TABLE 1

Combination therapy data from randomised controlled trials

Study name	Patients	PAH treatment at baseline	Investigational therapy	Comparator	Primary end-point	Study duration	Primary end-point met in overall population
Sequential combination
PACES-1 [18]	267	Epoprostenol i.v. 267 (100)	Sildenafil	Placebo	6MWD	16 weeks	Yes
Zhuang et al. 2014 [21]	124	Ambrisentan 124 (100)	Tadalafil	Placebo	6MWD	16 weeks	Yes
PHIRST [19]	405	None 189 (47) Bosentan 216 (53)	Tadalafil	Placebo	6MWD	16 weeks	Yes^#
PATENT-1 [20]	443	None 221 (50) ERA 194 (44) Prostanoids^¶ 28 (6)	Riociguat	Placebo	6MWD	12 weeks	Yes^#
COMBI [14]	40	Bosentan 40 (100)	Inhaled iloprost	None⁺	6MWD	12 weeks	No
STEP [15]	67	Bosentan 67 (100)	Inhaled iloprost	Placebo	6MWD	12 weeks	No
TRIUMPH [17]	235	Bosentan 165 (70) Sildenafil 70 (30)	Inhaled treprostinil	Placebo	6MWD	12 weeks	Yes
FREEDOM-C [23]	350	ERA, 106 (30) PDE-5i 88 (25) ERA and PDE-5i 156 (45)	Oral treprostinil	Placebo	6MWD	16 weeks	No
FREEDOM-C2 [24]	310	ERA 53 (17) PDE-5i 132 (43) ERA and PDE-5i 125 (40)	Oral treprostinil	Placebo	6MWD	16 weeks	No
EARLY [16]	185	None 156 (84) Sildenafil 29 (16)	Bosentan	Placebo	PVR and 6MWD	26 weeks	PVR: yes 6MWD: no^#
COMPASS-2 [25]	334	Sildenafil 334 (100)	Bosentan	Placebo	Composite of morbidity/mortality	Mean 114.4 weeks^§	No
SERAPHIN [8]	742	None 268 (36) PDE-5i 454 (61) Oral/inhaled prostanoid 40 (5)	Macitentan	Placebo	Composite of morbidity/mortality	Median 115 weeks	Yes^#
GRIPHON [10]	1156	None 236 (20) ERA 170 (15) PDE-5i 374 (32) ERA and PDE-5i 376 (33)	Selexipag	Placebo	Composite of morbidity/mortality	Median 67 weeks	Yes^#
Initial combination in treatment-naïve patients
BREATHE-2 [22]	33	None	Epoprostenol and bosentan	Epoprostenol and placebo	Total pulmonary resistance	16 weeks	No
AMBITION [9]	500^ƒ	None	Ambrisentan and tadalafil	Ambrisentan or tadalafil	Composite of clinical failure	Mean 73.9 weeks	Yes

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.