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Title: Pulmonary Hypertension occurs with Identifiable Risk Factors in Veterans with COPD and Predicts Higher Mortality and Worse Clinical Outcomes in Veterans with COPD .
Running Head: Pulmonary Hypertension Predicts Worse Outcomes in Veterans with COPD
Lavannya M. Pandit, MD 1&2 Andrew M. Spiegelman, PhD3
Arnav Kak, Amir Sharafkhaneh, MD, PhD 1&2
Affiliations: 1. Michael E. DeBakey Veterans Affairs Medical Center, Pulmonary/Critical Care/Sleep Medicine Section, Houston, Texas.2 .Baylor College of Medicine, Pulmonary/Critical Care/ Sleep Medicine Section, Department of Internal Medicine.3 Veterans Health Administration,Department of Defense/Veterans Affairs Vision Center of Excellence.
Correspondence to:Lavannya M. Pandit, MDAssistant Professor of MedicineSection of Pulmonary, Critical Care, and Sleep MedicineMichael E. DeBakey Veterans Affairs Medical Center/Baylor College of Medicine3rd Floor, Pulmonary SuiteHouston, Texas 77030E-mail: [email protected]
Acknowledgement: This work is supported by the office of Research and Development at the Department of Veterans Affairs.
Authors Contributions:
Dr. Pandit contributed to the Institutional Review Board application, data interpretation and primary manuscript composition and revision.
Dr. Sharafkhaneh led the project in data collection, study design, statistical analysis, and guided data interpretation, as well as manuscript revision. He is the guarantor of the content of the manuscript including the data and analysis.
Dr. Spiegelman, contributed to the study design, data collection, data interpretation, and manuscript composition and revision.
Mr. Arnav Kak contributed to data interpretation and manuscript preparation
Abstract
Background
Recent studies of chronic obstructive pulmonary disease (COPD) have identified
pulmonary hypertension (PH) as an independent risk factor for death and exacerbations,
but to our knowledge, no study has yet considered what, if any, are the identifiable risk
factors that determine which veterans with COPD develop pulmonary hypertension. In
patients with COPD and PH, we hypothesized that the presence of PH increases health care
utilization and mortality in a veteran population. Moreover, we predicted that those
veterans with increased markers of heart and lung disease are at increased risk for
developing PH.
Methods
We studied the records of 545,086 patients who were admitted to the South Central
Veterans Affairs healthcare network (VISN 16) between 2000 and 2012 and discharged
with a primary diagnosis of COPD. The first hospitalization with the discharge diagnosis of
COPD was called the “inception admission.” Within this cohort, the patients were
retrospectively stratified into patients with both COPD and pulmonary hypertension
(COPD-PH, 51,832 individuals) and COPD without pulmonary hypertension (COPD alone
cohort, 2,176 individuals). We compared rates of inpatient and outpatient encounters, long-
term mortality in the two study cohorts, and report the risk factors that predict a higher
rate of developing pulmonary hypertension in veterans with COPD.
Measurements and Main Results
Cumulative mortality was higher in the COPD-PH cohort throughout the 12 years
of the study compared to veterans with COPD alone. (72.4% for COPD-PHvs. 53.4% for
COPD alone; P < 0.001) . Veterans within the COPD-PH cohort had higher rates of
hospitals admission, outpatient encounters and mortality compared to veterans in the
COPD alone cohort. (Odds Ratio(OR)1.32; OR 1.22; OR 1.1) The presence of cardiac
comorbidities and a diagnosis of obstructive sleep apnea (OSA) predicted higher rates of
developing pulmonary hypertension. A prescription for HMG-CoA Reductase inhibitors
(statins) predicted lower rates of developing pulmonary hypertension within both the entire
VISN 16 as well as a single center.
Conclusions
IIn this study of veterans with COPD, the diagnosis of pulmonary hypertension predicted
higher mortality and increased health care utilization. Cardiac comorbidities and OSA
predicted those veterans with COPD who were at increased risk of developing pulmonary
hypertension. COPD with comorbid pulmonary hypertension and risk factors for
developing pulmonary hypertension, should be considered as a distinct COPD marker for
prognostic purposes in the veteran population.
