u-62840 and Lung-Diseases--Interstitial

Despite worse outcomes associated with the development of pulmonary hypertension in chronic lung disease, there are no approved treatments for this population. The present review summarizes the recent clinical trials in World Symposium on Pulmonary Hypertension (WSPH) Group 3 pulmonary hypertension, with a particular focus on the study of pulmonary arterial hypertension (PAH)-targeted therapy.. Multiple recent randomized controlled trials have studied a host of PAH-specific medications in the treatment of WSPH Group 3 pulmonary hypertension, including endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclins. In pulmonary hypertension associated with chronic obstructive lung disease (PH-COPD) and with interstitial lung disease (PH-ILD), most trials have shown conflicting or negative results, although they have been limited by variable patient populations and small sample sizes. Recent large-scale trial data demonstrate that inhaled treprostinil is associated with improved outcomes in the PH-ILD population.. Although most PAH medications have not shown consistent benefit in the WSPH Group 3 population, recent work suggests that inhaled treprostinil has an important role in the treatment of PH-ILD. Efforts are ongoing to evaluate the efficacy of other medications, identify optimal treatment candidates, and define clinically meaningful endpoints in WSPH Group 3 pulmonary hypertension.

Topics: Antihypertensive Agents; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Phosphodiesterase 5 Inhibitors; Prostaglandins I; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic

Pulmonary hypertension (PH) complicates the course of many patients with fibrotic interstitial lung disease (ILD). Inhaled treprostinil (iTre) has been shown to improve functional ability and to delay clinical worsening in patients with PH resulting from ILD.. Do higher dosages of iTre have greater benefits in preventing clinical worsening and achieving clinical improvement?. Post hoc analysis of the INCREASE study, a 16-week double-blind, randomized, placebo-controlled trial of iTre in patients with PH resulting from ILD. Four groups were identified based on the number of breaths per session (bps; < 9 and ≥ 9 bps) of active drug or placebo attained at 4 weeks. Patients were evaluated for clinical worsening (15% decrease in 6-min walkdistance, cardiopulmonary hospitalization, lung transplantation, or death) or clinical improvement (15% increase in the six-minute walk distance with a concomitant 30% reduction in N-terminal prohormone of brain natriuretic peptide without any clinical worsening event).. At 4 weeks, 70 patients were at a dose of ≥ 9 bps (high-dosage group) and 79 patients were at a dose of < 9 bps (low-dosage group) in the iTre arm vs 86 patients in the high-dose group and 67 patients in the low-dose group in the placebo arm. Between weeks 4 and 16, 17.1% of patients in the high-dose treprostinil group and 22.8% in the low-dose treatment group experienced a clinical worsening event vs 33.7% and 34.3% of patients in the two placebo arms, respectively (P = .006). By week 16, 15.7% and 12.7% of patients in the high- and low-dose iTre groups, respectively, demonstrated clinical improvement vs 7% and 1.5% patients in the placebo arms (P = .003) INTERPRETATION: Higher dosages of iTre overall show greater benefit in terms of preventing clinical worsening and achieving clinical improvement. These data support the early initiation and uptitration of therapy to a dosage of at least 9 bps four times daily in patients with PH resulting from ILD.. ClinicalTrials.gov; No.: NCT02630316; URL: www.. gov.

Topics: Antihypertensive Agents; Double-Blind Method; Epoprostenol; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Treatment Outcome

The 16-week randomised, placebo-controlled INCREASE trial (RCT) met its primary end-point by improving 6-min walk distance (6MWD) in patients receiving inhaled treprostinil for pulmonary hypertension due to interstitial lung disease (PH-ILD). The open-label extension (OLE) evaluated long-term effects of inhaled treprostinil in PH-ILD.. Of 258 eligible patients, 242 enrolled in the INCREASE OLE and received inhaled treprostinil. Assessments included 6MWD, pulmonary function testing, N-terminal pro-brain natriuretic peptide (NT-proBNP), quality of life and adverse events. Hospitalisations, exacerbations of underlying lung disease and death were recorded.. At INCREASE OLE baseline, patients had a median age of 70 years and a mean 6MWD of 274.2 m; 52.1% were male. For the overall population, the mean 6MWD at week 52 was 279.1 m and the mean change from INCREASE RCT baseline was 3.5 m (22.1 m for the prior inhaled treprostinil arm and -19.5 m for the prior placebo arm); the median NT-proBNP decreased from 389 pg·mL. These results support the long-term safety and efficacy of inhaled treprostinil in patients with PH-ILD, and are consistent with the results observed in the INCREASE RCT.

