The primary endpoint was change from baseline to the end kinase inhibitors of week 12 in the 6-minute walk distance (6MWD). Secondary endpoints included pulmonary vascular resistance changes, N-terminal prohormone brain-type natriuretic peptide (NT-proBNP), WHO functional class, time to clinical worsening, Borg scores, EuroQoL 5-dimensional Classification Component scores, and Living with Pulmonary Hypertension scores. At week 12, 6MWD had increased from baseline by a mean of 30 m
in the 2.5 mg–maximum group and had decreased by a mean of 6 m in the placebo group (least-squares mean difference, 36 m; 95% confidence interval: 20 to 52; P < 0.001). Significant benefits were seen in the 2.5 mg–maximum group, as compared with the placebo group, with respect to a range of secondary end points including pulmonary vascular resistance (P < 0.001), NT-proBNP (P < 0.001), WHO functional class (p = 0.003), time to clinical worsening (p = 0.005), and score on the Borg dyspnea scale (p = 0.002). Notably, patients who were receiving endothelin-receptor antagonists or non-intravenous prostanoids were permitted into the study and, accordingly, half
of patients were on background therapy for PAH: 44% with endothelin-receptor antagonists and 6% with nonintravenous prostanoids. Pre-specified subgroup analysis showed that riociguat improved the 6MWD in patients who had not received other PAH-targeted therapies and also in those who had been on endothelin-receptor
antagonists or prostanoids. Concerning the safety profile, riociguat was well tolerated with a discontinuation rate of 3% in the 2.5 mg–maximum group versus 7% in the placebo group. Syncope occurred less frequently in the 2.5-mg maximum (1%) compared to placebo (4%). The 2.5 mg maximum group had increased rates of hypotension (10%) and anemia (8%) compared to placebo group (2% for each), though without statistical significance. What have we learned? Both PDE-5 inhibitors and sGS stimulants target the NO-sGC-cGMP pathway. From a mechanistic point of view, sGC stimulators may have several advantages over PDE-5 inhibitors:  The therapeutic action of PDE-5 inhibitors is dependent on baseline NO availability (which is typically reduced in PAH). 13 In contrast, owing to its NO-independent mode of action, sGC stimulators are effective even when NO production is markedly reduced.  PDE-5 inhibitors Dacomitinib acts by prevention of cGMP degradation; accordingly in diseases where cGMP levels are low (as in PAH), the effectiveness of PDE-5 inhibitors is expected to be markedly limited. Furthermore, when PDE-5 is inhibited, the activity of other PDEs may compensate for it.  In PAH, sGC is upregulated in small pulmonary arteries 15 (as a compensatory mechanism) with increased opportunity for enhanced therapeutic actions of sGC stimulants.