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.

The isobaric pulmonary arterial compliance in pulmonary hypertension.

Pulmonary hypertension is associated with stiffening of pulmonary arteries which increases right ventricular pulsatile loading. High pulmonary artery wedge pressure (PAWP) in postcapillary pulmonary hypertension (Pc-PH) further decreases pulmonary arterial compliance (PAC) at a given pulmonary vascular resistance (PVR) compared with precapillary pulmonary hypertension, thus responsible for a higher total arterial load. In all other vascular beds, arterial compliance is considered as mainly determined by the distending pressure, due to non-linear stress-strain behaviour of arteries. We tested the applicability, advantages and drawbacks of two comparison methods of PAC depending on the level of mean pulmonary arterial pressure (mPAP; isobaric PAC) or PVR. Right heart catheterisation data including PAC (stroke volume/pulse pressure) were obtained in 112 Pc-PH (of whom 61 had combined postcapillary and precapillary pulmonary hypertension) and 719 idiopathic pulmonary arterial hypertension (iPAH). PAC could be compared over the same mPAP range (25-66 mmHg) in 792 (95.3%) out of 831 patients and over the same PVR range (3-10.7 WU) in only 520 (62.6%) out of 831 patients. The main assumption underlying comparisons at a given PVR was not verified as the PVR×PAC product (RC-time) was not constant but on the contrary more variable than mPAP. In the 788/831 (94.8%) patients studied over the same PAC range (0.62-6.5 mL·mmHg-1), PVR and thus total arterial load tended to be higher in iPAH. Our study favours comparing PAC at fixed mPAP level (isobaric PAC) rather than at fixed PVR. A reappraisal of the effects of PAWP on the pulsatile and total arterial load put on the right heart is needed, and this point deserves further studies.

Pulmonary Vascular Disease as a Systemic and Multisystem Disease.

Pulmonary arterial hypertension (PAH) is a disease of progressive pulmonary vascular remodeling due to abnormal proliferation of pulmonary vascular endothelial and smooth muscle cells and endothelial dysfunction. PAH is a multisystem disease with systemic manifestations and complications. This article covers the chronic heart failure syndrome, including the systemic consequences of right ventricle-pulmonary artery uncoupling and neurohormonal activation, skeletal and respiratory muscle effects, systemic endothelial dysfunction and coronary artery disease, systemic inflammation and infection, endocrine and metabolic changes, the liver and gut axis, sleep, neurologic complications, and skin and iron metabolic changes.

Screening for pulmonary arterial hypertension in adults carrying a BMPR2 mutation.

BACKGROUND: Heritable pulmonary arterial hypertension (PAH) is most commonly due to heterozygous mutations of the BMPR2 gene. Based on expert consensus, guidelines recommend annual screening echocardiography in asymptomatic BMPR2 mutation carriers. The main objectives of this study were to evaluate the characteristics of asymptomatic BMPR2 mutation carriers, assess their risk of occurrence of PAH and detect PAH at an early stage in this high-risk population. METHODS: Asymptomatic BMPR2 mutation carriers underwent screening at baseline and annually for a minimum of 2 years (DELPHI-2 study; ClinicalTrials.gov: NCT01600898). Annual screening included clinical assessment, ECG, pulmonary function tests, 6-min walk distance, cardiopulmonary exercise testing, chest radiography, echocardiography and brain natriuretic peptide (BNP) or N-terminal (NT)-proBNP level. Right heart catheterisation (RHC) was performed based on predefined criteria. An optional RHC at rest and exercise was proposed at baseline. RESULTS: 55 subjects (26 males; median age 37 years) were included. At baseline, no PAH was suspected based on echocardiography and NT-proBNP levels. All subjects accepted RHC at inclusion, which identified two mild PAH cases (3.6%) and 12 subjects with exercise pulmonary hypertension (21.8%). At long-term follow-up (118.8 patient-years of follow-up), three additional cases were diagnosed, yielding a PAH incidence of 2.3% per year (0.99% per year in males and 3.5% per year in females). All PAH cases remained at low-risk status on oral therapy at last follow-up. CONCLUSIONS: Asymptomatic BMPR2 mutation carriers have a significant risk of developing incident PAH. International multicentre studies are needed to confirm that refined multimodal screening programmes with regular follow-up allow early detection of PAH.

