Arno Fritsch

Riociguat for the Treatment of Pulmonary Arterial Hypertension

BACKGROUND Riociguat, a soluble guanylate cyclase stimulator, has been shown in a phase 2 trial to be beneficial in the treatment of pulmonary arterial hypertension. METHODS In this phase 3, double-blind study, we randomly assigned 443 patients with symptomatic pulmonary arterial hypertension to receive placebo, riociguat in individually adjusted doses of up to 2.5 mg three times daily (2.5 mg-maximum group), or riociguat in individually adjusted doses that were capped at 1.5 mg three times daily (1.5 mg-maximum group). The 1.5 mg-maximum group was included for exploratory purposes, and the data from that group were analyzed descriptively. Patients who were receiving no other treatment for pulmonary arterial hypertension and patients who were receiving endothelin-receptor antagonists or (nonintravenous) prostanoids were eligible. The primary end point was the change from baseline to the end of week 12 in the distance walked in 6 minutes. Secondary end points included the change in pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, World Health Organization (WHO) functional class, time to clinical worsening, score on the Borg dyspnea scale, quality-of-life variables, and safety. RESULTS By week 12, the 6-minute walk distance had increased by a mean of 30 m in the 2.5 mg-maximum group and had decreased by a mean of 6 m in the placebo group (least-squares mean difference, 36 m; 95% confidence interval, 20 to 52; P<0.001). Prespecified subgroup analyses showed that riociguat improved the 6-minute walk distance both in patients who were receiving no other treatment for the disease and in those who were receiving endothelin-receptor antagonists or prostanoids. There were significant improvements in pulmonary vascular resistance (P<0.001), NT-proBNP levels (P<0.001), WHO functional class (P=0.003), time to clinical worsening (P=0.005), and Borg dyspnea score (P=0.002). The most common serious adverse event in the placebo group and the 2.5 mg-maximum group was syncope (4% and 1%, respectively). CONCLUSIONS Riociguat significantly improved exercise capacity and secondary efficacy end points in patients with pulmonary arterial hypertension. (Funded by Bayer HealthCare; PATENT-1 and PATENT-2 ClinicalTrials.gov numbers, NCT00810693 and NCT00863681, respectively.).

Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension

BACKGROUND Riociguat, a member of a new class of compounds (soluble guanylate cyclase stimulators), has been shown in previous clinical studies to be beneficial in the treatment of chronic thromboembolic pulmonary hypertension. METHODS In this phase 3, multicenter, randomized, double-blind, placebo-controlled study, we randomly assigned 261 patients with inoperable chronic thromboembolic pulmonary hypertension or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy to receive placebo or riociguat. The primary end point was the change from baseline to the end of week 16 in the distance walked in 6 minutes. Secondary end points included changes from baseline in pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide (NT-proBNP) level, World Health Organization (WHO) functional class, time to clinical worsening, Borg dyspnea score, quality-of-life variables, and safety. RESULTS By week 16, the 6-minute walk distance had increased by a mean of 39 m in the riociguat group, as compared with a mean decrease of 6 m in the placebo group (least-squares mean difference, 46 m; 95% confidence interval [CI], 25 to 67; P<0.001). Pulmonary vascular resistance decreased by 226 dyn·sec·cm(-5) in the riociguat group and increased by 23 dyn·sec·cm(-5) in the placebo group (least-squares mean difference, -246 dyn·sec·cm(-5); 95% CI, -303 to -190; P<0.001). Riociguat was also associated with significant improvements in the NT-proBNP level (P<0.001) and WHO functional class (P=0.003). The most common serious adverse events were right ventricular failure (in 3% of patients in each group) and syncope (in 2% of the riociguat group and in 3% of the placebo group). CONCLUSIONS Riociguat significantly improved exercise capacity and pulmonary vascular resistance in patients with chronic thromboembolic pulmonary hypertension. (Funded by Bayer HealthCare; CHEST-1 and CHEST-2 ClinicalTrials.gov numbers, NCT00855465 and NCT00910429, respectively.)

