Effects of sotatercept on haemodynamics and right heart function: analysis of the STELLAR trial.

BACKGROUND: In the phase 3 STELLAR trial, sotatercept, an investigational first-in-class activin signalling inhibitor, demonstrated beneficial effects on 6-min walk distance and additional efficacy endpoints in pre-treated participants with pulmonary arterial hypertension (PAH). METHODS: This post hoc analysis evaluated data from right heart catheterisation (RHC) and echocardiography (ECHO) obtained from the STELLAR trial. Changes from baseline in RHC and ECHO parameters were assessed at 24 weeks. An analysis of covariance (ANCOVA) model was used to estimate differences in least squares means with treatment and randomisation stratification (mono/double versus triple therapy; World Health Organization functional class II versus III) as fixed factors, and baseline value as covariate. RESULTS: Relative to placebo, treatment with sotatercept led to significant (all p<0.0001 except where noted) improvements from baseline in mean pulmonary artery (PA) pressure (-13.9 mmHg), pulmonary vascular resistance (-254.8 dyn·s·cm-5), mean right atrial pressure (-2.7 mmHg), mixed venous oxygen saturation (3.84%), PA elastance (-0.42 mmHg·mL-1·beat-1), PA compliance (0.58 mL·mmHg-1), cardiac efficiency (0.48 mL·beat-1·mmHg-1), right ventricular (RV) work (-0.85 g·m) and RV power (-32.70 mmHg·L·min-1). ECHO showed improvements in tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure ratio (0.12 mm·mmHg-1), end-systolic and end-diastolic RV areas (-4.39 cm2 and -5.31 cm2, respectively), tricuspid regurgitation and RV fractional area change (2.04% p<0.050). No significant between-group changes from baseline were seen for TAPSE, heart rate, cardiac output, stroke volume or their indices. CONCLUSION: In pre-treated patients with PAH, sotatercept demonstrated substantial improvements in PA pressures, PA compliance, PA-RV coupling and right heart function.

Pulmonary Vascular and Right Ventricular Burden During Exercise in Interstitial Lung Disease.

BACKGROUND: Pulmonary hypertension (PH) adversely affects patient's exercise capacity in interstitial lung disease (ILD). The impact of pulmonary vascular and right ventricular (RV) dysfunction, however, has traditionally been believed to be mild and clinically relevant principally in advanced lung disease states. RESEARCH QUESTION: The aim of this study was to evaluate the relative contributions of pulmonary mechanics, pulmonary vascular function, and RV function to the ILD exercise limit. STUDY DESIGN AND METHODS: Forty-nine patients with ILD who underwent resting right heart catheterization followed by invasive exercise testing were evaluated. Patients with PH at rest (ILD + rPH) and with PH diagnosed exclusively during exercise (ILD + ePH) were contrasted with ILD patients without PH (ILD non-PH). RESULTS: Peak oxygen consumption was reduced in ILD + rPH (61 ± 10% predicted) and ILD + ePH (67 ± 13% predicted) compared with ILD non-PH (81 ± 16% predicted; P < .001 and P = .016, respectively). Each ILD hemodynamic phenotype presented distinct patterns of dynamic changes of pulmonary vascular compliance relative to pulmonary vascular resistance from rest to peak exercise. Peak RV stroke work index was increased in ILD + ePH (24.7 ± 8.2 g/m2 per beat) and ILD + rPH (30.9 ± 6.1 g/m2 per beat) compared with ILD non-PH (18.3 ± 6.4 g/m2 per beat; P = .020 and P = .014). Ventilatory reserve was reduced in ILD + rPH compared with the other groups at the anaerobic threshold, but it was similar between ILD + ePH and ILD non-PH at the anaerobic threshold (0.32 ± 0.13 vs 0.30 ± 0.11; P = .921) and at peak exercise (0.70 ± 0.17 vs 0.73 ± 0.24; P = .872). INTERPRETATION: ILD with resting and exercise PH is associated with increased exercise RV work, reduced pulmonary vascular reserve, and reduced peak oxygen consumption. The findings highlight the role of pulmonary vascular and RV burden to ILD exercise limit.