Soluble guanylate cyclase stimulator riociguat in the palette of modern specific therapy for precapillary pulmonary hypertension: from the pathophysiological basis to the results of current research
Authors: Musashaykhova S. A. , Trukhin D. I. , Valieva Z. S. , Martynyuk T. V. 
Published: January 2023

Among the forms of precapillary pulmonary hypertension (PH) are pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH) with a diagnostic triad of hemodynamic parameters: mean pulmonary artery pressure > 25 mm Hg (> 20 mm Hg according to the new version of European guidelines 2022), pulmonary artery wedge pressure ≥ 15 mm Hg; pulmonary vascular resistance > 3 Wood units (> 2 Wood units in the new version of European guidelines 2022) by right heart catheterization at rest. The leading factors in the pathogenesis of PAH are an endothelial dysfunction with an imbalance between vasodilating and vasoconstrictor substances, activation of endothelial/smooth muscle cell proliferation and the blood coagulation system, which lead to remodeling of the vessels of the pulmonary circulation. In CTEPH there is a morphological substrate as a chronic obstruction of large and medium branches of pulmonary arteries, as well as secondary changes in the microcirculatory bed of the lungs, and chronic/organized thrombi/emboli in the elastic type of pulmonary arteries are detected after three months of effective anticoagulant therapy.

As a result of a significant progress in the study of the pathophysiological aspects of PAH in recent years, specific therapy has been introduced into clinical practice with an impact on key targets of the pathogenesis of the disease. In CTEPH pulmonary endarterectomy remains the treatment of choice for all operable patients.  In case of inoperable and residual forms of CTEPH, if technically feasible, pulmonary artery balloon angioplasty is performed while taking PAH-specific drugs, in particular, the only officially approved stimulator of soluble guanylate cyclase (sGC) riociguat.

The most important aspects of PAH-specific therapy of patients with PAH, inoperable and residual forms of CTEPH; the targets of therapy are indicated, promising approaches to therapy with a focus on the sGC stimulator riociguat, the possibilities of combination therapy and switching strategies are discussed in the article. The optimal safety and efficacy profile of riociguat, demonstrated in large international studies and routine clinical practice, allows the drug to be widely used in the treatment of patients with PAH and CTEPH. Switching from phosphodiesterase type 5 (PDE5) inhibitors to riociguat is safe and appropriate, which is emphasized in the Eurasian and Russian clinical guidelines, in 2022. the strategy of switching to riociguat is approved in case of failure of PDE5 inhibitors as part of combination therapy with endothelin receptor antagonists in the new version of the European document.The originality of riociguat due to the presence of a dual mechanism of action by direct stimulation of sGC and sensitization of the enzyme to endogenous NO, allows its use not only as a long-term monotherapy, but also as part of a combination therapy, with the implementation of a switching strategy in case of clinical failure of PDE5 inhibitors.