Log-rank test: Chi-square (df=1): 23.07, p < 0.0001 0.00
Univariate and Kaplan-Meier Survival Analysis
0
A total of 2,100 patients were included in the univariate analysis, and 764 patients were included in the Kaplan-Meier survival analysis. Both mild and severe PH was associated with significantly increased risk of death. Analysis for mean PAP greater than or equal to 25 mm Hg identified HR, 1.747; 95% confidence interval (CI), 1.387–2.201; and P less than 0.001 (Table 3, Figure 2). Mean PAP greater than or equal to 35 mm Hg demonstrated HR, 2.299; 95% CI, 1.639–3.225; and P less than 0.001 (Table 4, Figure 3). Using either severity classification, variables that were protective included creatinine, FEV1, FVC, and 6-minute-walk distance, whereas the others had no significant effect. Multivariate Survival Analysis
A total of 687 patients were included in the multivariate survival analyses. Results from
1
Pulmonary hypertension Male Race White Black Other Age, yr Creatinine, mg/dl Body mass index FEV1, % pred FVC, % pred 6MWD, ft
multivariate survival analyses are illustrated in Tables 5 and 6. There were 76 cases excluded from the multivariate analyses because of missing data on serum creatinine, and one case excluded from the multivariate analyses because of missing data on BMI at waitlist entry. Cases excluded from the multivariate models had higher mean time at risk (mean, 1,173 d) compared with cases included in the multivariate models (mean, 423 d), but the proportion of cases ending in death on waitlist rather than censoring did not significantly differ between excluded and included cases (chi-square [df, 1] = 3.126;
N
HR
95% CI
P Value
764 2,100 2,100
2.299 0.943
(1.639–3.225) (0.822–1.082)
,0.001 0.403
ref. 1.227 1.263 1.002 0.744 0.950 0.971 0.977 0.9995
(0.795–1.894) (0.962–1.657) (0.996–1.009) (0.568–0.974) (0.929–0.972) (0.964–0.978) (0.972–0.982) (0.9992–0.9998)
0.355 0.093 0.488 0.032 ,0.001 ,0.001 ,0.001 0.001
2,100 1,549 1,961 1,379 1,370 222
3
Figure 2. Kaplan-Meier survival functions comparing pulmonary hypertension (PH) and no PH in patients with cystic fibrosis using mean pulmonary artery pressure greater than or equal to 25 mm Hg as the cutoff (n = 764). Log-rank test: chi-square (df = 1): 23.07; P , 0.0001.
Table 4. Univariate Survival Analysis with Mean Pulmonary Artery Pressure Greater Than or Equal to 35 mm Hg as the Pulmonary Hypertension Cutoff (n = 764) Variable
2
Time to Death (Years)
Definition of abbreviations: 6MWD = 6-minute-walk distance; CI = confidence interval; HR = hazard ratio.
Hayes, Tobias, Mansour, et al.: Pulmonary Hypertension in CF
P = 0.077). Cox proportional hazards model identified that both mild PH (HR, 1.757; 95% CI, 1.367–2.258; P , 0.001) and severe PH (HR, 2.284; 95% CI, 1.596–3.268; P , 0.001) were associated with significant risk for death. For both severity groups, age was associated with significantly higher risk for death, whereas BMI was protective. Propensity Score Matching
Survival analysis was performed on PH cases and controls matched on the propensity of mild or severe PH, respectively, with a total of 576 for the mean PAP greater than or equal to 25 threshold and 132 for the mean PAP greater than or equal to 35 threshold. A significant risk of death was confirmed for both PH severity cutoffs: mild PH (HR, 1.919; 95% CI, 1.290–2.855; P = 0.001) and severe PH (HR, 4.167; 95% CI, 1.709–10.157; P = 0.002). Hazard of PH in CF Compared with Other Lung Diseases
To compare the impact of PH between CF and other lung diseases, HRs from univariate analysis, multivariate Cox models, and propensity score matching were evaluated in the remaining entire UNOS database cohort (excluding LTx candidates diagnosed with CF or primary PH) during the same time period (Table 7). At both diagnostic mean PAP cutoffs for PH (>25 and >35 mm Hg), the HR of PH was 901
ORIGINAL ARTICLE 1.00
No PH PH
Survival Probability
0.80
0.60
0.40
0.20
Log-rank test: Chi-square (df=1): 24.65, p < 0.0001 0.00 0
1
2
3
Time to Death (Years) Figure 3. Kaplan-Meier survival functions comparing pulmonary hypertension (PH) and no PH in patients with cystic fibrosis using mean pulmonary artery pressure greater than or equal to 35 mm Hg as the cutoff (n = 764). Log-rank test: chi-square (df = 1): 24.65; P , 0.0001.
higher in all three analyses among patients with CF than the corresponding HR estimated among first-time LTx candidates with pulmonary disorders other than CF or primary PH.
Discussion The most important finding from the present study is the significant risk of death associated with PH in CF patients with advanced lung disease. Although the scientific understanding of PH is rapidly growing, the interactions of pulmonary and cardiovascular systems in patients with lung disease are not as well-defined because of the lack of rigorous research as
a result of symptomatic overlap and limited diagnostic capability. Because of the invasiveness of RHC, the predominance of research in PH, specifically in CF patients, uses transthoracic echocardiography for diagnostic purposes. However, this diagnostic technology requires estimates of tricuspid regurgitation jet velocity and is associated with underestimation of pressures in patients with high PAP and overestimation of PAP in patients without significant elevation (24, 25). The pathophysiology of PH in lung disease in general, including CF, involves alveolar hypoxemia (26), acidosis (26), and hypercapnia (3) playing important roles. The current classification of PH regarding
Table 5. Multivariate Survival Analysis with Mean Pulmonary Artery Pressure Greater Than or Equal to 25 mm Hg as the Pulmonary Hypertension Cutoff (n = 687) Variable Pulmonary hypertension Male Race White Black Other Age, yr Creatinine, mg/dl Body mass index
HR
95% CI
P Value
1.757 1.087
(1.367–2.258) (0.843–1.402)
,0.001 0.520
ref. 1.388 1.140 1.024 0.864 0.874
(0.647–2.979) (0.671–1.938) (1.011–1.038) (0.575–1.298) (0.833–0.917)
0.400 0.628 ,0.001 0.482 ,0.001
Definition of abbreviations: CI = confidence interval; HR = hazard ratio.