Cryobiopsy for Identification of Usual Interstitial Pneumonia and Other Interstitial Lung Disease Features. Further Lessons from COLDICE, a Prospective Multicenter Clinical Trial.

Rationale: Transbronchial lung cryobiopsy (TBLC) is an emerging technique for interstitial lung disease diagnosis. Good histopathologic agreement between TBLC and surgical lung biopsy (SLB) was demonstrated in the COLDICE (Cryobiopsy versus Open Lung Biopsy in the Diagnosis of Interstitial Lung Disease Alliance) study; however, diagnostic confidence was frequently lower for TBLC than SLB. Objectives: To characterize specific features of TBLC predictive of usual interstitial pneumonia (UIP) in corresponding SLB and to identify clinical indices predictive of biopsy concordance. Methods: The COLDICE study was a prospective, multicenter study investigating diagnostic agreement between TBLC and SLB. The participants underwent both procedures with blinded pathologist analysis of specimens, applying international guideline criteria. The TBLC features predictive of UIP in the paired SLB and predictive features of overall concordance were analyzed. Measurements and Main Results: A total of 65 patients (66.1 ± 9.3 yr; FVC, 84.7 ± 14.2%; DlCO, 63.4 ± 13.8%) participated in the COLDICE study. UIP was identified in 33/65 (50.8%) SLB, and 81.5% were concordant with corresponding TBLC (κ, 0.61; 95% confidence interval [CI], 0.38-0.77). The UIP guideline criteria of "predominantly subpleural or paraseptal fibrosis" was infrequently reported in TBLC (8/33, 24.2%), whereas "patchy fibrosis," "fibroblast foci," and the "absence of alternative diagnostic features" were frequently observed in TBLC. The combination of these three features strongly predicted UIP in paired SLB (odds ratio [OR], 23.4; 95% CI, 6.36-86.1; P < 0.0001). Increased numbers of TBLC samples predicted histopathologic concordance with SLB (OR, 1.8; 95% CI, 1.08-3.01; P = 0.03). The predictors of discordance included older age, family history, and radiologic asymmetry. Conclusions: Subpleural and/or paraseptal fibrosis were not essential for diagnosing UIP in TBLC, provided that other guideline criteria features were present. The diagnostic accuracy of TBLC was strengthened when increased numbers of samples were taken. Clinical trial registered with www.anzctr.org.au (ACTRN12615000718549).

Inspiratory Muscle Training Improves Inspiratory Muscle Strength and Functional Exercise Capacity in Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: A Pilot Randomised Controlled Study.

BACKGROUND: Exercise intolerance is present even in the early stages of pulmonary arterial hypertension (PAH) and is associated with poorer prognosis. Respiratory muscle dysfunction is common and may contribute to exercise limitation. We sought to investigate the effects of inspiratory muscle training (IMT) to improve exercise capacity in PAH. METHODS: Adults with PAH were prospectively recruited and randomly assigned to either IMT or a control group. At baseline and after 8 weeks, assessment of respiratory muscle function, pulmonary function, neurohormonal activation, 6-minute walk distance and cardiopulmonary exercise testing variables were conducted. Inspiratory muscle strength was assessed by maximal static inspiratory pressure (PImax). The IMT group performed two cycles of 30 breaths at 30-40% of their PImax 5 days a week for 8 weeks. RESULTS: Twelve (12) PAH patients (60±14 years, 10 females) were recruited and randomised (six in the IMT group and six in the control group). After 8 weeks, the IMT group improved PImax by 31 cmH2O compared with 10 cmH2O in controls, p=0.02. Following IMT, 6-minute walk distance improved by 24.5 m in the IMT group and declined by 12 m in the controls (mean difference 36.5 m, 95% CI 3.5-69.5, p=0.03). There was no difference in peak oxygen uptake between-groups (mean difference 0.4 mL/kg/min, 95% CI -2.6 to 3.4, p=0.77). There was no difference in the mean change between-groups in neurohormonal activation or pulmonary function. CONCLUSION: In this pilot randomised controlled study, IMT improved PImax and 6-minute walk distance in PAH patients.

Diagnostic accuracy of transbronchial lung cryobiopsy for interstitial lung disease diagnosis (COLDICE): a prospective, comparative study.