Topics: Aged; Antihypertensive Agents; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Male; Quality of Life; Treatment Outcome

No therapies are currently approved for the treatment of pulmonary hypertension in patients with interstitial lung disease. The safety and efficacy of inhaled treprostinil for patients with this condition are unclear.. We enrolled patients with interstitial lung disease and pulmonary hypertension (documented by right heart catheterization) in a multicenter, randomized, double-blind, placebo-controlled, 16-week trial. Patients were assigned in a 1:1 ratio to receive inhaled treprostinil, administered by means of an ultrasonic, pulsed-delivery nebulizer in up to 12 breaths (total, 72 μg) four times daily, or placebo. The primary efficacy end point was the difference between the two groups in the change in peak 6-minute walk distance from baseline to week 16. Secondary end points included the change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) level at week 16 and the time to clinical worsening.. A total of 326 patients underwent randomization, with 163 assigned to inhaled treprostinil and 163 to placebo. Baseline characteristics were similar in the two groups. At week 16, the least-squares mean difference between the treprostinil group and the placebo group in the change from baseline in the 6-minute walk distance was 31.12 m (95% confidence interval [CI], 16.85 to 45.39; P<0.001). There was a reduction of 15% in NT-proBNP levels from baseline with inhaled treprostinil as compared with an increase of 46% with placebo (treatment ratio, 0.58; 95% CI, 0.47 to 0.72; P<0.001). Clinical worsening occurred in 37 patients (22.7%) in the treprostinil group as compared with 54 patients (33.1%) in the placebo group (hazard ratio, 0.61; 95% CI, 0.40 to 0.92; P = 0.04 by the log-rank test). The most frequently reported adverse events were cough, headache, dyspnea, dizziness, nausea, fatigue, and diarrhea.. In patients with pulmonary hypertension due to interstitial lung disease, inhaled treprostinil improved exercise capacity from baseline, assessed with the use of a 6-minute walk test, as compared with placebo. (Funded by United Therapeutics; INCREASE ClinicalTrials.gov number, NCT02630316.).

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Double-Blind Method; Epoprostenol; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Least-Squares Analysis; Lung Diseases, Interstitial; Male; Middle Aged; Quality of Life; Walk Test

INCREASE was a randomised, placebo-controlled, phase 3 trial that evaluated inhaled treprostinil in patients with interstitial lung disease (ILD) and associated pulmonary hypertension. Treprostinil improved exercise capacity from baseline to week 16, assessed with the use of a 6-min walk test, compared with placebo. Improvements in forced vital capacity (FVC) were also reported. The aim of this post-hoc analysis was to further characterise the effects of inhaled treprostinil on FVC in the overall study population and in various subgroups of interest.. In this post-hoc analysis, we evaluated FVC changes in the overall study population and in various subgroups defined by cause of disease or baseline clinical parameters. The study population included patients aged 18 years and older who had a diagnosis of ILD based on evidence of diffuse parenchymal lung disease on chest CT done within 6 months before random assignment (not centrally adjudicated). All analyses were done on the intention-to-treat population, defined as individuals who were randomly assigned and received at least one dose of study drug. The INCREASE study is registered with ClinicalTrials.gov, NCT02630316.. Between Feb 3, 2017, and Aug 30, 2019, 326 patients were enrolled in the INCREASE trial. Inhaled treprostinil was associated with a placebo-corrected least squares mean improvement in FVC of 28·5 mL (SE 30·1; 95% CI -30·8 to 87·7; p=0·35) at week 8 and 44·4 mL (35·4; -25·2 to 114·0; p=0·21) at week 16, with associated percentage of predicted FVC improvements of 1·8% (0·7; 0·4 to 3·2; p=0·014) and 1·8% (0·8; 0·2 to 3·4; p=0·028). Subgroup analysis of patients with idiopathic interstitial pneumonia showed FVC differences of 46·5 mL (SE 39·9; 95% CI -32·5 to 125·5; p=0·25) at week 8 and 108·2 mL (46·9; 15·3 to 201·1; p=0·023) at week 16. Analysis of patients with idiopathic pulmonary fibrosis showed FVC differences of 84·5 mL (52·7; -20·4 to 189·5; p=0·11) at week 8 and 168·5 mL (64·5; 40·1 to 297·0; p=0·011) at week 16. The most frequent adverse events included cough, headache, dyspnoea, dizziness, nausea, fatigue, and diarrhoea.. In patients with ILD and associated pulmonary hypertension, inhaled treprostinil was associated with improvements in FVC versus placebo at 16 weeks. This difference was most evident in patients with idiopathic interstitial pneumonia, particularly idiopathic pulmonary fibrosis. Inhaled treprostinil appears to be a promising therapy for idiopathic pulmonary fibrosis that warrants further investigation in a prospective, randomised, placebo-controlled study.. United Therapeutics Corporation.