902
CF and other lung diseases is centered on alveolar hypoxemia as the major cause (1). Previous work has demonstrated that arterial hypoxemia is the primary limiting factor in CF patients afflicted with advanced lung disease, even by adding dead space used to overcome the suppressive effects of hyperoxia on minute ventilation (27). Unlike systemic arteries that dilate in response to hypoxemia to meet the metabolic need of tissue, the pulmonary arteries undergo vasoconstriction (28). Limited research exists in these cell types in CF with the only human studies reporting reduced endothelium-dependent relaxation of CF pulmonary arteries (29) and the need for CF transmembrane regulator for stress-induced apoptosis in lung endothelial cells by maintaining adequate intracellular acidification and ceramide activation (30). The explanation of why PH develops in lung diseases, including CF, is not as simple as a response to alveolar hypoxemia. This process is more complex with multiple pathophysiologic factors involved. Although not well-defined, chronic systemic inflammation plays a role with associated alterations of the endothelium (29–34) with differences reported between CF and other lung diseases (31). Recently, endothelial dysfunction was reported in young, healthy CF patients compared with matched control subjects (32). Using a validated technique to evaluate arterial wall integrity (35) in a cross-sectional study involving 50 adult CF patients, Hull and coworkers (33) found that arterial stiffness was significantly increased in the presence of a normal blood pressure and independent of diabetic status, while being associated with systemic inflammation detected by C-reactive protein levels. Important limitations of the study by Hull and coworkers (33) were the exclusion of confounders including hypoxemia, hypoventilation, and post-transplant patients. The present study is the largest to date investigating PH in the CF population. In addition to survival differences associated with both mild and severe PH, our models found confounding factors involving both PH severity groups. Although our analysis was limited because of missing data for these confounders, we did discover that older age was associated with higher risk of death and higher BMI was protective.
American Journal of Respiratory and Critical Care Medicine Volume 190 Number 8 | October 15 2014
ORIGINAL ARTICLE Table 6. Multivariate Survival Analysis with Mean Pulmonary Artery Pressure Greater Than or Equal to 35 mm Hg as the Pulmonary Hypertension Cutoff (n = 687) Variable Pulmonary hypertension Male Race White Black Other Age, yr Creatinine, mg/dl Body mass index
HR
95% CI
P Value
2.284 1.139
(1.596–3.268) (0.884–1.468)
,0.001 0.313
ref. 1.295 1.123 1.022 0.798 0.882
(0.604–2.775) (0.657–1.918) (1.009–1.035) (0.524–1.216) (0.841–0.925)
0.507 0.672 0.001 0.295 ,0.001
Definition of abbreviations: CI = confidence interval; HR = hazard ratio.
Unlike other patient groups with PH where females are more commonly afflicted while males have worse outcomes (36), the present study found no significant difference in prevalence and survival outcomes regarding sex and PH in the CF population. In our efforts to quantify the overall impact of PH, we identified that PH in CF has a higher impact on the risk of death in that patient population compared with patients with other lung diseases. This range of survival related to concomitant PH in the various pulmonary diseases would suggest differing factors related to etiology and contributing factors. Therefore, we speculate distinct pathophysiologic mechanisms for each of these various disorders, but a retrospective study cannot determine causality. Moreover, these findings begin a debate whether PH needs to be diagnosed earlier in the CF population. Few studies have focused on PH in the early stages of CF because there is no current recommended therapy for PH in this patient population and consequences of diagnosing it sooner are unclear.
Presently, PH is often viewed as a complication in CF with minimal data regarding treatment and intervention, whereas most of the medical literature consists of single-center experiences investigating clinical outcomes. Importantly, the presence and severity of PH does not alter outcomes after LTx as reported in a study of 831 CF patients from the UNOS/OPTN thoracic database (7). The results of the current study clearly demonstrate a need for modification in standard of care in the CF population before LTx. Limiting factors in CF include symptomatic overlap with PH and invasiveness of RHC. Despite a low complication rate at experienced centers (37), RHC is frequently not performed in CF until referral for LTx. Until the time for referral for LTx, transthoracic echocardiography is commonly used as a surrogate to assess right ventricular function and look for PH in CF, but it is limited (6, 10). The need for a tricuspid regurgitation jet velocity with limited acoustic windows complicated by parenchymal lung disease can be
associated with poor estimation of the hemodynamics of the pulmonary circulation (6, 25). Moving forward, we strongly believe the current standard of practice needs to focus on earlier identification of PH in the CF population. Noninvasive testing that clinicians should consider is cardiac magnetic resonance imaging because it is quickly becoming a widely used tool in the assessment and treatment of disorders affecting the right ventricle and pulmonary circulation (38–40). Our study is limited by the retrospective collection of data from a large database that could potentially not include confounding variables and that has risk for data entry errors. Moreover, some variables could not be used in the multivariate analysis because of the significant amount of missing data. Despite its limitations, our study draws results from a multiinstitutional, large registry database of transplant recipients and thus reduces potential biases observed in single-institution observational studies. In conclusion, the present study found significant risk for death associated with PH in a CF population with advanced lung disease. Although widespread use of RHC as a means to screen for PH in CF is not practical, noninvasive diagnostic testing is badly needed to assist in establishing a diagnosis earlier in the disease course. Evolving radiographic techniques with cardiac magnetic resonance imaging seem to be the best candidate because these methods may help provide biomarkers to define indications for RHC in CF patients, at least before referral for LTx. Moreover, research is needed to determine if medical interventions, such as lower
Table 7. HR for Univariate Analysis, Multivariate Cox Models, and PSM Associated with Pulmonary Hypertension by Threshold Comparing CF with All Other Diagnoses CF Diagnosis Threshold = 25 mm Hg Threshold = 35 mm Hg Univariate HR Multivariate HR PSM HR
1.747† 1.757† 1.919‡
2.299† 2.284† 4.167‡
All Other Diagnoses* Threshold = 25 mm Hg Threshold = 35 mm Hg 1.509† 1.747† 1.630†
2.054† 2.057† 2.047†
Definition of abbreviations: CF = cystic fibrosis; HR = hazard ratio; PSM = propensity score matching. *Other diagnoses include idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, a1-antitrypsin deficiency, and sarcoidosis. † P , 0.001, two-tailed t tests. ‡ P , 0.01, two-tailed t tests.
