RIOCIGUAT IN PULMONARY HYPERTENSION: EVIDENCE-TO-DATE AND PLACE IN THERAPY

Evance Alexander, MDa, Wei Huang, MD, PhDa and Zhicheng Jing MD, PhDb*

ABSTRACT

1.1 Introduction: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are rare and severe diseases, result in progressive right heart failure and death. Although recent novel pulmonary vasodilators improve the prognosis PAH, patients still have the high the mortality. Riociguat promotes the production of cyclic guanylate monophosphate (cGMP) by both sensitizing soluble guanylate cyclase (sGC) to endogenous nitric oxide (NO) and directly stimulating sGC that is independent of NO’s effect. Riociguat was approved to be use as the first agent for the treatment of CTEPH in 2013 and PAH in 2015. The approval of riociguat heralded a new era of drug therapy for both vasodilation and antiproliferation in PAH and CTEPH. This review covers the major clinical trials of riociguat, including studies of patients’ long-term survival rate, right heart function, change from phosphodiesterase type 5 inhibitor (PDE5i) to riociguat, new developments in treating connective tissue disease (CTD) and congenital heart disease (CHD), as well as drug interactions. 1.2 Objective: This review covers the major clinical trials of riociguat, including studies of patients’ long-term survival rate, right heart function, change from phosphodiesterase type 5 inhibitor (PDE5i) to riociguat, new developments in treating connective tissue disease (CTD) and congenital heart disease (CHD), as well as drug interactions. 1.3 Results/Findings: Six years long-term extension study of riociguat in PAH and CTEPH its phase II long term extension study was a multicenter, open-label, uncontrolled study, riociguat dose could be regulated accordingly to physician wish (range 0.5-2.5mg three times daily) with primary outcome was long-term safety and tolerability while secondary outcome include 6-MWD, WHO FC, survival and clinical worsening free survival. sixty eight patients (inoperable CTEPH n=41; PAH, n=27) were enrolled, the safety of riociguat was over a median treatment duration of >6 years in PAH patients and inoperable CTEPH patients. The efficacy including increased in 6MWD and WHO FC were all showed at 4years in patients with long-term treatment. this study supports for riociguat as a favorable long-term treatment option for patients with PAH and CTEPH Riociguat improved haemodynamic parameters in treatment-naïve and pre-treated PAH patients -12weeks of treatment with riociguat significantly lower pulmonary vascular resistance (PVR) and mean pulmonary artery pressure (mpap), improved mixed venous oxygen saturation SvO2, Cardiac index and 6MWD. 1.4 Conclusion: Emerging evidence reinforces that riociguat improves patient’s exercise capacity, hemodynamics, and biomarker profile in both PAH and inoperable CTEPH patients with persistent/recurrent PH after PEA(pulmonary endarterectomy). These results validate the long-term efficacy and safety of riociguat. However, head-to-head comparisons between riociguat and other pulmonary vasodilators are still lacking.[47] The current clinical trials demonstrate the efficacy of riociguat on the 6MWT, WHO FC,NT-proBNP, and hemodynamic parameters, but not on mortality. PAH currently remains an incurable and fatal disease in spite of the advanced therapy. Riociguat has both vasoactive and antifibrotic effects, thus, whether long-term riociguat treatment could decrease patient mortality and alleviate remodeling in distal pulmonary artery still awaits further studies.The approval of riociguat heralded a new era of drug therapy for both vasodilation and antiproliferation in PAH and CTEPH.

Keywords: The approval of riociguat heralded a new era of drug therapy for both vasodilation and antiproliferation in PAH and CTEPH.