Table 1. Summary of randomised controlled trials of sequential combination therapy in pulmonary arterial hypertension

Treatment tested	Study name	[Ref.]	Background therapy	Primary end-point	Duration	Patients n
Ambrisentan	ATHENA-1	[29]	Sildenafil or tadalafil	PVR	24 weeks	38
Bosentan	EARLY	[21]	None or sildenafil (16%)	PVR^#, Δ6MWD (ns)	24 weeks	185
Bosentan	COMPASS-2	[30]	Sildenafil	Morbidity/mortality	Up to 8 years	334
Iloprost	STEP	[19]	Bosentan	Δ6MWD (ns)	12 weeks	67
Inhaled iloprost	VISION	[31]	Sildenafil	Δ6MWD	16 weeks	67
Iloprost	COMBI	[20]	Bosentan	Δ6MWD (ns)	12 weeks	40
Imatinib		[32]	Bosentan and/or sildenafil and/or prostanoids	Δ6MWD (ns)	24 weeks	59
Macitentan	SERAPHIN	[28]	None, PDE-5i or inhaled iloprost	Morbidity/mortality^#	144 weeks^¶	742
Riociguat	PATENT	[14]	None, bosentan or prostanoids	Δ6MWD^#	12 weeks	443
Selexipag		[22]	Bosentan and/or sildenafil	PVR^#	17 weeks	43
Selexipag	GRIPHON	[33]	None, PDE-5i or ERAs	Morbidity/mortality	Up to 4.3 years	1156
Sildenafil		[34]	Bosentan	Δ6MWD (ns)	12 weeks	104
Sildenafil	PACES	[17]	Epoprostenol	Δ6MWD^#	16 weeks	264
Sildenafil		[23]	Bosentan	Δ6MWD^#	12 weeks	20
Tadalafil	PHIRST	[16]	None or bosentan (54%)	Δ6MWD^#	16 weeks	405
Inhaled trepostinil	TRIUMPH	[18]	Bosentan or sildenafil	Δ6MWD^#	12 weeks	235
Trepostinil	FREEDOM-C1 oral	[25]	Bosentan and/or sildenafil	Δ6MWD (ns)	16 weeks	354
Trepostinil	FREEDOM-C2 oral	[26]	Bosentan and/or sildenafil	Δ6MWD (ns)	16 weeks	310

PVR: pulmonary vascular resistance; Δ6MWD: change in 6-min walking distance; ns: nonsignificant; PDE-5i: phosphodiesterase type-5 inhibitor; ERAs: endothelin receptor antagonists. ^#: statistically significant; ^¶: event-driven study. Data from [10].