Cluster analysis identifies novel real-world lung disease-pulmonary hypertension subphenotypes: implications for treatment response.

Background: Clinical trials repurposing pulmonary arterial hypertension (PAH) therapies to patients with lung disease- or hypoxia-pulmonary hypertension (PH) (classified as World Health Organization Group 3 PH) have failed to show a consistent benefit. However, Group 3 PH clinical heterogeneity suggests robust phenotyping may inform detection of treatment-responsive subgroups. We hypothesised that cluster analysis would identify subphenotypes with differential responses to oral PAH therapy. Methods: Two k-means analyses were performed on a national cohort of US veterans with Group 3 PH; an inclusive model (I) of all treated patients (n=196) and a haemodynamic model (H) limited to patients with right heart catheterisations (n=112). The primary outcome was organ failure or all-cause mortality by cluster. An exploratory analysis evaluated within-cluster treatment effects. Results: Three distinct clusters of Group 3 PH patients were identified. In the inclusive model (C1I n=43, 21.9%; C2I n=102, 52.0%; C3I n=51, 26.0%), lung disease and spirometry drove cluster assignment. By contrast, in the haemodynamic model (C1H n=44, 39.3%; C2H n=43, 38.4%; C3H n=25, 22.3%), right heart catheterisation data surpassed the importance of lung disease and spirometry. In the haemodynamic model, compared to C3H, C1H experienced the greatest hazard for respiratory failure or death (HR 6.1, 95% CI 3.2-11.8). In an exploratory analysis, cluster determined treatment response (p=0.006). Conclusions regarding within-cluster treatment responses were limited by significant differences between select variables in the treated and untreated groups. Conclusions: Cluster analysis identifies novel real-world subphenotypes of Group 3 PH patients with distinct clinical trajectories. Future studies may consider this methodological approach to identify subgroups of heterogeneous patients that may be responsive to existing pulmonary vasodilatory therapies.

Real-world evidence to advance knowledge in pulmonary hypertension: Status, challenges, and opportunities. A consensus statement from the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative's Real-world Evidence Working Group.

This manuscript on real-world evidence (RWE) in pulmonary hypertension (PH) incorporates the broad experience of members of the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative Real-World Evidence Working Group. We aim to strengthen the research community's understanding of RWE in PH to facilitate clinical research advances and ultimately improve patient care. Herein, we review real-world data (RWD) sources, discuss challenges and opportunities when using RWD sources to study PH populations, and identify resources needed to support the generation of meaningful RWE for the global PH community.

A Clinical Decision Tool for Risk Stratifying Patients with Systemic Sclerosis-Related Pulmonary Hypertension.

We devised a scoring system to identify patients with systemic sclerosis (SSc) at risk for pulmonary hypertension (PH) and predict all-cause mortality. Using 7 variables obtained via pulmonary function testing, echocardiography, and computed tomographic chest imaging, we applied the score to a retrospective cohort of 117 patients with SSc. There were 60 (51.3%) who were diagnosed with PH by right heart catheterization. Using a scoring threshold ≥ 0, our decision tool predicted PH with a sensitivity, specificity, and accuracy of 0.87 (95% CI 0.75, 0.94), 0.74 (95% CI 0.60, 0.84), and 0.80 (95% CI 0.72, 0.87), respectively. When adjusted for age at PH diagnosis, sex, and receipt of pulmonary arterial vasodilators, each one-point score increase was associated with an adjusted HR of 1.19 (95% CI 1.05, 1.34) for all-cause mortality. With further validation in external cohorts, our simplified clinical decision tool may better streamline earlier detection of PH in SSc.

Hemodynamic Response to Oral Vasodilator Therapy in Systemic Sclerosis-Related Pulmonary Hypertension.

PURPOSE: Although classified as group 1 pulmonary arterial hypertension (PAH), patients with systemic sclerosis-related pulmonary hypertension (SSc-PH) experience poorer clinical response to PAH therapy and increased mortality compared to those with idiopathic PAH. Due to heterogeneity in phenotypes, identifying patients likely to respond to therapy is challenging. The goal of this study was to determine clinical factors associated with hemodynamic response, defined by a > 20% reduction in pulmonary vascular resistance on repeat right heart catheterization. METHODS: We applied a time-to-event model using a retrospective cohort of 39 patients with precapillary SSc-PH, defined by a mean pulmonary artery pressure of ≥ 25 mmHg and pulmonary arterial wedge pressure (PAWP) ≤ 15 mmHg on right heart catheterization. RESULTS: Patients with PAWP ≤ 8 mmHg were nearly fourfold more likely to achieve a hemodynamic response compared to those with PAWP > 8 mmHg (HR 3.88; 95% CI: 1.20, 12.57); each 1 mmHg increase in PAWP was associated with a decreased hazard for hemodynamic response (HR 0.84; 95% CI: 0.70, 1.00). CONCLUSION: In patients with precapillary SSc-PH, PAWP was associated with time to hemodynamic response, suggesting the importance of subclinical cardiac disease in determining hemodynamic response to oral vasodilator therapy.

