Galiè 2015.

Methods	Multicentre, double‐blind, randomised, placebo‐controlled trial 24 weeks duration
Participants	Inclusion criteria: 18 to 75 years of age weighed at least 40 kg WHO functional class II or III symptoms of PAH diagnosis of idiopathic PAH, hereditary PAH, or PAH that was associated with connective tissue disease, drugs or toxins, HIV (stable disease status), or repaired congenital heart defects (group 1 of the WHO classification of PH). The diagnosis of PAH was established by ruling out other known causes, according to the criteria in current guidelines. (WHO Group 1) For each participant, the mean PAP was required to be ≥ 25 mmHg. Enrolled participants had either not received previous treatment with an approved therapy for PAH or had received treatment for < 14 days and had not received any approved therapy for PAH within 7 days before enrolment WHO FC II/III n = 500
Interventions	There were 3 groups: 253 were assigned to the combination‐therapy group, 126 to the ambrisentan‐monotherapy group, and 121 to the tadalafil‐monotherapy group Ambrisentan monotherapy was compared to tadalafil monotherapy for the purpose of this meta‐analysis
Outcomes	6MWD Haemodynamics including PAP, cardiac index, PVR, RAP Improvement in WHO functional class ProBNP Adverse events
Notes	Industry funded Trial was conducted at 120 centers in 14 countries between October 18, 2010 (first visit), and July 31, 2014 (last study visit)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Not stated, but likely low risk
Allocation concealment (selection bias)	Low risk	Placebo was used
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The study design took into account that following each participant’s final assessment visit, investigators would need to make decisions regarding future treatment, and future treatment decisions would be informed by knowing what treatment participants had been randomised to. Therefore, investigators would need to be unblinded at a participant’s end‐of‐study visit so they could provide appropriate treatment for each participant upon study completion. To accommodate this, we included 2 database freezes. The first database freeze was planned after the last randomised participant had received ≥24 weeks of therapy and the 105th adjudicated first clinical failure event was projected to have occurred in the primary analysis set. At that time, all participants were notified to return for a final assessment visit or their Week 24 visit, whichever was later. The database was frozen for each participant’s visit‐based data through the final assessment visit. The primary analysis was performed on these data. Participants then returned to the clinic for their end‐of‐study visit, the investigator was unblinded and participants were treated per investigator discretion."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	As described above
Incomplete outcome data (attrition bias) All outcomes	Low risk	610 participants were enrolled, but only 500 completed the final primary analysis; the reasons for withdrawals were documented in the supplementary index
Selective reporting (reporting bias)	Low risk	Prespecified outcomes were reported
Other bias	Low risk	Other risk of bias is unlikely