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Background: Detection of pulmonary perfusion defects is the recommended approach for diagnosing chronic thromboembolic pulmonary hypertension (CTEPH). This is currently achieved in a clinical setting using scintigraphy. Phase‐resolved functional lung (PREFUL) magnetic resonance imaging (MRI) is an alternative technique for evaluating regional ventilation and perfusion without the use of ionizing radiation or contrast media. Purpose: To assess the feasibility and image quality of PREFUL‐MRI in a multicenter setting in suspected CTEPH. Study Type: This is a prospective cohort sub‐study. Population: Forty‐five patients (64 ± 16 years old) with suspected CTEPH from nine study centers. Field Strength/Sequence: 1.5 T and 3 T/2D spoiled gradient echo/bSSFP/T2 HASTE/3D MR angiography (TWIST). Assessment: Lung signal‐to‐noise ratio (SNR) and contrast‐to‐noise ratio (CNR) were compared between study centers with different MRI machines. The contrast between normally and poorly perfused lung areas was examined on PREFUL images. The perfusion defect percentage calculated using PREFUL‐MRI (QDPPREFUL) was compared to QDP from the established dynamic contrast‐enhanced MRI technique (QDPDCE). Furthermore, QDPPREFUL was compared between a patient subgroup with confirmed CTEPH or chronic thromboembolic disease (CTED) to other clinical subgroups. Statistical Tests: t‐Test, one‐way analysis of variance (ANOVA), Pearson's correlation. Significance level was 5%. Results: Significant differences in lung SNR and CNR were present between study centers. However, PREFUL perfusion images showed a significant contrast between normally and poorly perfused lung areas (mean delta of normalized perfusion −4.2% SD 3.3) with no differences between study sites (ANOVA: P = 0.065). QDPPREFUL was significantly correlated with QDPDCE (r = 0.66), and was significantly higher in 18 patients with confirmed CTEPH or CTED (57.9 ± 12.2%) compared to subgroups with other causes of PH or with excluded PH (in total 27 patients with mean ± SD QDPPREFUL = 33.9 ± 17.2%). Data Conclusion: PREFUL‐MRI could be considered as a non‐invasive method for imaging regional lung perfusion in multicenter studies. Level of Evidence: 3 Technical Efficacy: Stage 1 [ABSTRACT FROM AUTHOR]

Background: Interstitial lung diseases (ILD) comprise a heterogeneous group of mainly chronic lung diseases with more than 200 entities and relevant differences in disease course and prognosis. Little data is available on hospitalisation patterns in ILD. Methods: The EXCITING-ILD (Exploring Clinical and Epidemiological Characteristics of Interstitial Lung Diseases) registry was analysed for hospitalisations. Reasons for hospitalisation were classified as all cause, ILD-related and respiratory hospitalisations, and patients were analysed for frequency of hospitalisations, time to first non-elective hospitalisation, mortality and progression-free survival. Additionally, the risk for hospitalisation according to GAP index and ILD subtype was calculated by Cox proportional-hazard models as well as influencing factors on prediction of hospitalisation by logistic regression with forward selection. Results: In total, 601 patients were included. 1210 hospitalisations were recorded during the 6 months prior to registry inclusion until the last study visit. 800 (66.1%) were ILD-related, 59.3% of admissions were registered in the first year after inclusion. Mortality was associated with all cause, ILD-related and respiratory-related hospitalisation. Risk factors for hospitalisation were advanced disease (GAP Index stages II and III) and CTD (connective tissue disease)-ILDs. All cause hospitalisations were associated with pulmonary hypertension (OR 2.53, p = 0.005). ILD-related hospitalisations were associated with unclassifiable ILD and concomitant emphysema (OR = 2.133, p = 0.001) as well as with other granulomatous ILDs and a positive smoking status (OR = 3.082, p = 0.005). Conclusion: Our results represent a crucial contribution in understanding predisposing factors for hospitalisation in ILD and its major impact on mortality. Further studies to characterize the most vulnerable patient group as well as approaches to prevent hospitalisations are warranted. [ABSTRACT FROM AUTHOR]

