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Pulmonary arterial hypertension is a progressive disease involving proliferative remodeling of the pulmonary vessels. Despite therapeutic advances, the disease-associated morbidity and mortality remain high. Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension. We conducted a multicenter, double-blind, phase 3 trial in which adults with pulmonary arterial hypertension (World Health Organization [WHO] functional class II or III) who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was the change from baseline at week 24 in the 6-minute walk distance. Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro-B-type natriuretic peptide level, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores; all were assessed at week 24 except time to death or clinical worsening, which was assessed when the last patient completed the week 24 visit. A total of 163 patients were assigned to receive sotatercept and 160 to receive placebo. The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, -0.3 to 3.5) in the placebo group. The Hodges-Lehmann estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (95% CI, 27.5 to 54.1; P<0.001). The first eight secondary end points were significantly improved with sotatercept as compared with placebo, whereas the PAH-SYMPACT Cognitive/Emotional Impacts domain score was not. Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure. In patients with pulmonary arterial hypertension who were receiving stable background therapy, sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk test) than placebo. (Funded by Acceleron Pharma, a subsidiary of MSD; STELLAR ClinicalTrials.gov number, NCT04576988.).

Among adults with pulmonary arterial hypertension who had received the diagnosis less than 1 year earlier, the addition of sotatercept to background therapy resulted in a lower risk of clinical worsening than placebo.

Pulmonary arterial hypertension is a devastating disorder characterized by precapillary pulmonary hypertension not caused by respiratory disease, obstruction of the pulmonary arteries, or certain less-common conditions. Idiopathic pulmonary arterial hypertension, heritable pulmonary arterial hypertension, and pulmonary arterial hypertension associated with a connective-tissue disease or exposure to drugs such as methamphetamine account for most cases in the developed world. For years, pulmonary arterial hypertension was considered to be an untreatable, progressive, and rapidly fatal condition. 1 A new era of treatment for patients with pulmonary arterial hypertension began three decades ago. Investigations that were focused on imbalanced vasoconstriction and vasodilation produced groundbreaking . . .

Dietary nitrate supplementation, which improves skeletal muscle oxygen utilisation, vascular endothelial function and exercise capacity in people with chronic obstructive pulmonary disease, may benefit other lung conditions. In a double-blind, placebo-controlled, crossover study, in 19 adults with Group 3 pulmonary hypertension who desaturated during exercise, 140 mL of nitrate-rich beetroot juice improved endurance shuttle walk time compared with nitrate-depleted beetroot juice placebo (median (IQR) ESWT NR-BRJ 197 (140–273) s vs PL-BRJ 174 (107–229) s; median difference (MD) (95% CI) 30 (6.19 to 91.07) s, p=0.0281), endothelial function, flow-mediated dilatation (+3.40±5.47% vs −1.33±4.78; MD (95% CI) 4.73 (1.44 to 8.02), p=0.007) and lowered mean arterial blood pressure (−3.9 (−7.4 to −0.4) mm Hg, p=0.028).

Background In the EDITA trial, patients with systemic sclerosis (SSc) and mild pulmonary vascular disease (PVD) treated with ambrisentan had a significant decline of pulmonary vascular resistance (PVR) but not of mean pulmonary arterial pressure (mPAP) vs. placebo after six months. The EDITA-ON study aimed to assess long-term effects of open label therapy with ambrisentan vs. no pulmonary arterial hypertension (PAH) therapy. Methods Patients who participated in the EDITA study and received regular follow-up were included in EDITA-ON. Clinical, echocardiographic, laboratory, exercise and hemodynamic parameters during follow-up were analysed. The primary endpoint was to assess whether continued treatment with ambrisentan vs. no treatment prevented the development of PAH according to the new definition. Results Of 38 SSc patients included in the EDITA study four were lost to follow-up. Of the 34 remaining patients (age 55 ± 11 years, 82.1% female subjects), 19 received ambrisentan after termination of the blinded phase, 15 received no PAH medication. The mean follow-up time was 2.59 ± 1.47 years, during which 29 patients underwent right heart catheterization. There was a significant improvement of mPAP in catheterised patients receiving ambrisentan vs. no PAH treatment (-1.53 ± 2.53 vs. 1.91 ± 2.98 mmHg, p  = 0.003). In patients without PAH treatment 6/12 patients had PAH vs. 1/17 of patients receiving ambrisentan ( p  < 0.0001). Conclusion In SSc patients with early PVD, the development of PAH and/or deterioration was less frequent among patients receiving ambrisentan, indicating that early treatment and close follow-up could be beneficial in this high-risk group. Future trials in this field are needed to confirm these results.