Riociguat for the treatment of chronic thromboembolic pulmonary hypertension: a long-term extension study (CHEST-2)

Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of inoperable and persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH). In the 16-week CHEST-1 study, riociguat showed a favourable benefit–risk profile and improved several clinically relevant end-points in patients with CTEPH. The CHEST-2 open-label extension evaluated the long-term safety and efficacy of riociguat. Eligible patients from CHEST-1 received riociguat individually adjusted up to a maximum dose of 2.5 mg three times daily. The primary objective was the safety and tolerability of riociguat; exploratory efficacy end-points included 6-min walking distance (6MWD) and World Health Organization (WHO) functional class (FC). Overall, 237 patients entered CHEST-2 and 211 (89%) were ongoing at this interim analysis (March 2013). The safety profile of riociguat in CHEST-2 was similar to CHEST-1, with no new safety signals. Improvements in 6MWD and WHO FC observed in CHEST-1 persisted for up to 1 year in CHEST-2. In the observed population at 1 year, mean±sd 6MWD had changed by +51±62 m (n=172) versus CHEST-1 baseline (n=237), and WHO FC had improved/stabilised/worsened in 47/50/3% of patients (n=176) versus CHEST-1 baseline (n=236). Long-term riociguat had a favourable benefit–risk profile and apparently showed sustained benefits in exercise and functional capacity for up to 1 year. Riociguat shows favourable benefit–risk profile in CTEPH patients, with benefits in 6MWD and WHO FC for up to 1 year http://ow.ly/Co04L

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

BACKGROUND Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, debilitating, and life-threatening disease. We investigated associations between markers of disease severity and long-term outcomes in patients with inoperable CTEPH or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy (PEA) who were receiving the soluble guanylate cyclase stimulator riociguat. We also present safety and efficacy from the final data cutoff of CHEST-2, where most patients had received riociguat for at least 2 years. METHODS Eligible patients from the CHEST-1 study entered the CHEST-2 open-label extension study, in which all patients received riociguat individually adjusted to a maximum dose of 2·5 mg three times per day. The primary endpoint was safety and tolerability. We did exploratory assessments of associations between markers of disease severity (6-min walking distance [6MWD], N-terminal prohormone of brain natriuretic peptide [NT-proBNP] concentration, and WHO functional class) at baseline and follow-up with overall survival and clinical worsening-free survival. We used Kaplan-Meier and Cox proportional hazards analyses. CHEST-2 is registered at ClinicalTrials.gov, number NCT00910429. FINDINGS 237 patients entered CHEST-2. At 2 years, overall survival was 93% (95% CI 89-96) and clinical worsening-free survival was 82% (77-87). A significant association with overall survival was seen for 6MWD and NT-proBNP concentration at baseline (p=0·0199 and p=0·0183, respectively) and at follow-up (p=0·0385 and p=0·0068, respectively). Change from baseline in 6MWD was also significantly associated with survival (p=0·0047). WHO functional class at baseline and follow-up showed no significant association with overall survival but was associated with clinical worsening-free survival. Riociguat was well tolerated by most patients and no new safety signals were identified. Serious adverse events were seen in 129 (54%) of 237 patients, and 14 (6%) discontinued riociguat therapy because of adverse events. INTERPRETATION Riociguat may be used long term in patients with CTEPH. 6MWD and NT-proBNP concentration are good prognostic markers. FUNDING Bayer Pharma AG.

Riociguat for pulmonary arterial hypertension associated with congenital heart disease

