Is Pulmonary Hypertension Be Considered A Service Connected Disorder Or Disease
Pulm Circ. 2019 January-Mar; 9(1): 2045894019825763.
Bloodshed in US veterans with pulmonary hypertension: a retrospective analysis of survival by subtype and baseline factors
Aaron W. Trammell
1Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Section of Medicine, Emory University School of Medicine, Atlanta, Georgia, The states
twoAtlanta VA Medical Middle, Decatur, Georgia, U.s.
Amit J. Shah
2Atlanta VA Medical Heart, Decatur, Georgia, USA
iiiDepartment of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA
Lawrence S. Phillips
2Atlanta VA Medical Center, Decatur, Georgia, United states
fourDivision of Endocrinology, Metabolism, and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, The states
C. Michael Hart
onePartitioning of Pulmonary, Allergy, Disquisitional Intendance and Sleep Medicine, Department of Medicine, Emory Academy School of Medicine, Atlanta, Georgia, USA
2Atlanta VA Medical Center, Decatur, Georgia, Us
Received 2018 Oct 31; Accepted 2018 Dec xix.
Abstruse
Pulmonary hypertension (PH) occurs when the pulmonary vasculature is itself diseased or becomes afflicted secondarily by comorbid weather condition, commonly left center or lung disease. The loftier prevalence of chronic cardiopulmonary atmospheric condition amidst patients served by Veterans Wellness Administration (VHA) suggests this population may exist peculiarly susceptible to PH. We sought to identify clinical features and outcomes in veterans diagnosed with PH. Nosotros utilized the VHA Corporate Data Warehouse to place veterans diagnosed between January one, 2003 and September 30, 2015, appraise relevant patient characteristics and their survival fourth dimension. The effects of PH subtype and baseline factors on outcome were estimated by Cox modeling. At that place were 110,564 veterans diagnosed with PH during the written report period. These veterans were predominantly male person, had median age seventy.2, and had a loftier burden of comorbid conditions. PH was oft due to left middle and/or lung disease. Average survival later PH diagnosis was 3.88 years. Compared with other types, PH due to left centre disease, lung disease or both had shorter survival. This big retrospective study of veterans demonstrates the significance of PH due to left center and/or lung disease which was mutual and had high chance of decease. Multi-comorbidity was common and added to risk. These findings underscore the need for run a risk assessment tools for subjects with non-Group i PH and novel management strategies to improve their upshot. This written report details the largest retrospective cohort assembled for evaluation of secondary PH and allows hypothesis-generating inquiries into these common conditions that are rarely prospectively studied.
Keywords: pulmonary hypertension, comorbidity, retrospective cohort report, survival, risk factors
Pulmonary hypertension (PH) is an abnormal state of elevated blood pressure in the pulmonary circulation that presents with non-specific symptoms including shortness of breath, edema, poor exertion tolerance, palpitations, syncope, and rarely sudden death. PH is uncommon as an isolated status; information technology most oft occurs secondary to a separate underlying disorder. The Globe Symposium on PH categorizes PH into five clinically recognizable groups based on the underlying cause of the disorder.1Pulmonary arterial hypertension (PAH; Grouping 1) is an intrinsic pulmonary vascular disease with an estimated prevalence of x–25 cases per one thousand thousand adults in U.s.a. and European registry studies.i,2PAH differs from other types of PH which may be secondary to left heart disease (PH-LHD; Group 2), parenchymal lung diseases and/or hypoxemia (Group 3), chronic thromboembolism (CTEPH; Group 4), or other unclear or multifactorial mechanisms (Group 5).1
The evaluation and management of Group 1 PAH has evolved substantially over the terminal 25 years. Iteratively revised testify-based guidelines have been developed for assessment, diagnosis, management, and series follow-upwards of patients with PAH.1,threeProspectively enrolled registries form much of the basis for guideline recommendations of evaluation and series monitoring of PAH, and randomized clinical trials take led to the handling recommendations. While pulmonary vascular diseases included in Group 1 PAH take been traditionally considered the nearly lethal,ivrecent data propose that PH secondary to underlying heart or lung diseases has equal or higher take a chance of death.5–viiiThis risk is compounded by the fact that PH due to underlying heart or lung disease—Groups ii and three, respectively—are the most mutual forms of PH.2,9–12Further, recognition of PH in those with underlying cardiac or pulmonary disease is of import, equally the occurrence of PH is a known independent risk gene for morbidity and mortality in diverse disease populations such as chronic obstructive pulmonary affliction (COPD), interstitial lung diseases, and chronic systolic or diastolic center failure (CHF).9,12While existing registries have improved our understanding of Group 1 PAH, fewer registries are dedicated to understanding the epidemiology, risk factors, and outcome of subjects with these other more prevalent forms of PH.two
For patients with Group 2 and iii PH, evaluation and treatment guidelines recommend expert assessment and management of the underlying disorder.iAll the same, due to insufficient supporting evidence from clinical trials, targeted pulmonary vascular therapies are not recommended. To date, but small studies that are often underpowered to discover clinically meaningful improvements have examined PAH-targeted therapies in patients with Group ii or 3 PH. It is unclear whether a benign issue of those therapies should be expected, as the mechanisms of increased bloodshed risk due to PH are unknown. For case, it may be due to increased CHF severity, a specific pulmonary vascular or correct ventricular component of the illness, coexisting non-cardiopulmonary comorbid diseases, or other factors. Nonetheless, without data regarding motive, and lacking supporting evidence, PAH-targeted therapies are often pragmatically used in subjects with PH acquired by lung or left middle illness.eleven,13,14
In an try to ascertain the relative prevalence of PH subtypes and associated comorbidities, this study employed data from the Veterans Health Administration (VHA). VHA has one of the largest resources of administrative and healthcare information available.15Veterans have increased incidence of chronic left-sided heart disease and lung disease and higher prevalence of risk factors for other cardiopulmonary diseases compared with the general The states population.sixteen–eighteenWe designed a retrospective longitudinal cohort study utilizing nationwide VHA data from January one, 2003, to September xxx, 2016 to evaluate non-PAH forms of PH. We identified veterans newly diagnosed with PH, assessed the subtypes of PH present, and evaluated the influence of PH subtype and other comorbid conditions on bloodshed. We hypothesized that veterans with PH would commonly take comorbid heart or lung affliction every bit the underlying crusade, and that issue would depend on PH subtype, with better outcome in WHO Groups 1 and 4 PH every bit a event of the availability of targeted therapies and more than effective management strategies for these groups.