Abstract Word Count: ---386---
Introduction
Pulmonary hypertension is a very severe and increasingly prevalent problem in the
United States. The global burden of pulmonary hypertension (PH) is currently unknown
and largely underestimated. 1 PH is the principal cardiovascular complication encountered
in COPD with evidence of right heart failure found in 40% of patients with COPD in one
autopsy study. 2 Those who suffer from severe pulmonary hypertension have a
progressively downhill clinical course because the elevated pulmonary arterial pressures
lead to right-sided heart failure or cor pulmonale. The National Heart Discharge Survey
and the Journal of the American Academy of Cardiology reported 4 million admissions
yearly for heart failure (2004), and the proportion of heart failure due to respiratory
diseases and noncardiovascular, nonrespiratory diseases as the first-listed diagnoses
increased from 11 to 18%. 3 Thus, non-cardiac causes such as PH with its complications of
cor pulmonale are playing a steadily increasing role in heart failure hospitalizations in the
United States.
PH is classified into five (I through V) by the World Health Organization (WHO). 4
Specifically, Group III PH is associated with hypoxemic diseases such as chronic
obstructive lung disease (COPD), pulmonary fibrosis, and obstructive sleep apnea (OSA.)
In the veteran population, PH most often occurs secondary to chronic heart and lung
disease and is classified by the World Health Organization as Class II and III PH
respectively. The prevalence of PH in COPD varies from 5 to 60% depending on the
definition of PH (mPAP > 20 versus >25 mm Hg), and the severity of COPD (forced
expiratory volume in the first second: FEV1). However, even with this broad variability in
prevalence of PH in COPD, given that 12.7 million U.S. adults are estimated to have
COPD, 5 the amount of patients in the U.S. with COPD and PH would still be estimated at
least ½ million. Summarily, patients with WHO group III PH disease are much more
common than other groups, making up the second largest group of patients with PH,
behind left sided heart disease.3
Importantly, the presence of PH adversely affects survival and exercise capacity in
patients with COPD and is associated with an increased risk of acute exacerbations. 4,5
Although hypoxemia is thought to be a causal factor in the development PH in those with
chronic lung diseases such as COPD, it is unclear which patients with COPD go on to
develop PH. Moreover, the best prognostic factor in outcomes in Group III PH are not
pulmonary function tests, but rather the measured (mean pulmonary artery pressures)
mPAP. 6 In fact, the 5-year survival rate in patients with PH is only 36% in patients with
initial mPAP > 25mmHg compared to 62% in those with initial mPAP≤25mmHg. 7 Mean
PAP is measured by right heart catheterization, which is not routinely performed patients
with COPD, thus further increasing the challenge of accurately identifying those COPD
patients with PH and its associated health care costs.
As PH is a marker for morbidity and mortality in COPD, establishing an accurate
diagnosis of PH in patients with COPD is important. COPD itself is a major cause of
morbidity and mortality worldwide with resultant major short- and long-term implications
on the patient and healthcare system. Early detection and prompt treatment of
exacerbations are essential to ensure optimal outcomes and to reduce the burden of
COPD.8 Several factors can identify populations at risk of exacerbations, and PH is an
established risk factor for exacerbations.9,10 Thus, it is important to identify those patients
with COPD who are at risk for developing PH, and the associated risk factors. Currently,
no studies exist in detailing the prevalence and demographic data of PH in the veteran
COPD population. Given the substantial burden that COPD imposes on the veteran
population, it is critical to 1.)measure the prevalence of PH in the veteran COPD
population and 2.) identify prognostic factors that affect long-term mortality and
morbidity in veterans who develop PH secondary to COPD.
Methods
All data in this study was obtained from the Veterans Health Administration (VHA)
Corporate Data Warehouse (CDW). Patients that were included in the study came from
the region 16 network of hospitals during VHA fiscal years (FYs) 2000-2012. Patients who
receive their care in multiple VA facility during the study follow up were excluded. This
study was approved by the Institutional Review Board of Baylor College of Medicine (H-
30464), the Research and Development Committee of Michael E. DeBakey Veterans Affairs
Medical Center, and the region 16 Data Warehouse.
We created a cohort retrospectively using ICD-9 codes (Table 1 in supplement for
various ICD-9 codes used in this study). Patients entered the study by either having one
hospitalization in which COPD was the primary discharge diagnosis or by having two
outpatient encounters in which COPD was the primary diagnosis. The inception time for
each subject was earlier of either the first admission with primary discharge diagnosis of
COPD or second outpatient encounter with primary diagnosis of COPD. We further
classified the main cohort into two sub-cohorts using ICD-9 codes: (1) patients having
concurrent primary or secondary diagnoses of COPD and pulmonary hypertension
(COPD-PH cohort); and (2) patients having COPD as the primary diagnosis with no
concurrent pulmonary hypertension diagnostic code (COPD cohort).
We extracted variables related to preinception periods. In addition to demographic
data (age, sex, and race), we extracted pre-inception period data including chronic
comorbid conditions; the annual number of all cause hospitalizations; emergency room
visits and outpatient encounters; annual number COPD exacerbations. Patient-level
variables at the time of inception COPD diagnosis were also extracted. This included BMI,
post-diagnosis study duration period (2000 -2012) mortality data, and respiratory and
cardiac medications on discharge.
Statistical Analysis:
We used STATA SE version 12.1 (StataCorp, College Station, TX, USA) for data
analysis. The primary analysis compared all patients in the two study cohorts. All study
variables, including baseline and outcome measures, were analyzed descriptively.
Percentages and counts were provided for dichotomous and polychotomous variables.
Means and standard deviations were provided for continuous variables. For dichotomous
variables, Chi-square tests were used to evaluate the statistical significance of differences,
and Student’s t-test was used for the means of continuous variables. We used multivariate
logistic regression analysis for in-patient and 30-day mortality and Cox regression analysis
for overall mortality . P value < 0.01 was considered significant in this large population
database.
Results
Patient Characteristics
During the 12-year study period, 545,086 (correct) patients’ records from the
Veterans Health Administration (VHA) Corporate Data Warehouse (CDW) were assessed
and sorted bywith a primary diagnosis of COPD, and then further sroted for a concomitant
diagnosis of pulmonary hypertension (PH) were analyzed. Table 1 shows demographics,
Charlson Co-morbidity Index 11 respiratory and cardiac medication and admission data
from both cohorts during the pre-inception period.
TABLE 1.
VISN 16 COPD with PH
COPD without PH
p-value
N (correct) 2,176 51,832
Age at COPD diagnosis (Mean)
67.2 66.7 0.023
Female 2.5% (55) 2.5% (1272) 0.828
BMI at COPD dx (Mean) 29.3 27.6 0.000
Cardiac comorbidities 88.7%(1930)
66.1%(34237) 0.000
Charlson (Mean) 4.1 3.2 0.000
COPD exacerbations (Mean)
1.7 0.5 0.000
Admissions 5.2 2.3 0.000
OSA diagnosis % (n) 34.8%(757) 16.0%(8311) 0.000
Beta blocker (n) 65.8%(1431)
52.6%(27277) 0.000
Beta blocker days (Mean) 1,021 775 0.000
Statin (n) 67.6%(1470)
65.4%(33877) 0.035
Anti-coagulant/ASA (n) 74.3%(1617)
53.35%(27615)
0.000
There were significant differences between the COPD alone vs. COPD-PH groups in
this VHA-CDW population as depicted in Table 1. The COPD-PH group was slightly older
at the time of COPD diagnosis, had a higher BMI at the time of COPD diagnosis increased
cardiac comorbidities and a higher mean Charlson comorbidity score, compared to
veterans with COPD alone. Importantly,a diagnosis of OSA was more prevalent in veterans
in the COPD-PH cohort compared to those with COPD alone. These differences at baseline
may account for the higher number of annual COPD exacerbations and inpatient
admissions in the COPD-PH group. Of note, cardiac medication (Beta-blocker, HMG-CoA
reductase inhibitors (statins), anticoagulants/aspirin) usage was significantly higher in the
COPD-PH group compared to COPD-alone.
