Predictors of long-term outcomes in patients treated with riociguat for pulmonary arterial hypertension: data from the PATENT-2 open-label, randomised, long-term extension trial

Ghofrani, Hossein Ardeschir; Grimminger, Friedrich; Grünig, Ekkehard; Huang, Yigao; Jansa, Pavel; Jing, Zhi‐Cheng; Kilpatrick, D; Langleben, David; Rosenkranz, Stephan; Menezes, Flavia; Fritsch, Arno; Nikkho, Sylvia; Humbert, Marc

doi:10.1016/s2213-2600(16)30019-4

Cited by 97 publications

(160 citation statements)

References 32 publications

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“…What is known comes from analysis of the PATENT-2 long-term extension trial and, not unsurprisingly, 6WMD, WHO functional class, and NT-proBNP levels at baseline and after 12 weeks of therapy were significantly associated with time to clinical worsening and long-term survival. 61 Similar findings have been seen in large patient registries, regardless of pharmacotherapy. 13,62 While helpful in establishing prognosis in PAH patients as a population, this offers little insight to clinicians charged with the task of choosing a first-line agent for PAH patients, and presently we have no way of predicting which individual patients may be “super responders” to riociguat and which should be treated with alternative drugs or initial combination therapy.…”

Section: Guanylate Cyclase Stimulatorssupporting

confidence: 71%

Identifying “super responders” in pulmonary arterial hypertension

Halliday

Hemnes

2017

Pulm. circ.

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Pharmacotherapeutic options for pulmonary arterial hypertension (PAH) have increased dramatically in the last two decades and along with this have been substantial improvements in survival. Despite these advances, however, PAH remains a progressive and ultimately fatal disease for most patients and only epoprostenol has been shown to improve survival in a randomized control trial. Clinical observations of the heterogeneity of treatment response to different classes of medications across the phenotypically diverse PAH population has led to the identification of patients who derive significantly more benefit from certain medications than the population mean, the so-called “super responders.” This was first recognized among PAH patients with acute vasodilator response during invasive hemodynamic testing, a subset of whom have dramatically improved survival when treated with calcium channel blocker (CCB) therapy. Retrospective studies have now suggested a sex discrepancy in response to endothelin receptor antagonists (ERA) and phosphodiesterase inhibitors, and more recently a few studies have found genomic associations with response to CCBs and ERAs. With increasing availability of “omics” technologies, recognition of these “super responders,” combined with careful clinical and molecular phenotyping, will lead to advances in pharmacogenomics, precision medicine, and continued improvements in survival among PAH patients.

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Section: Guanylate Cyclase Stimulatorssupporting

confidence: 71%

Identifying “super responders” in pulmonary arterial hypertension

Halliday

Hemnes

2017

Pulm. circ.

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“…In PATENT-1, riociguat treatment significantly increased exercise capacity and improved a range of secondary endpoints, including hemodynamic variables, WHO FC, and time to clinical deterioration [15, 16]. The PATENT-2 long-term open-label extension trial demonstrated sustained benefits with riociguat treatment at 2 years, with an average increase of 47 m in 6MWD versus baseline, a 2-year survival rate of 93%, and clinical worsening-free survival rate of 79% [17, 18]. …”

Section: Discussionmentioning

confidence: 99%

Initial Riociguat Monotherapy and Transition from Sildenafil to Riociguat in Patients with Idiopathic Pulmonary Arterial Hypertension: Influence on Right Heart Remodeling and Right Ventricular–Pulmonary Arterial Coupling

