RESPITE: switching to riociguat in pulmonary arterial hypertension patients with inadequate response to phosphodiesterase-5 inhibitors

Hoeper, Marius M.; Simonneau, Gérald; Corris, Paul A.; Ghofrani, Hossein Ardeschir; Klinger, James R.; Langleben, David; Naeije, Robert; Jansa, Pavel; Rosenkranz, Stephan; Scelsi, Laura; Grünig, Ekkehard; Vizza, Carmine Dario; Chang, Mikyung; Colorado, Pablo; Meier, Christian; Busse, Dennis; Benza, Raymond L.

doi:10.1183/13993003.02425-2016

Cited by 123 publications

(161 citation statements)

References 32 publications

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“…Hoeper et al. have reported improvements in 6 minute walk distance, hemodynamics, NT-proBNP levels, and WHO functional class in PAH patients with an inadequate response to PDE5 inhibitor therapy and then transitioned to riociguat [10]. Further, patients in the Patent 1 trial demonstrated significant improvement when riociquat was added to existing prostacyclin therapy [11].…”

Section: Discussionmentioning

confidence: 99%

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

Swisher

Elliott

2017

Respiratory Medicine Case Reports

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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.

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Section: Discussionmentioning

confidence: 99%

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

Swisher

Elliott

2017

Respiratory Medicine Case Reports

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“…An open‐label, international, multi‐centre, single‐arm, uncontrolled, phase IIIb study of riociguat in patients with PAH who demonstrate an insufficient response to treatment with phosphodiesterase‐5 inhibitors (PDE‐5i) ( RESPITE ) …”

Section: Methodsmentioning

confidence: 99%

A focus on riociguat in the treatment of pulmonary arterial hypertension

Toxvig

Wehland

Grimm

et al. 2019

Basic Clin Pharma Tox

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Current treatment of pulmonary arterial hypertension (PAH) targets three signalling pathways: the nitric oxide (NO) pathway, the endothelin pathway and the prostacyclin pathway. Riociguat is a soluble guanylate cyclase stimulator, acting via the NO pathway in a new way: unlike other common drugs targeting this pathway (eg tadalafil and sildenafil), riociguat acts independently of endogenous NO. This MiniReview focuses on PAH treatment with riociguat and on its advantages and disadvantages compared with other drugs targeting the NO pathway. In the PATENT‐1 trial (NCT00810693), riociguat improved significantly the 6‐minute walking distance in patients suffering from PAH, with a mean difference (MD) of 36 m compared with a placebo group. The results are comparable to those found for its competitors tadalafil (MD of 33 m) and sildenafil (MD of 50 m) in the PHIRST‐1 trial (NCT00125918) and the SUPER‐1 trial (NCT00644605). No obvious advantages were found regarding pharmacokinetic features and adverse events. In the RESPITE study (NCT02007629), patients with PAH with insufficient response to treatment with tadalafil or sildenafil were switched to riociguat. These results indicate that riociguat might be superior regarding efficacy to PDE‐5 inhibitors in a patient group, where endogenous NO production might be insufficient. This finding was further examined in the REPLACE study (NCT02891850). Moreover, riociguat has shown promising anti‐proliferative, anti‐inflammatory and anti‐fibrotic effects in animal models. Further investigations are needed to determine whether this applies also to human beings. Taken together, riociguat induces vasodilation of the pulmonary arteries and leads to an improvement in the ability to carry out physical activity.

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“…It is not yet well established whether there is a role for switching between PDE-5is and sGC stimulators in patients who are not responding to one type of drug. A trial investigating this has recently been completed and another is ongoing [68,69]. In general, data to support transitions from one agent to another are currently limited, but we anticipate the potential benefits and risks to be better understood as this experience grows.…”

Section: Future Perspectives: Managing Transitionsmentioning

confidence: 99%

Pulmonary arterial hypertension: tailoring treatment to risk in the current era

Gaine

McLaughlin

2017

Eur Respir Rev

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Recent advances in the treatment of pulmonary arterial hypertension (PAH) have led to improved patient outcomes. Multiple PAH therapies are now available and optimising the use of these drugs in clinical practice is vital. In this review, we discuss the management of PAH patients in the context of current treatment guidelines and supporting clinical evidence. In clinical practice, considerable emphasis is placed on the importance of making treatment decisions guided by each patient's risk status, which should be assessed using multiple prognostic parameters. As PAH is a progressive disease, regular assessments are essential to ensure that any change in risk is detected in a timely manner and treatment is adjusted accordingly. With the availability of therapies that target three different pathogenic pathways, combination therapy is now the standard of care. For most patients, this involves dual combination therapy with agents targeting the endothelin and nitric oxide pathways. Therapies targeting the prostacyclin pathway should be added for patients receiving dual combination therapy who do not achieve a low-risk status. There is also a need for a holistic approach to treatment beyond pharmacological therapies. Implementation of all these approaches will ensure that PAH patients receive maximal benefit from currently available therapies.

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RESPITE: switching to riociguat in pulmonary arterial hypertension patients with inadequate response to phosphodiesterase-5 inhibitors

Cited by 123 publications

References 32 publications

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

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

A focus on riociguat in the treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension: tailoring treatment to risk in the current era

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