The incidence of concurrent pulmonary hypertension (PH) within the COPD
VISN 16 population has not been studied and even in the general population is difficult to
measure given the lack of screening for PH in patients with lung disease. In this
longitudinal study, we found that the incidence of concomitant PH in the veteran COPD
population stably ranged from 0.39 to 0.57% relatively unchanged over 12 years, while the
prevalence steadily increased to 4.9% over the12 year study period. (see Figure 1). This
data suggests that while the annual rate of diagnosis of PH in the Veteran COPD
population has not changed in over a decade, these veterans are living longer with COPD
and PH, perhaps in part due to cardiovascular medications (Beta-blockers, statins,
anticoagulants) noted in Table 1.
Figure 1.
Regression analysis on the COPD-PH cohort revealed that the diagnosis of
pulmonary hypertension within the COPD population occurred in patients that are older
that those with COPD alone, and with an increased BMI. The concomitant diagnosis of PH
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 20120
5
10
15
20
25
30
35
40
45
PH Prevalence/Incidence per 1,000 COPD Pts:VISN 16, FY00-FY12
PH prev per 1,000 COPD pts PH inc per 1,000 COPD pts
within the COPD population significantly increased the rate of COPD exacerbations by
11% and inpatient admission by 7%. These veterans with COPD & PH had significantly
increased associated usage of Beta-blockers, anticoagulants/aspirin and an likelihood of
having a diagnosis of obstructive sleep apnea. Moreover, regression analysis demonstrated
that the use of HMG CoA reductase inhibitors appeared to confer a “protective” effect
within the veteran COPD population against developing pulmonary hypertension.
TABLE 2. Predictors of COPD patients being diagnosed with PH: VISN 16
Variable (n=359, 900) Odds ratio p-value 95% CI
Age at COPD diagnosis 1.027 0.000 1.025 1.028
female 1.137 0.517 0.771 1.676
BMI at COPD diagnosis 1.023 0.000 1.021 1.025
COPD exacerbations 1.109 0.000 1.101 1.116
admissions 1.068 0.000 1.065 1.071
Beta-blocker 1.572 0.000 1.506 1.641
HMG-CoA reductase inhibitors
0.835 0.000 0.802 0.870
Anticoagulants/aspirin 2.027 0.000 1.941 2.117
OSA diagnosis 2.269 0.000 2.181 2.360
We then analyzed the COPD cohort within one center and analyzed the charts of 51,520
veterans with COPD
TABLE 3. Predictors of COPD patients being diagnosed with PH: Single Center
Variable (n=51,520) odds p- 95 % CI
ratio value
Age at inception COPD diagnosis 1.008 0.001 1.003 1.013
female 1.348 0.039 1.015 1.791
Charlson 1.056 0.000 1.038 1.074
Beta-blocker 1.090 0.102 0.983 1.209
Ace-inhibitors or ARB 1.296 0.000 1.151 1.461
HMG CoA reductase inhibitor 0.710 0.000 0.637 0.791
aspirin 0.717 0.000 0.610 0.842
Short-acting bronchodilators 1.472 0.001 1.174 1.846
Long-acting bronchodilators 1.487 0.033 1.033 2.142
Systemic steroids 2.055 0.000 1.645 2.568
Cardiac comorbidities 2.543 0.000 2.184 2.961
Exacerbations per year 1.604 0.000 1.447 1.778
BMI 1.013 0.000 1.007 1.019
OSA 2.192 0.000 1.964 2.446
anticoagulants 1.976 0.000 1.653 2.363
Within this one center, the factors within the COPD cohort that predicted the
subsequent/concurrent diagnosis of PH were female gender, use of cardiac medications
(Beta blockers and Ace-inhibitors), increased use of respiratory medications
(short-acting/long acting bronchodilators, systemic steroids), increased number of
exacerbations per year, presence of cardiac comorbidities and the concomitant presence of
OSA . This data was similar to the predictors of PH in the general VISN 16. Importantly in
both the VISN and single center COPD veteran population, the use of statins conferred a
“protective” effect against the development of PH. This data overall suggests that veterans
with COPD who had more severe underlying cardiac and pulmonary disease at greater
risk for developing PH.
