Faculty Opinions recommendation of Safety and efficacy of IV treprostinil for pulmonary arterial hypertension: a prospective, multicenter, open-label, 12-week trial.

Pulmonary arterial hypertension (PAH) is a deadly disease with no cure. Alternate conversion of angiotensin II (AngII) to angiotensin-(1–7) (Ang-(1–7)) by angiotensin-converting enzyme 2 (ACE2) resulting in Mas receptor (Mas1) activation improves rodent models of PAH. Effects of recombinant human (rh) ACE2 in human PAH are unknown. Our objective was to determine the effects of rhACE2 in PAH.We defined the molecular effects of Mas1 activation using porcine pulmonary arteries, measured AngII/Ang-(1–7) levels in human PAH and conducted a phase IIa, open-label pilot study of a single infusion of rhACE2 (GSK2586881, 0.2 or 0.4 mg·kg−1 intravenously).Superoxide dismutase 2 (SOD2) and inflammatory gene expression were identified as markers of Mas1 activation. After confirming reduced plasma ACE2 activity in human PAH, five patients were enrolled in the trial. GSK2586881 was well tolerated with significant improvement in cardiac output and pulmonary vascular resistance. GSK2586881 infusion was associated with reduced plasma markers of inflammation within 2–4 h and increased SOD2 plasma protein at 2 weeks.PAH is characterised by reduced ACE2 activity. Augmentation of ACE2 in a pilot study was well tolerated, associated with improved pulmonary haemodynamics and reduced markers of oxidant and inflammatory mediators. Targeting this pathway may be beneficial in human PAH.

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Safety and efficacy of transitioning from the combination of bosentan and sildenafil to alternative therapy in patients with pulmonary arterial hypertension

Pulmonary Circulation ◽

10.1177/2045894020945523 ◽

2020 ◽

Vol 10 (4) ◽

pp. 204589402094552

Author(s):

Nathan J. Verlinden ◽

Raymond L. Benza ◽

Amresh Raina

Keyword(s):

Drug Interaction ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Alternative Therapy ◽

Functional Class ◽

World Health ◽

Risk Scores ◽

Safety And Efficacy ◽

Significant Drug Interaction ◽

Pulmonary Arterial

The combination of bosentan and sildenafil is commonly used to treat patients with pulmonary arterial hypertension (PAH); however, there is evidence of a significant drug interaction between these two medications. We sought to evaluate the safety and efficacy of transitioning patients with PAH from the combination of bosentan and sildenafil to alternative therapy. A retrospective database review was performed on 16 patients with PAH who were treated with the combination of bosentan and sildenafil and transitioned to alternative treatment at our center. Invasive and non-invasive patient parameters were collected at baseline and after transition. 56.3% of patients were in World Health Organization functional class (WHO FC) III and a majority of patients (68.7%) were on background prostacyclin therapy. The most common reason for transition was concern for a drug interaction in seven patients (43.8%). The most common transition was bosentan to macitentan in eight patients (50%). Fifteen patients (93.8%) tolerated the transition after a median follow-up of 6.5 months with minor adverse events occurring in four patients (25%). In 11 patients, 6-min walk distance (6MWD) was unchanged comparing baseline to post transition measurements with a median change of +8 m (range: −50 to + 70; P = 0.39). Nine patients (81.8%) had stable (within 15% margin) or significant improvement (increase by ≥15%) in 6MWD after transition. All patients demonstrated stable or improved WHO FC after transition. There were no significant changes after transition in hemodynamics, N-terminal pro-brain natriuretic peptide (NT-proBNP) values, or Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk scores. In our study, transitioning patients from bosentan and sildenafil to alternative therapy was safe and resulted in clinical stability.

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