Results of long-term riociguat therapy, including a switching strategy from sildenafil, in patients with pulmonary hypertension of various genesis

Aim: to study the influence of riociguat on the functional and hemodynamic status, remodeling of the right heart, as well as the safety of therapy in both previously untreated patients with idiopathic pulmonary arterial hypertension (IPAH) and inoperable chronic thromboembolic PH (CTEPH), and those not achieved treatment goals with sildenafil therapy and switching to riociguat. Materials and methods. A total of 161 pts with precapillary PH were included in the study; 137 pts completed the three-year observation period. Of 55 IPAH pts riociguat was started after diagnosis verification in 39 pts (subgroup 1); 16 pts previously taking sildenafil who did not achieve treatment goals comprised subgroup 2 of switching to riociguat. Of 82 inoperable CTEPH pts riociguat was started in 45 naїve pts; a switching strategy riociguat was implemented in 37 pts after 24-hour withdrawal of sildenafil. The dose titration of riociguat was started from 1 mg TID according to the standard algorithm up to 7.5 mg/day. By month 36 92.4% and 94.8% of pts with IPAH and CTEPH, respectively, received 7.5 mg/day. At baseline, at month 12, 24 and 36 all pts underwent a 6-minute walking test (6MWT) with the assessment of the dyspnea index according to the Borg scale and SpO 2 , echocardiography (Echo), right heart catheterization (RHC), and the safety profile was assessed. Results. At baseline, the proportion of pts with FC III-IV in CTEPH group compared to IPAH group, was significantly higher (70.7% vs 41.8%)); the distance in T6MX (d6MWT) was 291 [232;385] m vs 379 [300;448] m (p<0.001). CTEPH pts had lower values of sPAP, PVR, SaO2 and SvO2 assessed by RHC. In the switching subgroups 2 of pts with IPAH and CTEPH, achieved levels of sPAP (p=0.01), sRAP (p=0.001) and PVR (p=0.01) (RHC) were significantly lower than in subgroups 1. The baseline levels of CI and SV were significantly higher in subgroups 2 (p<0.05). During riociguat treatment in both subgroups of IPAH, a significant increase in d6MWT was achieved by 6 months with FC I-II (WHO) in 75% and 70% of patients. In the subgroup 1 to 36 months the greatest increase by 97m was achieved; in the switching subgroup the increase in d6MWT was noticed by month 6, which was maintained by month 36. In CTEPH patients, there was a significant improvement in FC (p=0.001) with ∆dT6MX 48m (p=0.001). In subgroup 1 with CTEPH, the d6MWT increase was 68.2m (p = 0.001), reaching 82.6m by month 36. In subgroup 2 the significant change of d6MWT were noted by the 1st year of FU, reaching 136.6m by month 36. In IPAH and CTEPH pts by month 36 of riociguat therapy, a significant decrease of mPAP, SPAP were found by echo, which was confirmed by RHC; there was a decrease in the basal size of the right ventricle (RV) (p=0.04) and an increase in RV FAC (p=0.04 and p=0.03, respectively). In subgroups 1, ∆SvO 2 in ts with IPAH and CTEPH were significantly higher compared to subgroups 2. During FU period the proportion of low-risk pts increased to 26.7% in IPAH group and 44.8% in CTEPH group at month 36. In subgroups 2 riociguat therapy resulted in maintenance of treatment regimens throughout the year. Only 6.2% of pts by month 24 and 36 required the prescription of a 3d specific drug. No serious adverse events (AEs) were observed during treatment. The most common AEs were nasopharyngitis, nasal congestion, and dyspnea. Conclusions: Riociguat therapy for 36 months demonstrated a persistent positive effect on the functional and hemodynamic status, remodeling of the right heart both in previously untreated patients with IPH and inoperable CTEPH, and in patients from the switching groups who did not achieve treatment goals with sildenafil therapy.