The PATENT PLUS study evaluated the safety and efficacy of riociguat in combination with sildenafil in PAH patients and found that the incidence of hypotension was significantly higher in the combination group, with no significant differences in hemodynamic parameters or exercise capacity compared with controls, and therefore the combination of riociguat and PDE5 inhibitors is not recommended [62]. This evidence concerns the gene PDE5A and pulmonary arterial hypertension.