Early intervention: should we conduct therapeutic trials for mild pulmonary hypertension before onset of symptoms?

Fig. 1.. Schematic representation of the relationship between pulmonary microcirculation loss and PAP. The high capacitance of the pulmonary circulation implies that early microcirculation loss is not accompanied by a change in resting PAP. Many of the current screening modalities are dependent on detecting a rise in PAP and thus will fail to detect the early stages of PVD. PAP, pulmonary artery pressure; PVD, pulmonary vascular disease; PAH, pulmonary arterial hypertension; PVR, pulmonary vascular resistance; CO, cardiac output; RV, right ventricle.28

Fig. 2.. Schematic of alternative trial designs. Different potential trial designs in pulmonary hypertension include Random Discontinuation, Crossover, Factorial, N-of-1, and Nested. 6MWD, 6-min walk distance.

Fig. 3.. Examples of alternative trial designs in mild PH. (a) Schematic of a factorial trial design in mild PH testing tadalafil and ambrisentan in a two-factor design. (b) Schematic of a Nested Design of a phase II and phase III PAH trial. Primary endpoint differs depending on disease severity at study entry. NTproBNP, N terminal pro brain natriuretic peptide; PVR, pulmonary vascular resistance; 1°, primary; 2°, secondary.