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Among adults with pulmonary arterial hypertension at high risk for death, sotatercept reduced the risk of a composite of death from any cause, lung transplantation, or hospitalization for worsening pulmonary arterial hypertension.

Patients with pulmonary arterial hypertension were randomly assigned to receive sotatercept at a dose of 0.3 mg per kilogram or 0.7 mg per kilogram or placebo, in addition to standard therapy. At 24 weeks, both sotatercept groups had a greater reduction in pulmonary vascular resistance than the placebo group.

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.).

ObjectivesTo evaluate initial combination therapy with ambrisentan plus tadalafil (COMB) compared with monotherapy of either agent (MONO), and the utility of baseline characteristics and risk stratification in predicting outcomes, in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) and the systemic sclerosis (SSc)–pulmonary arterial hypertension (PAH) subpopulation.MethodsThis post hoc analysis of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) study included patients with CTD-PAH from the modified intention-to-treat population. Time to clinical failure (TtCF) was assessed by baseline characteristics, treatment assignment and risk group (low, intermediate and high) at baseline and week 16. TtCF was compared between groups using Kaplan-Meier curves and Cox proportional hazards regression modelling.ResultsThe analysis included 216 patients (COMB, n=117; MONO, n=99). The risk of clinical failure was lower with COMB versus MONO (risk reduction: CTD-PAH 51.7%, SSc-PAH 53.7%), particularly in patients with haemodynamic parameters characteristic of typical PAH without features of left heart disease and/or restrictive lung disease at baseline. The risk of clinical failure was lower with COMB versus MONO in the baseline low-risk group (HR not calculated due to no events in COMB), baseline intermediate-risk group (HR 0.519, 95% CI 0.297 to 0.905) and in the week 16 low-risk group (HR 0.069, 95% CI 0.009 to 0.548).ConclusionsThe benefit of COMB over MONO was demonstrated in patients with CTD-PAH, particularly in those with typical PAH haemodynamic characteristics at baseline. COMB is appropriate for patients categorised as low risk and intermediate risk at baseline and low risk at follow-up.Trial registration number NCT01178073.

Without effective treatment, pulmonary arterial hypertension results in high morbidity and mortality. This review discusses the pathogenesis of the disorder, the thorough clinical evaluation required to establish the diagnosis, available therapies, and future directions.

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).

Background The StratosPHere 2 trial will evaluate the efficacy of hydroxychloroquine and phenylbutyrate in pulmonary arterial hypertension caused by mutations in BMPR2 by focussing on the novel biomarker and other endpoints including safety. Study design StratosPHere 2 is a three armed, placebo-controlled, phase 2 trial with two strata based on the mutation groups. It is response adaptive where the allocation of treatments follows a Bayesian response-adaptive randomisation algorithm. An expected number of 20 patients will be randomised in each stratum to one of the three arms containing hydroxychloroquine, phenylbutyrate and placebo. The primary outcome is a novel endpoint considering the change in the bone morphogenetic receptor type 2 (BMPR2). Method The final primary analysis on the efficacy of each active treatment against control is assessed using a one-sided nonparametric Wilcoxon test computed on the continuous biomarker data collected up to 8 weeks from the start of treatment. Discussion This manuscript presents the key elements of the StratosPHere 2 implementation and statistical analysis plan. This is submitted to the journal before the first interim analysis to preserve the scientific integrity under a response-adaptive design framework. The StratosPHere 2 trial closely follows published guidelines for the content of Statistical Analysis Plans in clinical trials. Trial registration The ISRCTN Registry ISRCTN10304915 (22/09/2023)

Limited research exists regarding nonpharmacologic management of pulmonary arterial hypertension (PAH), except for exercise training. The objective of this study was to investigate the effects of osteopathic manipulative treatment (OMT) alone and combined with respiratory training on fractional exhaled nitric oxide (FeNO), and cardiopulmonary function in patients with PAH. This single-blind, prospective, randomized controlled study included 54 patients with PAH who were randomly allocated to OMT, combined intervention, and control groups. The OMT group (n = 16) and combined intervention group (n = 16) received OMT and yoga respiratory training plus OMT, respectively, twice a week for 8 weeks. The control group (n = 16) received no intervention. All patients undertook an educational lecture. FeNO level, pulmonary function, 6-minute walk distance (6MWD), maximal inspiratory and expiratory pressures, and handgrip strength were assessed at baseline and 8 weeks. Combined intervention and OMT groups significantly improved all outcome measures after 8 weeks of treatment (p <0.01), except mean forced expiratory flow between 25% and 75% of forced vital capacity, which did not change in the OMT group (p >0.05). The control group showed significant deteriorations in 6MWD, inspiratory and peripheral muscle strength, and pulmonary function except peak expiratory flow at 8 weeks (p <0.05). The combined intervention group revealed significantly greater improvements of FeNO, 6MWD, respiratory and peripheral muscle strength, and pulmonary function except mean forced expiratory flow between 25% and 75% of forced vital capacity compared with the OMT group (p <0.05). All outcomes significantly improved in both intervention groups versus the control group (p <0.05). Our study demonstrated that adding respiratory training to OMT provided further benefit to FeNO level and cardiopulmonary function compared with OMT alone and that the OMT might be a useful and safe intervention for patients who cannot attend cardiac rehabilitation programs.

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.

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.