BACKGROUND: Transbronchial lung cryobiopsy (TBLC) is a novel technique for sampling lung tissue for interstitial lung disease diagnosis. The aim of this study was to establish the diagnostic accuracy of TBLC compared with surgical lung biopsy (SLB), in the context of increasing use of TBLC in clinical practice as a less invasive biopsy technique. METHODS: COLDICE was a prospective, multicentre, diagnostic accuracy study investigating diagnostic agreement between TBLC and SLB, across nine Australian tertiary hospitals. Patients with interstitial lung disease aged between 18 and 80 years were eligible for inclusion if they required histopathological evaluation to aid diagnosis, after detailed baseline evaluation. After screening at a centralised multidisciplinary discussion (MDD), patients with interstitial lung disease referred for lung biopsy underwent sequential TBLC and SLB under one anaesthetic. Each tissue sample was assigned a number between 1 and 130, allocated in a computer-generated random sequence. Encoded biopsy samples were then analysed by masked pathologists. At subsequent MDD, de-identified cases were discussed twice with either TBLC or SLB along with clinical and radiological data, in random non-consecutive order. Co-primary endpoints were agreement of histopathological features in TBLC and SLB for patterns of definite or probable usual interstitial pneumonia, indeterminate for usual interstitial pneumonia, and alternative diagnosis; and for agreement of consensus clinical diagnosis using TBLC and SLB at MDD. Concordance and κ values were calculated for each primary endpoint. This study is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12615000718549. FINDINGS: Between March 15, 2016, and April 15, 2019, we enrolled 65 patients (31 [48%] men, 34 [52%] women; mean age 66·1 years [SD 9·3]; forced vital capacity 83·7% [SD 14·2]; diffusing capacity for carbon monoxide 63·4% [SD 12·8]). TBLC (7·1 mm, SD 1·9) and SLB (46·5 mm, 14·9) samples were each taken from two separate ipsilateral lobes. Histopathological agreement between TBLC and SLB was 70·8% (weighted κ 0·70, 95% CI 0·55-0·86); diagnostic agreement at MDD was 76·9% (κ 0·62, 0·47-0·78). For TBLC with high or definite diagnostic confidence at MDD (39 [60%] of 65 cases), 37 (95%) were concordant with SLB diagnoses. In the 26 (40%) of 65 cases with low-confidence or unclassifiable TBLC diagnoses, SLB reclassified six (23%) to alternative high-confidence or definite MDD diagnoses. Mild-moderate airway bleeding occurred in 14 (22%) patients due to TBLC. The 90-day mortality was 2% (one of 65 patients), following acute exacerbation of idiopathic pulmonary fibrosis. INTERPRETATION: High levels of agreement between TBLC and SLB for both histopathological interpretation and MDD diagnoses were shown. The TBLC MDD diagnoses made with high confidence were particularly reliable, showing excellent concordance with SLB MDD diagnoses. These data support the clinical utility of TBLC in interstitial lung disease diagnostic algorithms. Further studies investigating the safety profile of TBLC are needed. FUNDING: University of Sydney, Hunter Medical Research Institute, Erbe Elektromedizin, Medtronic, Cook Medical, Rymed, Karl-Storz, Zeiss, and Olympus.

Cryobiopsy versus open lung biopsy in the diagnosis of interstitial lung disease (COLDICE): protocol of a multicentre study.

Introduction: Transbronchial lung cryobiopsy (TBLC) is a novel, minimally invasive technique for obtaining lung tissue for histopathological assessment in interstitial lung disease (ILD). Despite its increasing popularity, the diagnostic accuracy of TBLC is not yet known. The COLDICE Study (Cryobiopsy versus Open Lung biopsy in the Diagnosis of Interstitial lung disease allianCE) aims to evaluate the agreement between TBLC and surgical lung biopsy sampled concurrently from the same patients, for both histopathological and multidisciplinary discussion (MDD) diagnoses. Methods and analysis: This comparative, multicentre, prospective trial is enrolling patients with ILD requiring surgical lung biopsy to aid with their diagnosis. Participants are consented for both video-assisted thoracoscopic surgical (VATS) biopsy and TBLC within the same anaesthetic episode. Specimens will be blindly assessed by three expert pathologists both individually and by consensus. Each tissue sample will then be considered in conjunction with clinical and radiological data, within a centralised MDD. Each patient will be presented twice in random order, once with TBLC data and once with VATS data. Meeting participants will be blinded to the method of tissue sampling. The accuracy of TBLC will be assessed by agreement with VATS at (1) histopathological analysis and (2) MDD diagnosis. Data will be collected on interobserver agreement between pathologists, interobserver agreement between MDD participants, and detailed clinical and procedural characteristics. Ethics and dissemination: The study is being conducted in accordance with the International Conference on Harmonisation Guideline for Good Clinical Practice and Australian legislation for the ethical conduct of research. Trial registration number: ACTRN12615000718549.