Hayes, Tobias, Mansour, et al.: Pulmonary Hypertension in CF
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ORIGINAL ARTICLE thresholds for supplemental oxygen for hypoxemia or pharmaceutical therapies used in other forms of PH, can significantly improve symptoms or alter the disease course. Although it is unclear whether an earlier diagnosis of PH in CF and
subsequent intervention will impact clinical outcomes, the present study confirms a diagnosis of PH in CF is clinically relevant and warrants further scrutiny at least in patients with advanced lung disease. n
References 1. Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, Elliott CG, Gaine SP, Gladwin MT, Jing ZC, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54(Suppl 1):S43–S54. 2. Fauroux B, Pepin JL, Boelle PY, Cracowski C, Murris-Espin M, Nove-Josserand R, Stremler N, Simon T, Burgel PR. Sleep quality and nocturnal hypoxaemia and hypercapnia in children and young adults with cystic fibrosis. Arch Dis Child 2012;97:960–966. 3. Hayes D Jr, Daniels CJ, Kirkby S, Kopp BT, Nicholson KL, Nance AE, Splaingard ML. Polysomnographic differences associated with pulmonary hypertension in patients with advanced lung disease due to cystic fibrosis. Lung 2014;192:413–419. 4. Fraser KL, Tullis DE, Sasson Z, Hyland RH, Thornley KS, Hanly PJ. Pulmonary hypertension and cardiac function in adult cystic fibrosis: role of hypoxemia. Chest 1999;115:1321–1328. 5. Stern RC, Borkat G, Hirschfeld SS, Boat TF, Matthews LW, Liebman J, Doershuk CF. Heart failure in cystic fibrosis: treatment and prognosis of cor pulmonale with failure of the right side of the heart. Am J Dis Child 1980;134:267–272. 6. Ionescu AA, Ionescu AA, Payne N, Obieta-Fresnedo I, Fraser AG, Shale DJ. Subclinical right ventricular dysfunction in cystic fibrosis. A study using tissue Doppler echocardiography. Am J Respir Crit Care Med 2001;163:1212–1218. 7. Hayes D Jr, Higgins RS, Kirkby S, McCoy KS, Wehr AM, Lehman AM, Whitson BA. Impact of pulmonary hypertension on survival in patients with cystic fibrosis undergoing lung transplantation: an analysis of the UNOS registry. J Cyst Fibros 2014;13:416–423. 8. Belle-van Meerkerk G, Cramer MJ, Kwakkel-van Erp JM, Nugroho MA, Tahri S, de Valk HW, van de Graaf EA. Pulmonary hypertension is a mild comorbidity in end-stage cystic fibrosis patients. J Heart Lung Transplant 2013;32:609–614. 9. Tonelli AR, Fernandez-Bussy S, Lodhi S, Akindipe OA, Carrie RD, Hamilton K, Mubarak K, Baz MA. Prevalence of pulmonary hypertension in end-stage cystic fibrosis and correlation with survival. J Heart Lung Transplant 2010;29:865–872. 10. Hayes D Jr, Daniels CJ, Mansour HM, Kopp BT, Yates AR, McCoy KS, Patel AV, Kirkby S. Right heart catheterization measuring central hemodynamics in cystic fibrosis during exercise. Respir Med 2013; 107:1365–1369. 11. Belkin RA, Henig NR, Singer LG, Chaparro C, Rubenstein RC, Xie SX, Yee JY, Kotloff RM, Lipson DA, Bunin GR. Risk factors for death of patients with cystic fibrosis awaiting lung transplantation. Am J Respir Crit Care Med 2006;173:659–666. 12. Goldring RM, Fishman AP, Turino GM, Cohen HI, Denning CR, Andersen DH. Pulmonary hypertension and cor pulmonale in cystic fibrosis of the pancreas. J Pediatr 1964;65:501–524. 13. Manika K, Pitsiou GG, Boutou AK, Tsaoussis V, Chavouzis N, Antoniou M, Fotoulaki M, Stanopoulos I, Kioumis I. The impact of pulmonary arterial pressure on exercise capacity in mild-to-moderate cystic fibrosis: a case control study. Pulm Med 2012;2012:252345. 14. Bright-Thomas RJ, Ray SG, Webb AK. Pulmonary artery pressure in cystic fibrosis adults: characteristics, clinical correlates and longterm follow-up. J Cyst Fibros 2012;11:532–538. 15. Damy T, Burgel PR, Pepin JL, Boelle PY, Cracowski C, Murris-Espin M, Nove-Josserand R, Stremler N, Simon T, Adnot S, et al. Pulmonary acceleration time to optimize the timing of lung transplant in cystic fibrosis. Pulm Circ 2012;2:75–83. 16. Venuta F, Tonelli AR, Anile M, Diso D, De Giacomo T, Ruberto F, Russo E, Rolla M, Quattrucci S, Rendina EA, et al. Pulmonary
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Author disclosures are available with the text of this article at www.atsjournals.org.
Acknowledgment: The authors acknowledge Dmitry Tumin for his statistical expertise in the data analysis.
