Long-term treprostinil in pulmonary arterial hypertension: is the glass half full or half empty?

Pulmonary arterial hypertension (PAH) has traditionally been considered as an inevitably fatal disease. In the 1980s, a national registry funded by the National Institutes of Health (NIH) described the natural history of idiopathic PAH 1. The median survival was <3 yrs and prognosis was mostly related to baseline functional capacity and pulmonary haemodynamics. In case series, the long-term outcome of patients with PAH associated with connective tissue disease, portal hypertension and HIV infection appeared to be even worse 2. This was before the era of PAH-specific therapies. In the last decade, significant advances in the current understanding of the disease have led to the development of new specific treatments. In 1996, a placebo-controlled trial demonstrated significant survival benefit with i.v. epoprostenol in idiopathic PAH patients 3. Several other therapies, including prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase type-5 inhibitors, were subsequently evaluated in short-term randomised placebo-controlled trials. These studies demonstrated improvements in pulmonary haemodynamics, exercise capacity and quality of life 4–6. This new era of therapy has clearly brought enthusiasm among physicians. From a clinician's perspective, the glass has been half filled. Treprostinil s.c. was evaluated in a large randomised placebo-controlled trial involving 470 PAH patients randomised to either s.c. treprostinil or placebo 7. Over a 12-week period, s.c. treprostinil improved patients’ exercise capacity, PAH-related symptoms and haemodynamics. The median placebo-corrected increase in 6-min walking distance was 16 m, with greater improvements in severely ill patients at baseline and in those who could tolerate the highest doses. Unfortunately, this short-term trial, as with others, was underpowered and not designed to detect survival benefit. Indeed, the most ill patients are no longer entered into placebo-controlled …