Methods
We performed a retrospective cohort study of veterans receiving medical care in the VHA arrangement and diagnosed with PH between Jan 1, 2003 and September xxx, 2015. The written report was approved by the Emory University Institutional Review Board and the Atlanta VA Medical Center Enquiry & Development Committee. The need for informed consent was waived for this study.
Data sources
Data for the analyses were from the national VHA Corporate Data Warehouse (CDW) accessed via Veterans Administrations Informatics and Computing Infrastructure (VINCI). VINCI is a secure calculating surroundings enabling researcher access to wide datasets including CDW that facilitates information analysis. The CDW includes >xvi years of longitudinal data on >22.3 million veterans.15Data include medical and authoritative data from within the VHA system as well as data on selected aspects of medical care obtained past enrolled veterans outside the VHA organisation.
Report population
Adult veterans with data available in the CDW were eligible for inclusion. Subjects were included if a diagnosis of PH by International Nomenclature of Diseases, Ninth Revision(ICD-nine) diagnosis code—including 416.0, 416.2, 416.viii, 416.9—was starting time entered during the inclusion period, divers every bit January 1, 2003 through September 30, 2015. The end of the inclusion period was chosen to coincide with the major alter from using ICD-ninediagnosis codes to the more recent International Classification of Diseases, Tenth Revision, ICD-10. Patients were excluded if they were not a veteran, were less than eighteen years of historic period at the time of possible accomplice entry, or if an ICD-ixcode for PH was used and stored in CDW at any indicate prior to January i, 2003. Data are available in CDW first with fiscal yr 1999. Follow-upwards data including dates of hospitalizations and expiry were extracted for the elapsing of the inclusion period and through one additional year (through September thirty, 2016) constituting the full written report menses. Follow-up was administratively censored at the end of this report period. Censoring was besides performed prior to death or the end of the study menstruum by using data stored in CDW that tape veterans' last healthcare utilization date (e.g. dispensary visit, chemist's outcome, physical therapy appointment, radiology exam).
Definition of the accomplice and measured covariates
PH was identified by ICD-ninediagnosis code as described to a higher place. Because diagnosis codes may be improperly used to "dominion out" a disorder, patients were excluded if the ICD-9lawmaking for PH did non: (1) appear at to the lowest degree once on an inpatient claim, or (2) appear on at least two outpatient records/claims separated by at least 30 days during the study period.19For each veteran in the accomplice, the subtype of PH was classified based on comorbid diagnoses utilizing a modification of the currently accepted clinical classification of PH (Tabular array 1).oneThe presence of those relevant comorbid conditions was assessed at baseline, defined as the period of time prior to PH diagnosis and up to six months after diagnosis. The use of diagnosis codes to allocate subtypes of PH for epidemiologic study has been practical in the by14,20and the method used in this study was minimally adjusted. In the method used past Kim et al. to clarify appropriateness of phosphodiesterase type 5 inhibitor prescribing for PH, the classification algorithm was developed with a preference for Grouping 1 PAH.xivIn this study, veterans are excluded from being classified as Group 1 PAH if they have any underlying comorbid condition that may relate to a non-Grouping 1 PH classification. For case, if an ICD-ninelawmaking indicating systolic eye failure (428.8×) was present, the patient was categorized as Group 2 PH (PH-LHD), while if an ICD-9lawmaking for idiopathic pulmonary fibrosis (516.31) was nowadays, the patient was categorized equally Grouping 3 PH (PH due to lung diseases and/or hypoxemia). Because some patients take ICD-9codes spanning more than 1 clinical classification group (eastward.grand. ICD-9codes for both systolic heart failure and idiopathic pulmonary fibrosis), we classified such patients equally "Multiple causes, unclassifiable PH," which is not part of the clinical classification of PH.1Selected covariates available within the national CDW were collected based on review of existing literature and suspicion of playing a function in the evolution, progression, and/or issue of PH-LHD. Covariates included demographics, comorbid conditions, medication apply, and measures of PH illness severity, as well as the outcomes of involvement. Comorbid weather condition included in the extended Elixhauser comorbidity alphabetize were assessed at PH diagnosis.21
Tabular array one.
Schema for nomenclature of pulmonary hypertension in veterans by ICD-9 diagnosis lawmaking usage.