A Multimodal Prediction Model for Diagnosing Pulmonary Hypertension in Systemic Sclerosis.

OBJECTIVE: Diagnosis of pulmonary hypertension (PH) in systemic sclerosis (SSc) requires an invasive right heart catheterization (RHC), often based on an elevated estimated pulmonary artery systolic pressure on screening echocardiography. However, because of the poor specificity of echocardiography, a greater number of patients undergo RHC than necessary, exposing patients to potentially avoidable complication risks. The development of improved prediction models for PH in SSc may inform decision-making for RHC in these patients. METHODS: We conducted a retrospective study of 130 patients with SSc; 66 (50.8%) were diagnosed with PH by RHC. We used data from pulmonary function testing, electrocardiography, echocardiography, and computed tomography to identify and compare the performance characteristics of 3 models predicting the presence of PH: 1) random forest, 2) classification and regression tree, and 3) logistic regression. For each model, we generated receiver operating curves and calculated sensitivity and specificity. We internally validated models using a train-test split of the data. RESULTS: The random forest model performed best with an area under the curve of 0.92 (95% confidence interval [95% CI] 0.83-1.00), sensitivity of 0.95 (95% CI 0.75-1.00), and specificity of 0.80 (95% CI 0.56-0.94). The 2 most important variables in our random forest model were pulmonary artery diameter on chest computed tomography and diffusing capacity for carbon monoxide on pulmonary function testing. CONCLUSIONS: In patients with SSc, a random forest model can aid in the detection of PH with high sensitivity and specificity and may allow for better patient selection for RHC, thereby minimizing patient risk.

Organization of pulmonary hypertension care in non-expert care settings: Lessons learned from a multi-site study.

OBJECTIVE: To examine how select Veterans Health Administration (VA) sites organized care for patients with pulmonary hypertension (PH), with a focus on describing existing practices and identifying unmet needs within the sites. DATA SOURCES AND STUDY SETTING: Semi-structured interviews across seven diverse VA sites. STUDY DESIGN: Qualitative multiple-site study. DATA COLLECTION/EXTRACTION METHODS: We interviewed 54 key informants including pulmonologists, cardiologists, primary care providers, advanced care practitioners, pharmacists, and clinical leaders to assess the structures and processes of PH care delivery. We analyzed transcripts using directed content analysis and constructed site profiles for each site, comparing profiles to existing guidelines for PH expert centers. PRINCIPAL FINDINGS: Sites varied considerably in how they organized PH care, with wide variation in the availability of structures and processes recommended for expert centers, including availability of PH expertise and PH-specific resources, multidisciplinary approach to care, establishment of clear referral pathways, and presence of PH education. Further, participants identified three areas of unmet need not directly addressed within current guidelines, including better integration of pharmacists into multidisciplinary teams, early and routine involvement of palliative care, and improved care coordination efforts. CONCLUSIONS: The rising prevalence of PH and evolution of treatments for common PH subgroups underscore the need to standardize PH care delivery in non-expert care settings to improve care quality and patient outcomes. The insight gained from this study may inform the development of guidance appropriate for care settings outside of expert centers.

Scoping Review of Pulmonary Telemedicine Consults: Current Knowledge and Research Gaps.

