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CTEPH: treatment

obstruction distal to the segmental arteries or a discrepancy between pulmonary vascular resistance and vascular obstruction suggesting extensive small vessel arteriopathy.10

This study demonstrated a significant median increase in six-minute walking distance (6MWD) of 55m against baseline.14


this group of patients, alternative therapies that reduce PH severity and improve functional capacity could significantly alter the prognosis. The justification for the use of PAH-targeted therapies in this patient population has been taken from the observation of some shared pathophysiological features. The histopathological examination of distal, precapillary pulmonary arteries in patients with CTEPH demonstrates changes similar to those observed in patients with idiopathic PAH. In addition, plasma levels of endothelin-1 are increased in CTEPH and correlate closely with the haemodynamic and clinical severity of the disease.5

Mechanism of action for riociguat Nitric oxide (NO) is produced by endothelial cells from L-arginine via NO synthase. In the pulmonary circulation, it is one of the main compounds to regulate perfusion depending on ventilation. NO diffuses across the cell membrane of vascular smooth muscle cells and stimulates the action of sGC to convert guanosine triphosphate to cGMP. This results in increased intracellular calcium and promotes the relaxation of smooth muscle.11


pathophysiology of PAH involves impairment of the NO synthesis and signalling through the NO sGC–cGMP pathway. Riociguat has a dual mode of action, directly stimulating sGC independently of NO, and increasing the sensitivity of sGC to NO. This results in increased levels of cGMP, which results in vasorelaxation, antiproliferation and antifibrotic effects.2

actions of riociguat are in contrast to phoshodiesterase type 5 inhibitors, which depend on NO to induce similar effects.11

Preclinical experience with

riociguat, including in vitro studies, hypoxic animal models, monocrotaline models and the recent chronic hypoxia SU5416 model12,13

a significant vasodilatory and antiproliferative effect of riociguat in PAH.

Clinical studies in CTEPH An early Phase II study of riociguat was completed in 42 patients with CTEPH.

There have been a number of open-label studies with PAH-targeted therapies involving CTEPH patients prior to the CTEPH sGC stimulator trial (CHEST),2

and two randomised

controlled trials on CTEPH patients alone. The first randomised 19 patients with CTEPH to sildenafil or placebo and demonstrated no improvement after 12 weeks of treatment.15

The second trial,

Bosentan effects in inoperable forms of CTEPH (BENEFIT), randomised 157 CTEPH patients with inoperable disease or persistent PH following

endarterectomy to bosentan or placebo. This study demonstrated no significant improvement in 6MWD at 16 weeks, despite a significant reduction in pulmonary vascular resistance.16


The CHEST-1 study is the pivotal Phase III study evaluating riociguat in patients with CTEPH.2

This study enrolled The NO-independent have all demonstrated

CTEPH patients with inoperable disease (72% of patients) or persistent PH post-pulmonary endarterectomy (28%). A total of 261 patients were randomised from 89 centres in 26 countries in a 1:2 ratio of placebo to riociguat with an adjusted dose up to 2.5mg three times a day. Prior to enrolment, patients underwent a systematic assessment of operability to ensure that they were not suitable for surgical intervention, which could be potentially curative. The findings of the CHEST-1 study confirmed the results of the Phase II study. The primary endpoint of change in 6MWD was statistically significant, with an increase in 39m in the riociguat group and a decrease of 6m in the placebo group from a baseline of 342m (p<0.0001) This effect was seen in patients with both inoperable and residual forms of CTEPH; however, the magnitude of benefit was greater for the inoperable group (54 versus 26m). Riociguat was also associated with significant improvements in the secondary endpoints of pulmonary vascular resistance, N-terminal of the prohormone brain natriuretic peptide (NT-proBNP), and World Health Organization (WHO) functional class. There was no significant evidence of a reduction in time to clinical worsening due to the overall low number of events

(clinical worsening events in 2% in riociguat and 6% in the placebo arm). By the end of the study duration, 77% of patients were taking the maximum dose of 2.5mg. Riociguat was well tolerated with a good safety profile. Headache, dizziness, dyspepsia and nasopharyngitis were the most frequent side effects.


The CHEST-1 results were confirmed by CHEST-2. A total of 98% of patients who completed the trial were transferred into the ongoing CHEST-2 study. CHEST-2 was a multicentre, open-label, single- group study conducted at 71 out of the 89 centres (across 25 out of the 26 countries) that participated in CHEST-1. The open label phase of this study involved a blinded eight-week titration phase for all study participants. Patients previously on placebo were titrated to active riociguat and patients who had received the active drug during CHEST-1 underwent a sham upward titration. This ensured blinding was maintained throughout. At the end of the eight-week titration phase, 82% of former riociguat patients and 90% of former placebo patients were able to tolerate a dose of 2.5mg three times a day.

Patients who had been randomised to riociguat in CHEST-1 maintained their 6MWD at 1 and 2 years in CHEST-2 (Figure 1).17,18

Patients who had been

randomised to placebo in CHEST-1 rapidly improved their 6MWD upon receiving riociguat and maintained the improvement in CHEST-2. At one year of CHEST-2, 6MWD had changed by +59±58m for the former riociguat group (n=5114),+37±69m in the former placebo group (n=558) and +51±62m in the overall population (n=5172; Figure 1). In addition, data suggest that 6MWD correlates with event free survival for patients in the CHEST-2 study. It was observed that in CHEST-2, patients with 6MWD ≥380m at baseline and at follow-up, or those with 6MWD <380m at baseline but ≥380m at follow-up, had a better chance of survival versus those with 6MWD <380m at baseline and at follow-up.17

The decreases in NT-proBNP in the riociguat groups of CHEST-1 were sustained for up to one year in CHEST-2. Patients in the placebo group of CHEST-1 showed a similar decrease in NT-proBNP following transition to riociguat in CHEST-2. At one year in the


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