Lyapina

Belevskaya

Saidova

et al. 2018

Lung

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PurposeTo evaluate the influence of riociguat on World Health Organization functional class (WHO FC), 6-min walk distance (6MWD), right heart remodeling, and right ventricular–pulmonary arterial (RV–PA) coupling in patients with idiopathic pulmonary arterial hypertension (IPAH) who are treatment-naïve or who have failed to achieve treatment goals with sildenafil therapy.MethodsTwenty patients with IPAH were enrolled: 12 had not previously received PAH-targeted therapy (treatment-naïve subgroup) and 8 had been receiving sildenafil therapy but failed to achieve treatment goals; on entering this pilot study these 8 patients were switched from sildenafil to riociguat therapy (treatment-switch subgroup). Patients received riociguat individually dose-adjusted up to a maximum of 2.5 mg three times daily. After 12 weeks, patients were assessed for WHO FC, 6MWD, right heart remodeling, and RV–PA coupling.ResultsRiociguat significantly improved WHO FC in treatment-naïve patients (from 0/4/8/0 patients in WHO I/II/III/IV at baseline to 1/6/5/0 at week 12) and in treatment-switch patients (from 0/4/4/0 patients in WHO I/II/III/IV at baseline to 1/4/3/0 at week 12). Additionally, treatment-naïve and treatment-switch patients showed significant improvements at week 12 versus baseline in 6MWD (increases of + 76.8 m and + 71.6 m, respectively), RV systolic function, and RV–PA coupling.ConclusionThese results support the proven efficacy of riociguat in patients with IPAH, including treatment-naïve patients and those switching to riociguat following failure to achieve treatment goals with sildenafil, and suggest that it may be possible to delay disease progression in this patient group.Electronic supplementary materialThe online version of this article (10.1007/s00408-018-0160-4) contains supplementary material, which is available to authorized users.

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“…Riociguat is generally well tolerated and has a similar good safety profile in patients with CTEPH and in patients with treatment-naïve or pretreated PAH 7,45,47,50,51,57. Most AEs are related to the mechanism of action of riociguat34 and are of mild-to-moderate intensity 7,45.…”

Section: Safetymentioning

confidence: 99%

“…After 2 years of PATENT-2, 275 patients were ongoing, 307 had received ≥2 years of treatment, and 13 patients had switched to the commercial drug 56,57. At 2 years, improvements in 6MWD were maintained, and the estimated survival was 93%.…”

Section: Clinical Trialsmentioning

confidence: 99%

Riociguat: a soluble guanylate cyclase stimulator for the treatment of pulmonary hypertension

Lian

Jiang

Jing

2017

DDDT

Self Cite

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Despite advances in treatments and improved survival, patients with pulmonary hypertension still experience poor exercise and functional capacity, which has a significant detrimental impact on their quality of life. The nitric oxide (NO)–soluble guanylate cyclase (sGC)–cyclic guanosine 3′,5′-monophosphate (cGMP) pathway has been shown to play an important role in cardiovascular physiology, especially in vasodilation and pulmonary vascular tone. The oral sGC stimulator riociguat has a dual mode of action on the NO–sGC–cGMP pathway: direct stimulation of sGC independent of NO and indirect simulation via sensitization of sGC to endogenous NO. Riociguat is now licensed in >50 countries worldwide, including in Europe, the USA, Canada, and Japan. Approval for the treatment of pulmonary arterial hypertension (PAH) was based on Phase III data from the PATENT studies, in which riociguat significantly improved exercise capacity, pulmonary vascular resistance, a range of secondary end points, and hemodynamic parameters in patients with symptomatic PAH. In the Phase III CHEST studies, riociguat consistently improved exercise capacity in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) or persistent/recurrent CTEPH after pulmonary endarterectomy and is now the only drug to be approved for this indication. Riociguat was well tolerated in long-term studies of PAH and CTEPH. This review describes the role of the NO–sGC–cGMP pathway in the pathophysiology of pulmonary hypertension, and reviews the clinical efficacy and safety of riociguat in patients with PAH and inoperable or persistent/recurrent CTEPH. Based on its demonstrated efficacy and established safety profile, riociguat is a promising treatment option for patients with PAH and CTEPH.

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Predictors of long-term outcomes in patients treated with riociguat for pulmonary arterial hypertension: data from the PATENT-2 open-label, randomised, long-term extension trial

Cited by 97 publications

References 32 publications

Identifying “super responders” in pulmonary arterial hypertension

Identifying “super responders” in pulmonary arterial hypertension

Initial Riociguat Monotherapy and Transition from Sildenafil to Riociguat in Patients with Idiopathic Pulmonary Arterial Hypertension: Influence on Right Heart Remodeling and Right Ventricular–Pulmonary Arterial Coupling

Riociguat: a soluble guanylate cyclase stimulator for the treatment of pulmonary hypertension

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