The benefit of sildenafil in patients with advanced idiopathic pulmonary fibrosis (IPF) at risk of poor outcomes from pulmonary hypertension, whether already present or likely to develop, is uncertain. We aimed to assess the efficacy and safety of sildenafil added to pirfenidone versus placebo added to pirfenidone for 52 weeks in patients with advanced IPF and at risk of group 3 pulmonary hypertension. We did a multicentre, international, double-blind, randomised, placebo-controlled, phase 2b study at 56 university clinics, research hospitals, and tertiary sites in Canada, Europe (Belgium, Czech Republic, Germany, Greece, Hungary, Italy, the Netherlands, Spain, and Turkey), Israel, and Africa (Egypt and South Africa). Eligible patients (aged 40–80 years) had advanced IPF (carbon monoxide diffusing capacity ≤40% predicted at screening), and were at risk of group 3 pulmonary hypertension (mean pulmonary artery pressure of ≥20 mm Hg with pulmonary artery wedge pressure of ≤15 mm Hg on previous right-heart catheterisation, or intermediate or high probability of group 3 pulmonary hypertension on echocardiography as defined by the 2015 European Society of Cardiology and European Respiratory Society guidelines). Patients were randomly assigned 1:1 to oral sildenafil tablets (20 mg three times daily) or placebo, both in addition to oral pirfenidone capsules (801 mg three times daily), using a validated interactive voice-based or web-based response system with permuted block randomisation, stratified by previous right-heart catheterisation (yes or no) and forced expiratory volume in 1 s to forced vital capacity ratio (<0·8 or ≥0·8). The composite primary endpoint was disease progression, defined as either a relevant decline in 6-min walk distance, respiratory-related admission to hospital, or all-cause mortality, after 52 weeks and was assessed in the intention-to-treat population; safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov , NCT02951429 , and is no longer recruiting. The 11-month safety follow-up is ongoing. Between Jan 13, 2017, and Aug 30, 2018, 247 patients were screened for eligibility, 177 of whom were randomly assigned to a treatment group (n=88 sildenafil; n=89 placebo) and were assessed for the primary outcome. There was no difference in the proportion of patients with disease progression over 52 weeks between the sildenafil (64 [73%] of 88 patients) and placebo groups (62 [70%] of 89 patients; between-group difference 3·06% [95% CI −11·30 to 17·97]; p=0·65). Serious treatment-emergent adverse events were reported in 54 (61%) patients in the sildenafil group and 55 (62%) patients in the placebo group. Treatment-emergent adverse events leading to mortality occurred in 22 (25%) patients in the sildenafil group and 26 (29%) in the placebo group. Addition of sildenafil to pirfenidone did not provide a treatment benefit versus pirfenidone plus placebo up to 52 weeks in patients with advanced IPF and risk of pulmonary hypertension. No new safety signals were identified with either treatment. Although the absence of a beneficial treatment effect suggests that sildenafil is not an appropriate treatment in the overall population, further research is required to establish if specific subgroups of patients with IPF might benefit from sildenafil. F Hoffmann-La Roche. [ABSTRACT FROM AUTHOR]

An editorial is presented on pulmonary hypertension in the context of interstitial lung disease (PH-ILD). Topics include significant positive effect of inhaled treprostinil, a stable prostacyclin analogon with potent vasodilative effects on pulmonary vasculature; distributed preferentially to the well-ventilated areas of the lungs even reducing intrapulmonary mismatch and shunting.

