Combination therapy for pulmonary arterial hypertension: still more questions than answers

As pulmonary arterial hypertension (PAH) is a disease with varying patho-aetiology 1, attempting to arrest its natural progression with a single type of pharmacological molecule might, sometimes, simply not be enough. As with systemic arterial hypertension, combination therapy has been proposed as an attractive, and logical, concept for the treatment of PAH in the future 2, and this concept is slowly creeping into today's clinical practice. The prospect of combination treatment is, theoretically, highly promising. However, the evidence supporting this concept remains weak. In the past few years, three classes of substances have emerged as effective treatments for PAH: prostanoids, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors 2. These substances act by different modes of action. Prostanoids replace endogenous prostacyclin, production of which is decreased or absent in the pulmonary vessels of PAH patients 3, 4, and exert vasodilatory and antiproliferative effects predominantly via the intracellular second messenger, cyclic adenosine 5′-monophosphate (cAMP). Endothelin-1 is overexpressed in PAH and causes deleterious effects such as pulmonary vasoconstriction and vascular smooth muscle cell proliferation 5; …