SERAPHIN haemodynamic substudy: the effect of the dual endothelin receptor antagonist macitentan on haemodynamic parameters and NT-proBNP levels and their association with disease progression in patients with pulmonary arterial hypertension.
The effect of macitentan on haemodynamic parameters and NT-proBNP levels was evaluated in pulmonary arterial hypertension (PAH) patients in the SERAPHIN study. Association between these parameters and disease progression, assessed by the primary endpoint (time to first morbidity/mortality event), was explored.



Of the 742 randomized patients, 187 with right heart catheterization at baseline and month 6 participated in a haemodynamic sub-study. Prespecified endpoints included change from baseline to month 6 in cardiac index (CI), right atrial pressure (RAP), mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), mixed-venous oxygen saturation, and NT-proBNP. Exploratory analyses examined associations between CI, RAP, and NT-proBNP and disease progression using the Kaplan-Meier method and Cox regression models. Macitentan improved CI, RAP, mPAP, PVR and NT-proBNP vs. placebo at month 6. Absolute levels of CI, RAP and NT-proBNP at baseline and month 6, but not their changes, were associated with morbidity/mortality events. Patients with CI > 2.5 L/min/m2, RAP < 8 mmHg, or NT-proBNP < 750 fmol/ml at month 6 had a lower risk of morbidity/mortality than those not meeting these thresholds (HR 0.49, 95% CL 0.28-0.86; HR 0.72, 95% CL 0.42-1.22; and HR 0.22, 95% CL 0.15-0.33, respectively).



For all treatment groups, baseline and month 6 values of CI, RAP, and NT-proBNP, but not their changes, were associated with morbidity/mortality events, confirming their relevance in predicting disease progression in patients with PAH. By improving those parameters, macitentan increased the likelihood of reaching threshold values associated with lower risk of morbidity/mortality.
Department of Experimental, Diagnostic and Specialty Medicine-DIMES, via Massarenti 9, Bologna 40138, Italy.
Nazzareno
N
Galiè
Clinical Department of Cardiology and Angiology, 1st Faculty of Medicine, 2nd Medical Department, Charles University, Prague, Czech Republic.
Pavel
P
Jansa
Cardiopulmonary Department, Ignacio Chávez, National Heart Institute, Mexico City, Mexico.
Tomás
T
Pulido
Pulmonary and Critical Care, Massachusetts General Hospital, Boston, MA, USA.
Richard N
RN
Channick
Department of Pneumology, Gasthuisberg University Hospital, Leuven, Belgium.
Marion
M
Delcroix
University of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany, Member of the German Center of Lung Research (DZL), and Department of Medicine, Imperial College London, London, UK.
Hossein-Ardeschir
HA
Ghofrani
Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
Franck-Olivier
FO
Le Brun
Division of Respirology, Department of Medicine, London Health Sciences Centre, Victoria Hospital, Western University, London, ON, Canada.
Sanjay
S
Mehta
Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
Loïc
L
Perchenet
Division of Pulmonary and Critical Care Medicine, University of California, San Diego Medical School, San Diego, CA, USA.
Lewis J
LJ
Rubin
Department of Cardiology, CARE Hospitals, Hyderabad, India.
B K S
BKS
Sastry
Assistance Publique-Hôpitaux de Paris, Service de Pneumologie, Hôpital Bicêtre, Université Paris-Sud, Laboratoire d'Excellence en Recherche sur le Médicament et Innovation Thérapeutique, and INSERM U-999, Le Kremlin-Bicêtre, France.
Gérald
G
Simonneau
Assistance Publique-Hôpitaux de Paris, Service de Pneumologie, Hôpital Bicêtre, Université Paris-Sud, Laboratoire d'Excellence en Recherche sur le Médicament et Innovation Thérapeutique, and INSERM U-999, Le Kremlin-Bicêtre, France.
Olivier
O
Sitbon
Pulmonary Department, Heart Institute, University of São Paulo Medical School, São Paulo, Brazil.
Rogério
R
Souza
Department of Pulmonary Circulation and Thromboembolic Diseases, Medical Center for Postgraduate Education, ECZ-Otwock, Poland.
Adam
A
Torbicki
D006328:Cardiac Catheterization; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D012307:Risk Factors; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D018497:Ventricular Dysfunction, Right / Q000401:mortality / Q000503:physiopathology
D065128:Endothelin Receptor Antagonists; D010446:Peptide Fragments; D011743:Pyrimidines; D013449:Sulfonamides; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; C533860:macitentan
Haemodynamics; Macitentan; Prognosis ; Pulmonary hypertension; Right ventricular function