Nocturnal hypoxaemia is associated with adverse outcomes in interstitial lung disease.

BACKGROUND AND OBJECTIVE: Sleep-disordered breathing (SDB) has been reported as highly prevalent in idiopathic pulmonary fibrosis (IPF) and other interstitial lung disease (ILD) populations. Nocturnal oxygen desaturation (NOD), or the total sleep time spent with SpoO2 < 90% (TST < 90), can occur both with and without associated apnoeas, and is common in ILD. This study aimed to characterize abnormal SDB and extent of TST < 90 in ILD patients and evaluate relationships between TST < 90 and markers of disease severity, development of pulmonary hypertension (PH) and mortality. METHODS: Consecutive, newly referred ILD patients attending a specialist clinic underwent polysomnography (PSG). Serial lung function tests, echocardiography and other clinical variables were recorded. Predictors of PH and mortality were evaluated using logistic regression and Cox proportional hazards regression analyses. RESULTS: A total of 92 ILD patients (including 44 with IPF) underwent PSG. At least mild obstructive sleep apnoea (OSA) was observed in 65.2%, with rapid eye movement (REM)-related events occurring frequently. At least 10% TST < 90 (designated 'significant NOD') was present in 35.9% of patients, and was associated with PH at baseline echocardiography. Multiple indices of hypoxaemia during sleep, including significant NOD, predicted the development of new or worsening PH. TST < 90 predicted overall and progression-free survival. CONCLUSION: Nocturnal oxygen saturation is associated with poorer prognosis in ILD patients and may contribute towards the pathogenesis of pulmonary vascular disease.

Golden Ratio and the Proportionality Between Pulmonary Pressure Components in Pulmonary Arterial Hypertension.

BACKGROUND: The golden ratio (phi, Φ = 1.618) is a proportion that has been found in many phenomena in nature, including the cardiovascular field. We tested the hypothesis that the systolic over mean pulmonary artery pressure ratio (sPAP/mPAP) and the mean over diastolic pressure ratio (mPAP/dPAP) may match Φ in patients with pulmonary arterial hypertension (PAH) and in control patients. METHODS: In the first, theoretical part of the study, we discuss why our hypothesis is consistent with three known hemodynamic features of the pulmonary circulation: (1) the 0.61 slope of the mPAP vs sPAP relationship, (2) pulmonary artery pulse pressure and mPAP have an almost 1:1 ratio, and (3) the proportional relationship among sPAP, mPAP, and dPAP. In the second part of the study, fluid-filled pressures were analyzed in 981 incident, untreated PAH and high-fidelity pressures were also analyzed in 44 historical control patients (mPAP range, 9-113 mm Hg). RESULTS: In PAH (non-normal distribution), median values of sPAP/mPAP and mPAP/dPAP were 1.591 (98%Φ) and 1.559 (96%Φ), respectively. In control patients (normal distribution), mean sPAP/mPAP and mPAP/dPAP were 1.572 (97%Φ) and 1.470 (91%Φ), respectively. In both PAH and control patients, this was consistent with the Φ hypothesis, assuming < 1 mm Hg error in estimation of sPAP, mPAP, and dPAP on average. CONCLUSIONS: In PAH and in control patients, the fluctuations in sPAP and dPAP around mPAP exhibited a constant scaling factor matched to Φ. This remarkable property allows linkage of various empirical observations on pulmonary hemodynamics that were hitherto apparently unrelated. These findings warrant further confirmation in other types of pulmonary hypertension and warrant explanation.

Pulmonary vasodilator therapies are of no benefit in pulmonary hypertension due to left heart disease: A meta-analysis.