ObjectivesTo investigate clinical characteristics, symptom profile, testing practices, treatment patterns and quality of life (QoL) among patients with pulmonary arterial hypertension (PAH) in Latin America.DesignData from the Adelphi Real World PAH Disease Specific Programme, a cross-sectional survey with retrospective data collection.SettingUniversity/teaching hospital, regional centres, private practices and government institutions in Argentina, Brazil, Colombia and Mexico.Participants246 physicians provided data for 958 patients, of which 533 patients also self-reported data.ResultsMean (SD) patient age was 53.7 (17) years, 70% of patients were female and 79% were WHO functional class (WHO FC) I–II. Overall, 76% had undergone a right heart catheterisation, ranging from 92% in Argentina to 64% in Brazil (p<0.0001). Only 28% underwent a simplified risk assessment strategy in the past 12 months, ranging from 46% in Argentina to 16% in Brazil. Fatigue and dyspnoea on exertion were reported most commonly by physicians (37% and 53%) and patients (68% and 67%). Patient–physician agreement on symptom reporting was minimal-to-weak (kappa, 0.21–0.42). PAH-specific combination therapy varied across countries (21% Mexico, 30% Brazil, 70% Colombia and 79% Argentina, p<0.0001)). Overall, 73% of patients received a phosphodiesterase type 5 inhibitor; 52% an endothelin receptor antagonist, 15% a prostacyclin pathway agent and 11% a soluble guanylate cyclase stimulator. The mean (SD) EQ-5D (generic instrument to define quality of life)utility ranged from 0.66 (0.20) to 0.70 (0.20) across countries and the mean (SD) EQ-5D Visual Analogue Scale (VAS) was 67.0 (18.10). Lower VAS and utility scores were reported among patients with higher WHO FC (p<0.05).ConclusionsPatients reported a high burden of PAH in terms of symptoms and QoL, particularly within higher WHO FC. Low usage of risk assessment strategies and PAH-specific combination therapy was seen in Brazil and Mexico. Further research could identify barriers to prescribing optimal treatment.

Background Pulmonary arterial hypertension is a life-threatening progressive disorder characterised by high blood pressure (hypertension) in the arteries of the lungs (pulmonary artery). Although treatable, there is no known cure for this rare disorder, and its exact cause is unknown. Mutations in the bone morphogenetic protein receptor type-2 (BMPR2) are the most common genetic cause of familial pulmonary arterial hypertension. This study represents the first-ever trial of treatments aimed at directly rescuing the BMPR2 pathway, repurposing two drugs that have shown promise at restoring levels of BMPR2 signalling: hydroxychloroquine and phenylbutyrate. Methods This three-armed phase II precision medicine study will investigate BMPR2 target engagement and explore the efficacy of two repurposed therapies in pulmonary arterial hypertension patients with BMPR2 mutations. Patients will be stratified based on two BMPR2 mutation classes: missense and haploinsufficient mutations. Eligible subjects will be randomised to one of the three arms (two active therapy arms and a placebo arm, all plus standard of care) following a Bayesian response-adaptive design implemented independently in each stratum and updated in response to a novel panel of primary biomarkers designed to assess biological modification of the disease. Discussion The results of this trial will provide the first randomised evidence of the efficacy of these therapies to rescue BMPR2 function and will efficiently explore the potential for a differential response of these therapies per mutation class to address causes rather than consequences of this rare disease. Trial registration The study has been registered with ISRCTN (ISRCTN10304915, 22/09/2023).