Rationale: Telemedicine consults, including video consults, telephone consults, electronic consults, and virtual conferences, may be particularly valuable in the management of chronic pulmonary diseases, but there is limited guidance on best practices for pulmonary telemedicine consults. Objectives: This scoping review aims to identify, characterize, and analyze gaps in the published literature on telemedicine consults health providers use to manage patients with chronic pulmonary diseases. Methods: We searched PubMed, Embase, Web of Science, and Cochrane Library from database origin through July 10, 2021. We included manuscripts describing applications of telemedicine consults for patients with chronic pulmonary diseases (asthma, chronic obstructive pulmonary disease, lung cancer, pulmonary hypertension, and interstitial lung disease). We restricted our review to full-length articles published in English about provider-led (as opposed to nurse-led) telemedicine consults. Results: Our search yielded 3,118 unique articles; 27 articles met the inclusion criteria. All telemedicine consult modalities and chronic pulmonary conditions were well represented in the review except for pulmonary hypertension and interstitial lung disease, which were represented by one and no articles, respectively. Most articles described a small, single-center, observational study that focused on the acceptability, feasibility, use, and/or clinical effectiveness of the telemedicine consult. Few studies had objectively measured clinical outcomes or included a comparator group, and none compared telemedicine consult modalities against one another. Conclusions: Our scoping review identified limited literature describing pulmonary telemedicine consults and highlighted several gaps in the literature that warrant increased attention. Providers treating chronic pulmonary diseases are left with limited guidance on best practices for telemedicine consults.

Socioeconomically disadvantaged veterans experience treatment delays for pulmonary arterial hypertension.

Prompt initiation of therapy after pulmonary arterial hypertension (PAH) diagnosis is critical to improve outcomes; yet delays in PAH treatment are common. Prior research demonstrates that individuals with PAH belonging to socially disadvantaged groups experience worse clinical outcomes. Whether these poor outcomes are mediated by delays in care or other factors is incompletely understood. We sought to examine the association between race/ethnicity and socioeconomic status and time-to-PAH treatment. We conducted a retrospective cohort study of Veterans diagnosed with incident PAH between 2006 and 2019 and treated with PAH therapy. Our outcome was time-to-PAH treatment. Our primary exposures were race/ethnicity, annual household income, health insurance status, education, and housing insecurity. We calculated time-to-treatment using multivariable mixed-effects Cox proportional hazard models. Of 1827 Veterans with PAH, 27% were Black, 4% were Hispanic, 22.1% had an income < $20,000, 53.3% lacked non-VA insurance, 25.5% had

Clinical characteristics and outcomes in pulmonary manifestations of systemic sclerosis: Contribution from pulmonary hypertension and interstitial lung disease severity.

Patients with systemic sclerosis complicated by both pulmonary hypertension (SSc-PH) and interstitial lung disease (SSc-PH-ILD) have poor prognosis compared to those with SSc-PH or SSc-ILD alone. Little is known of how ILD severity affects outcomes in those with SSc-PH, or how PH severity affects outcomes in those with SSc-ILD. Herein, we aimed to delineate clinical features of patients with SSc-PH and SSc-ILD and determine to what degree PH and ILD severity contribute to mortality in patients with SSc. We conducted parallel retrospective studies in cohorts of patients with SSc-PH and SSc-ILD. We categorized ILD severity by pulmonary function testing and PH severity by cardiopulmonary hemodynamics. Our primary outcome was all-cause mortality from time of PH or ILD diagnosis for the SSc-PH and SSc-ILD cohorts, respectively. We calculated adjusted risks of time to all-cause mortality using Cox proportional hazards models. In patients with SSc-PH, severe ILD (HR: 3.54; 95% CI: 1.05, 11.99) was associated with increased hazards for all-cause mortality. By contrast, mild and moderate ILD were not associated with increased mortality risk. In patients with SSc-ILD, both moderate (HR: 2.65; 95% CI: 1.12, 6.31) and severe PH (HR: 6.60; 95% CI: 2.98, 14.61) were associated with increased hazards for all-cause mortality, while mild PH was not. Through our parallel study design, the risk of all-cause mortality increases as severity of concomitant ILD or PH worsens. Therapies that target slowing disease progression earlier in the disease course may be beneficial.

Inhaled Nitric Oxide vs Epoprostenol During Acute Respiratory Failure: An Observational Target Trial Emulation.

