Macitentan in pulmonary hypertension due to left ventricular dysfunction

Abstract

The MELODY-1 study evaluated macitentan for pulmonary hypertension because of left heart disease (PH-LHD) in patients with combined post- and pre-capillary PH.63 patients with PH-LHD and diastolic pressure gradient ≥7 mmHg and pulmonary vascular resistance (PVR) >3WU were randomised to macitentan 10 mg (n=31) or placebo (n=32) for 12 weeks. The main end-point assessed a composite of significant fluid retention (weight gain ≥5% or ≥5 kg because of fluid overload or parenteral diuretic administration) or worsening in New York Heart Association functional class from baseline to end of treatment. Exploratory end-points included changes in N-terminal pro-brain natriuretic peptide (NT-proBNP) and haemodynamics at week 12.Seven macitentan-treated and four placebo-treated patients experienced significant fluid retention/worsening functional class; treatment difference, 10.08% (95% CI -15.07-33.26; p=0.34). The difference, driven by the fluid retention component, was apparent within the first month. At week 12, placebo, the macitentan group showed no change in PVR, mean right atrial pressure or pulmonary arterial wedge pressure; a non-significant increase in cardiac index (treatment effect 0.4 (95% CI 0.1-0.7) L·min·m) and decrease in NT-proBNP (0.77 (0.55-1.08)) was observed. Adverse events and serious adverse events were numerically more frequent with macitentan placebo.Macitentan-treated patients were quantitatively more likely to experience significant fluid retention placebo. Macitentan resulted in no significant changes in any exploratory end-points.

Pulmonary hypertension associated with left heart disease: Updated Recommendations of the Cologne Consensus Conference 2018

“…Moreover, there are numerous examples of neutral studies in this area [2,3,8]. Recent examples include the ENABLE and MELODY-1 studies, showing that the two ERAs bosentan and macitentan failed to improve clinical measures or outcome in patients with HFrEF or HFpEF, respectively, and in both studies ERA therapy was associated with an increased occurrence of fluid retention [91,92]. In addition, the SIOVAC trial has shown that the use of sildenafil was associated with an increased risk of clinical deterioration and worse outcome versus placebo in patients with PH after VHD intervention (aortic, mitral, or tricuspid) [93], thus indicating that such therapies may even be harmful in the context of LHD.…”

“…Furthermore, treatment discontinuations (due to side effects and/or lack of efficacy) were higher among patients with PH-HFpEF, with ERA less well tolerated than PDE-5 inhibitors. The MELODY-1 study, investigating the ERA macitentan, showed no benefit and significantly more edemas than placebo in patients with CpcPH [92]. This, together with the distinct tolerability of drug classes in patients with PH-HFpEF observed in COMPERA [7], may be indicative of differences with respect to efficacy and tolerability among targeted PH therapies in patients with LHD.…”

Endothelin-1, cardiac morphology, and heart failure: the MESA angiogenesis study

“…This is different than left heart failure where endothelin-receptor blockade remains an active area of investigation, the pulmonary vasculature is not the primary problem, and results are less encouraging. 11 The MELODY-1 trial of endothelin-receptor blockade in individuals with significant pre-and post-capillary disease was recently published and did not suggest benefit. Instead, there was worse volume retention in treated individuals and no significant impact on pre-capillary parameters.…”

“…Instead, there was worse volume retention in treated individuals and no significant impact on pre-capillary parameters. 11,28 Some have speculated that endothelin-receptor blockade may be similar to beta-blockade where short-term worsening may be offset by long-term disease stability and improved mortality. 29−32 None of the participants in the current study are known to have pulmonary arterial hypertension, and our results spanning over a decade on average, suggesting that high levels of ET1 may prevent heart failure, cautiously argue against the idea that reduced ET1 levels or an ET1 blockade will lead to a long term benefit in the absence of pulmonary arterial hypertension.…”

Pulmonary hypertension in chronic heart failure: definitions, advances, and unanswered issues

“…In the MELODY-1 trial, including 63 patients with Cpc-PH, macitentan showed numerically more frequent adverse events and fluid retention than did placebo and did not improve any exploratory endpoints (PVR, pulmonary capillary wedge pressure, cardiac index, and NT-pro-BNP), suggesting that macitentan may be harmful in WHO Group 2 PH as well. 46 Endothelin receptor antagonists and prostacyclin analogues have been studied in post-capillary PH. While short-term changes in haemodynamics have been seen, there has been either no clinical benefit or the suggestion for harm.…”