Riociguat for patients with chronic thromboembolic pulmonary hypertension: Usefulness of transitioning from phosphodiesterase type 5 inhibitor

doi:10.1016/j.resinv.2017.04.004

Respiratory Investigation

Volume 55, Issue 4, July 2017, Pages 270-275

https://doi.org/10.1016/j.resinv.2017.04.004 Get rights and content

Abstract

Background

Riociguat, the first approved drug for patients with chronic thromboembolic pulmonary hypertension (CTEPH), is a soluble guanylate cyclase (sGC) Stimulator. It directly stimulates sGC independently of nitric oxide (NO) and increases sGC sensitivity for NO. The safety and efficacy of transitioning from a phosphodiesterase 5 inhibitor (PDE5i) to riociguat is unknown.

Methods and results

Twenty-three patients were prospectively enrolled: 8 symptomatic patients with inadequate clinical responses to PDE5i were changed to riociguat (transitioned group); 15 started riociguat anew (new or add-on group). We analyzed the change from baseline to 6–12 months of riociguat treatment for the 6-minute walk distance (6MWD), mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index (CI), partial pressure of oxygen in arterial blood (PaO2), brain natriuretic peptide (BNP), World Health Organization (WHO) functional class, safety and adverse events.

The mPAP, BNP and WHO functional class significantly improved in total. In the transitioned group, BNP significantly decreased by −116.5±188.6 pg/ml (P=0.0156). The 6MWD, mPAP, PVR, CI, and PaO2 improved but not significantly. The baseline condition was significantly more severe in the transitioned than in the new or add-on group. No patients discontinued riociguat. Relatively rapid transitioning from PDE5i to riociguat was safe under careful observation.

Conclusions

Transitioning to riociguat may be safe and effective in CTEPH patients with inadequate clinical responses to PDE5i.

Introduction

Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening disease that is characterized by increased pulmonary vascular remodeling, which can ultimately lead to right heart failure and death [1].

Pulmonary endarterectomy (PEA) is a promising treatment for the patients with surgically accessible lesions. However, in the large European CTEPH registry, 37% of patients were considered inoperable, and 17% of the patients had persistent pulmonary hypertension (PH) after PEA [2]. Riociguat belongs to a novel class of the soluble guanylate cyclase stimulators (sGCs) and was approved worldwide as the first medication for CTEPH. In a recent, large, randomized controlled trial (RCT), the Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1 (CHEST-1), riociguat significantly improved the 6-minute walk distance (6MWD), pulmonary vascular resistance (PVR), N-terminal pro-brain natriuretic peptide (NT-Pro BNP), and World Health Organization (WHO) functional class at week 16 for patients with inoperable CTEPH or persistent or recurrent pulmonary hypertension after PEA [3].　The long-term extension study, CHEST-2, also showed that improvements in the 6MWD and WHO functional class persisted for up to 1 year [1].

So far, specific treatments for pulmonary arterial hypertension (PAH) including phosphodiesterase 5 inhibitors (PDE5i) have revealed varying degrees of efficacy even in CTEPH [4], [5], [6].

Endothelium-derived nitric oxide (NO) stimulates intracellular sGC resulting in increased levels of cGMP, which then acts to mediate smooth muscle relaxation. PDE5i prevent the degradation of cGMP by PDE 5 and prolong the actions of cGMP [7]. In contrast with PDE5i, stimulators of sGC have a double action. They directly stimulate sGC, both independently of and in synergy with NO [8]. There were potentially undesired effects with sildenafil plus riociguat and no evidence of a positive benefit/risk ratio. Therefore, the concomitant use of riociguat with PDE5i is contraindicated [9]. Accordingly, the change from PDE5i to riociguat is an obvious choice. However, in the CHEST-1 study, 37% of screened patients were excluded only by the judgment of experienced surgeons in expert surgical centers. In the clinical setting, the candidates for riociguat are CTEPH patients whose risk-benefit for PEA is low, patients who have comorbidities, and patients with a relatively peripheral type of disease. Also, patients who were treated with ERA, PDE5i and prostacyclin analogues were excluded in CHEST-1 [3]. Accordingly, the effectiveness and safety in the clinical setting are not clear.

In this study, our hypothesis was that riociguat is safe and effective in the real world, including in the above-mentioned patients, and we evaluated the efficacy and safety of riociguat for the patients who were naïve to pulmonary vasodilators, who received riociguat newly added to previous vasodilators, and who were transitioned from PDE5i to riociguat.