| PH Grouping Designation | Included ICD-9Codes |
|---|---|
| Group 1, PAH | 416.0, 416.ii, 416.8, 416.ix (Excluded if meeting whatsoever of the beneath) |
| Grouping two, PH due to left heart disease | 402.01, 402.11, 402.91, 404.01, 404.03, 404.11, 404.xiii, 404.91, 404.93, 428.xx |
| Group 3, PH due to lung diseases and/or hypoxemia | 490.twenty–496.xx, 500.20–508.20, 515.20, 516.xx, 517.ane, 517.2, 327.23 |
| Group four, chronic thromboembolic PH | 416.2 |
| Grouping v, PH with unclear multifactorial mechanisms | 282.0x, 282.4x, 282.6x, 271.20, 272.seven |
| Multiple causes, unclassifiable | Patients with ICD-9 diagnosis codes included in more than 1 of Groups 2, 3, 4, and/or 5 in a higher place |
Outcome
The relevant outcome for this study was fourth dimension to death from any crusade. Death data are available within CDW's Vital Status Files which collate death data from several sources including deaths in VA facilities, VA benefits claims, Social Security Assistants, and Centers for Medicare & Medicaid Services. The CDW Vital Condition Files take been validated confronting the National Decease Index with a sensitivity of 98.3% and specificity of 99.8%.22The outset of the risk period for fourth dimension to outcome assay was the date of initial PH diagnosis lawmaking use (index appointment). Survival afterwards PH diagnosis was compared with estimated average life expectancy for the US population from the Center from Disease Command National Heart for Health Statistics and for United states veterans from the National Center for Veterans Analysis and Statistics.23,24
Statistical analyses
All statistical analyses were performed utilizing SAS Enterprise Guide software, version seven.1 (SAS Institute, Cary, NC). Continuous variables are reported as means and standard departure or median with interquartile ranges (IQRs). Categorical variables are reported equally percentages unless otherwise noted. Variables displaying strongly not-normal distribution, such as levels of brain natriuretic peptide (BNP), were transformed and parametric tests were utilized for multivariable analysis. Nosotros utilized date of initial PH diagnosis and date of death with censoring to estimate survival in veterans with PH which was our primary aim. Univariate and multivariable Cox proportional hazards regression assay were used to generate unadjusted and adjusted risk ratios for death with 95% confidence intervals (CI). P-values were calculated as two-sided and considered statistically significant when P < 0.05.
Missing data
Data were missing for some variables. No variable used in the analysis had a high caste of missingness (>10%). With variables with small-scale rate of missingness (3–10%), we chose to categorize data and include a category for missing data. For variables with <three% missing values, we used complete case analysis.
Results
From an estimated 22 million unique veterans with data available in the VHA CDW,15205,147 were selected for evaluation through an automatic query performed on 09/08/2017 based on having an ICD-9diagnosis code for PH used between 01/01/2003 and 09/30/2015. Of these, 94,583 were excluded (Fig. ane) and did not contribute to analyses or results. The most frequent exclusion was because the ICD-9diagnosis code was not utilized for ≥ 30 days as an outpatient or e'er used as an inpatient. The remaining 110,564 patients constituted the cohort utilized for all reported analyses. Meaning longitudinal VHA data were available, over 12 years on average, in these veterans who were predominantly male person (n = 106,629, 96.4%), overweight or obese (68.2%) and had a median age of 70.2 years (IQR 62.one–79.6) (Tabular array 2).
Flow diagram for cohort development. Cohort generation query was performed 09/08/2017. Note that if a discipline had the diagnosis code used as an outpatient simply and for a elapsing <thirty days, the diagnosis code use was considered a "Rule Out" use and the subject area was excluded (see reference xix). CDW: corporate data warehouse; ICD-9: International Classification of Diseases 9th version; PH: pulmonary hypertension.
Table 2.
Characteristics of U.s.a. veterans diagnosed with pulmonary hypertension in the Veteran Health Administration system, 01/01/2003-09/30/2015.
| Clinical variable | Full accomplice |
|---|---|
| Due north = 110,564 | |
| Age, median [IQR] | seventy.ii [62.one, 79.6] |
| Gender, N(%) | |
| Male | 106,629 (96.four%) |
| Female person | 3,933 (3.6%) |
| Unknown/Missing | 2 (0.0%) |
| Race, N(%) | |
| Black | 18,211 (16.5%) |
| White | 81,265 (73.v%) |
| Other race | 2,119 (ane.nine%) |
| Race missing | viii,969 (viii.ane%) |
| BMI, median [IQR], kg/m2 | 29.1 [24.8, 34.8] |
| BMI classification, N(%) | |
| Underweight | 2,834 (ii.6%) |
| Normal | 23,632 (21.4%) |
| Overweight | 29,247 (26.v%) |
| Obese | 46,086 (41.7%) |
| Missing | 8,765 (7.nine%) |
| Studies inside i yr of diagnosis, Northward(%) | |
| Echocardiogram | 95,636 (86.five%) |
| Breast CT | threescore,717 (54.9%) |
| Five/Q imaging scan | 12,667 (11.5%) |
| Pulmonary role testing | 57,136 (51.68%) |
| Left heart catheterization | 8,646 (7.eight%) |
| Right middle catheterization | 8,341 (vii.5%) |
| 6-infinitesimal walk examination | 6,489 (5.9%) |
| Workup with echocardiogram, V/Q, RHC, CT Chest, and PFT, N(%) | |
| Within 1 year of PH diagnosis | 1,241 (1.1%) |
| Always | two,613 (2.4%) |
| Workup with echocardiogram, V/Q, and RHC, plus either CT chest or PFT, N(%) | |
| Inside 1 year of PH diagnosis | 1,630 (i.v%) |
| Ever | 3,171 (two.9%) |
| Workup with echocardiogram, Five/Q, plus either CT chest or PFT (no RHC required), N(%) | |
| Within 1 year of PH diagnosis | 10,843 (9.8%) |
| Ever | xiv,925 (13.5%) |
| Rurality, centre of initial intendance | |
| Highly rural | 10 (0.0%) |
| Rural | viii,082 (seven.3%) |
| Urban | 101,706 (92.0%) |
| Missing | 766 (0.7%) |
| Census region, patient | |
| Northeast | 15,963 (fourteen.4%) |
| South | xl,693 (36.8%) |
| Midwest | 26,342 (23.8%) |
| West | 26,176 (23.seven%) |
| Information Missing | one,390 (ane.3%) |
| Lab data, median [IQR] | |
| BNP (pg/mL) | 368 [127, 886] |
| N terminal Pro-BNP (pg/mL) | 2,180 [568, 6076] |
| Creatinine (mg/dL) | 1.ii [0.ix, 1.5] |
| Sodium (mEq/L) | 139 [136, 141] |
| PH subtype, N(%) | |
| Group i PAH | 8,839 (8.0%) |
| Group 2 PH-LHD | 17,831 (16.1%) |
| Grouping three PH, lung illness | 18,382 (xvi.6%) |
| Group 4 CTEPH | 1,562 (1.4%) |
| Grouping 5 miscellaneous PH | 309 (0.3%) |
| PH with multiple causes | 63,641 (57.6%) |
| With left heart affliction contributing | 78,191 (70.7%) |
| With lung affliction contributing | 80,154 (72.5%) |
| Person time available, median [IQR] | |
| Total data availability, person-years | 12.3 [eight.6, fifteen.5] |
| Time earlier PH diagnosis, person-years | 8.0 [five.0, 11.ane] |
| Follow-up time after PH diagnosis, person-years | 2.nine [1.2, five.5] |
Relevant PH evaluation studies performed within the VHA frequently included echocardiogram and computed tomography (CT) chest imaging (Table 2). All the same, right middle catheterization (RHC) procedures occurred in less than 10% of patients. Up to 1 year after PH diagnosis, 8.4% of patients had echocardiogram, ventilation/perfusion (5/Q) browse, chest CT and RHC. Very few subjects had PH evaluation that included RHC or completed the following elements of a comprehensive evaluation for pulmonary parenchymal disease (pulmonary function tests (PFTs) and/or CT chest), chronic thromboembolism (V/Q browse), and left-sided cardiac disease (echocardiogram). Omitting RHC, about 9.8% of subjects had evaluation for lung affliction, left center illness, and chronic thromboembolism inside 1 twelvemonth of PH diagnosis.