hypertension is associated with higher mortality in cystic fibrosis patients awaiting lung transplantation. J Cardiovasc Surg (Torino) 2012;53:817–820. 17. Rovedder PM, Ziegler B, Pinotti AF, Menna Barreto SS, Dalcin PdeT. Prevalence of pulmonary hypertension evaluated by Doppler echocardiography in a population of adolescent and adult patients with cystic fibrosis. J Bras Pneumol 2008;34:83–90. 18. Rovedder PM, Ziegler B, Pasin LR, Rampon G, Pinotti AF, de Tarso Roth Dalcin P, Menna-Barreto SS. Doppler echocardiogram, oxygen saturation and submaximum capacity of exercise in patients with cystic fibrosis. J Cyst Fibros 2007;6:277–283. 19. Florea VG, Florea ND, Sharma R, Coats AJ, Gibson DG, Hodson ME, Henein MY. Right ventricular dysfunction in adult severe cystic fibrosis. Chest 2000;118:1063–1068. 20. Panidis IP, Ren JF, Holsclaw DS, Kotler MN, Mintz GS, Ross J. Cardiac function in patients with cystic fibrosis: evaluation by twodimensional and Doppler echocardiography. J Am Coll Cardiol 1985; 6:701–706. 21. Jacobstein MD, Hirschfeld SS, Winnie G, Doershuk C, Liebman J. Ventricular interdependence in severe cystic fibrosis. A twodimensional echocardiographic study. Chest 1981;80:399–404. 22. United Network for Organ Sharing/Organ Procurement and Transplantation Network Standard Transplant Analysis and Research Database [accessed 2013 Sept 6]. Available from: http:// optn.transplant.hrsa.gov/data/about/OPTNDatabase.asp 23. Weitzenblum E, Hirth C, Ducolone A, Mirhom R, Rasaholinjanahary J, Ehrhart M. Prognostic value of pulmonary artery pressure in chronic obstructive pulmonary disease. Thorax 1981;36: 752–758. 24. Brecker SJ, Gibbs JS, Fox KM, Yacoub MH, Gibson DG. Comparison of Doppler derived haemodynamic variables and simultaneous high fidelity pressure measurements in severe pulmonary hypertension. Br Heart J 1994;72:384–389. 25. Arcasoy SM, Christie JD, Ferrari VA, Sutton MS, Zisman DA, Blumenthal NP, Pochettino A, Kotloff RM. Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease. Am J Respir Crit Care Med 2003;167: 735–740. 26. Enson Y, Giuntini C, Lewis ML, Morris TQ, Ferrer MI, Harvey RM. The influence of hydrogen ion concentration and hypoxia on the pulmonary circulation. J Clin Invest 1964;43:1146–1162. 27. McKone EF, Barry SC, Fitzgerald MX, Gallagher CG. Role of arterial hypoxemia and pulmonary mechanics in exercise limitation in adults with cystic fibrosis. J Appl Physiol (1985) 2005;99:1012–1018. 28. Evans AM. Hypoxic pulmonary vasoconstriction. Essays Biochem 2007;43:61–76. 29. Dinh Xuan AT, Higenbottam TW, Pepke-Zaba J, Clelland C, Wallwork J. Reduced endothelium-dependent relaxation of cystic fibrosis pulmonary arteries. Eur J Pharmacol 1989;163:401–403. 30. Noe J, Petrusca D, Rush N, Deng P, VanDemark M, Berdyshev E, Gu Y, Smith P, Schweitzer K, Pilewsky J, et al. CFTR regulation of intracellular pH and ceramides is required for lung endothelial cell apoptosis. Am J Respir Cell Mol Biol 2009;41:314–323. 31. Solic N, Wilson J, Wilson SJ, Shute JK. Endothelial activation and increased heparan sulfate expression in cystic fibrosis. Am J Respir Crit Care Med 2005;172:892–898. 32. Poore S, Berry B, Eidson D, McKie KT, Harris RA. Evidence of vascular endothelial dysfunction in young patients with cystic fibrosis. Chest 2013;143:939–945. 33. Hull JH, Garrod R, Ho TB, Knight RK, Cockcroft JR, Shale DJ, Bolton CE. Increased augmentation index in patients with cystic fibrosis. Eur Respir J 2009;34:1322–1328.
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ORIGINAL ARTICLE 34. Romano M, Collura M, Lapichino L, Pardo F, Falco A, Chiesa PL, Caimi G, Dav`ı G. Endothelial perturbation in cystic fibrosis. Thromb Haemost 2001;86:1363–1367. 35. Hamilton PK, Lockhart CJ, Quinn CE, McVeigh GE. Arterial stiffness: clinical relevance, measurement and treatment. Clin Sci (Lond) 2007; 113:157–170. 36. Martin YN, Pabelick CM. Sex differences in the pulmonary circulation: implications for pulmonary hypertension. Am J Physiol Heart Circ Physiol 2014;306:H1253–H1264. 37. Hoeper MM, Lee SH, Voswinckel R, Palazzini M, Jais X, Marinelli A, Barst RJ, Ghofrani HA, Jing ZC, Opitz C, et al. Complications of right heart catheterization procedures in patients with pulmonary hypertension in experienced centers. J Am Coll Cardiol 2006;48:2546–2552. ´ 38. Garc´ıa-Alvarez A, Fernandez-Friera ´ L, Garc´ıa-Ruiz JM, Nuño-Ayala M, Pereda D, Fernandez-Jim ´ enez ´ R, Guzman ´ G, Sanchez-Quintana D,
Hayes, Tobias, Mansour, et al.: Pulmonary Hypertension in CF
Alberich-Bayarri A, Pastor-Escuredo D, et al. Noninvasive monitoring of serial changes in pulmonary vascular resistance and acute vasodilator testing using cardiac magnetic resonance. J Am Coll Cardiol 2013;62:1621–1631. 39. Peacock AJ, Crawley S, McLure L, Blyth K, Vizza CD, Poscia R, Francone M, Iacucci I, Olschewski H, Kovacs G, et al. Changes in right ventricular function measured by cardiac magnetic resonance imaging in patients receiving pulmonary arterial hypertensiontargeted therapy: the EURO-MR study. Circ Cardiovasc Imaging 2014;7:107–114. 40. Swift AJ, Wild JM, Nagle SK, Roldan-Alzate ´ A, François CJ, Fain S, Johnson K, Capener D, van Beek EJ, Kiely DG, et al. Quantitative magnetic resonance imaging of pulmonary hypertension: a practical approach to the current state of the art. J Thorac Imaging 2014;29: 68–79.
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Department of Pediatrics, 2Department of Internal Medicine, 4Department of Anesthesiology, and 8Department of Surgery, The Ohio State University College of Medicine, Columbus, Ohio; 3Section of Pulmonary Medicine, 5Department of Anesthesiology and Pain Medicine, and 7Section of Cardiology, Nationwide Children’s Hospital, Columbus, Ohio; and 6Skaggs Center of Pharmaceutical Sciences, The University of Arizona College of Pharmacy, Tucson, Arizona
Abstract Rationale: The impact of pulmonary hypertension (PH) on survival in cystic fibrosis (CF) remains unclear. Objectives: To determine the influence of PH on survival in the CF population. Methods: The United Network for Organ Sharing database was
queried from 1987 to 2013 to identify first-time lung transplant candidates who were tracked from wait list entry date until death or censoring to determine influence of PH. Using right heart catheterization measurements, mild PH was defined as mean pulmonary artery pressure greater than or equal to 25 mm Hg and severe greater than or equal to 35 mm Hg.
