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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: Lpandit@bcm.edu

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.