Pulmonary Arterial Hypertension - Future Directions

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Citation
US Cardiology, 2007;4(2):82-4

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Pulmonary arterial hypertension (PAH) is a rare but life-threatening condition that has traditionally required treatment with continuous intravenous epoprostenol via an indwelling central catheter.1–3 Such therapy improves outcome, but is fraught with side effects, expense, and risk of catheter-related complications. Therapy of PAH has evolved tremendously in recent years, reflecting the development of novel therapeutic agents and modes of delivery that target either vasodilator pathways that are deficient or vasoconstrictor pathways that are activated in PAH patients. These agents include oral endothelin antagonists (bosentan,4–6 sitaxsentan,7,8 ambrisentan9), phosphodiesterase (PDE)-5 inhibitors (sildenafil,10 tadalafil), and prostanoids that do not necessarily require intravenous delivery (inhaled iloprost,11,12 subcutaneous treprostinil13).

Treprostinil

Treprostinil is a prostacyclin analog with a half-life of three hours, which, unlike epoprostenol, is stable at room temperature. It is US Food and Drug Administration (FDA)-approved for both intravenous and subcutaneous use. Owing to its stability, longer half-life, and equivalent hemodynamic effect when given subcutaneously, it has been clinically applied in this manner. Compared with placebo, subcutaneous treprostinil tends to improve exercise capacity on six-minute walk testing, quality of life, and hemodynamics, but the benefits in the randomized trial were quite small, probably reflecting low dosing in the short-term trial. At higher doses and among more symptomatic patients, the beneficial effects are much more pronounced.
Treprostinil exhibits a similar side-effect profile to epoprostenol, but also often produces pain at the infusion site. This may limit the ability to raise subcutaneous doses to a level likely to produce optimal benefit in some patients. However, it can be effective in patients who can tolerate appropriate subcutaneous doses. The expense of treprostinil is greater than that of epoprostenol, since it is less potent on a per milligram basis. The advantages of treprostinil are the potential absence of a central venous catheter if given subcutaneously, smaller infusion pump apparatus, and the use of a drug that does not need to be mixed with diluent by the patient immediately prior to administration. It is also effective for intravenous use, and its longer half-life compared with epoprostenol may be an advantage in the situation of an inadvertent disconnect during therapy of a highly dependent patient. Randomized placebo-controlled trials of inhaled and oral preparations of treprostinil are in progress.

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