Measurements and Main Results: Of 2,781 CF patients, 2,100
were used for univariate analysis, 764 for Kaplan-Meier survival function, 687 for multivariate Cox models, and 576 and 132 for matching on the propensity of mild PH and severe PH, respectively. Univariate Cox analysis found significant differences in survival for mild PH (hazard ratio [HR], 1.747; 95% confidence interval [CI], 1.387–2.201; P , 0.001) and severe PH (HR, 2.299; 95% CI, 1.639–3.225; P , 0.001). Further assessment by multivariate Cox models identified significant risk for death associated with mild PH (HR, 1.757; 95% CI, 1.367–2.258; P , 0.001) and severe PH (HR,
Cystic fibrosis (CF) is an inherited multisystem disease associated with chronic respiratory infections and the development of bronchiectasis. As the lung disease progresses in CF, patients develop
2.284; 95% CI, 1.596–3.268; P , 0.001). Cox regression stratified on matched pairs of PH cases and control subjects confirmed the risk for death for mild PH (HR, 1.919; 95% CI, 1.290–2.85; P = 0.001) and severe PH (HR, 4.167; 95% CI, 1.709–10.157; P = 0.002). Conclusions: The manifestation of PH is associated with
significantly increased risk for death in CF patients with advanced lung disease. Keywords: advanced lung disease; cystic fibrosis; pulmonary
hypertension; survival
At a Glance Commentary Scientific Knowledge on the Subject: Because of limited research, the influence of pulmonary hypertension in patients with cystic fibrosis is unclear What This Study Adds to the Field: The current study
reveals that pulmonary hypertension significantly reduces survival in patients with cystic fibrosis with advanced lung disease. Earlier diagnosis and interventions need to be considered to determine if they could modify the disease course.
progressive respiratory failure resulting in hypoxemia and hypoventilation (1–3). Subsequently, patients are at risk for developing pulmonary hypertension (PH) and right ventricular dysfunction (4–7).
With no sizeable epidemiologic studies using right heart catheterization (RHC), the gold standard diagnostic test for PH, the prevalence of PH in the general CF population is unknown. Despite limitations,
( Received in original form July 30, 2014; accepted in final form September 13, 2014 ) Author Contributions: Conception and design, acquisition of data, interpretation of data, and drafting of the manuscript, D.H. Interpretation of data and revision of the manuscript, J.D.T., H.M.M., S.K., K.S.M., and C.J.D. Conception and design, interpretation of data, and revision of the manuscript, B.A.W. Correspondence and requests for reprints should be addressed to Don Hayes, Jr., M.D., M.S., The Ohio State University, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205. E-mail: [email protected] Am J Respir Crit Care Med Vol 190, Iss 8, pp 898–905, Oct 15, 2014 Copyright © 2014 by the American Thoracic Society Originally Published in Press as DOI: 10.1164/rccm.201407-1382OC on September 15, 2014 Internet address: www.atsjournals.org
898
American Journal of Respiratory and Critical Care Medicine Volume 190 Number 8 | October 15 2014
ORIGINAL ARTICLE several studies have identified that PH occurs frequently in advanced lung disease caused by CF (5–21). A recent study found that 57% (470 of 831) of CF patients had PH before lung transplantation (LTx), but the PH did not significantly alter the risk of death after transplant (7). Because of this gap in the medical literature, we sought to assess the effect of PH on survival in lung transplant candidates with a CF diagnosis by tracking them until death or censoring before LTx using an available database in the United States.
All organ transplant candidates N = 136,498 Exclude cases if transplant performed and if diagnosis not cystic fibrosis Cases listed with cystic fibrosis N = 2781
Exclude cases with identical waiting list entry and exit dates
Cases for univariate analysis N = 2100
Exclude cases with missing PH-related data
Cases for Kaplan-Meier survival curve N = 764
Methods
Exclude cases with missing covariate data
Cases for multivariate Cox analysis N = 687
Data Collection
We retrospectively evaluated data from lung transplant candidates who were registered in the Organ Procurement and Transplant Network (OPTN) Standard Transplant Analysis and Research Database administered by United Network for Organ Sharing (UNOS) since 1987 (22). 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 CF listed from January 1, 1987 to September 6, 2013. Each first-time lung transplant candidate who did not receive LTx was tracked until death or censoring. RHC data were entered into the UNOS dataset including mean pulmonary
Exclude unmatched cases of pulmonary hypertension
Cases for propensity score matching N = 576 ( 25 mmHg) N = 132 ( 35 mmHg) Figure 1. Patient inclusion and exclusion criteria for patients with cystic fibrosis and subsequent univariate analysis, Kaplan-Meier survival curve, multivariate Cox analysis, and propensity score matching. PH = pulmonary hypertension.
artery pressure (PAP) measurements. In our analysis, we used two mean PAP cutoffs at greater than or equal to 25 mm Hg for mild PH and at greater than or equal to 35 mm Hg for severe PH to assess if there were differences in survival based on severity of PH. These cutoff parameters were chosen arbitrarily because there are no published severity guidelines for PH caused by hypoxemia and lung disease with
previous reports (1, 23) describing 25–35 mm Hg as modest PH. Statistical Methods
All analyses were performed using Stata/ MP, version 13.0 (StataCorp LP, College Station, TX). All values are expressed as means 6 SD for continuous measures, and numbers and percentages for categorical variables. For all analyses, a P value less
Table 1. Patient Characteristics with PH Cutoff of Mean Pulmonary Artery Pressure Greater Than or Equal to 25 mm Hg
Variable Male Race White Black Other Age, yr Creatinine, mg/dl Body mass index FEV1 ,% pred FVC, % pred 6MWD, ft
All (n = 2,781)* N (%) Mean (SD)
PH (n = 465) N (%) Mean (SD)
No PH (n = 434) N (%) Mean (SD)
P Value t Test Chi-Square
1,260 (45.31%) — 2,573 (92.52%) 50 (1.80%) 158 (5.68%) — —
— — — — — 26.21 (10.33) 0.71 (0.38)
219 (47.10%) — 432 (92.90%) 11 (2.37%) 22 (4.73%) — —
— — — — — 30.50 (10.26) 0.68 (0.25)
198 (45.62%) — 415 (95.62%) 5 (1.15%) 14 (3.23%) — —
— — — — — 30.91 (10.51) 0.78 (0.46)
— — — — — 0.549 ,0.001
—
18.91 (3.59)
—
19.56 (3.38)
—
19.47 (2.96)
0.663
—
—
26.48 (12.18)
—
24.73 (10.50)
—
28.51 (9.50)
,0.001
—
—
43.26 (15.48)
—
40.72 (14.52)
—
48.30 (13.62)
,0.001
—
—
978.42 (611.31)
—
1023.75 (631.27)
—
1111.92 (536.85)
0.481
—
0.658 0.192 — — — — —
Definition of abbreviations: 6MWD = 6-minute-walk distance; PH = pulmonary hypertension. *A total of 899 cases have data on PH.