TABLE 4. Presence of PH in Veterans with COPD increases mortality and health care utilization within the VISN 16
Variable Odds ratio p-value 95% CIOutpatient encounters 1.221 0.000 1.184 1.258Mortality 1.108 0.000 1.053 1.166Inpatient Admissions 1.318 0.000 1.267 1.371Emergency room visits 1.27 0.000 1.177 1.372
We then analyzed the health care utilization of the COPD-PH cohort within the
VISN 16. Within the VISN 16 COPD cohort, the presence of PH conferred a 10% increase
in mortality (P<0.00001), a 32% increase in inpatient hospitalizations (P<0.0001), a 20%
increase in outpatient appointments (P<0.00001), and a 27% increase in ER visits
(P<0.0001) compared to having COPD alone. Overall, the presence of PH within the
COPD veteran population increased mortality by 10% and increased health care
utilization. See Figure 2.
Figure 2: Kaplan Meier Survival Curve for VISN 16 veterans with COPD with and without PH over 12 years
Discussion:
This study is the first large-scale, long-term, retrospective assessment of the veteran
population afflicted with COPD and pulmonary hypertension (PH). The results of a twelve
year analysis reflect that the prevalence of PH in the veteran COPD population is steadily
increasing over time and the presence of PH is an independent risk factor for death,
increased health care utilization. Moreover, we identified certain risk factors in the COPD
veteran population that increased the propensity for developing PH; these risk factors
includes concomitant cardiac disease, increased use of systemic steroids and respiratory
medications, increased BMI and concomitant diagnosis of OSA. Although these individual
factors themselves may only indicate that those veterans with COPD who develop Group
III PH tend to be more ill (as reflected by higher Charlson Comobidity index), we can
make an argument that it may be beneficial to identify these at-risk veteran sooner rather
than later in the course of their disease.
Diagnosing Group III PH is particularly important in a specific group of patients
afflicted with COPD and lung disease as these patients have elevated mPAP (>35 mmHg)
at the time of diagnosis. Previously termed “out-of-proportion PH,” these patients tend to
develop right heart failure and die of their PH despite oxygen and vasodilator therapy. 9,12
Our study reveals that not only do veterans with COPD and PH have higher rates of cumulative
mortality (72%) compared to veterans with COPD alone (53%), but that the veterans population
in this study was arguably a more ill population that the expansive COPD population studied in
the multicenter, multinational TORCH trial which showed a cumulative three-year mortality of
15.2%.13 Given that this subset of patients with lung diseaseGiven that veterans with COPD have
a higher cumulative mortality in this study, those that have have Group III PH diseaselikely
develop PH not merely as a consequence of hypoxemia alone, and may have other contributing
comorbidities such as advanced heart and liver disease, both of which can also cause PH (Group
II and I, respectively) that is not due to hypoxemic mechanisms alone. It is therefore, it is
arguably important in a veteran population to identify these patients with PH sooner and
refer them for transplantation at earlier stage in their disease.
Using data from large COPD cohorts such as COPD Gene Study and the Evaluation
of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study, has
enabled investigatorstigaotrs to describe an ‘exacerbator’ phenotype for COPD 14,15 3,14 In
ECLIPSE, the single best predictor of exacerbations, across all GOLD stages, was a past
history of exacerbations. 14 Our large scale cohort study similarily indicates that veterans
with COPD and concomitant PH have higher rates of exacerbations, thus assigning the
diagnosis of PH as part of the ‘exacerbator’ phenotype, and potentially raising the
consideration that screening for PH needs to be part of the management of COPD in a
high-risk veteran population.
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