The safety and effectiveness of riociguat to treat chronic thromboembolic pulmonary hypertension

Abstract

Chronic thromboembolic pulmonary hypertension (CTEPH) is an insidious, progressive disease with a poor prognosis. The treatment of choice is pulmonary thromboendarterectomy, although not all patients benefit from surgery at a specialized center. Riociguat, an oral soluble guanylate cyclase (sGC) stimulator is the first pharmacotherapeutic agent that has been shown to improve exercise capacity and hemodynamics in a large multicenter, double-blind, randomized placebo-controlled trial for the treatment of patients with inoperable or persistent CTEPH. Riociguat stimulates sGC directly in a nitric oxide (NO)-independent manner, thereby increasing the sensitivity of sGC to NO, and also in synergy with NO, leading to increased production of cyclic guanosine monophosphate, an intracellular messenger involved in regulating vascular tone, smooth muscle cell proliferation, fibrosis and inflammation. This review will summarize the pharmacodynamics, pharmacokinetics as well as safety and efficacy data of riociguat in inoperable or persistent CTEPH.

Keywords:

• chronic thromboembolic pulmonary hypertension
• pulmonary hypertension
• pulmonary thromboendarterectomy
• riociguat
• soluble guanylate cyclase

Financial & competing interests disclosure

SA DeSouza has received grants and/or consultant fees from Actelion and United Therapeutics. IR Preston has received grants and/or consultant fees from Actelion, Aires, Bayer, Gilead, GeNO and United Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Chronic thromboembolic pulmonary hypertension (CTEPH) is an insidious disease with a poor prognosis.

• Pulmonary thromboendarterectomy (PEA) is the treatment of choice for CTEPH, with a real potential for cure.

• Patients should be evaluated at specialized centers for PEA eligibility.

• Riociguat, a soluble guanylate cyclase stimulator, is the first medical therapy approved by the US FDA for patients with inoperable CTEPH or persistent pulmonary hypertension after PEA.

• In a large, multicenter, placebo-controlled trial, riociguat up to 2.5 mg three-times a day, significantly improved exercise capacity, hemodynamics, functional class, quality of life and markers of right ventricular load.

• In the long-term open-label study, which followed the randomized trial, riociguat was associated with maintenance of improvements achieved initially.

• Side effects associated with riociguat include hypotension and bleeding (especially in patients on chronic anticoagulation).

• Riociguat use is contraindicated concomitant with phosphodiesterase inhibitors or nitrates.

• Emerging treatments for CTEPH include percutaneous pulmonary balloon angioplasty.

Notes