We utilized the presence of diagnosed comorbid conditions to identify factors contributing to PH etiology. If a patient had comorbid weather that would cause PH of ii different subtypes (east.g. Group 2 and 3 PH), so they were considered unclassifiable. Of the 110,564 patients in our cohort, eight.0% (n = 8,839) had just atmospheric condition that would be classified in Group 1 PAH. Underlying left heart disease or underlying lung disease were identified as the only correspondent in sixteen.1% (n = 17,831) and 16.6% (northward = 18,382), respectively, representing those with presumed Group two and Grouping 3 PH (Table 2). The bulk of patients (57.6%, northward = 63,641) had comorbid conditions that could signal inclusion in more than than one PH subgroup and thus were not able to exist classified into one of the traditional WHO PH Groups. These patients frequently had comorbid left heart disease, comorbid lung disease or both.
Given the frequency of left centre illness and lung disease in veterans with PH, we assessed the presence of other comorbidities using the extended Elixhauser comorbidity alphabetize which includes diseases classified into 31 separate organ systems or processes including pulmonary vascular disease which all patients had (Table 3).21On average, at or before baseline, these veterans with PH had 10 (IQR 7, 13) Elixhauser conditions present. The about frequently represented conditions were chronic pulmonary disease, essential hypertension, and congestive heart failure. Several non-cardiopulmonary comorbidities were present in a large proportion including diabetes (46.iv%), depression (41.three%), and obesity (twoscore.nine%). HIV was uncommon in our accomplice (<ane%).
Table 3.
Comorbid weather condition in US veterans diagnosed with pulmonary hypertension, 01/01/2003-09/30/2015.
| Full cohort | |
|---|---|
| Comorbidity | Due north = 110,564 |
| Elixhauser21extended comorbidity count present at baseline (range 0-31 conditions), median [IQR] | 10.0 [vii.0, 13.0] |
| Specific Elixhauser components, Northward(%) | – |
| Congestive heart failure | 73,771 (66.7%) |
| Cardiac arrhythmias | 69,724 (63.1%) |
| Valvular disease | 55,544 (50.two%) |
| Peripheral vascular disorders | 38,734 (35.0%) |
| Hypertension (any) | 99,569 (ninety.1%) |
| Hypertension, simple | 98,968 (89.5%) |
| Hypertension, complicated | 33,100 (29.ix%) |
| Paralysis | 4,124 (three.seven%) |
| Other neurological disorders | 13,307 (12.0%) |
| Chronic pulmonary disease | 105,850 (95.vii%) |
| Diabetes, uncomplicated | 53,250 (48.2%) |
| Diabetes, complicated | 32,594 (29.v%) |
| Hypothyroidism | 16,388 (14.8%) |
| Renal failure | 36,989 (33.five%) |
| Liver illness | 17,777 (16.i%) |
| Peptic ulcer disease excluding haemorrhage | 8,701 (7.9%) |
| AIDS/HIV | 797 (0.seven%) |
| Lymphoma | 2,661 (ii.4%) |
| Metastatic cancer | 4,863 (four.iv%) |
| Solid tumor without metastasis | 26,869 (24.three%) |
| Rheumatoid arthritis/collagen vascular diseases | 39,331 (35.6%) |
| Coagulopathy | 19,151 (17.iii%) |
| Obesity | 47,099 (42.half-dozen%) |
| Weight loss | 18,373 (xvi.six%) |
| Fluid and electrolyte disorders | 51,534 (46.six%) |
| Claret loss anemia | 4,567 (iv.i%) |
| Deficiency anemia | 24,822 (22.five%) |
| Alcohol corruption | 23,078 (20.9%) |
| Drug abuse | xvi,155 (14.six%) |
| Psychoses | 14,642 (13.ii%) |
| Depression | 48,656 (44.0%) |
| Selected comorbidities (ever documented), Due north(%) | |
| Left centre disease | 86,444 (78.2%) |
| Diabetes | 61,309 (55.5%) |
| COPD | 72,501 (65.6%) |
| Interstitial lung affliction | xiii,032 (eleven.eight%) |
| HIV | 861 (0.8%) |
| Liver cirrhosis | 21,307 (19.3%) |
| Chronic kidney disease | 63,033 (57.0%) |
| Connective tissue disease | 8,117 (vii.iii%) |
Veterans with PH were shown to have poor overall survival after PH diagnosis (Fig. ii, Tables 4and 5). Overall survival at i, 3, and five years was 77.9%, 57.0%, and 42.3%, respectively, with the median overall survival existence 3.88 years (95% CI 3.85, 3.92) (Fig. 2a). The life expectancy after PH diagnosis was reduced compared with the full general population of the Us and with US veterans. While the average life expectancy of a 70-twelvemonth-old U.s. male and United states veteran is xiv.5 and xiii.0 years, respectively, the boilerplate survival in this cohort for a male veteran diagnosed with PH at historic period 70 was 4.2 years. Women were underrepresented in this accomplice, only had better overall survival compared with men (median vii.05 years vs. three.81 years) (Fig. 2b). With each decade increment in age at PH diagnosis, at that place was a 46% increase in take chances for mortality (95% CI 45%, 47%). The presumed underlying cause of PH was also predictive of outcome (Fig. 2c). Patients with more than one crusade of PH had poorest survival. Likewise, increasing brunt of comorbid conditions was associated with shorter survival (Fig. twod).
