Right ventricular size and function under riociguat in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (the RIVER study)

Alberto M Marra, Michael Halank, Nicola Benjamin, Eduardo Bossone, Antonio Cittadini, Christina A Eichstaedt, Benjamin Egenlauf, Satenik Harutyunova, Christine Fischer, Henning Gall, Hossein Ardeschir Ghofrani, Marius M Hoeper, Tobias J Lange, Karen M Olsson, Hans Klose, Ekkehard Grünig, Alberto M Marra, Michael Halank, Nicola Benjamin, Eduardo Bossone, Antonio Cittadini, Christina A Eichstaedt, Benjamin Egenlauf, Satenik Harutyunova, Christine Fischer, Henning Gall, Hossein Ardeschir Ghofrani, Marius M Hoeper, Tobias J Lange, Karen M Olsson, Hans Klose, Ekkehard Grünig

Abstract

Background: Riociguat is a soluble guanylate cyclase stimulator approved for pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTPEH). The objective of this study was to evaluate right heart size and function assessed by echocardiography during long term treatment with riociguat.

Methods: Patients who started riociguat treatment (1.0-2.5 mg tid) within the trials phase II, PATENT, PATENTplus, EAS, CHEST and continued treatment for 3-12 months were included in this study. Echocardiography was analysed off-line at baseline, after 3, 6 and 12 months by investigators who were blinded to clinical data. Last and baseline observation carried forward method (LOCF, BOCF) were performed as sensitivity analysis.

Results: Seventy-one patients (45% PAH, 55% CTEPH; 53.5% female; 60 ± 13 years, mean pulmonary arterial pressure 46 ± 10 mmHg, mean PVR 700 ± 282dynes·sec·cm-5) were included. After 6 months, RA and RV area, RV thickness tricuspid regurgitation velocity showed a significant reduction. After 12 months, patients receiving riociguat therapy showed a significant reduction in right atrial (- 2.6 ± 4.4 cm2, 95% CI -3.84, - 1.33; p < 0.001, n = 49) and right ventricular (RV) area (- 3.5 ± 5.2 cm2, 95% CI -5.1, - 1.9; p < 0.001; n = 44), RV thickness (- 0.76 ± 2.2 mm, 95% CI -1.55, 0.03; n = 32), and a significant increase in TAPSE (2.95 ± 4.78 mm, 95% CI 1.52, 4.39; n = 45) and RV fractional area change (8.12 ± 8.87 mm, 95% CI 4.61, 11.62; n = 27). Both LOCF and BOCF showed similar results but lower effect sizes.

Conclusion: Patients under long-term treatment with riociguat show significantly reduced right heart size and improved RV function in PAH and CTEPH. Further controlled prospective studies are needed to confirm these results.

Keywords: Chronic thromboembolic pulmonary hypertension; Echocardiography; Pulmonary arterial hypertension; Pulmonary hypertension; Right atrial area; Right heart size; Right ventricular function; Riociguat; Soluble guanylate cyclase stimulator.

Conflict of interest statement

Ethics approval and consent to participate

All riociguat studies were approved by the ethics committees of the respective centers. All data were double-pseudonymized. The ethics committee of the medical faculty, University of Heidelberg had no objection against the retrospective analysis of echocardiographic data within this study (S668–2015).

Consent for publication

Not applicable

Competing interests

AMM: received grants from Italian Helthcare Ministry, grant for young researchers “Ricerca finalizzata 2016 per giovani ricercatori” n. GR-2016-02364727, personal lecture fee from Bayer Healthcare.

MH: Fees for consulting and/or lectures and conference expenses from Actelion, Bayer, Gilead, GSK, Merck, Novartis, OMT and Pfizer.

NB: speaker honoraria from Actelion pharmaceuticals.

EB: nothing to disclose.

AC: nothing to disclose.

CAE: nothing to disclose.

BE: nothing to disclose.

CF: nothing to disclose.

HG: has received support and/or honoraria from Actelion, AstraZeneca, Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Janssen Cilag, Lilly, Merck Sharp Dohme, Novartis, Pfizer, and United Therapeutics/OMT.

HAG: received fees for lectures and/or consulting from Actelion, Bayer, Gilead, GSK, MSD, Novartis, Pfizer and United Therapeutics.

MMH: Fees for consulting and/or lectures from Actelion, Bayer, Gilead, GSK, Merck and Pfizer.

TJL: received fees for lectures and/or consulting and/or research support to institution from Actelion, AOP orphan/OMT, Bayer, GSK, Pfizer, United Therapeutics.

KMO: speaker and consultancy fees from Actelion pharmaceuticals.

HK: received fees for talks and/or consulting work from Actelion, Bayer, MSD, GSK and Pfizer; research funding from GSK, Actelion and Bayer.

EG: received fees for talks and/or consulting work from Actelion, Bayer, GSK, MSD, Novartis, Pfizer and United Therapeutics. Research funding from GSK, Actelion and Bayer.

Publisher’s Note

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Figures

Fig. 1
Fig. 1
RIVER study Flow-Chart. All patients with PAH (PATENT-1 and 2, PATENTplus) or CTEPH (CHEST-1 and 2, Early Access Study) randomized into one of the trials (i.e. for whom study medication had been assigned and a package had been opened) and who had at least once been administered study medication were eligible for the study, if echocardiography had been routinely performed at baseline and at least once during the course of the trial
Fig. 2
Fig. 2
Right atrial and right ventricular areas in patients who completed all four echocardiographic assessments. Patients who completed echocardiographic assessments at baseline, 3, 6 and 12 months showed a significant reduction of right atrial and right ventricular areas for all time points. Values are given as mean ± standard error of the mean

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