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

First author [ref.]Year (trial acronym)Background therapyDrugPatients nDurationPrimary end-pointPrimary end-point met?
 Rubin [37]1990Nonei.v. epoprostenol248 weeksChange in total pulmonary resistanceYes
 Barst [38]1996Nonei.v. epoprostenol8112 weeksChange in 6MWDYes
 Badesch [39]2000Nonei.v. epoprostenol11112 weeksChange in 6MWDYes
 Badesch [40]2009Nonei.v. epoprostenol1023 yearsSurvivalNo
 Humbert [41]2004 (BREATHE-2)Nonei.v. epoprostenol with bosentan or placebo3316 weeksChange in total pulmonary resistanceNo
 Simonneau [42]2008 (PACES)i.v. epoprostenolSildenafil or placebo26716 weeksChange in 6MWDYes
 Olschewski [43]2002NoneInhaled iloprost or placebo20312 weeksComposite ≥10% increase in 6MWD and improvement in WHO FCYes
 Hoeper [44]2006 (COMBI)BosentanInhaled iloprost4012 weeksChange in 6MWDNo
 McLaughlin [45]2006BosentanInhaled iloprost6712 weeksChange in 6MWD and WHO FCYes
 Simonneau [46]2002Nones.c. treprostinil or placebo47012 weeksChange in 6MWDYes
 Jing [47]2013 (FREEDOM-M)NoneOral treprostinil or placebo34912 weeksChange in 6MWDYes
 Tapson [48]2012 (FREEDOM-C)ERA, PDE-5i or bothOral treprostinil or placebo35016 weeksChange in 6MWDNo
 Tapson [49]2013 (FREEDOM-C2)ERA, PDE-5i or bothOral treprostinil or placebo31016 weeksChange in 6MWDNo
 McLaughlin [50]2010 (TRIUMPH-I)Bosentan or sildenafilInhaled treprostinil or placebo23512 weeksChange in 6MWD 10–60 min after inhalationYes
 Galiè [51]2002 (ALPHABET)NoneOral beraprost or placebo13012 weeksChange in 6MWDYes
 Barst [52]2003NoneOral beraprost or placebo11612 monthsDifference in disease progressionYes
 McLaughlin [53]2015 (GRIPHON)None, ERA, PDE-5i or bothOral selexipagƒ11563 yearsTime to first morbidity or mortality eventYes
  • 6MWD: 6-min walking distance; WHO: World Health Organization; FC: functional class; ERA: endothelin receptor antagonist; 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.