Galiè 2005a.

Methods	Randomised, parallel, placebo‐controlled trial 12‐week study with an additional open‐label extension study
Participants	Inclusion criteria: People with pulmonary arterial hypertension (idiopathic, associated with connective‐tissue disease, occurring after surgical repair of congenital systemic‐to‐pulmonary shunts at least 5 years previously) Pulmonary arterial hypertension defined as mean PAP of 25 mmHg or more and a pulmonary‐capillary wedge pressure (PCWP) of 15 mmHg or less at rest. (WHO Group 1) Exclusion criteria: Treatment with IV epoprostenol oral bosentan, IV or inhaled iloprost or subcutaneous treprostinil and supplementation with L‐arginine prohibited. People with 6MWD of < 100 m or > 450 m excluded WHO FC II/III n = 277
Interventions	20 mg Sildenafil n = 69 40 mg Sildenafil n = 67 80 mg Sildenafil n = 71 compared to placebo n = 70 People assigned to 80 mg sildenafil 3 times daily received 40 mg of sildenafil 3 times daily for the first 7 days before the dose was escalated to 80 mg; people randomised to the other 3 treatment groups underwent dummy dose escalation after 7 days Study medication added to their currently prescribed conventional therapy
Outcomes	6MWD Haemodynamics Improvement in WHO functional class Borg dyspnoea score Mortality was reported, but the study was not powered to assess mortality Adverse events
Notes	Industry funded Trial was conducted in 53 centers in the United States, Mexico, South America, Europe, Asia, Australia, South Africa, and Israel between October 2002 and November 2003
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Stratified randomisation with respect to baseline walking distance and cause of pulmonary hypertension A stratified central‐randomisation scheme was used
Allocation concealment (selection bias)	Low risk	Placebo was used Participants randomly assigned to the other 3 treatment groups underwent dummy dose escalation after 7 days.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants and personnel were blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	It is likely outcome assessment was blinded although it is not explicitly stated
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Intention‐to‐treat analyses were used Very few (only 2) exclusions and balanced attrition between groups: 1 not treated 277 treated 4 died 8 withdrew ‐ 2 protocol violation, 2 withdrew consent, 4 side effects (reduced renal function, lower leg oedema, cardiac arrhythmias, headache) 265 completed 12 weeks 259 entered long‐term study 222 completed 1 year of treatment with monotherapy with sildenafil
Selective reporting (reporting bias)	Low risk	All outcomes proposed in Methods were described in the report, non‐significant outcomes reported
Other bias	Low risk	Other bias is unlikely