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PAH treatment


increased cardiac index to a significantly greater extent than inhaled NO at doses of 1 and 2.5mg. Neither dose produced any deterioration in gas exchange, indicating that ventilation/perfusion matching was maintained. Although riociguat also had significant systemic effects and showed no pulmonary selectivity, mean systolic blood pressure remained >110mmHg. In a Phase II study,18


riociguat was tested in 78


subjects with the PH subforms of PAH (n=33) and CTEPH (n=42). In this 12-week, multicentre, open-label, uncontrolled Phase II study, patients received oral riociguat 1.0–2.5mg three times a day, titrated according to systemic systolic blood pressure. Median six-minute walking distance (6MWD) increased significantly in patients with CTEPH and PAH. Riociguat treatment led to a decrease in PVR by 215 dynes.s.cm-5


. In PAH In PATENT-1,19 a randomised, double-


blind, placebo-controlled, multi-centre study, the efficacy and safety of oral riociguat was tested in 443 patients with symptomatic PAH (treatment-naïve and pre-treated with an endothelin receptor antagonist or a prostacyclin analogue) over 12 weeks. During the eight-week titration phase, the dose of study medication was adjusted every two weeks based on the subject’s monitoring of systolic blood pressure and wellbeing. Riociguat was given in individually adjusted doses of up to 2.5mg


three times a day (2.5mg–maximum group), or riociguat in individually adjusted doses that were capped at 1.5mg three times a day (1.5mg–maximum group). By week 12, the 6MWD had increased by a mean of 30 metres in the 2.5mg–maximum group and had decreased by a mean of six metres in the placebo group (p<0.001). There were significant improvements in PVR (p<0.001), N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (p<0.001), World Health Organization (WHO) functional class (p=0.003), time to clinical worsening (p=0.005) and Borg dyspnoea score (p=0.002). One of the main features of the study was the significant benefit in treatment-naive and pre-treated patients. The most common serious adverse event in the placebo group and the 2.5mg–maximum group was syncope (4% and 1%, respectively). The dose of the study drug was decreased in 31 patients (12%) in the riociguat group. PATENT-220


is an open-


label study assessing the long-term safety and tolerability of riociguat in 363 patients who had completed PATENT-1, additionally including efficacy assessments of the long-term treatment. The mean change in 6MWD from baseline to week 12 in PATENT-2 was 52.5 metres in the former riociguat group (1–2.5mg) and 42.3 metres in the former placebo group and 54.2 metres in the former 1.0–1.5mg riociguat group. Of 405 patients completing PATENT-1, 396 entered PATENT-2. At the cut-off (March 2014), 275 patients were ongoing,


307 had received ≥2 years of treatment and 13 had switched to the commercial drug. At two years, survival was 93% and 17% of former therapy-naïve patients were receiving additional PAH therapy.21,22


The analyses of efficacy variables indicate long-term maintenance of the riociguat treatment effect and improvement in those patients treated with placebo in PATENT-1. The adverse event profiles in PATENT-1 and PATENT-2 were in agreement with those observed in previous clinical trials with riociguat, reflecting the vasodilator mode of action of the drug and the fact that effects of the drug on smooth muscles may lead to gastrointestinal symptoms. Bleeding cases (mostly not drug-related) occurred during both studies including three cases with fatal outcomes.


In CTEPH CHEST-123


was a randomised, double-


blind, placebo-controlled, multicentre, study assessing the efficacy and safety of oral riociguat in 261 patients with either inoperable CTEPH (n=189) or recurrent or persisting PH after pulmonary endarterectomy (PEA) (n=72). Riociguat at doses of 1.0–2.5mg as a titration regimen for 16 weeks resulted in a statistically significant and clinically meaningful improvement in 6MWD (mean increase of 39 metres in the riociguat group compared with a mean decrease of six metres in the


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