Rationale: In the INSTAGE trial in patients with idiopathic pulmonary fibrosis (IPF) and severely impaired gas exchange, nintedanib plus sildenafil was associated with numerical benefits on St. George's Respiratory Questionnaire (SGRQ) total score, brain natriuretic peptide (BNP), and FVC decline versus nintedanib alone. Exploratory analyses of the STEP-IPF (Sildenafil Trial of Exercise Performance in IPF) trial suggested that sildenafil may have a greater effect on SGRQ score in patients with IPF who have right heart dysfunction (RHD).Objectives: Assess whether RHD influenced the effects of nintedanib plus sildenafil versus nintedanib alone in the INSTAGE trial.Methods: Subgroup analyses of patients with (n = 117) versus those without (n = 156) echocardiographic signs of RHD at baseline.Measurements and Main Results: There was no heterogeneity between subgroups by presence of RHD in the effect of nintedanib plus sildenafil versus nintedanib alone on change in SGRQ total score at Week 12 (P = 0.74) or Week 24 (P = 0.90), or change in FVC at Week 12 (P = 0.58) or Week 24 (P = 0.55). In both subgroups, nintedanib plus sildenafil had a numerically greater effect on reducing FVC decline versus nintedanib alone. Between-group differences in change in BNP at Week 24 were -119.9 ng/L (95% confidence interval = -171.3 to -68.5) and -3.6 ng/L (95% confidence interval = -47.2 to 40.0) in patients with and without signs of RHD at baseline, respectively (P < 0.01).Conclusions: In the INSTAGE trial, there were no significant differences in the effects of nintedanib plus sildenafil versus nintedanib alone on changes in SGRQ and FVC between patients with or without echocardiographic signs of RHD at baseline. The benefit of combination therapy on stabilizing BNP was more pronounced in patients with RHD at baseline.Clinical trial registered with www.clinicaltrials.gov (NCT02802345). [ABSTRACT FROM AUTHOR]

Idiopathic interstitial pneumonias are often complicated by pulmonary hypertension, increasing morbidity and mortality. There are no approved treatments for pulmonary hypertension associated with idiopathic interstitial pneumonia (PH-IIP). We aimed to evaluate the efficacy and safety of riociguat in patients with PH-IIP. RISE-IIP was a double-blind, randomised, placebo-controlled study done at 65 pulmonary hypertension and interstitial lung disease centres in 19 countries to evaluate the efficacy and safety of riociguat in patients with PH-IIP. Eligible patients were adults (aged 18–80 years) diagnosed with idiopathic interstitial pneumonia (as per American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines), forced vital capacity (FVC) of at least 45%, 6MWD of 150–450 m, WHO functional classes II–IV, precapillary pulmonary hypertension confirmed by right heart catheterisation, systolic blood pressure of at least 95 mm Hg, and no signs or symptoms of hypotension. Patients were randomly allocated (1:1) using an interactive voice and web response system to riociguat (0·5–2·5 mg three times daily) or placebo for 26 weeks (main study), after which they could enter an open-label extension in which all patients received riociguat. The primary endpoint was change in 6-min walking distance (6MWD) in the intention-to-treat population. Prespecified safety variables included adverse events and serious adverse events, laboratory parameters, and adverse events of special interest (haemoptysis and symptomatic hypotension), assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov , number NCT02138825. Between June 4, 2014, and May 5, 2016, we enrolled 229 participants. After the exclusion of 82 participants, 147 were randomly allocated to treatment (73 to riociguat, 74 to placebo). The study was terminated early (median treatment duration 157 days [range 6–203]) at the request of the data monitoring committee owing to increased serious adverse events (main study: 27 [37%] of 73 participants in the riociguat group vs 17 [23%] of 74 in the placebo group) and mortality in patients receiving riociguat, and the absence of efficacy signals in the riociguat group. 11 patients died in the main study (eight in the riociguat group, three in the placebo group), and nine died in the extension phase (one in the riociguat group, eight in the former placebo group; all received riociguat). In the main study, the most common adverse events were peripheral oedema (16 [22%] of 73 in the riociguat group vs seven [9%] of 74 in the placebo group) and diarrhoea (11 [15%] vs seven [9%]). The most common serious adverse events were worsening of interstitial lung disease (main study: six [8%] of 73 in the riociguat group vs five [7%] of 74 in the placebo group) and pneumonia (four [5%] vs one [1%]). Riociguat did not improve 6MWD versus placebo at 26 weeks (least-squares mean difference 21 m; 95% CI −9 to 52). In patients with PH-IIP, riociguat was associated with increased serious adverse events and mortality, and an unfavourable risk–benefit profile. Riociguat should not be used in patients with PH-IIP. Bayer AG and Merck & Co. [ABSTRACT FROM AUTHOR]