Kaplan–Meier survival curve for veterans with pulmonary hypertension receiving intendance in the Veteran Wellness Administration system, 01/01/2003-09/30/2015. (a) Overall survival. Median overall survival afterward diagnosis of PH is 3.88 years. (b) Overall survival stratified by gender. Median survival for females is 7.05 years compared with three.81 years for males. (c) Overall survival stratified past PH subtype. There is lower survival in those with PH due to left heart disease (Grouping two), lung disease (Group 3) and multiple causes, when compared with patients with presumed Group 1 PAH. (d) Overall survival stratified by Elixhauser comorbidity deciles. College comorbidity burden is associated with lower survival from time of PH diagnosis.
Table 4.
Bloodshed in veterans with PH, effect of baseline factors.
| Survival | Expiry during follow-up | ||||||
|---|---|---|---|---|---|---|---|
| Covariate | Median [IQR] | 1-yr | 3-year | 5-year | HR* | 95% CI | P-value |
| Overall cohort | iii.88 [3.85, 3.92] | 77.9% | 57.0% | 42.3% | |||
| Female gender | seven.05 [6.60, seven.46] | 86.ane% | 71.two% | lx.1% | Ref | ||
| Male person gender | 3.81 [iii.76, three.85] | 77.6% | 56.5% | 41.6% | 1.73 | 1.65, 1.82 | <.0001 |
| Age at diagnosis (each x y) | one.46 | i.45, 1.47 | <.0001 | ||||
| PH Group | |||||||
| Group 1 PAH | viii.35 [eight.10, 8.65] | ninety.2% | 77.nine% | 66.1% | Ref | ||
| Group 2 PH-LHD | 3.92 [iii.82, iv.02] | 77.6% | 57.four% | 42.4% | two.02 | one.95, 2.09 | <.0001 |
| Group iii PH, lung disease | 5.41 [5.27, 5.55] | 86.2% | 67.4% | 52.3% | 1.53 | i.47, 1.58 | <.0001 |
| Grouping 4 CTEPH | thirteen.08 [9.89, –] | 89.2% | 81.iv% | 72.7% | 0.75 | 0.68, 0.83 | <.0001 |
| Grouping v miscellaneous PH | 9.19 [8.28, 10.54] | 91.6% | 79.iii% | 67.8% | 0.91 | 0.76, 1.08 | 0.28 |
| PH with multiple causes | three.03 [ii.98, 3.07] | 73.6% | 50.2% | 34.9% | 2.49 | 2.41, 2.57 | <.0001 |
| Elixhauser comorbidity alphabetize, quintile | |||||||
| 1st quintile (lowest) | 6.80 [six.64, vi.93] | 89.half dozen% | 73.five% | threescore.0% | Ref | ||
| 2nd quintile | 5.12 [v.00, 5.25] | 83.8% | 65.iii% | 50.viii% | 1.33 | ane.xxx, 1.37 | <.0001 |
| 3rd quintile | iv.10 [four.02, 4.nineteen] | 79.4% | 59.0% | 43.vii% | 1.62 | i.58, ane.66 | <.0001 |
| 4th quintile | 2.99 [ii.93, 3.05] | 73.0% | 49.9% | 34.1% | two.eleven | ii.06, two.16 | <.0001 |
| fifth quintile (highest) | 2.03 [1.97, 2.09] | 65.7% | 39.v% | 24.0% | two.80 | 2.73, 2.87 | <.0001 |
Tabular array 5.
Multivariable analyses of risk of death in veterans with PH.