Hayes, Tobias, Mansour, et al.: Pulmonary Hypertension in CF
899
ORIGINAL ARTICLE Table 2. Patient Characteristics with PH Cutoff of Mean Pulmonary Artery Pressure Greater Than or Equal to 35 mm Hg
Variable Male Race White Black Other Age, yr Creatinine, mg/dl Body mass index FEV1, % pred FVC, % pred 6MWD, ft
All (n = 2,781)* N (%) Mean (SD)
PH (n = 97) N (%) Mean (SD)
No PH (n = 802) N (%) Mean (SD)
P Value t Test Chi-Square
1,260 (45.31%) — 2,573 (92.52%) 50 (1.80%) 158 (5.68%) — —
— — — — — 26.21 (10.33) 0.71 (0.38)
47 (48.45%) — 88 (90.72%) 4 (4.12%) 5 (5.15%) — —
— — — — — 30.99 (11.67) 0.65 (0.23)
370 (46.13%) — 759 (94.64%) 12 (1.50%) 31 (3.87%) — —
— — — — — 30.66 (10.22) 0.74 (0.38)
— — — — — 0.771 0.052
0.665 0.145 — — — — —
—
18.91 (3.59)
—
20.17 (4.16)
—
19.43 (3.04)
0.032
—
—
26.48 (12.18)
—
23.90 (12.73)
—
26.96 (9.80)
0.044
—
—
43.26 (15.48)
—
34.72 (13.35)
—
45.69 (14.28)
,0.001
—
—
978.42 (611.31)
—
1141.00 (602.75)
—
1062.97 (580.34)
0.691
—
Definition of abbreviations: 6MWD = 6-minute-walk distance; PH = pulmonary hypertension. *A total of 899 cases have data on PH.
than 0.05 was considered statistically significant. For evaluation of mean differences in baseline characteristics between patients with and without PH, we used unpaired t tests for continuous measures and chi-square tests for dichotomous measures. The date of entry into the transplant registry for patients who entered the registry January 1, 1987 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. Survival was first estimated using univariate analysis and Kaplan-Meier survival models with log-rank tests for comparison of curves between patients with and without PH. A Cox proportional hazards model was used to adjust for potential confounders, which included sex, race, age, creatinine, and body mass index (BMI) at the time of listing, with exclusion of pulmonary function testing measures from this multivariate analysis because of missing data. Propensity score matching was completed to confirm risk. The propensity of PH in patients with CF awaiting LTx was calculated as a logit function of the covariates included in the multivariate Cox analysis. Nearest-neighbor matching without replacement was performed between patients with PH and patients without PH. Patients with PH outside the region of common support were not eligible to be matched. Each remaining patient with PH was matched to one patient without 900
PH having the most similar logit of the propensity score, and not having been previously matched to a different patient with PH. A caliper with a width equal to 0.2 standard deviations of the logit of the propensity score was used to ensure that patients with PH were not matched to excessively dissimilar patients without PH. Because patients with PH accounted for a minority of cases in the analytic sample, some patients without PH were not matched to a patient with PH, and therefore were not included in the analysis of matched pairs. Cox proportional hazards regression stratified on the matched pairs was used to estimate a hazard ratio (HR) of PH in CF before LTx.
Results Study Population
Figure 1 presents inclusion and exclusion criteria for our study. Of all 136,498 listed organ transplant candidates, 2,781 had a diagnosis of CF and were first-time lung transplant candidates who did not undergo LTx. Further exclusions included identical waiting list entry and exit dates for univariate analysis, missing PH-related data for Kaplan-Meier survival curve analysis, missing covariate data for multivariate survival analysis, and unmatched cases of PH for propensity score matching. Tables 1 and 2 summarize the patient characteristics of the respective cohorts
Table 3. Univariate Survival Analysis with Mean Pulmonary Artery Pressure Greater Than or Equal to 25 mm Hg as the Pulmonary Hypertension Cutoff (n = 764) Variable Pulmonary hypertension Male Race White Black Other Age, yr Creatinine, mg/dl Body mass index FEV1, % pred FVC, % pred 6MWD, ft
N
HR
95% CI
P Value
764 2,100 2,100
1.747 0.943
(1.387–2.201) (0.822–1.082)
,0.001 0.403
ref. 1.227 1.263 1.002 0.744 0.950 0.971 0.977 0.9995
(0.795–1.894) (0.962–1.657) (0.996–1.009) (0.568–0.974) (0.929–0.972) (0.964–0.978) (0.972–0.982) (0.9992–0.9998)
0.355 0.093 0.488 0.032 ,0.001 ,0.001 ,0.001 0.001
2,100 1,549 1,961 1,379 1,370 222
Definition of abbreviations: 6MWD = 6-minute-walk distance; CI = confidence interval; HR = hazard ratio.
American Journal of Respiratory and Critical Care Medicine Volume 190 Number 8 | October 15 2014
ORIGINAL ARTICLE used for the analysis with mean PAP cutoffs of greater than or equal to 25 and greater than or equal to 35 mm Hg. In both severity groups, FEV1 and FVC were significantly lower in patients with PH. In the group with mild PH, creatinine was significantly lower in patients with PH, but that was not the case in patients with severe PH. In the group with severe PH, BMI was significantly higher in patients with PH, but that did not occur using the mild PH cutoff. Otherwise, there were no significant differences comparing patients with and without PH for both severity classifications.