Objective The Pulmonary Arterial hyperTENsion sGC-stimulator Trial-1 (PATENT-1) was a randomised, double-blind, placebo-controlled phase III trial evaluating riociguat in patients with pulmonary arterial hypertension (PAH). PATENT-2 was an open-label long-term extension to PATENT-1. Here, we explore the efficacy and safety of riociguat in the subgroup of patients with persistent/recurrent PAH after correction of congenital heart disease (PAH-CHD) from the PATENT studies. Methods In PATENT-1, patients received riociguat (maximum 2.5 or 1.5 mg three times daily) or placebo for 12 weeks; efficacy assessments included change from baseline to study end in 6-min walking distance (6MWD; primary), pulmonary vascular resistance (PVR), N-terminal of the prohormone of brain natriuretic peptide (NT-proBNP), WHO functional class (WHO FC) and time to clinical worsening. In PATENT-2, eligible patients from PATENT-1 received long-term riociguat (maximum 2.5 mg three times daily); the primary assessment was safety and tolerability. All PAH-CHD patients had a corrected cardiac defect. Results In PATENT-1, riociguat increased mean±SD 6MWD from baseline to week 12 by 39±60 m in patients with PAH-CHD versus 0±42 m for placebo. Riociguat also improved several secondary variables versus placebo, including PVR (−250±410 vs −66±632 dyn·s/cm5), NT-proBNP (−164±317 vs −46±697 pg/mL) and WHO FC (21%/79%/0% vs 8%/83%/8% improved/stabilised/worsened). One patient experienced clinical worsening (riociguat 1.5 mg group). Riociguat was well tolerated. In PATENT-2, riociguat showed sustained efficacy and tolerability in patients with PAH-CHD at 2 years. Conclusions Riociguat was well tolerated in patients with PAH-CHD and improved clinical outcomes including 6MWD, PVR, WHO FC and NT-proBNP. Trial registration number The clinical trials numbers are NCT00810693 for PATENT-1 and NCT00863681 for PATENT-2.

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

BACKGROUND Pulmonary arterial hypertension is a chronic disease associated with poor long-term outcomes. Identifying predictors of long-term outcome in pulmonary arterial hypertension is important to assess disease severity and guide treatment. We investigate associations between efficacy parameters and long-term outcomes in patients with pulmonary arterial hypertension receiving riociguat in the PATENT-2 study. We also present safety and efficacy data from the final data cutoff of PATENT-2, where most patients had received at least 2 years of riociguat treatment. METHODS Eligible patients from the PATENT-1 study entered the PATENT-2 open-label extension, which will continue until all patients transition to the commercial drug. All patients received riociguat individually adjusted to a maximum dose of 2·5 mg three times a day. The primary endpoint was safety and tolerability, assessed with recording adverse events, serious adverse events, discontinuations, and deaths; exploratory assessments included 6-min walking distance (6MWD), WHO functional class, N-terminal prohormone of brain natriuretic peptide (NT-proBNP)concentrations, Borg dyspnoea score, health-related quality of life (EQ-5D score), survival, and clinical worsening-free survival. Association between efficacy parameters and long-term outcomes was assessed using Kaplan-Meier analyses and a Cox proportional-hazards regression model. PATENT-2 is registered at ClinicalTrials.gov, number NCT00863681. FINDINGS 396 patients entered PATENT-2, of whom 197 patients were receiving riociguat monotherapy and 199 were receiving riociguat in combination with endothelin receptor antagonists or prostanoids, or both. A significant association was noted between 6MWD, NT-proBNP concentration, and WHO functional class and overall survival at baseline (p=0·0006, 0·0225, and 0·0191, respectively), and at follow-up (p=0·021, 0·0056, and 0·0048, respectively). Riociguat was well tolerated in PATENT-2. Serious adverse events were recorded in 238 (60%) of the total population, and 45 (11%) patients discontinued treatment because of an adverse event. Improvements in 6MWD, WHO functional class, and NT-proBNP concentrations were maintained after 2 years of treatment. INTERPRETATION These results support the long-term use of riociguat in patients with pulmonary arterial hypertension, and emphasise the prognostic value of 6MWD, WHO functional class, and NT-proBNP concentrations. FUNDING Bayer Pharma AG.

