New paradigm for pulmonary arterial hypertension treatment

Pulmonary arterial hypertension (PAH) was previously considered a uniformly fatal disease, with patients succumbing to right heart failure and death at an average of 3 years after diagnosis. The past 20 years, however, have seen the development of numerous targeted therapies that have changed the natural history of PAH. As more pharmacologic agents have been approved and utilized, further advances in the design of and endpoints for clinical trials. This study will review some of these notable developments.

The successful design and completion of long-term, event-driven trials is exemplified in three recent studies: SERAPHIN, GRIPHON, and AMBITION. SERAPHIN and GRIPHON evaluated the newer agents, macitentan, an endothelin receptor antagonist, and selexipag, a prostacyclin receptor agonist, respectively. Both trials were large-scale studies that, in addition to showing marked effect on the primary endpoint of morbidity/mortality, clearly demonstrated that assessment of long-term effects of PAH therapies is feasible for new compounds. The AMBITION study evaluated a treatment strategy, namely up-front combination therapy with tadalafil and ambrisentan compared with monotherapy and showed the combination approach to be superior at decreasing the likelihood of clinical failure.

The evolution of clinical trials in PAH has direct implications for care of these patients. The short and long-term benefits of combination regimens suggest that the multidrug approach to PAH should, in fact, be standard of care for this disease.