@ERSpublications Two studies in this month's ERJ report results of combination therapy for PAH http://ow.ly/OlgID Despite substantial advances in the treatment of pulmonary arterial hypertension (PAH) over the past two decades, with 13 drugs approved by regulatory agencies worldwide, the responses to medical therapy are often incomplete or unsatisfactory [1]. As with other conditions with complex pathogenesis, PAH is probably the result of multiple stimuli, both genetic and epigenetic, whose interplay over the course of the disease is poorly understood. Combination therapy trials in cancer, heart failure and HIV infection have demonstrated the value of targeting multiple pathogenic pathways in complex diseases, and this strategy has become the therapeutic mainstay for these chronic conditions. Unlike these common diseases, however, PAH is considered an "orphan" disease, making large-scale clinical trials of multiple therapies more challenging, both logistically and practically [2,3]. Two articles in this issue of the European Respiratory Journal provide new information regarding the effects of adding a second approved oral medication to PAH patients who are not achieving a satisfactory clinical response to initial oral monotherapy [4,5].The COMPASS trial [4] enrolled 334 subjects over 6 years who were failing on first line therapy with sildenafil into a randomised trial to receive either the addition of bosentan 125 mg twice daily or placebo. The primary end-point was the time to first composite end-point of morbidity and mortality. There was no difference between the groups in the time to the primary end-point, and there were only modest differences in placebo-adjusted 6-min walk distance (+21 m) and N-terminal pro-brain natriuretic peptide (NT-ProBNP) in favour of the combination therapy group.The study reported by DARDI et al. [5] was an open label single-centre observational trial performed over 10 years in which subjects receiving first-line monotherapy with either sildenafil or bosentan then received the addition of the other drug if they failed to meet pre-specified treatment goals. While there was no pre-specified primary end-point of this study, the authors report the survival and describe improvements compared to baseline in exercise capacity, haemodynamics and symptoms in their cohort after treatment with combination therapy.Taken together, the results of these two studies leave us with a "cup half-full" feeling. Most disappointing is the COMPASS trial, which expended precious resources for a study that took far too long to complete enrolment -a problematic signal of design issues at the onset -and was underpowered to detect a meaningful treatment effect based on our current knowledge from larger time-to-clinical worsening end-point clinical trials in PAH. A likely important contributor to the negative outcome of COMPASS was the unproven primary end-point component of a patient self-assessment of status, although this has been