Macitentan in Pulmonary Hypertension Due To Left Ventricular Dysfunction: MELODY-1 Jean-Luc Vachièry, Marion Delcroix, Hikmet Al-Hiti, Michela Efficace, Martin Hutyra, Gabriela Lack, Kelly Papadakis and Lewis J. Rubin Eur Respir J 2018; 51: 1701886

MELODY-1: Rationale PH is a common in HF and is associated with significant morbidity and poor prognosis. Recent guidelines defined two types of group 2 PH: isolated post capillary PH (IpcPH) and combined pre and post capillary PH (CpcPH). In HF patients, endothelin-1 levels are elevated and associated with increased pulmonary pressures and higher mortality. Macitentan is an endothelin-1 receptor antagonist (ETRA) approved for the long term treatment of PAH (group 1 PH). Potential benefit of ETRAs has not been proven yet in HF. Primary objective of Macitentan in Subjects with Combined prE and post CapiLlary PulmOnary Hypertension due to Left Ventricular DYsfunction (MELODY-1) was to evaluate the safety and tolerability of macitentan in patients with CpcPH. Vachièry J-L, Delcroix M, Al-Hiti H, et al. Macitentan in pulmonary hypertension due to left ventricular dysfunction. Eur Respir J 2018; 51: 1701886

Methodology Multicenter (28 sites), double-blind, randomized, placebo-controlled, phase II study. Patients were included if were ≥ 18 years old with: Confirmed CpcPH by RHC (mean PA ≥ 25 mmHg, PCWP 15-25 mmHg, PVR ≥ 3 WU and DPG ≥ 7 mmHg) EF ≥ 30% by echocardiogram NYHA functional class II or III 6 minute walk test ≥ 150 meters Stable dose of diuretics Patients were excluded if were taking prostacyclin analogues, phosphodiesterase type 5 inhibitors, guanylate cyclase or ERAs. Randomization 1:1 to macitentan 10 mg or placebo. Primary safety end point: composite of significant fluid retention or worsening NYHA FC. Increase in body weight by ≥ 5 % or 5 kg due to fluid overload Use of parenteral diuretics Selected secondary endpoints: Change in hemodynamics Change in NT-proBNP Vachièry J-L, Delcroix M, Al-Hiti H, et al. Macitentan in pulmonary hypertension due to left ventricular dysfunction. Eur Respir J 2018; 51: 1701886

Methodology 63 patients underwent randomisation 31 were assigned to receive macitentan 32 were assigned to receive placebo 7 discontinued macitentan prior to week 12 4 adverse event 2 patient decision 1 death 24 completed 12 weeks of macitentan 4 discontinued placebo prior to week 12 4 patient decision 28 completed 12 weeks of placebo 2 discontinued from the study due to: 1 death 1 patient decision 1 discontinued from the study due to death 28 patients completed study 32 patients completed study Vachièry J-L, Delcroix M, Al-Hiti H, et al. Macitentan in pulmonary hypertension due to left ventricular dysfunction. Eur Respir J 2018; 51: 1701886

