Switching to riociguat: a potential treatment strategy for the management of CTEPH and PAH

Abstract

Currently, five classes of drug are approved for the treatment of pulmonary arterial hypertension (PAH): phosphodiesterase 5 inhibitors (PDE5i); endothelin receptor antagonists; prostacyclin analogs; the IP receptor agonist selexipag; and the soluble guanylate cyclase (sGC) stimulator riociguat. For patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), riociguat is currently the only approved pharmacotherapy. Despite the development of evidence-based guidelines on appropriate use of specific drugs, in clinical practice patients are often prescribed PAH-targeted therapies off label or at inadequate doses. PDE5i are the most often prescribed class of drugs as initial therapy, either alone or in combination with other drug classes. However, a proportion of patients receiving PAH therapies do not reach or maintain treatment goals. As PDE5i and riociguat target different molecules in the nitric oxide-sGC-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling pathway, for patients with PAH without an initial or sustained response to PDE5i, there is a biological rationale for switching to riociguat. However, robust data from randomized controlled trials on the safety and efficacy of switching are lacking, as is formal guidance for clinicians. Here we review studies of sequential combination therapy, and trial data and case studies that have investigated switching between PAH-approved therapies, particularly from PDE5i to riociguat in patients with PAH with an insufficient response to PDE5i, and in patients with CTEPH who were receiving off-label treatment. These studies summarize the current evidence and practical real-life experience on the concept of switching treatments.

Risk Stratification of Patients with Pulmonary Arterial Hypertension: The Role of Echocardiography

“…This is important from a clinical standpoint since the management of patients with intermediate risk is not straightforward, unlike that of patients with low-risk who need no further change in therapy or those with high-risk who obviously require more aggressive interventions, such as parenteral therapy or lung transplantation referral [ 4 , 30 ]. Therapeutic options for patients who remain in the intermediate-risk category despite dual oral combination therapy with a PDE5-I and an ERA include adding selexipag [ 31 , 32 ], switching from PDE5-I to riociguat [ 33 , 34 , 35 ], initiating parenteral prostanoids [ 12 ] and lung transplantation referral [ 12 ]. Based on this, we believe that the further risk stratification of patients in the intermediate-risk category may help clinicians decide how aggressive subsequent interventions should be.…”

Decoding signaling mechanisms: unraveling the targets of guanylate cyclase agonists in cardiovascular and digestive diseases

“…The sGC stimulators have a dual role in that they directly stimulate the native form of the enzyme, making it more sensitive to endogenous NO and increasing sGC activity regardless of NO and cGMP levels, leading to an increase in cGMP. ( Benza et al, 2019 ). The vasodilation effect of cGMP in the pulmonary circulation is mediated by a variety of subcellular mechanisms, one of which is the activation of cGMP-dependent protein kinase, phosphorylating calcium-sensitive potassium channels (BKCa), leading to potential hyperpolarization of the pulmonary artery smooth muscle membrane and inhibiting calcium inflow through L-type Ca 2+ channels (LTCCs).…”

Evaluating Riociguat in the Treatment of Pulmonary Arterial Hypertension: A Real-World Perspective

“…Subsequent publications endorsed the safety and potential benefit of switching to riociguat since REPLACE. [29][30][31][32][33][34][35] Risk calculator scoring models, such as the REVEAL 2.0 risk assessment, have been used as practical clinical tools to predict treatment response to riociguat and disease progression. 36 A recent Delphi consensus of expert opinion supported considerations for treatment escalations and for switching from a PDE5 inhibitor to riociguat in PAH patients not achieving treatment goals or at high-risk of progression.…”