1.00
No PH PH
Survival Probability
0.80
0.60
0.40
0.20 Log-rank test: Chi-square (df=1): 23.07, p < 0.0001 0.00
Univariate and Kaplan-Meier Survival Analysis
0
A total of 2,100 patients were included in the univariate analysis, and 764 patients were included in the Kaplan-Meier survival analysis. Both mild and severe PH was associated with significantly increased risk of death. Analysis for mean PAP greater than or equal to 25 mm Hg identified HR, 1.747; 95% confidence interval (CI), 1.387–2.201; and P less than 0.001 (Table 3, Figure 2). Mean PAP greater than or equal to 35 mm Hg demonstrated HR, 2.299; 95% CI, 1.639–3.225; and P less than 0.001 (Table 4, Figure 3). Using either severity classification, variables that were protective included creatinine, FEV1, FVC, and 6-minute-walk distance, whereas the others had no significant effect. Multivariate Survival Analysis
A total of 687 patients were included in the multivariate survival analyses. Results from
1
Pulmonary hypertension Male Race White Black Other Age, yr Creatinine, mg/dl Body mass index FEV1, % pred FVC, % pred 6MWD, ft
multivariate survival analyses are illustrated in Tables 5 and 6. There were 76 cases excluded from the multivariate analyses because of missing data on serum creatinine, and one case excluded from the multivariate analyses because of missing data on BMI at waitlist entry. Cases excluded from the multivariate models had higher mean time at risk (mean, 1,173 d) compared with cases included in the multivariate models (mean, 423 d), but the proportion of cases ending in death on waitlist rather than censoring did not significantly differ between excluded and included cases (chi-square [df, 1] = 3.126;
N
HR
95% CI
P Value
764 2,100 2,100
2.299 0.943
(1.639–3.225) (0.822–1.082)
,0.001 0.403
ref. 1.227 1.263 1.002 0.744 0.950 0.971 0.977 0.9995
(0.795–1.894) (0.962–1.657) (0.996–1.009) (0.568–0.974) (0.929–0.972) (0.964–0.978) (0.972–0.982) (0.9992–0.9998)
0.355 0.093 0.488 0.032 ,0.001 ,0.001 ,0.001 0.001
2,100 1,549 1,961 1,379 1,370 222
3
Figure 2. Kaplan-Meier survival functions comparing pulmonary hypertension (PH) and no PH in patients with cystic fibrosis using mean pulmonary artery pressure greater than or equal to 25 mm Hg as the cutoff (n = 764). Log-rank test: chi-square (df = 1): 23.07; P , 0.0001.
Table 4. Univariate Survival Analysis with Mean Pulmonary Artery Pressure Greater Than or Equal to 35 mm Hg as the Pulmonary Hypertension Cutoff (n = 764) Variable
2
Time to Death (Years)
Definition of abbreviations: 6MWD = 6-minute-walk distance; CI = confidence interval; HR = hazard ratio.
Hayes, Tobias, Mansour, et al.: Pulmonary Hypertension in CF
P = 0.077). Cox proportional hazards model identified that both mild PH (HR, 1.757; 95% CI, 1.367–2.258; P , 0.001) and severe PH (HR, 2.284; 95% CI, 1.596–3.268; P , 0.001) were associated with significant risk for death. For both severity groups, age was associated with significantly higher risk for death, whereas BMI was protective. Propensity Score Matching
Survival analysis was performed on PH cases and controls matched on the propensity of mild or severe PH, respectively, with a total of 576 for the mean PAP greater than or equal to 25 threshold and 132 for the mean PAP greater than or equal to 35 threshold. A significant risk of death was confirmed for both PH severity cutoffs: mild PH (HR, 1.919; 95% CI, 1.290–2.855; P = 0.001) and severe PH (HR, 4.167; 95% CI, 1.709–10.157; P = 0.002). Hazard of PH in CF Compared with Other Lung Diseases
To compare the impact of PH between CF and other lung diseases, HRs from univariate analysis, multivariate Cox models, and propensity score matching were evaluated in the remaining entire UNOS database cohort (excluding LTx candidates diagnosed with CF or primary PH) during the same time period (Table 7). At both diagnostic mean PAP cutoffs for PH (>25 and >35 mm Hg), the HR of PH was 901
ORIGINAL ARTICLE 1.00
No PH PH
Survival Probability
0.80
0.60
0.40
0.20
Log-rank test: Chi-square (df=1): 24.65, p < 0.0001 0.00 0
1
2
3
Time to Death (Years) Figure 3. Kaplan-Meier survival functions comparing pulmonary hypertension (PH) and no PH in patients with cystic fibrosis using mean pulmonary artery pressure greater than or equal to 35 mm Hg as the cutoff (n = 764). Log-rank test: chi-square (df = 1): 24.65; P , 0.0001.
higher in all three analyses among patients with CF than the corresponding HR estimated among first-time LTx candidates with pulmonary disorders other than CF or primary PH.
Discussion The most important finding from the present study is the significant risk of death associated with PH in CF patients with advanced lung disease. Although the scientific understanding of PH is rapidly growing, the interactions of pulmonary and cardiovascular systems in patients with lung disease are not as well-defined because of the lack of rigorous research as
a result of symptomatic overlap and limited diagnostic capability. Because of the invasiveness of RHC, the predominance of research in PH, specifically in CF patients, uses transthoracic echocardiography for diagnostic purposes. However, this diagnostic technology requires estimates of tricuspid regurgitation jet velocity and is associated with underestimation of pressures in patients with high PAP and overestimation of PAP in patients without significant elevation (24, 25). The pathophysiology of PH in lung disease in general, including CF, involves alveolar hypoxemia (26), acidosis (26), and hypercapnia (3) playing important roles. The current classification of PH regarding
Table 5. Multivariate Survival Analysis with Mean Pulmonary Artery Pressure Greater Than or Equal to 25 mm Hg as the Pulmonary Hypertension Cutoff (n = 687) Variable Pulmonary hypertension Male Race White Black Other Age, yr Creatinine, mg/dl Body mass index
HR
95% CI
P Value
1.757 1.087
(1.367–2.258) (0.843–1.402)
,0.001 0.520
ref. 1.388 1.140 1.024 0.864 0.874
(0.647–2.979) (0.671–1.938) (1.011–1.038) (0.575–1.298) (0.833–0.917)
0.400 0.628 ,0.001 0.482 ,0.001
Definition of abbreviations: CI = confidence interval; HR = hazard ratio.