| Take a chance of death | |||
|---|---|---|---|
| Covariate | Hour | 95% CI | P-value |
| Effect of PH Group, adjusted for historic period at PH diagnosis, gender, race | |||
| Age at PH Dx (each 10 y) | 1.46 | 1.45, 1.47 | <.0001 |
| Sex (M vs. F) | 1.36 | 1.thirty, 1.43 | <.0001 |
| White race | Ref | ||
| Black race | 1.05 | 1.02, i.07 | <.0001 |
| Other race | 0.98 | 0.93, 1.04 | 0.48 |
| PH Group | |||
| Group i PAH | Ref | ||
| Group 2 PH-LHD | 1.97 | i.89, 2.04 | <.0001 |
| Group 3 PH, lung disease | 1.58 | 1.52, 1.65 | <.0001 |
| Group four CTEPH | 0.88 | 0.79, 0.97 | 0.01 |
| Group 5 miscellaneous PH | 1.06 | 0.88, i.27 | 0.53 |
| PH with multiple causes | 2.54 | 2.45, 2.63 | <.0001 |
| Event of comorbidity, adjusted for age at PH diagnosis, gender, race | |||
| Age at PH Dx (each 10 y) | 1.42 | ane.41, 1.44 | <.0001 |
| Sex (1000 vs. F) | one.31 | i.25, 1.38 | <.0001 |
| White race | Ref | ||
| Black race | 0.92 | 0.90, 0.94 | <.0001 |
| Other race | 0.91 | 0.86, 0.96 | 0.0012 |
| Elixhauser condition | |||
| Congestive Middle Failure | i.59 | one.56, 1.62 | <.0001 |
| Cardiac Arrhythmia | 0.98 | 0.97, 1.00 | 0.08 |
| Valvular Disease | 0.91 | 0.89, 0.92 | <.0001 |
| Peripheral Vascular Affliction | 1.eleven | 1.09, 1.xiii | <.0001 |
| Hypertension, Uncomplicated | 0.79 | 0.76, 0.81 | <.0001 |
| Hypertension, Complicated | 1.01 | 0.99, 1.03 | 0.52 |
| Paralysis | ane.07 | one.03, i.xi | 0.0009 |
| Other Neurological Disorders | 1.10 | 1.07, one.13 | <.0001 |
| Chronic Pulmonary Disease | one.40 | ane.34, 1.47 | <.0001 |
| Diabetes, Elementary | 1.06 | 1.04, 1.08 | <.0001 |
| Diabetes, Complicated | 1.10 | 1.07, 1.12 | <.0001 |
| Hypothyroidism | one.00 | 0.98, 1.02 | 0.99 |
| Renal Failure | i.23 | 1.twenty, i.26 | <.0001 |
| Liver Disease | 1.21 | 1.xix, 1.24 | <.0001 |
| Peptic Ulcer Disease | 0.98 | 0.95, 1.01 | 0.15 |
| AIDS/HIV | 0.98 | 0.89, one.08 | 0.71 |
| Lymphoma | 1.21 | one.sixteen, one.27 | <.0001 |
| Cancer, Metastatic | 1.81 | 1.74, 1.87 | <.0001 |
| Solid Tumor, Without Metastasis | one.09 | 1.07, one.xi | <.0001 |
| Collagen Vascular Illness | 0.97 | 0.95, 0.98 | 0.0001 |
| Coagulopathy | one.15 | one.13, 1.17 | <.0001 |
| Obesity | 0.79 | 0.78, 0.fourscore | <.0001 |
| Weight Loss | ane.32 | 1.xxx, ane.35 | <.0001 |
| Fluid and Electrolyte Disorders | 1.36 | 1.34, i.38 | <.0001 |
| Claret Loss Anemia | 1.x | 1.06, 1.14 | <.0001 |
| Deficiency Anemia | i.08 | 1.06, 1.ten | <.0001 |
| Alcohol Corruption | one.15 | i.12, ane.17 | <.0001 |
| Drug Corruption | i.03 | i.00, one.05 | 0.06 |
| Psychoses | i.17 | i.14, 1.19 | <.0001 |
| Depression | i.01 | 0.99, 1.03 | 0.40 |
Both underlying PH etiology and Elixhauser comorbidities had relevant influence on risk of death, both statistically and in magnitude, later on correcting for age at PH diagnosis, race and gender (Table 5, Fig. threeand four). Of the traditional PH Groups, Group 2 was associated with highest risk of death with an adjusted take a chance ratio (Hr) of 1.97 (95% CI 1.89, 2.04) compared with that for PAH and median survival nether 4 years. Group 3 PH had the second highest run a risk with adapted Hour of one.58 (95% CI 1.52, 1.65). Those patients with comorbid conditions that would be associated with more than than one form of PH had the highest adventure of death (Fig. 3). Not-cardiopulmonary comorbid conditions were also associated with effect (Fig. 4). Notably, obesity, often observed in this cohort, was protective. Uncomplicated essential hypertension and valvular heart disease were too protective. Not unexpectedly, metastatic malignancy was associated with a very high risk of death. The presence of renal failure, liver disease, alcohol abuse, and diabetes were independently associated with poor upshot (Tabular array v).
Effect of PH subtype on risk of death. In a multivariable model, male gender, increasing age at PH diagnosis, and PH due to lung affliction, heart illness or multiple causes are each associated with increasing risk of death. Open diamonds indicate reference categories. PH: pulmonary hypertension; PAH: pulmonary arterial hypertension; CTEPH: chronic thromboembolic pulmonary hypertension; CI: confidence interval.
Effect of Elixhauser comorbidity categories on outcome of veterans with pulmonary hypertension. A multivariable regression model of the influence of age, gender, race and comorbidities on take a chance of decease from time of PH diagnosis. Increased age and male gender significantly increase risk of decease. Notably, weight loss, renal failure, liver disease, and diabetes increment risk of decease while obesity is protective. Open diamonds indicate reference categories. PH: pulmonary hypertension; CI: confidence interval.
Discussion
In this retrospective analysis, nosotros identified a large cohort of veterans diagnosed with PH, the bulk presumed due to underlying comorbid left eye and/or lung disease. These veterans with PH are predominantly male, an expected finding given the cohort'southward source population. Even so, they are older and have essentially more comorbidities than the limited prior reports that evaluate PH in veterans. Longitudinal follow-upwardly from the fourth dimension of PH diagnosis demonstrates high risk of death with median survival of 3.88 years and 22.1% dying inside 1 year. The recognition of this high-gamble population has pregnant potential implications for healthcare systems that manage subjects with increasing historic period and comorbidities, including VHA as well as the aging Medicare population, every bit information technology is known that a big proportion of healthcare spending is in the final few years of life.25,26
Data on race were known for the majority of this accomplice. The cohort was bulk white, only in an unadjusted analysis, black race was associated with lower risk of death. About eight% of the cohort had no identifiable race. These subjects had poorer consequence. This is postulated to exist due to opposite causality; for example, subjects that have poor survival accept lower likelihood of having race entered into their medical record.
