Combination therapy with oral treprostinil for pulmonary arterial hypertension. A double-blind placebo-controlled clinical trial

Rationale: Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown. Objectives: To evaluate the effect of oral treprostinil compared with placebo on time to first adjudicated clinical worsening event in participants with PAH who recently began approved oral monotherapy. Methods: In this event-driven, double-blind study, we randomly allocated 690 participants (1:1 ratio) with PAH to receive placebo or oral treprostinil extended-release tablets three times daily. Eligible participants were using approved oral monotherapy for over 30 days before randomization and had a 6-minute-walk distance 150 m or greater. The primary endpoint was the time to first adjudicated clinical worsening event: death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response. Measurements and Main Results: Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56–0.97; P = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro–brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil–assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12–60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting. Conclusions: In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening. Clinical trial registered with www.clinicaltrials.gov (NCT01560624)

Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood

Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease diagnosed by right heart catheterisation and the exclusion of other forms of pulmonary arterial hypertension, producing a heterogeneous population with varied treatment response. Here we show unsupervised machine learning identification of three major patient subgroups that account for 92% of the cohort, each with unique whole blood transcriptomic and clinical feature signatures. These subgroups are associated with poor, moderate, and good prognosis. The poor prognosis subgroup is associated with upregulation of the ALAS2 and downregulation of several immunoglobulin genes, while the good prognosis subgroup is defined by upregulation of the bone morphogenetic protein signalling regulator NOG, and the C/C variant of HLA-DPA1/DPB1 (independently associated with survival). These findings independently validated provide evidence for the existence of 3 major subgroups (endophenotypes) within the IPAH classification, could improve risk stratification and provide molecular insights into the pathogenesis of IPAH

Medical image of the week: lung cancer with vascular invasion

A 73-year-old woman presented to the emergency department with seizures and a subacute history of mild dyspnea on exertion. Her admission chest x-ray demonstrated a large right upper lobe lung mass, and MRI of the brain demonstrated multiple bilateral enhancing lesions concerning for a cardiac embolic source. Representative axial (Figure 1A) and coronal (Figure 1B) images from her chest CT scan demonstrate tumor invading the left atrium via the right superior pulmonary vein (arrow). The tumor was confirmed to be small cell carcinoma of the lung

Exercise-Induced Pulmonary Hypertension: Translating Pathophysiological Concepts Into Clinical Practice

Exercise stress testing of the pulmonary circulation for the diagnosis of latent or early-stage pulmonary hypertension (PH) is gaining acceptance. There is emerging consensus to define exercise-induced PH by a mean pulmonary artery pressure > 30 mm Hg at a cardiac output 3 Wood units at maximum exercise, in the absence of PH at rest. Exercise-induced PH has been reported in association with a bone morphogenetic receptor-2 gene mutation, in systemic sclerosis, in left heart conditions, in chronic lung diseases, and in chronic pulmonary thromboembolism. Exercise-induced PH is a cause of decreased exercise capacity, may precede the development of manifest PH in a proportion of patients, and is associated with a decreased life expectancy. Exercise stress testing of the pulmonary circulation has to be dynamic and rely on measurements of the components of the pulmonary vascular equation during, not after exercise. Noninvasive imaging measurements may be sufficiently accurate in experienced hands, but suffer from lack of precision, so that invasive measurements are required for individual decision-making. Exercise-induced PH is caused either by pulmonary vasoconstriction, pulmonary vascular remodeling, or by increased upstream transmission of pulmonary venous pressure. This differential diagnosis is clinical. Left heart disease as a cause of exercise-induced PH can be further ascertained by a pulmonary artery wedge pressure above or below 20 mm Hg at a cardiac output < 10 L/min or a pulmonary artery wedge pressure-flow relationship above or below 2 mm Hg/L/min during exercise

Incremental value of cardiopulmonary exercise testing in intermediate-risk pulmonary arterial hypertension

Background: Risk assessment in pulmonary arterial hypertension (PAH) is essential for prognostication. However, the majority of patients end-up in an intermediate risk status, offering insufficient guidance in clinical practice. The added value of cardiopulmonary exercise testing in this setting remains undefined. Methods: Two independent cohorts with idiopathic PAH at intermediate risk were used to develop (n = 124) and externally validate (n = 143) the prognostic model. Cross-validation on the overall population was used to strengthen the results of the analysis. Risk assessment was based on the simplified version of the ESC/ERS guidelines score. Discrimination and calibration were assessed. Results: A risk score was constructed based on the beta-coefficient of the cross-validated model, including the stroke volume index (SVI) and the peak oxygen uptake (VO2 peak). Patients were grouped based on cutoff values of the risk score allowing the highest discrimination in the overall cohort. Group 1, score ≤2 (101 patients) with VO2 peak ≥14 ml/kg/min and SVI &gt;30 ml/m2; Group 2, score between 2 and 5 (112 patients) with VO2 peak between 9 and 14 ml/kg/min, and SVI between 20 and 50 ml/m2; Group 3, score &gt;5 (46 patients) with VO2 peak &lt;10 ml/kg/min and SVI &lt;30 ml/m2. The event-free survival rates at 1, 2 and 3 years, were 96%, 83% and 79% for Group 1, respectively; 82%, 67% and 52% for Group 2; 69%, 50% and 41% for Group 3. Conclusions: Combinations of VO2 peak and SVI may provide important information to further stratify intermediate-risk prevalent patients with idiopathic PAH