Abstract The 2015 European Guidelines on Pulmonary Hypertension did not only cover pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) associated with chronic lung disease. The European Guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists, phosphodiesterase‑5 inhibitors, sGC stimulators) have not been sufficiently investigated in other forms of PH. Therefore, the European Guidelines do not recommend the use of these drugs in patients with chronic lung disease and PH. This recommendation, however, is not always in agreement with medical ethics as physicians sometimes feel inclined to treat other forms of PH which may affect quality of life and survival of these patients in a similar manner. To this end, it is crucial to consider the severity of both PH and the underlying lung disease. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Paediatric Cardiology (DGPK) was held in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. Several working groups were created, one of which was dedicated to the diagnosis and treatment of PH in patients with chronic lung disease. The 2018 updated recommendations of this working group are summarized in the present paper. [ABSTRACT FROM AUTHOR]

Ambrisentan [Volibris (EU), Letairis (USA)] is an effective and well-tolerated oral option for the treatment of pulmonary arterial hypertension (PAH) classified as WHO functional class (FC) II or III. It is recommended as initial mono- or combination treatment in patients with non-vasoreactive WHO FC II or III PAH. Clinical trials have shown that ambrisentan monotherapy provides sustained clinical benefits in patients with idiopathic PAH (IPAH) and PAH associated with connective tissue diseases (CTD-PAH), including improvements in exercise capacity, and that initial combination treatment with ambrisentan + tadalafil provides greater clinical benefits, including a reduced risk of clinical failure, than initial monotherapy with either ambrisentan or tadalafil. Mono- or combination therapy with ambrisentan has an acceptable tolerability and safety profile. [ABSTRACT FROM AUTHOR]

A deficiency of the pulmonary vasodilative vasoactive intestinal peptide (VIP) has been suggested to be involved in the pathophysiology of pulmonary hypertension (PH). Supplementation of VIP as an aerosol is hampered by the fact that it is rapidly inactivated by neutral endopeptidases (NEP) located on the lung surface. Coapplication of thiorphan, an NEP 24.11 inhibitor, could augment the biological effects of inhaled VIP alone. A stable pulmonary vasoconstriction with a threefold increase of pulmonary artery pressure was established by application the thromboxane mimetic U46619 in the isolated rabbit lung model. VIP and thiorphan were either applied intravascularly or as an aerosol. VIP caused a significant pulmonary vasodilation either during intravascular application or inhalation. These effects were of short duration. Thiorphan application had no effects on pulmonary vasoconstriction per se but significantly augmented the effects of VIP aerosol. Thiorphan, not only augmented the maximum hemodynamic effects of VIP aerosol, but also led to a significant prolongation of these effects. VIP causes pulmonary vasodilation in a model of acute experimental PH. The hemodynamic effects of VIP aerosol can be significantly augmented via coapplication of an NEP inhibitor. [ABSTRACT FROM AUTHOR]

Ambrisentan [Volibris (EU), Letairis (USA)] is an effective and well-tolerated first-line option for the treatment of adults with pulmonary arterial hypertension (PAH) classified as WHO functional class II or III. Ambrisentan provides sustained improvements in exercise capacity and dyspnoea, stabilizes WHO functional class, increases time to clinical worsening, and has an acceptable tolerability and safety profile. Ambrisentan is associated with fewer drug interactions than other available endothelin-1 receptor antagonists, may be used concomitantly with other common PAH medications, is associated with a low risk of liver function abnormalities, and has a convenient once-daily oral administration regimen. [ABSTRACT FROM AUTHOR]