Abstract Translational research is essential to the development of reverse-remodeling strategies for the treatment of pulmonary vascular disease, pulmonary hypertension, and heart failure via mechanistic in vivo studies using animal models resembling human pulmonary arterial hypertension (PAH), cardiovascular remodeling, and progressive right heart failure. Since 2007, peroxisome proliferator–activated receptor γ (PPARγ) agonists have emerged as promising novel, antiproliferative, antiinflammatory, insulin-sensitizing, efficient medications for the treatment of PAH. However, early diabetes study results, their subsequent misinterpretations, errors in published review articles, and rumors regarding potential adverse effects in the literature have dampened enthusiasm for considering pharmacological PPARγ activation for the treatment of cardiovascular diseases, including PAH. Most recently, the thiazolidinedione class PPARγ agonist pioglitazone underwent a clinical revival, especially based on the IRIS (Insulin Resistance Intervention After Stroke) study, a randomized controlled trial in 3,876 patients without diabetes status post–transient ischemic attack/ischemic stroke who were clinically followed for 4.8 years. We discuss preclinical basic translational findings and randomized controlled trials related to the beneficial and adverse effects of PPARγ agonists of the thiazolidinedione class, with a particular focus on the last 5 years. The objective is a data-driven approach to set the preclinical and clinical study record straight. The convincing recent clinical trial data on the lack of significant toxicity in high-risk populations justify the timely conduct of clinical studies to achieve “repurposing” or “repositioning” of pioglitazone for the treatment of clinical PAH.

This open-label, extension study assessed long-term safety, tolerability, and efficacy of ambrisentan in a pediatric population (age 8– < 18 years) with pulmonary arterial hypertension (PAH). Following completion of a 6-month, randomized study, participants entered the long-term extension at individualized ambrisentan dosages (2.5/5/7.5 or 10 mg/day). Safety assessments included adverse events (AEs), AEs of special interest, and serious AEs (SAEs); efficacy outcomes included 6-min walking distance (6MWD) and World Health Organization functional class (WHO FC). Thirty-eight of 41 (93%) randomized study participants entered the extension; 21 (55%) completed (reaching age 18 years). Most participants received concomitant phosphodiesterase-5 inhibitors ( n  = 25/38, 66%). Median ambrisentan exposure was 3.5 years. Most participants experienced ≥ 1 AE ( n  = 34/38, 89%), and 21 (55%) experienced SAEs, most commonly worsening PAH ( n  = 3/38, 8%), acute cardiac failure, pneumonia, or anemia ( n  = 2/38; 5% each); none considered ambrisentan-related. Seven participants (18%) died, with recorded reasons (MedDRA preferred term): cardiac failure ( n  = 2), PAH ( n  = 2), COVID-19 ( n  = 1), acute right ventricular failure ( n  = 1), and failure to thrive ( n  = 1); median time to death: 5.2 years. Anemia and hepatotoxicity AEs were generally mild to moderate and did not require ambrisentan dose adjustment. Assessed at study end in 29 participants (76%), mean 6MWD improved by 17% (standard deviation: 34.3%), and all (29/29, 100%) had improved or unchanged WHO FC.     Conclusion : Long-term weight-based ambrisentan dosing, alone or combined with other PAH therapies in children with PAH aged 8– < 18 years, exhibited tolerability and clinical improvements consistent with prior randomized study results.     Trial registration : NCT01342952, April 27, 2011. What is Known: • The endothelin receptor antagonist, ambrisentan, is indicated for treatment of pulmonary arterial hypertension (PAH). Previous studies have shown similar efficacy and tolerability in pediatric patients as in adults. What is New: • This open-label extension study assessed the long-term use of ambrisentan in pediatric patients (8–<18 years) with PAH, most of whom were also receiving recommended background PAH treatment. •  Weight-based dosing of ambrisentan, given alone or in combination with other PAH therapies, was well tolerated with clinical improvements consistent with prior randomized study results .