Combination therapy with riociquat and inhaled treprostinil in inoperable and progressive chronic thromboembolic pulmonary hypertension

Abstract

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by formation of chronic, organized thrombus in pulmonary arteries resulting in development of pulmonary hypertension. We describe the favorable recovery of a patient with inoperable CTEPH treated with combination riociguat and inhaled treprostinil.The patient is a 77 year old female who presented with bilateral pulmonary emboli and was anticoagulated with warfarin for six months. One year later the patient developed recurrent dyspnea and multiple bilateral pulmonary emboli were again noted. Pulmonary arterial pressure (PAP) was estimated at 91 mmHg by echocardiography. The patient was treated with warfarin and sildenafil. Eighteen months later the PAP was estimated at 106 mmHg with significant right ventricular enlargement. The patient was referred to our center for pulmonary hypertension consultation. Right heart catheterization confirmed severe pulmonary hypertension with preserved cardiac output. The patient was not a candidate for thromboendarterectomy due to the peripheral location of chronic obstructing thrombi. Systemic prostacyclin therapy was declined by the patient. Inhaled treprostinil was added to sildenafil and warfarin. The patient maintained good performance status for 2 years, but then developed progressive activity limitation with depressed cardiac output on right heart catheterization. Systemic prostacyclin therapy was declined again. Sildenafil was replaced with riociguat, and 1 year later the patient demonstrated significant recovery of functional capacity and improved hemodynamic profile.We describe significant recovery in a patient with inoperable, progressive CTEPH treated with riociguat and inhaled treprostinil after failing sequential addition of sildenafil and inhaled treprostinil to warfarin. The reported benefits may relate to riociguat's ability to directly stimulate production of cyclic GMP independent of nitric oxide levels in pulmonary artery smooth muscle. There may also be a unique interaction between riocguat and treprostinil that enhanced treatment outcome. Further investigation of this combination of agents may be warranted.

Switching from sildenafil to riociguat for the treatment of PAH and inoperable CTEPH: Real-life experiences

“…The third patient experienced some general discomfort along with worsening dyspnoea and reduction in functional capacity after receiving riociguat. The safety findings in the three cases presented are consistent with a previous case study of a patient with CTEPH who transitioned from sildenafil/treprostinil to riociguat/treprostinil with no adverse effects [34] , and with clinical trial data. In the PATENT-1 and CHEST-1 clinical trials, adverse events occurring more frequently (by ≥3%) in patients receiving riociguat than in those receiving placebo were headache (27% vs 18%), dyspepsia/gastritis (21% vs 8%), dizziness (20% vs 13%), nausea (14% vs 11%), diarrhoea (12% vs 8%), hypotension (10% vs 4%), vomiting (10% vs 7%), anaemia (7% vs 2%), gastroesophageal reflux disease (5% vs 2%) and constipation (5% vs 1%) [27] , [28] , [35] .…”

“…A recent interim analysis of data from the open-label, uncontrolled, Phase IIIb RESPITE (Riociguat Clinical Effects Studied in Patients With Insufficient Treatment Response to PDE5 Inhibitor) study suggested that switching from PDE5 inhibitors to riociguat improved a range of clinical and haemodynamic endpoints in patients with PAH who have had an inadequate response to PDE5 inhibition [33] . In addition, a recent case study described substantial improvements in exercise capacity and haemodynamics in a patient with progressive CTEPH after switching from sildenafil to riociguat while continuing inhaled treprostinil [34] . However, real-world data regarding the switching of patients with CTEPH or PAH from PDE5 inhibitors to riociguat are scarce.…”

Comparative Efficacy and Safety of Targeted Therapies for Chronic Thromboembolic Pulmonary Hypertension: A Systematic Review and Network Meta-Analysis

“…In clinical practice, many other targeted drugs are also used to treat patients with CTEPH. One previous study reported the significant recovery of a patient with inoperable and progressive CTEPH who was treated with riociguat and inhaled treprostinil [ 27 ]. An open-label study observed significant improvements in the WHO FC, 6MWD, PVR, BNP, and 5-year survival rate, in patients with severe and inoperable CTEPH [ 28 ].…”

Combination Therapy in Pulmonary Arterial Hypertension—Targeting the Nitric Oxide and Prostacyclin Pathways

“… 24 In PAH, a deficiency of NO synthase in pulmonary vascular endothelial cells results in reduced NO production which affects vascular tone and other cellular activities in the vessel wall. 25 …”

“…24 In PAH, a deficiency of NO synthase in pulmonary vascular endothelial cells results in reduced NO production which affects vascular tone and other cellular activities in the vessel wall. 25 Since the 1990s, several agents targeting the NO pathway have been approved for the treatment of PAH including PDE5is (tadalafil, sildenafil) and sGC stimulators (riociguat). PDE5is are vasodilators that enhance and prolong cGMP action by selectively inhibiting the cGMP specific PDE5 isoenzyme that catalyzes the breakdown of cGMP.…”