Riociguat is licensed for the therapy of inoperable chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to investigate whether age and comorbidities influence its tolerability and efficacy. Retrospectively, we analyzed data of tolerability, non-invasive, and invasive efficacy at baseline and follow up (FU) of all patients with CTEPH treated with riociguat at the Department of Internal Medicine V, University of Munich (n = 47), grouping patients according to age (<65 versus 65–79 versus ≥80 years) and risk factors for heart failure with preserved ejection fraction (HFpEF) (<2 versus ≥2 risk factors). During dose titration patients >80 years reported side effects more frequently (40%) than the other age groups (23% and 21% for patients <65 years and patients 65–79, respectively). Cessation of riociguat was rare and occurred independent of age. When looking at the total cohort of 47 patients, three patients stopped therapy and three patients had a reduced maintenance dosage, while 41/47 (87%) and all octogenarians reached the highest maintenance dosage of 7.5 mg/d. The frequency of any side effect was similar in patients in both risk factor groups, and hypotension was only observed in those with <2 risk factors. Parameters of efficacy improved significantly under riociguat treatment. Improvement in 6-min walk distance (6 mwd), N-terminal pro brain natriuretic peptide (Nt-proBNP) and hemodynamics did not differ between age or risk factor groups. In this small real-life cohort, riociguat was well-tolerated and effective in advanced age and risk factors for HFpEF. [ABSTRACT FROM AUTHOR]

Background: Pulmonary hypertension (PH) of various causes leads to a poor prognosis. Pulmonary vasoreactivity testing during right heart catheterization (RHC) has prognostic and therapeutic consequences. Objective: To characterize the acute hemodynamic response to short-term oxygen supplementation (SHOT) in adult PH patients and its impact on prognosis. Methods: After a stable baseline period, 104 patients with PH [pulmonary arterial hypertension (PAH; n = 56), chronic thromboembolic (PH; n = 22) or respiratory diseases (PH; n = 26)], who were mainly therapy-naïve (86.5%) (mean pO2 64.5 ± 1.2 mm Hg), received a standardized SHOT during RHC and hemodynamic response was assessed for its prognostic potential. Results: SHOT significantly reduced heart rate (HR: 78.9 ± 1.5 to 74 ± 1.5 beats/min), cardiac output (4 ± 0.1 to 3.8 ± 0.1 l/min), pulmonary arterial pressure (46.4 ± 1.3 to 42.3 ± 1.3 mm Hg) and pulmonary vascular resistance (10.1 ± 0.5 to 9.6 ± 0.5 Wood units; all p < 0.001) compared to baseline. The magnitude of this effect varied between the different PH groups. During a median follow-up of 25.1 months (range: 0.2-73.3 months), HR <72 beats/min in response to SHOT was associated with a better prognosis in patients with PH due to chronic thromboembolism to the lung and PH from chronic lung disease. Conclusions: SHOT leads to characteristic hemodynamic responses across different forms of PH. The preserved capability to acutely respond to SHOT with HR reduction is of prognostic significance in patients with non PAH PH. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The article presents an overview of the development of the drug ambrisentan and discusses the mechanisms by which it works. A discussion of patients for whom the drug may be suitable, and of the ways that it should be used in patients with pulmonary arterial hypertension that is classified as World Health Organization functional class two or three, is presented.

Leuchte HH, Meis T, El-Nounou M, Michalek J, Behr J. Inhalation of endothelin receptor blockers in pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 294: L772-L777, 2008. First published February 22, 2008; doi:10.1152/ajplung.00405.2007.- Endothelin 1 (ET- 1) is a potent pulmonary vasoconstrictor and me- diator of lung diseases. Antagonism of the ET- 1-mediated effects has become an important therapeutic approach. ET- 1 (A and B) receptors are differentially distributed in the lung vasculature. Whereas the ETA receptors mainly mediate vasoconstriction, the endothelial ETB recep- tor seems to have vasodilative properties. We sought to determine if antagonism of ET receptors can be achieved by inhalation of specific blockers in a model of ET-1-mediated pulmonary hypertension. [ABSTRACT FROM AUTHOR]

