TABLE 2

Key randomised controlled clinical trials of drugs that target the prostacyclin pathway

First author [ref.]	Year (trial acronym)	Background therapy	Drug	Patients n	Duration	Primary end-point	Primary end-point met?
Epoprostenol^#
Rubin [37]	1990	None	i.v. epoprostenol	24	8 weeks	Change in total pulmonary resistance	Yes
Barst [38]	1996	None	i.v. epoprostenol	81	12 weeks	Change in 6MWD	Yes
Badesch [39]	2000	None	i.v. epoprostenol	111	12 weeks	Change in 6MWD	Yes
Badesch[40]	2009	None	i.v. epoprostenol	102	3 years	Survival	No
Humbert[41]	2004 (BREATHE-2)	None	i.v. epoprostenol with bosentan or placebo	33	16 weeks	Change in total pulmonary resistance	No
Simonneau [42]	2008 (PACES)	i.v. epoprostenol	Sildenafil or placebo	267	16 weeks	Change in 6MWD	Yes
Iloprost^¶
Olschewski [43]	2002	None	Inhaled iloprost or placebo	203	12 weeks	Composite ≥10% increase in 6MWD and improvement in WHO FC	Yes
Hoeper [44]	2006 (COMBI)	Bosentan	Inhaled iloprost	40	12 weeks	Change in 6MWD	No
McLaughlin [45]	2006	Bosentan	Inhaled iloprost	67	12 weeks	Change in 6MWD and WHO FC	Yes
Treprostinil⁺
Simonneau [46]	2002	None	s.c. treprostinil or placebo	470	12 weeks	Change in 6MWD	Yes
Jing [47]	2013 (FREEDOM-M)	None	Oral treprostinil or placebo	349	12 weeks	Change in 6MWD	Yes
Tapson [48]	2012 (FREEDOM-C)	ERA, PDE-5i or both	Oral treprostinil or placebo	350	16 weeks	Change in 6MWD	No
Tapson [49]	2013 (FREEDOM-C2)	ERA, PDE-5i or both	Oral treprostinil or placebo	310	16 weeks	Change in 6MWD	No
McLaughlin [50]	2010 (TRIUMPH-I)	Bosentan or sildenafil	Inhaled treprostinil or placebo	235	12 weeks	Change in 6MWD 10–60 min after inhalation	Yes
Beraprost^§
GaliÉ [51]	2002 (ALPHABET)	None	Oral beraprost or placebo	130	12 weeks	Change in 6MWD	Yes
Barst [52]	2003	None	Oral beraprost or placebo	116	12 months	Difference in disease progression	Yes
Selexipag
McLaughlin [53]	2015 (GRIPHON)	None, ERA, PDE-5i or both	Oral selexipag^ƒ	1156	3 years	Time to first morbidity or mortality event	Yes

6MWD: 6-min walking distance; WHO: World Health Organization; FC: functional class; ERA: endothelin receptor agonist; PDE-5i: phosphodiesterase type 5 inhibitor. ^#: approved for continuous i.v. administration for pulmonary arterial hypertension (PAH) WHO FC III–IV by the US Food and Drug Administration (FDA) in 1995; ^¶: approved for aerosol administration for PAH WHO FC III in the European Union and Australia in 2003, and PAH WHO FC III–IV by the FDA in 2004; ⁺: approved for s.c. administration for PAH WHO FC II–IV by the FDA and Health Canada in 2002; ^§: approved for oral administration for idiopathic PAH in Japan in 1995 [36]; ^ƒ: not approved at time of publication.