Section snippets

Patients and methods

This study prospectively evaluated 32 consecutive patients with CTEPH who were first prescribed riociguat between June 2014 and July 2015 at Chiba University Hospital. CTEPH was defined as a mean pulmonary arterial pressure (mPAP) of ≥25 mmHg with normal wedge pressure on right heart catheterization (RHC) and dyspnea for more than 6 months [10]. Lung perfusion scans were also required that revealed segmental or larger defects concomitant with normal ventilation scans. Findings suggestive of

Results

When we compared the clinical characteristics between the transitioned and the new or add-on groups, the mean age was significantly higher in the transitioned group. The mPAP and PVR were significantly higher in the transitioned group. The 6MWD also significantly deteriorated in the transitioned group (Table 1). The detailed clinical characteristics are also shown in the supplemental file (see the Supplemental file, Table 1), in which we divided the new or add-on group into two: the patients

Discussion

In this study, we prescribed riociguat safely in the patients transitioned from PDE5i as well as in new or add-on patients. We demonstrated the efficacy of this drug on mPAP, BNP and WHO functional class in the real world similar to a report from a previous RCT [11]. More importantly, we found that riociguat improved BNP in patients transitioned from PDE5i to riociguat treatment. In the transitioned group, there was no significant hemodynamic improvement. However, a tendency toward improvement

Limitations

There are several limitations of this study. It was a single-institution study and did not have a control group. There was a selection bias because some patients, especially in the transitioned group, were prescribed riociguat because of an unsatisfactory clinical response to previous treatments. The number of subjects was small, especially in the subclassified groups, and the statistical power was low. We did not evaluate the long-term effects.

Conclusion

In conclusion, riociguat for patients with CTEPH was safe and showed clinical efficacy.

Transitioning to riociguat may be safe and effective in CTEPH patients with inadequate clinical responses to PDE5i.

Conflicts of interest statement

NT is a member of an endowed department sponsored by Acterion Pharmaceuticals Japan Ltd and received lecture honoraria from Acterion Pharmaceuticals Japan Ltd, Bayer Yakuhin Ltd, and DAIICHI SANKYO COMPANY, Ltd. NT received donations from Nippon Shinnyaku Co., Ltd. SS received Lecture honoraria from Nippon Shinyaku Co., Ltd.TJ, RN and AS are members of an endowed department sponsored by Acterion Pharmaceuticals Japan Ltd. We declare that no funding sources influenced the preparation of any part

Acknowledgement

This study was supported in part by a grant of the Respiratory Failure Research Group from the Ministry of Health, Labor and Welfare of Japan (H26-Intractable Diseases-General-076), and a grant of the Pulmonary Hypertension Research Group from the Japan Agency for Medical Research and Development, AMED (15ek0109127h0001).