Background: Inhalation of iloprost, a stable prostacyclin analog, is an effective therapy for pulmonary hypertension with few side effects. This approach may, however, be handicapped by limitations of currently available nebulization devices. We assessed whether the physical characterization of a device is sufficient to predict drug deposition and pharmacologic effects. Methods: We investigated the effects of a standardized iloprost aerosol dose (5 µg; inhaled within approximately 10 min) in 12 patients with severe pulmonary hypertension in a crossover design employing three well-characterized nebulizers. The nebulizers use different techniques to increase efficiency and alveolar targeting (Ilo-Neb/Aerotrap [Nebu-Tec; Elsenfeld, Germany], Ventstream [MedicAid; Bognor Regis, UK], and HaloLite [Profile Therapeutics; Bognor Regis, UK]). Measurements were performed using a Swan-Ganz catheter and determination of arterial floprost plasma levels. Results: During inhalation of iloprost, the pulmonary vascular resistance decreased substantially (baseline, approximately 1,250 dyne·s·cm[sup -5]; decrease, -35.5 to -38.0%) and pulmonary artery pressure decreased substantially (baseline, approximately 58 mm Hg; decline, -18.4 to -21.8%), whereas the systemic arterial pressure was largely unaffected. Cardiac output and mixed venous and arterial oxygen saturation displayed a marked increase. The pharmacodynamic profiles with the three devices were superimposable. Moreover, rapid entry of iloprost into the systemic circulation was noted, peaking immediately after termination of the inhalation maneuver, with very similar maximum serum concentrations (158 pg/mL, 155 pg/mL, and 157 pg/mL), and half-lives of serum levels (6.5 min, 9.4 min, and 7.7 min) for the three nebulizers, respectively. Interestingly, the "half-life" of the pharmacodynamic effects in the pulmonary vasculature (eg, decrease in pulmonary vascular resistance, ranging between 21 and 25 min) clearly outlasted this serum level-based pharmacokinetic haft-life. Conclusions: A standardized dose of aerosolized iloprost delivered by different nebulizer types induces comparable pharmacodynamic and pharmacokinetic responses. Pulmonary vasodilation, persisting after disappearance of the drug from the systemic circulation, supports the hypothesis that local drug deposition largely contributes to the preferential pulmonary vasodilation in response to inhaled iloprost. [ABSTRACT FROM AUTHOR]

A secondary analysis of survival outcomes in the modified intent-to-treat population of AMBITION. [ABSTRACT FROM AUTHOR]

Correction to: Drugs & Therapy Perspectives 10.1007/s40267-018-0531-1 [ABSTRACT FROM AUTHOR]

A correction to the article "Ambrisentan: A Guide to Its Use in Pulmonary Arterial Hypertension in the EU" by Jürgen Behr and Katherine A. Lyseng-Williamson published on line on July 3, 2014 is presented.

Abstract: Introduction: Inhalation of vasoactive substances is an effective treatment of pulmonary hypertension. The B-type natriuretic peptide (BNP) leads to relaxation of smooth muscle cells, caused by an increased formation of cyclic guanosine monophosphate (cGMP). The biologic activity of BNP using an inhalative approach has not been addressed. Methods: In order to assess the vasorelaxing capacity of exogenous BNP in the isolated ventilated and buffer perfused rabbit lung model, a stable pulmonary vasoconstriction was established by either the application of endothelin-1 or the thromboxane A2 mimetic U46619. This was followed by an intravascular or aerosol application of BNP. CGMP was measured in the recirculating buffer fluid using a radioimmunoassay technique. Results: During a stable plateau of U46619 induced pulmonary vasoconstriction (mean pulmonary artery pressure, PAP 25.5±0.23mmHg), the intravascular administration of BNP induced a rapid vasodilation (mean PAP 18.13±0.95mmHg, p <0.001). This vasodilation was dose dependent and was paralleled by a 6-fold increase of cGMP. When BNP was aerosolized, pulmonary vasoconstriction was also significantly alleviated in the U46619 model (mean PAP 22±2.1mmHg) and during endothelin-1 induced vasoconstriction (mean PAP 17.1±2.47mmHg). Correspondingly, inhalation caused a significant augmentation of cGMP levels was. Conclusion: The vasodilative capability of BNP as an indicator of the biologic activity of this peptide is preserved during its aerosolization. Presumably these vascular actions are caused at least in part by an increased availability of cGMP. [Copyright &y& Elsevier]