902
CF and other lung diseases is centered on alveolar hypoxemia as the major cause (1). Previous work has demonstrated that arterial hypoxemia is the primary limiting factor in CF patients afflicted with advanced lung disease, even by adding dead space used to overcome the suppressive effects of hyperoxia on minute ventilation (27). Unlike systemic arteries that dilate in response to hypoxemia to meet the metabolic need of tissue, the pulmonary arteries undergo vasoconstriction (28). Limited research exists in these cell types in CF with the only human studies reporting reduced endothelium-dependent relaxation of CF pulmonary arteries (29) and the need for CF transmembrane regulator for stress-induced apoptosis in lung endothelial cells by maintaining adequate intracellular acidification and ceramide activation (30). The explanation of why PH develops in lung diseases, including CF, is not as simple as a response to alveolar hypoxemia. This process is more complex with multiple pathophysiologic factors involved. Although not well-defined, chronic systemic inflammation plays a role with associated alterations of the endothelium (29–34) with differences reported between CF and other lung diseases (31). Recently, endothelial dysfunction was reported in young, healthy CF patients compared with matched control subjects (32). Using a validated technique to evaluate arterial wall integrity (35) in a cross-sectional study involving 50 adult CF patients, Hull and coworkers (33) found that arterial stiffness was significantly increased in the presence of a normal blood pressure and independent of diabetic status, while being associated with systemic inflammation detected by C-reactive protein levels. Important limitations of the study by Hull and coworkers (33) were the exclusion of confounders including hypoxemia, hypoventilation, and post-transplant patients. The present study is the largest to date investigating PH in the CF population. In addition to survival differences associated with both mild and severe PH, our models found confounding factors involving both PH severity groups. Although our analysis was limited because of missing data for these confounders, we did discover that older age was associated with higher risk of death and higher BMI was protective.
American Journal of Respiratory and Critical Care Medicine Volume 190 Number 8 | October 15 2014
ORIGINAL ARTICLE Table 6. Multivariate Survival Analysis with Mean Pulmonary Artery Pressure Greater Than or Equal to 35 mm Hg as the Pulmonary Hypertension Cutoff (n = 687) Variable Pulmonary hypertension Male Race White Black Other Age, yr Creatinine, mg/dl Body mass index
HR
95% CI
P Value
2.284 1.139
(1.596–3.268) (0.884–1.468)
,0.001 0.313
ref. 1.295 1.123 1.022 0.798 0.882
(0.604–2.775) (0.657–1.918) (1.009–1.035) (0.524–1.216) (0.841–0.925)
0.507 0.672 0.001 0.295 ,0.001
Definition of abbreviations: CI = confidence interval; HR = hazard ratio.
Unlike other patient groups with PH where females are more commonly afflicted while males have worse outcomes (36), the present study found no significant difference in prevalence and survival outcomes regarding sex and PH in the CF population. In our efforts to quantify the overall impact of PH, we identified that PH in CF has a higher impact on the risk of death in that patient population compared with patients with other lung diseases. This range of survival related to concomitant PH in the various pulmonary diseases would suggest differing factors related to etiology and contributing factors. Therefore, we speculate distinct pathophysiologic mechanisms for each of these various disorders, but a retrospective study cannot determine causality. Moreover, these findings begin a debate whether PH needs to be diagnosed earlier in the CF population. Few studies have focused on PH in the early stages of CF because there is no current recommended therapy for PH in this patient population and consequences of diagnosing it sooner are unclear.
Presently, PH is often viewed as a complication in CF with minimal data regarding treatment and intervention, whereas most of the medical literature consists of single-center experiences investigating clinical outcomes. Importantly, the presence and severity of PH does not alter outcomes after LTx as reported in a study of 831 CF patients from the UNOS/OPTN thoracic database (7). The results of the current study clearly demonstrate a need for modification in standard of care in the CF population before LTx. Limiting factors in CF include symptomatic overlap with PH and invasiveness of RHC. Despite a low complication rate at experienced centers (37), RHC is frequently not performed in CF until referral for LTx. Until the time for referral for LTx, transthoracic echocardiography is commonly used as a surrogate to assess right ventricular function and look for PH in CF, but it is limited (6, 10). The need for a tricuspid regurgitation jet velocity with limited acoustic windows complicated by parenchymal lung disease can be
associated with poor estimation of the hemodynamics of the pulmonary circulation (6, 25). Moving forward, we strongly believe the current standard of practice needs to focus on earlier identification of PH in the CF population. Noninvasive testing that clinicians should consider is cardiac magnetic resonance imaging because it is quickly becoming a widely used tool in the assessment and treatment of disorders affecting the right ventricle and pulmonary circulation (38–40). Our study is limited by the retrospective collection of data from a large database that could potentially not include confounding variables and that has risk for data entry errors. Moreover, some variables could not be used in the multivariate analysis because of the significant amount of missing data. Despite its limitations, our study draws results from a multiinstitutional, large registry database of transplant recipients and thus reduces potential biases observed in single-institution observational studies. In conclusion, the present study found significant risk for death associated with PH in a CF population with advanced lung disease. Although widespread use of RHC as a means to screen for PH in CF is not practical, noninvasive diagnostic testing is badly needed to assist in establishing a diagnosis earlier in the disease course. Evolving radiographic techniques with cardiac magnetic resonance imaging seem to be the best candidate because these methods may help provide biomarkers to define indications for RHC in CF patients, at least before referral for LTx. Moreover, research is needed to determine if medical interventions, such as lower
Table 7. HR for Univariate Analysis, Multivariate Cox Models, and PSM Associated with Pulmonary Hypertension by Threshold Comparing CF with All Other Diagnoses CF Diagnosis Threshold = 25 mm Hg Threshold = 35 mm Hg Univariate HR Multivariate HR PSM HR
1.747† 1.757† 1.919‡
2.299† 2.284† 4.167‡
All Other Diagnoses* Threshold = 25 mm Hg Threshold = 35 mm Hg 1.509† 1.747† 1.630†
2.054† 2.057† 2.047†
Definition of abbreviations: CF = cystic fibrosis; HR = hazard ratio; PSM = propensity score matching. *Other diagnoses include idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, a1-antitrypsin deficiency, and sarcoidosis. † P , 0.001, two-tailed t tests. ‡ P , 0.01, two-tailed t tests.
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ORIGINAL ARTICLE thresholds for supplemental oxygen for hypoxemia or pharmaceutical therapies used in other forms of PH, can significantly improve symptoms or alter the disease course. Although it is unclear whether an earlier diagnosis of PH in CF and
subsequent intervention will impact clinical outcomes, the present study confirms a diagnosis of PH in CF is clinically relevant and warrants further scrutiny at least in patients with advanced lung disease. n
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Acknowledgment: The authors acknowledge Dmitry Tumin for his statistical expertise in the data analysis.
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