Selected Patient Baseline Characteristics Macitentan Placebo Total Subjects, n 31 32 63 Median (IQR) age years 70 (67–73) 72 (68-75.5) 71(67–75) Female sex, n (%) 25 (80.6) 16 (50) 41 (65.1) Median (IQR) BMI kg·m2 33.3 (28.8–38.3) 31.2 (27.6–34.5) 32.4 (28.7–36) Specific medical conditions, n (%) Atrial fibrillation 22 (71) 24 (75) 46 (73) Diabetes mellitus type 2 14 (45.2) 13 (40.6) 27 (42.9) Obesity (BMI >30 kg·m2) 20 (64.5) 20 (62.5) 40 (63.5) Renal impairment, n (%) Moderate 11 (34.4) 25 (39.7) None/mild 17 (54.8) 21 (65.6) 38 (60.3) Systemic hypertension, n (%) 30 (96.8) 27 (84.4) 57 (90.5) LVEF, n (%) <50% 6 (19.4) 9 (28.1) 15 (23.8) >50% 23 (71.9) 48 (76.2) NYHA functional class, n (%) II 5 (16.1) 10 (31.3) III 26 (83.9) 22 (68.8) Median (IQR) 6MWD m 300 (216–435) 305 (207–380) 300 (215–410) Median (IQR) NT-proBNP pg·mL−1 1458 (830-2700) 1756 (992–3503) 1515 (959–2921) Median (IQR) hemodynamic parameters PVR, dyn·s·cm−5 450 (296-590) 483.5(362–738.5) 462 (341-605) mPAP, mmHg 44 (40-54) 48.5 (38.5-53.5) 47 (40-54) mRAP, mmHg 13 (10-17) 12.5 (10–16.5) PAWP, mmHg 20 (18-21) 20 (16-23) 20 (17-22) Cardiac index, L/min/m2 2.40 (2.40–3.00) 2.20 (1.90–2.60) 2.35 (1.90–2.70) DPG, mmHg 10 (8–15) 10 (8–13.5) 10 (8–14) Vachièry J-L, Delcroix M, Al-Hiti H, et al. Macitentan in pulmonary hypertension due to left ventricular dysfunction. Eur Respir J 2018; 51: 1701886

Results: Primary Safety End Point Macitentan Placebo p-value Subjects, n 31 32 Significant fluid retention or worsening in NYHA FC, n (%) 7 (22.6) 4 (12.5) 0.34 Significant fluid retention, n (%) 3 (9.4) 0.18 Increased body weight due to fluid overload, n (%) 3 (9.7) 0 (0) Parenteral administration of diuretics, n (%) 5 (16.1) Worsening in NYHA FC, n (%) 1 (3.2) 2 (6.3) More numerical Main Safety Events in the macitentan arm. Driven By More fluid retention Vachièry J-L, Delcroix M, Al-Hiti H, et al. Macitentan in pulmonary hypertension due to left ventricular dysfunction. Eur Respir J 2018; 51: 1701886

Results: Other Secondary End Points   Macitentan Placebo n Baseline, mean (SD) Week 12, mean (SD) PVR, dyn∙sec/cm5 20 525.5 (270.9) 357.2 (195.0) 24 521.4 (233.9) 438.7 (255.4) mPAP, mmHg 21 44.6 (8.7) 41.1 (10.7) 25 45.9 (10.2) 42.1 (11.2) mRAP, mmHg 12.1 (4.6) 11.2 (5.7) 13.0 (4.7) 11.3 (5.2) PAWP, mmHg 19.1 (3.6) 19.9 (7) 19.7 (3.6) 20.8 (7) Cardiac index, L/min/m2 2.3 (0.6) 2.7 (0.7) DPG, mmHg 11.8 (5.9) 7.0 (6.1) 11.4 (4.4) 7.0 (7.9) No significant change in hemodynamics between groups Reduction in NT-proBNP at 12 weeks in macitentan group Vachièry J-L, Delcroix M, Al-Hiti H, et al. Macitentan in pulmonary hypertension due to left ventricular dysfunction. Eur Respir J 2018; 51: 1701886

Summary and Conclusions MELODY-1 was the first randomized controlled trial to evaluate the effect of ERA in CpcPH. Overall, macitentan was associated with more fluid retention or worsening FC than placebo. Interestingly, there was no change in RAP or PCWP, and there was a decrease in NT-proBNP in the patients assigned to macitentan. In conclusion, in patients with CpcPH macitentan is associated with a numerically higher incidence of significant fluid retention compared with placebo despite no evidence of increased filling pressures. Limitations: Pilot study with a small study population and absence of formal power calculations. Vachièry J-L, Delcroix M, Al-Hiti H, et al. Macitentan in pulmonary hypertension due to left ventricular dysfunction. Eur Respir J 2018; 51: 1701886