Figures
- FIGURE 1
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 [8] with permission from the publisher.
- FIGURE 2
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 [37].
- FIGURE 3
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 [9] with permission from the publisher.
- FIGURE 4
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.
Tables
- 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] 500ƒ 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.