Our study is the largest study of veterans diagnosed with PH and extends prior reports of PH in veterans by identifying the distribution of PH subtypes clinically encountered in the VHA, the frequency with which diagnostic procedures are used, and prevalence of comorbid conditions. Compared with earlier reports in non-veterans, patients in this study with PH are generally older and more oft male, only are similarly more likely to take not-Group ane causes of PH.20Survival of subjects with presumed Group ii and three PH was significantly worse than those with presumed PAH, a finding consequent with recent reports from other single centers.5,eightMaron et al. identified veterans who had RHC, the golden standard diagnostic examination for PH.27It should be noted that at that place is no recommendation that RHC be universally used in all subjects with or subtypes of PH, nor would all who had RHC exist expected to have PH (e.g. subjects who have RHC prior to high-risk procedures).1The written report by Maron et al. included fewer subjects than our accomplice, probable considering our cohort arose from diagnoses ascribed in clinical practice and not all patients would be expected to benefit from invasive hemodynamic measurement. This consideration, and the possibility of choice bias for invasive procedures such as RHC, is supported past the fact that the earlier-reported accomplice is younger (the median age of the Maron accomplice was 65 versus seventy years in this cohort). Also noteworthy was that our accomplice was less frequently of minority race (20.0% versus 24.i% reported by Maron and colleagues).27Thus, our accomplice may provide a more than comprehensive assessment of the population of veterans with PH that are encountered in clinical care within VHA. While Maron et al. identified that PH and even borderline summit of PA pressures are associated with increased adventure of death, the current study further emphasizes that the comorbidities that subjects have, especially those that are associated with PH, further increase a given patients risk.
Veterans in this study were frequently lacking components of the diagnostic evaluation of suspected PH.1While studies may have been obtained outside the VHA system, veterans in this accomplice received medical care in the VHA system for an boilerplate of 8 years prior to the diagnosis of PH, demonstrating that they consistently accessed medical care via the VHA system. We acknowledge that this cohort was frequently of Medicare-eligible age, and therefore may have also obtained care exterior VHA. Guidelines recommend referral of subjects with PH to centers with expertise, and part of such a center's evaluation includes guideline-recommended studies to ascertain correctly the underlying etiology of PH. This tin can be a challenging task and requires methodical evaluation and disquisitional review of diagnostic testing. Whether patients included in our cohort were evaluated by providers with expertise in PH cannot exist known, only would at almost be exceptional given the accomplice'south size. RHC, the gold standard diagnostic test to confirm PH, was obtained in merely 7.5% of subjects. In our cohort, diagnostic studies that are widely bachelor and/or less invasive were used more frequently than RHC. At least one echocardiogram was obtained in 86.5% of subjects, pulmonary function testing was performed in 51.7%, and chest CT was performed in 54.9%. Yet, these diagnostic testing procedures were used less ordinarily than reported in a cohort of subjects with suspected PH referred to specialty centers (the RePHerral studyxi), who had the above diagnostic tests in 100%, lxx.vii% and 79.3%, respectively. Ventilation/perfusion (V/Q) lung scanning was obtained in 11.v% of our cohort. Although recommended by guidelines for evaluation of possible CTEPH, utilise of 5/Q scans is generally felt to be underutilized.1,28,29In our study, the proportion of patients having a 5/Q scan was lower than in patients in the RePHerral study (11.5% versus 23.half dozen% earlier expert referral in the RePHerral study and 51.4% mail-referral).11Considering of low utilization of V/Q scan, the proportion with presumed CTEPH may be underestimated in our cohort. Differences in the frequency with which diagnostic testing was performed may be explained by a clinician'south identification of a articulate cause of secondary PH and decision that further evaluation of other causes was not indicated. This retrospective accomplice study cannot identify whether the diagnostic testing performed was sufficient, or whether the determination of PH subtype was correct.
Acknowledging this study's reliance on comorbid conditions for PH subtype determination, some noteworthy findings regarding those subtypes are evident. Similar to reports including fewer subjects, our written report identified that subjects with PH due to left middle affliction or lung disease (Groups two and iii PH) have poorer consequence than other groups, including presumed PAH.five–7Compared with presumed PAH, patients with PH due to left eye disease or lung disease were shown to have 1.97 and 1.58 fold increased risk of death, respectively, accounting for differences in historic period, race, and gender betwixt groups. This finding underscores the importance of recognizing PH in subjects with chronic left heart and/or lung disease as they may be at especially loftier take chances of death. However, this clan could exist due to differences in other comorbidities. For this reason, we utilized the Elixhauser comorbidity index adapted by Quan et al.,21which is commonly used to predict issue in administrative datasets similar ours and constitutes 31 separate disease categories.
Comorbid conditions were common in this accomplice. At the time of PH diagnosis (within six months after to ever beforehand), the average patient had 10 of the 31 possible Elixhauser comorbidity categories. While methods for assessing comorbid conditions may vary betwixt other authoritative studies and ours, this frequency is higher than those reported in other studies of like patients, including veterans in principal intendance, with heart failure, and with stroke.30–32In the study from Bates et al.32which evaluated mortality after stroke, veterans were marginally younger (mean 68.three years) but had significantly lower prevalence of cardiopulmonary and non-cardiopulmonary comorbidities. Chronic liver disease, renal disease, and depression were all substantially more prevalent in veterans with PH compared with stroke (xvi% vs. 3%, 34% vs. 24%, and 44% vs. twenty%, respectively). The minor deviation in age between these cohorts would not exist expected to cause such differences in comorbid conditions. Rather, nosotros hypothesize that the PH diagnosed in veterans in our cohort is oft the event of a chronic disease milieu frequently including cardiac, pulmonary, metabolic, and other chronic weather condition. In addition to existence more frequent, these comorbid conditions have a big touch on patient consequence. The Elixhauser index, which is the sum of the 31 categories present in any single patient, and most private Elixhauser categories were associated with increased risk of death. These findings further compound the dilemma facing physicians caring for PH of how best to accost this high-gamble condition and suggesting that a monotonic intervention may underestimate the complexity of PH.
