1. 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:

2. 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:

3. 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 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:

4. 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:

5. Selected Patient Baseline Characteristics
Macitentan
Placebo
Total
Subjects, n 31 32 63
Median (IQR) age years
70 (67–73)
72 ( )
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 ( )
1756 (992–3503)
1515 (959–2921)
Median (IQR) hemodynamic parameters
PVR, dyn·s·cm−5
450 ( )
483.5(362–738.5)
462 ( )
mPAP, mmHg
44 (40-54)
48.5 ( )
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:

6. 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:

7. 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:

8. 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: