Challenging the concept of adding more drugs in pulmonary arterial hypertension

The management of pulmonary arterial hypertension (PAH) has evolved significantly in the last three decades based on the development of drugs which target three biochemical pathways involved in pulmonary vascular homeostasis: the nitric oxide (NO) pathway, the endothelin pathway and the prostacyclin pathway [1]. Initially employed as monotherapies, these new drugs changed PAH outcomes and had a direct impact on survival [2]. However, monotherapy proved over time to be insufficient for the vast majority of PAH patients and the next natural step in decreasing the still unacceptable lethality of PAH was the association of two or more drugs targeting distinct pathways. Results from two large randomised controlled trials demonstrated that the addition of a second or third drug in combination with an already established background therapy could significantly slow disease progression [3, 4], reinforcing the concept that more drugs can lead to greater benefit. This concept was further stressed by studying the upfront use of combination therapy. In the ambrisentan and tadalafil in patients with pulmonary arterial hypertension (AMBITION) trial [5], the combined use of an endothelin receptor antagonist (ERA) and a phosphodiesterase-5 inhibitor (PDE5i) proved to be better than the use of either compound alone in decreasing the risk of clinical failure events. Successful use of initial double or triple combination therapies was also reported in multi-centre registry studies [6, 7]. These large trials and registries provided the basis for the current European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines in which the use of combination therapy should be considered early, according to the stratification of the risk of death [8] (figure 1).