Beyond a single pathway: combination therapy in pulmonary arterial hypertension
European Respiratory Review 2016 25: 408-417; DOI: 10.1183/16000617.0085-2016
Univ. Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, FranceAP-HP, Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Hôpital Bicêtre, Le Kremlin-Bicêtre, FranceINSERM UMR_S 999, Le Plessis Robinson, France
Macitentan as part of combination therapy significantly reduced the risk of morbidity/mortality events (composite primary end-point) versus placebo in incident and prevalent pulmonary arterial hypertension (PAH) patients. Kaplan–Meier curves for PAH patients receiving background PAH-specific therapy at baseline. HR: hazard ratio. #: log rank. Reproduced and modified from  with permission from the publisher.
Selexipag significantly reduced the risk of morbidity/mortality (composite primary end-point) versus placebo in incident and prevalent pulmonary arterial hypertension (PAH) patients. Kaplan–Meier curves for a) patients not on background PAH therapy at baseline; b) patients on phosphodiesterase type-5 inhibitor (PDE-5i) monotherapy at baseline; c) patients on endothelin receptor antagonist (ERA) monotherapy at baseline; and d) patients on dual combination therapy (ERA + PDE-5i). HR: hazard ratio. Reproduced with permission .
Initial combination therapy with ambrisentan and tadalafil significantly reduced the risk of clinical failure (composite primary end-point) versus pooled monotherapy in incident pulmonary arterial hypertension patients. Kaplan–Meier curves for treatment-naïve pulmonary arterial hypertension patients. HR: hazard ratio. Reproduced from  with permission from the publisher.
Future perspectives on the use of combination therapy to treat pulmonary arterial hypertension. The choice of combination therapy regimen will be influenced by the risk status at diagnosis and the response to initial medical therapy. Inadequate clinical response is defined as a patient who does not achieve or maintain a low-risk profile [11, 12]. WHO FC: World Health Organization functional class; NO: nitric oxide; ET: endothelin; PGI2: prostacyclin; inh.: inhaled. #: for eligible patients.
None 236 (20) ERA 170 (15) PDE-5i 374 (32) ERA and PDE-5i 376 (33)
Composite of morbidity/mortality
Median 67 weeks
Initial combination in treatment-naïve patients
Epoprostenol and bosentan
Epoprostenol and placebo
Total pulmonary resistance
Ambrisentan and tadalafil
Ambrisentan or tadalafil
Composite of clinical failure
Mean 73.9 weeks
Data are presented as n or n (%), unless otherwise stated. Patients were randomised as follows: BREATHE-2 (2:1 bosentan:placebo); AMBITION (2:1:1 ambrisentan/tadalafil combination:ambrisentan monotherapy:tadalafil monotherapy); SERAPHIN (1:1:1 macitentan 10 mg:macitentan 3 mg:placebo); PHIRST (1:1:1:1:1/placebo:tadalafil 2.5 mg:10 mg:20 mg:40 mg); PATENT-1 (2:4:1 placebo:riociguat 2.5 mg max:1.5 mg max). For all other studies the patients were randomised 1:1 between treatment arms. PAH: pulmonary arterial hypertension; 6MWD: 6-min walking distance; ERA: endothelin receptor antagonist; PDE-5i: phosphodiesterase type-5 inhibitor; PVR: pulmonary vascular resistance. #: the result in the subgroup of patients who were on background therapy was consistent with that for the overall population in the PATENT-1, EARLY, SERAPHIN and GRIPHON trials. In PHIRST, the primary end-point was not met in the subgroup of patients who were receiving background therapy; ¶: patients receiving i.v. prostanoids were excluded; +: patients in this study either received bosentan only (no placebo inhalations) or bosentan with inhaled iloprost; §: duration of active treatment (bosentan arm); ƒ : 610 participants were randomised and 500 included in the primary analysis set.