BACKGROUND: The inhaled vasodilators nitric oxide and epoprostenol may be initiated to improve oxygenation in mechanically ventilated patients with severe acute respiratory failure (ARF); however, practice patterns and head-to-head comparisons of effectiveness are unclear. RESEARCH QUESTION: What are the practice patterns and comparative effectiveness for inhaled nitric oxide and epoprostenol in severe ARF? STUDY DESIGN AND METHODS: Using a large US database (Premier Healthcare Database), we identified adult patients with ARF or ARDS who were mechanically ventilated and started on inhaled nitric oxide, epoprostenol, or both. Leveraging large hospital variation in the choice of initial inhaled vasodilator, we compared the effectiveness of inhaled nitric oxide with that of epoprostenol by limiting analysis to patients admitted to hospitals that exclusively used either inhaled nitric oxide or epoprostenol. The primary outcome of successful extubation was modeled using multivariate Fine-Grey competing risk (death or hospice discharge) time-to-event models. RESULTS: Among 11,200 patients (303 hospitals), 6,366 patients (56.8%) received inhaled nitric oxide first, 4,720 patients (42.1%) received inhaled epoprostenol first, and 114 patients (1.0%) received both therapies on the same day. One hundred four hospitals (34.3%; 1,666 patients) exclusively used nitric oxide and 118 hospitals (38.9%; 1,812 patients) exclusively used epoprostenol. No differences were found in the likelihood of successful extubation between patients admitted to nitric oxide-only hospitals vs those admitted to epoprostenol-only hospitals (subdistribution hazard ratio, 0.97; 95% CI, 0.80-1.18). Also no differences were found in total hospital costs or death. Results were robust to multiple sensitivity analyses. INTERPRETATION: Large variation exists in the use of initial inhaled vasodilator for respiratory failure across US hospitals. Comparative effectiveness analyses identified no differences in outcomes based on inhaled vasodilator type.

Smartphone-Guided Self-prone Positioning vs Usual Care in Nonintubated Hospital Ward Patients With COVID-19: A Pragmatic Randomized Clinical Trial.

BACKGROUND: Safe, effective, and easily implementable treatments that reduce the progression of respiratory failure in COVID-19 are urgently needed. Despite the increased adoption of prone positioning during the pandemic, the effectiveness of this technique on progression of respiratory failure among nonintubated patients is unclear. RESEARCH QUESTION: What is the effectiveness of smartphone-guided self-prone positioning recommendations and instructions compared with usual care in reducing progression of respiratory failure among nonintubated patients with COVID-19? STUDY DESIGN AND METHODS: Awake Prone Position for Early Hypoxemia in COVID-19 (APPEX-19) is a multicenter randomized clinical trial that randomized nonintubated adults with COVID-19 on < 6 L/min of supplemental oxygen to receive a smartphone-guided self-prone positioning intervention or usual care. The primary outcome was the composite of respiratory deterioration (an increase in supplemental oxygen requirement) or ICU transfer. Using a Bayesian statistical approach, the posterior probability of superiority within each treatment arm (superiority threshold 95%) was calculated. RESULTS: The trial was stopped early for slow enrollment. A total of 293 participants were included in the modified intention-to-treat analysis (159 self-prone positioning intervention and 134 usual care). Among participants who self-reported body positioning (n = 139 [70 intervention, 69 usual care]), 71.4% in the intervention arm and 59.4% in the usual care arm attempted prone positioning. Thirty-one participants (posterior mean, 24.7%; 95% credible interval, 18.6-31.4) receiving usual care and 32 participants (posterior mean, 22.1%; 95% credible interval, 16.6-28.1) receiving the self-prone positioning intervention experienced the primary outcome; the posterior probability of superiority for the self-prone positioning intervention was 72.1%, less than the 95% threshold for superiority. Adverse events occurred in 26.9% of participants in the usual care arm and in 11.9% of participants in the intervention arm. INTERPRETATION: Among nonintubated patients with COVID-19, smartphone-guided self-prone positioning recommendations and instructions did not promote strong adherence to prone positioning. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04344587; URL: www. CLINICALTRIALS: gov.

Outcomes of pulmonary vasodilator use in Veterans with pulmonary hypertension associated with left heart disease and lung disease.

Randomized trials of pulmonary vasodilators in pulmonary hypertension due to left heart disease (Group 2) and lung disease (Group 3) have demonstrated potential for harm. Yet these therapies are commonly used in practice. Little is known of the effects of treatment outside of clinical trials. We aimed to establish outcomes of vasodilator treatment for Groups 2/3 pulmonary hypertension in real-world practice. We conducted a retrospective cohort study of 132,552 Medicare-eligible Veterans with incident Groups 2/3 pulmonary hypertension between 2006 and 2016, and a secondary nested case-control study. Our primary outcome was a composite of death by any cause or selected acute organ failures. In our cohort analysis, we calculated adjusted risks of time to our outcome using Cox proportional hazards models with facility-specific random effects. In our case-control analysis, we used logistic mixed-effects models to estimate the effect of any past, recent, and cumulative exposure on our outcome. From our cohort study, 3249 (2.5%) Veterans were exposed to pulmonary vasodilators. Exposure to vasodilators was associated with increased risk of our primary outcome, in both Group 3 (HR: 1.58 (95% CI: 1.37-1.82)) and Group 2 (HR: 1.26 (95% CI: 1.12-1.41)) pulmonary hypertension patients. The case-control study determined odds of our outcome increased by 11% per year of exposure (OR: 1.11 (95% CI: 1.07-1.16)). Treating Groups 2/3 pulmonary hypertension with vasodilators in clinical practice is associated with increased risk of harm. This extension of trial findings to a real-world setting offers further evidence to limit use of vasodilators in Groups 2/3 pulmonary hypertension outside of clinical trials.

Development and Validation of Algorithms to Identify Pulmonary Arterial Hypertension in Administrative Data.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease, and much of our understanding stems from single-center studies, which are limited by sample size and generalizability. Administrative data offer an appealing opportunity to inform clinical, research, and quality improvement efforts for PAH. Yet, currently no standardized, validated method exists to distinguish PAH from other subgroups of pulmonary hypertension (PH) within this data source. RESEARCH QUESTION: Can a collection of algorithms be developed and validated to detect PAH in administrative data in two diverse settings: all Veterans Health Administration (VA) hospitals and Boston Medical Center (BMC), a PAH referral center. STUDY DESIGN AND METHODS: In each setting, we identified all adult patients with incident PH from 2006 through 2017 using International Classification of Diseases PH diagnosis codes. From this baseline cohort of all PH subgroups, we sequentially applied the following criteria: diagnosis codes for PAH-associated conditions, procedure codes for right heart catheterizations (RHCs), and pharmacy claims for PAH-specific therapy. We then validated each algorithm using a gold standard review of primary clinical data and calculated sensitivity, specificity, positive predictive values (PPVs), and negative predictive values. RESULTS: From our baseline cohort, we identified 12,012 PH patients in all VA hospitals and 503 patients in BMC. Sole use of PH diagnosis codes performed poorly in identifying PAH (PPV, 16.0% in VA hospitals and 36.0% in BMC). The addition of PAH-associated conditions to the algorithm modestly improved PPV. The best performing algorithm required ICD diagnosis codes, RHC codes, and PAH-specific therapy (VA hospitals: specificity, 97.1%; PPV, 70.0%; BMC: specificity, 95.0%; PPV, 86.0%). INTERPRETATION: This set of validated algorithms to identify PAH in administrative data can be used by the PAH scientific and clinical community to enhance the reliability and value of research findings, to inform quality improvement initiatives, and ultimately to improve health for PAH patients.

Factors Associated With Potentially Inappropriate Phosphodiesterase-5 Inhibitor Use for Pulmonary Hypertension in the United States, 2006 to 2015.

BACKGROUND: Use of phosphodiesterase-5 inhibitors (PDE5i) for groups 2 and 3 pulmonary hypertension (PH) is rising nationally, despite guidelines recommending against this low-value practice. Although receiving care across healthcare systems is encouraged to increase veterans' access to specialists critical for PH management, receiving care in 2 systems may increase risk of guideline-discordant prescribing. We sought to identify factors associated with prescribing of PDE5i for group 2/3 PH, particularly, to test the hypothesis that veterans prescribed PDE5i for PH in the community (through Medicare) will have increased risk of subsequently receiving potentially inappropriate treatment in Veterans Health Administration (VA). METHODS AND RESULTS: We constructed a retrospective cohort of 34 775 Medicare-eligible veterans with group 2/3 PH by linking national patient-level data from VA and Medicare from 2006 to 2015. We calculated adjusted odds ratios (ORs) of receiving daily PDE5i treatment for PH in VA using multivariable models with facility-specific random effects. In this cohort, 1556 veterans received VA prescriptions for PDE5i treatment for group 2/3 PH. Supporting our primary hypothesis, the variable most strongly associated with PDE5i treatment in VA for group 2/3 PH was prior treatment through Medicare (OR, 6.5 [95% CI, 4.9-8.7]). Other variables strongly associated with increased likelihood of VA treatment included more severe disease as indicated by recent right heart failure (OR, 3.3 [95% CI, 2.8-3.9]) or respiratory failure (OR, 3.7 [95% CI, 3.1-4.4]) and prior right heart catheterization (OR, 3.8 [95% CI, 3.4-4.3]). CONCLUSIONS: Our data suggest a missed opportunity to reassess treatment appropriateness when pulmonary hypertension patients seek prescriptions from VA-a relevant finding given policies promoting shared care across VA and community settings. Interventions are needed to reinforce awareness that pulmonary vasodilators are unlikely to benefit group 2/3 pulmonary hypertension patients and may cause harm.