Notably, diabetes mellitus (both with and without diabetic complications) was common in veterans with PH and was associated with increased risk of death, fifty-fifty when bookkeeping for the presence of all other comorbidity categories, race, age, and gender. Multiple prior investigators—using varied methods including cell and creature models, translational inquiry, and epidemiologic studies—have shown that metabolic conditions such every bit glucose intolerance, diabetes mellitus, and the metabolic syndrome are closely linked to pulmonary vascular conditions such as PAH and hypoxia-mediated PH.33–40One prior report on the impact of diabetes mellitus on PAH survival showed increased risk for death, consistent with our findings.40Whether intervention on these metabolic processes would mitigate the increase in risk of illness is unknown; although a prior report had been posed ({"blazon":"clinical-trial","attrs":{"text":"NCT00825266","term_id":"NCT00825266"}}NCT00825266 at clinicaltrials.gov41), no study has been completed.
In contrast to the presence of diabetes, a diagnosis of obesity was shown to be protective consequent with the "obesity paradox" described in patients with diverse cardiovascular illness, including Group 1 PAH.42,43Baseline body mass alphabetize (BMI) and the BMI category were associated with survival with improved result as BMI increased. Compared with those with a normal BMI, overweight and obese veterans had 27% and 41% lower risk of mortality, respectively, and those who were underweight had 44% college adventure of mortality. Similar findings were seen when using ICD-ixdiagnosis codes via the Elixhauser categories which include both obesity and weight loss. A discipline having a diagnosis in those categories was associated with 21% lower and 32% higher risk of death, respectively.
Our retrospective analysis of clinical and administrative data has several of import limitations that merit consideration. First, our report relied on ICD-9codes for determining whether patients had PH and to which subtype they all-time fit. While this is an inherent limitation that could result in misclassification bias, it allowed us to capture a larger accomplice for analysis. We are reassured that the captured cohort resembled those in previous minor single-center studies.5,27The same concern applies to other covariates assessed at baseline, chiefly the presence of comorbid conditions. The cohort assembled is generally older and may seek care outside the VHA organisation, as a majority of them would be Medicare eligible. Indeed, others take observed that analysis of external Medicare data adds to the understanding of comorbidities in veterans.44In add-on, we written report hither the presence of diagnostic testing obtained within the VHA system on patients with PH, but these studies could also have been obtained elsewhere. An important role of PH patient assessment is that of disease severity (e.m. NYHA/WHO Functional Classification).1We were unable to account for disease severity in our models of outcome as this information is non recorded in CDW. In addition, RHC is a ways to confirm and mensurate the severity of PH. This invasive exam is often performed at VHA centers and we were able to assess for whether it had been performed, but were unable to include information from the study itself, which may accept confirmed or refuted the presence of PH, and provided information on PH severity. Manual chart review to include that data is impractical in a dataset the size presented here. Lastly, because our written report included only veterans receiving care in the VHA system our findings may not exist generalizable to other populations with PH, including veterans outside the VHA system or non-veterans. Similarly, our accomplice was predominantly male, so interpretation and application of our findings to females should exist done with caution. Despite limitations, this cohort is a valuable tool for ongoing study of PH, especially that due to comorbid middle or lung disease.
In conclusion, we take developed a large cohort of veterans diagnosed with PH, unremarkably due to underlying heart or lung disease. These underlying commonly acknowledged causes of PH are deterministic for effect of these veterans, with those having PH presumed resulting from lung disease, heart illness, or a combination of the two having worsened survival compared with all other subtypes of PH. Diabetes, neurologic/psychiatric, renal and hepatic disease were predictors of poor outcome, while higher BMI or a diagnosis of obesity was protective.
Acknowledgements
The authors would like to acknowledge the assistance provided in data conquering by Ms. Christine Jasien.
Contributorship
All authors contributed significantly to the report design and estimation of data and results. AWT acquired all data and performed all statistical analyses. All authors assisted in drafting the manuscript or critically revising it for intellectual content and have approved the last version.
Declaration of conflicting interests
Dr. Phillips reports that he has served on Scientific Advisory Boards for Janssen, and the Profil Institute for Clinical Enquiry, and has or had research back up from Merck, Amylin, Eli Lilly, Novo Nordisk, Sanofi, PhaseBio, Roche, Abbvie, Vascular Pharmaceuticals, Janssen, Glaxo SmithKline, Pfizer, Kowa, and the Cystic Fibrosis Foundation. In the past, he was a speaker for Novartis and Merck, but not for the last v years. Dr. Phillips is also a cofounder and Officeholder and Lath member and stockholder of a visitor, DIASYST, Inc., which is developing software aimed to help better diabetes management. All other authors report no conflicts of interests are present with regard to the work reported.
Ethical approving
Approving for the study was approved by the Emory Institutional Review Board and the Atlanta VA Inquiry and Development Committee.
Funding
This work was supported past the National Middle for Advancing Translational Sciences of the National Institutes of Health under Accolade number UL1TR002378. The content is solely the responsibility of the authors and does not necessarily correspond the official views of the National Institutes of Health.
This work was supported in part past funding from the Department of Veterans Affairs, Biomedical Laboratory Research and Development Office, Merit Review Honor (1I01BX001910 to CMH), by NIH NHLBI R01 (HL102167 to CMH), and with resource and the apply of facilities at the Atlanta Veterans Affairs Medical Center. The contents practice non correspond the views of the U.S. Department of Veterans Affairs or the United states of america Government.
Guarantor
All authors take responsibleness for the validity of the work and the study results reported.
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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381440/
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