Haemodynamic effects of riociguat in inoperable/recurrent chronic thromboembolic pulmonary hypertension

Objective We compared the haemodynamic effects of riociguat in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) or persistent/recurrent CTEPH after pulmonary endarterectomy in the Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1 study. Methods Patients with inoperable or persistent/recurrent CTEPH (n=261; mean± SD age 59±14 years; 66% women) were randomised to riociguat (up to 2.5 mg three times daily) or placebo. Haemodynamic parameters were assessed at baseline and week 16. Results Riociguat decreased pulmonary vascular resistance (PVR) in inoperable (n=189; least-squares mean difference: −285 dyn s/cm5 (95% CI −357 to −213); p<0.0001) and persistent/recurrent (n=72; −131 dyn s/cm5 (95% CI −214 to −48); p=0.0025) patients. Cardiac index improved in inoperable patients by a least-squares mean difference of +0.6 L/min/m2 (95% CI 0.4 to 0.7; p<0.0001), while in persistent/recurrent patients the change was +0.2 L/min/m2 (95% CI −0.1 to 0.5; p=0.17). Mean pulmonary artery pressure decreased in inoperable and persistent/recurrent patients(−4.7 mm Hg (95% CI −6.9 to −2.6; p<0.0001 and −4.8 mm Hg (–8.2 to −1.5; p=0.0055), respectively). For all patients, changes in 6 min walk distance correlated with changes in PVR (r=−0.29 (95% CI −0.41 to −0.17); p<0.0001) and cardiac index (r=0.23 (95% CI 0.10 to 0.35); p=0.0004). Conclusions Riociguat improved haemodynamics in patients with inoperable CTEPH or persistent/recurrent CTEPH. Trial registration number NCT00855465.

Comparison of hemodynamic parameters in treatment-naïve and pre-treated patients with pulmonary arterial hypertension in the randomized phase III PATENT-1 study

BACKGROUND Detailed hemodynamic data from the phase III PATENT-1 study of riociguat in patients with pulmonary arterial hypertension (PAH) were investigated. METHODS Patients with PAH who were treatment naïve or pre-treated with endothelin receptor antagonists or non-intravenous prostanoids were randomly assigned to riociguat up to 2.5 mg 3 times a day or placebo. Hemodynamic parameters were assessed at baseline and week 12. RESULTS Riociguat significantly decreased pulmonary vascular resistance in treatment-naïve (n = 221; least squares [LS] mean difference -266 dyne∙sec∙cm-5 [95% confidence interval (CI) -357 to -175; p < 0.0001]) and pre-treated (n = 222; LS mean difference -186 dyne∙sec ∙cm-5 [95% CI -252 to -120; p < 0.0001]) patients and significantly increased cardiac index (LS mean difference +0.7 [95% CI 0.5 to 0.8] and +0.5 [95% CI 0.3 to 0.7], respectively [both p < 0.0001]). Mean pulmonary artery pressure (p = 0.0056 and p = 0.0019 for treatment-naïve and pre-treated patients, respectively), mean arterial pressure (both p < 0.0001), and systemic vascular resistance (both p < 0.0001) were significantly reduced, and there was an increase in mixed venous oxygen saturation (p < 0.0001 and p = 0.0004, respectively). Results were similar in patients pre-treated with endothelin receptor antagonists and patients pre-treated with non-intravenous prostanoids. Improvements in 6-minute walking distance correlated very weakly with improvements in pulmonary vascular resistance (r = -0.21 [95% CI -0.30 to -0.11; p < 0.0001]) and cardiac index (r = 0.16 [95% CI 0.06 to 0.25; p < 0.0016]). CONCLUSIONS Riociguat significantly improved hemodynamic parameters in pre-treated and treatment-naïve patients with PAH.

Riociguat treatment for portopulmonary hypertension: a subgroup analysis from the PATENT-1/-2 studies

In patients with portopulmonary hypertension (n = 13) included in the 12-week randomized placebo-controlled PATENT-1 trial, riociguat was well tolerated and improved 6-min walking distance (6MWD), World Health Organization functional class (WHO FC), and other efficacy parameters; 6MWD and WHO FC improvements were sustained over two years in the open-label extension, PATENT-2.

Riociguat for pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD): A subgroup analysis from the PATENT studies

Background Pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) is a common associated form of PAH [1]. Riociguat, a soluble guanylate cyclase stimulator, was shown to be a safe and effective treatment for patients with PAH in the Phase III PATENT-1 study and the PATENT-2 long-term extension [2,3]. Here we report data for the subgroup of patients with PAH-CHD in PATENT-1 and PATENT-2.