Topics: Adolescent; Adult; Double-Blind Method; Epoprostenol; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Prospective Studies; Treatment Outcome; Vital Capacity

Topics: Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial

Topics: Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Naphazoline; Treatment Outcome

Topics: Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial

Topics: Epoprostenol; Humans; Hypertension; Hypertension, Pulmonary; Lung Diseases, Interstitial

Topics: Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial

Topics: Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial

Topics: Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial

Topics: Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial

Topics: Antihypertensive Agents; Epoprostenol; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial

Topics: Anti-Asthmatic Agents; Antibodies, Monoclonal, Humanized; Antihypertensive Agents; Asthma; COVID-19; COVID-19 Vaccines; Cytokines; Epoprostenol; Humans; Hypertension, Pulmonary; Infection Control; Injections, Subcutaneous; Intensive Care Units; Lung Diseases, Interstitial; Nursing Homes; Oxygen; Oxygen Inhalation Therapy; Respiratory Insufficiency; Symptom Flare Up; Thymic Stromal Lymphopoietin; Walk Test

A 50-year-old woman with a medical history significant for limited scleroderma (SSc) complicated by interstitial lung disease (ILD) and pulmonary arterial hypertension presented to our institution with acute on chronic shortness of breath. Ten years before presentation, she was diagnosed with SSc. Two years before presentation, she was found to have ILD, for which she was started on mycophenolate mofetil and low-dose prednisone. One year before presentation, she noted worsening dyspnea on exertion (New York Heart Association Functional Class III) and required supplemental oxygen, up to 5 L, despite findings of stable ILD on a maintenance dose of mycophenolate mofetil. A subsequent right heart catheterization showed findings consistent with severe pulmonary arterial hypertension: right atrial pressure of 19 mm Hg, pulmonary arterial pressure of 98/39 mm Hg with a mean pulmonary arterial pressure of 58 mm Hg, right ventricular pressure of 59/6 mm Hg, pulmonary arterial wedge pressure of 10 mm Hg, cardiac output of 4.2 L/min with a cardiac index of 2.7 L/min/m

Topics: Antihypertensive Agents; Dyspnea; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Middle Aged; Scleroderma, Limited

The development of pulmonary hypertension (PH) in non-World Health Organization group I PH adversely affects exercise capacity. It is unclear whether pulmonary artery hypertension (PAH)-specific drugs improve pulmonary hemodynamics and exercise capacity in such patients.. We performed a retrospective chart review of consecutive patients with non-World Health Organization group I PH treated with PAH-specific therapy.. We identified 24 patients. The mean (standard deviation) age was 48 (14.8) years. Seventeen (71%) patients were women. The 6-minute walk distance improved significantly for the whole group in an initial follow-up period of 4.6 (2.3) months; however, the improvement was seen only in patients with obstructive sleep apnea (OSA) or severe PH and it was not sustained during a longer follow-up period of 11.5 (4.1) months, except in patients with OSA. PH was treated with a variety of PAH-specific drugs, including combination therapy in five patients.. The use of PAH-specific therapy in selected patients with PH secondary to lung diseases, OSA, or sarcoidosis may result in significant improvement in 6-minute walk distance, particularly in patients with OSA or severe PH.

Topics: Adult; Antihypertensive Agents; Cohort Studies; Endothelin Receptor Antagonists; Epoprostenol; Exercise Test; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Prostaglandins; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Retrospective Studies; Sarcoidosis; Severity of Illness Index; Sleep Apnea, Obstructive; Treatment Outcome; World Health Organization