Combination therapy data from randomised controlled trials

Study namePatientsPAH treatment at baselineInvestigational therapyComparatorPrimary end-pointStudy durationPrimary end-point met in overall population
Sequential combination
 PACES-1 [18]267Epoprostenol i.v. 267 (100)SildenafilPlacebo6MWD16 weeksYes
 Zhuang et al. 2014 [21]124Ambrisentan 124 (100)TadalafilPlacebo6MWD16 weeksYes
 PHIRST [19]405None 189 (47)
Bosentan 216 (53)
TadalafilPlacebo6MWD16 weeksYes#
 PATENT-1 [20]443None 221 (50)
ERA 194 (44)
Prostanoids 28 (6)
RiociguatPlacebo6MWD12 weeksYes#
 COMBI [14]40Bosentan 40 (100)Inhaled iloprostNone+6MWD12 weeksNo
 STEP [15]67Bosentan 67 (100)Inhaled iloprostPlacebo6MWD12 weeksNo
 TRIUMPH [17]235Bosentan 165 (70)
Sildenafil 70 (30)
Inhaled treprostinilPlacebo6MWD12 weeksYes
 FREEDOM-C [23]350ERA, 106 (30)
PDE-5i 88 (25)
ERA and PDE-5i 156 (45)
Oral treprostinilPlacebo6MWD16 weeksNo
 FREEDOM-C2 [24]310ERA 53 (17)
PDE-5i 132 (43)
ERA and PDE-5i 125 (40)
Oral treprostinilPlacebo6MWD16 weeksNo
 EARLY [16]185None 156 (84)
Sildenafil 29 (16)
BosentanPlaceboPVR and 6MWD26 weeksPVR: yes
6MWD: no#
 COMPASS-2 [25]334Sildenafil 334 (100)BosentanPlaceboComposite of morbidity/mortalityMean 114.4 weeks§No
 SERAPHIN [8]742None 268 (36)
PDE-5i 454 (61)
Oral/inhaled prostanoid 40 (5)
MacitentanPlaceboComposite of morbidity/mortalityMedian 115 weeksYes#
 GRIPHON [10]1156None 236 (20)
ERA 170 (15)
PDE-5i 374 (32)
ERA and PDE-5i 376 (33)
SelexipagPlaceboComposite of morbidity/mortalityMedian 67 weeksYes#
Initial combination in treatment-naïve patients
 BREATHE-2 [22]33NoneEpoprostenol and bosentanEpoprostenol and placeboTotal pulmonary resistance16 weeksNo
 AMBITION [9]500ƒNoneAmbrisentan and tadalafilAmbrisentan or tadalafilComposite of clinical failureMean 73.9 weeksYes
  • 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.