BACKGROUND: Pulmonary hypertension complicating left heart disease (PH-LHD) is the most common cause of PH. Off-label use of pulmonary arterial hypertension (PAH) medications for PH-LHD is prevalent, despite a lack of clinical data supporting their use. METHODS: A systematic review and meta-analysis was performed. Comprehensive search of all available literature to date identified ten randomised, placebo controlled trials comprising 439 treated (Phosphodiesterase 5 inhibitors: n = 206; guanylate cyclase stimulators: n = 132; endothelin receptor antagonists: n = 101) and 338 placebo patients. Random effects model was employed to assess outcomes in the treatment compared to the placebo control arm. RESULTS: The risks of all-cause mortality, cardiovascular mortality and worsening heart failure were numerically higher in the treated compared to the control group, although not statistically (all-cause mortality: RR = 1.97, 95% CI: 0.64-6.05, p = 0.24; cardiovascular mortality: RR = 2.01, 95% CI: 0.39-10.34, p = 0.4; worsening heart failure: RR = 1.23, 95% CI: 0.68-2.25, p = 0.49). Conversely, right heart hemodynamics improved numerically in the treated group, also without being significant (mean pulmonary artery pressure: MWD = -5.13 mm Hg, 95% CI: -13.2-2.9, p = 0.21; pulmonary vascular resistance: MWD = -0.87 WU, 95% CI: -1.75-0.1, p = 0.053). CONCLUSIONS: The current meta-analysis demonstrated that there is no current evidence to support the widespread use of PAH therapy in PH-LHD. On the basis of a numerically increased risk of clinical harm, these agents should not be prescribed in this setting, unless further evidence of benefit arises in the future.

Clinical and Hemodynamic Correlates of Pulmonary Arterial Stiffness in Incident, Untreated Patients With Idiopathic Pulmonary Arterial Hypertension.

BACKGROUND: The role of decreased pulmonary arterial (PA) compliance (C), equivalent to increased PA stiffness (1/C), as a critical determinant of right ventricular dysfunction and prognosis has been emphasized in pulmonary arterial hypertension (PAH). METHODS: This study retrospectively reviewed all incident patients diagnosed with idiopathic PAH according to right heart catheterization who were enrolled in the French Pulmonary Arterial Hypertension Network registry between 2006 and 2016 and who had complete baseline data allowing calculation of stiffness (PA pulse pressure/stroke volume index). RESULTS: In the 719 patients included (median age: 66 years; 53.7% female), PA stiffness was 1.49 mm Hg × m2/mL (interquartile ratio: 1.08-2.04 mm Hg × m2/mL). Stiffness was related to mean pulmonary artery pressure (mPAP) (r2 = 0.33) and heart rate (r2 = 0.15) but not to age or sex. Higher PA stiffness and higher pulmonary vascular resistance (PVR) were documented in high-risk vs low-risk patients, as defined according to the European Society of Cardiology/European Respiratory Society guidelines. The dispersion of the PVR × C product was as variable as patient age and mPAP, and C could not be estimated on the basis of PVR alone (95% limits of agreement of the bias: -50% to 54%). Although transplant-free survival differed across PA stiffness quartiles (P = .04), stiffness was not an independent predictor of long-term outcome (median follow-up duration: 2.43 years). CONCLUSIONS: In incident idiopathic PAH, PA stiffness was related to mPAP and heart rate, and this finding outperformed the potential influences of age and sex. Baseline PA stiffness did not independently predict outcome. The great dispersion of the PVR × C product implied that PVR and PA stiffness were differently affected by the disease process.

Pathophysiology of exercise intolerance in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a chronic disease with poor prognosis and important exercise limitation despite the proliferation of treatment options in the last decade. Chronically increased right ventricular (RV) afterload results in right heart failure and without treatment, rapid clinical deterioration is common. Exercise intolerance is the cardinal feature of the disease impacting upon quality of life and clinical outcome. The pathophysiological mechanisms that lead to reduced exercise capacity in this population are complex with ventriculoarterial uncoupling likely to be the predominant feature. The relative contributions of additional factors that contribute to exercise limitation beyond ventriculoarterial uncoupling have not been characterized. This review addresses these factors with a focus on recent developments and uncertainties. RV maladaptation and the intricate interplay between the heart, abnormal pulmonary vascular bed and peripheral factors such as dysfunction of the respiratory and peripheral muscles are discussed in detail.