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Up to 50 % of patients surviving a pulmonary embolism (PE) report persisting shortness of breath, reduced physical capacity and psychological distress. As the PE population is heterogeneous compared to other cardiovascular patient groups, outcome measures for assessing physical capacity traditionally used in cardiac populations may not be reliable for the PE population as a whole. This scoping review aims to 1) map performance-based outcome measures (PBOMs) used for assessing physical capacity in PE research, and 2) to report the psychometric properties of the identified PBOMs in a PE population.
The review was conducted according to the Joanna Briggs Institute framework for scoping reviews and reported according to the PRISMA-Extension for Scoping Reviews guideline.
The systematic search of five databases identified 4585 studies, of which 243 studies met the inclusion criteria. Of these, 185 studies focused on a subgroup of patients with chronic thromboembolic pulmonary hypertension. Ten different PBOMs were identified in the included studies. The 6-minute walk test (6MWT) and cardiopulmonary exercise test (CPET) were the most commonly used, followed by the (Modified) Bruce protocol and Incremental Shuttle Walk test. No studies reported psychometric properties of any of the identified PBOMs in a PE population.
Publication of studies measuring physical capacity within PE populations has increased significantly over the past 5–10 years. Still, not one study was identified, reporting the validity, reliability, or responsiveness for any of the identified PBOMs in a PE population. This should be a priority for future research in the field.
Successful Transition From Phosphodiesterase-5 Inhibitors to Riociguat Without a Washout Period in Patients With Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: A Pilot Cohort Study
2020, Heart Lung and Circulation
Citation Excerpt :
Ten (10) patients had episodes of hypotension and six experienced clinical worsening. Yamamoto et al. [14] studied the transition from a PDE5i to riociguat in eight patients with CTEPH and an inadequate response to PDE5i. Brain natriuretic peptide levels were significantly improved, and 6MWD, mean PAP, PVR, and CI were improved, but this was not significant.
Transition to pulmonary arterial hypertension (PAH)-specific drugs is considered in patients with PAH and chronic thromboembolic pulmonary hypertension who do not respond to combination therapy or who experience side effects to the combination drugs. Riociguat directly stimulates soluble guanylate cyclase independently of nitric oxide. Therefore, transition from a phosphodiesterase type 5 inhibitor (PDE5i), which requires nitric oxide to exert its effects, to riociguat might be effective. The length of time of washout periods for transition is important because haemodynamic instability sometimes occurs during these periods or during transition with no washout period.
We investigated the feasibility of transitioning from a PDE5i to riociguat without washout periods by monitoring haemodynamics under right heart catheterisation in six patients with PAH and one with chronic thromboembolic pulmonary hypertension who had already received dual- or triple-combination therapy.
Reasons for transition were headache caused by a PDE5i in three patients, and an inadequate response to combination therapy in four. Transition was successful in all patients, with no haemodynamic instability observed. Pulmonary vascular resistance (from 797 ± 241 to 518 ± 230 dyne/s/cm^–5) and systemic blood pressure (from 121 ± 13 to 100 ± 15 mmHg) were significantly reduced immediately after transition. There were no significant differences in the tricuspid regurgitation pressure gradient or systemic blood pressure during the post-transition and follow-up periods. Headaches caused by a PDE5i were diminished after transition to riociguat.
Transition from a PDE5i to riociguat without a washout period is safe. This transition may be a viable option for patients with headaches caused by a PDE5i, or who have an inadequate response to combination therapy that includes a PDE5i.
Long-term clinical value and outcome of riociguat in chronic thromboembolic pulmonary hypertension
2019, IJC Heart and Vasculature
Citation Excerpt :
In our cohort we also included patients with a longer CTEPH disease history or who were already on other PAH medication, as patients in daily practice often switch between therapies to achieve maximal treatment effect or due to adverse events. In addition, a recent study reported improved WHO FC and pulmonary hemodynamics after a switch from sildenafil to riociguat [17], although another research showed that a switch may not be as effective as direct initiation of riociguat [18]. However, the patients in this transition group were older and had more severe CTEPH disease [18].
To improve clinical outcome, patients with inoperable and residual chronic thromboembolic pulmonary hypertension (CTEPH) can be treated with riociguat. The aim of this study is to explore long-term outcomes and to compare our ‘real world’ data with previous research.
We included all consecutive patients with technical inoperable and residual CTEPH, in whom riociguat therapy was initiated from January 2014 onwards, with patients followed till January 2019. Survival, clinical worsening (CW), functional class (FC), N-terminal pro brain natriuretic peptide (NT-proBNP) and 6-minute walking distance (6MWD) were described yearly after riociguat initiation.
Thirty-six patients (50% female, mean age 64.9 ± 12.1 years, 54% WHO FC III/IV and 6MWD 337 ± 138 m could be included, with a mean follow-up of 2.3 ± 1.2 years. Survival and CW-free survival three years after initiation of riociguat were 94% and 78%, respectively. The 6MWD per 10 m at baseline was a significant predictor (HR 0.90 [0.83–0.97], p = 0.009) for CW. At three years follow-up the WHO FC and 6MWD improved and NT-proBNP decreased compared to baseline.
Our study confirms that riociguat is an effective treatment in patients with technical inoperable and residual CTEPH at long-term follow-up. Although our results are consistent with previous studies, more ‘real world’ research is necessary to confirm long-term results.
Efficacy and safety of riociguat replacing PDE-5is for patients with pulmonary arterial hypertension: A systematic review and meta-analysis
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Optimization of specific therapy for pulmonary hypertension: The possibilities of riociguat
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Comparison of Balloon Pulmonary Angioplasty and Pulmonary Vasodilators for Inoperable Chronic Thromboembolic Pulmonary Hypertension: A Systematic Review and Meta-Analysis
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Original articleRiociguat for patients with chronic thromboembolic pulmonary hypertension: Usefulness of transitioning from phosphodiesterase type 5 inhibitor

Abstract

Background

Methods and results

Conclusions

Introduction

Section snippets

Patients and methods

Results

Discussion

Limitations

Conclusion

Conflicts of interest statement

Acknowledgement

J Am Coll Cardiol

Chest

Rev Esp Cardiol

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

Eur Respir J

Riociguat for the treatment of chronic thromboembolic pulmonary hypertension

New Engl J Med

Sildenafil for long-term treatment of nonoperable chronic thromboembolic pulmonary hypertension

Am J Respir Crit Care Med

Long-term treatment with sildenafil in chronic thromboembolic pulmonary hypertension

Eur Respir J

Sildenafil in the treatment of pulmonary hypertension

Vasc Health Risk Manag

Riociguat: patent-1 study

Glob Cardiol Sci Pract

Original article
Riociguat for patients with chronic thromboembolic pulmonary hypertension: Usefulness of transitioning from phosphodiesterase type 5 inhibitor