CHEST

CHEST

Volume 161, Issue 2, February 2022, Pages 448-457
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Diffuse Lung Disease: Original Research
Riociguat for Sarcoidosis-Associated Pulmonary Hypertension: Results of a 1-Year Double-Blind, Placebo-Controlled Trial

https://doi.org/10.1016/j.chest.2021.07.2162Get rights and content

Background

Riociguat is effective in delaying the time to clinical worsening (TCW) in patients with groups 1 and 4 pulmonary hypertension.

Research Question

Is riociguat more effective than placebo in prolonging TCW in sarcoidosis-associated pulmonary hypertension (SAPH)?

Study Design and Methods

This was a double-blind placebo-controlled trial. Patients with SAPH confirmed by right heart catheterization were randomized 1:1 to riociguat or placebo. Patients underwent 6-min walk distance (6MWD) and spirometry testing every 8 weeks. The primary end point was TCW, which was defined by the time to the first of the following: (1) all-cause mortality, (2) need for hospitalization because of worsening cardiopulmonary status attributable to progression of disease, (3) > 50 m decrease in the 6MWD test, or (4) worsening of World Health Organization functional class.

Results

A total of 16 patients were randomized to riociguat (n = 8) or placebo (n = 8). No difference was found in pulmonary artery mean, pulmonary vascular resistance, initial 6MWD, or FVC between the two groups. Five of eight patients who received placebo met TCW criteria, whereas none of the patients who received riociguat experienced a qualifying event. By log-rank analysis, patients who received riociguat were in the study for a significantly longer period (χ 2 = 6.259; P = .0124). The 6MWD decreased in the placebo group (median, –55.9 m; range, –176.8 to 60 m), but rose in the riociguat group (median, +42.7 m; range, –7.5 to +91.4 m; P = .0149), with a placebo-corrected difference of 94 m (P < .01). Four of eight patients who received riociguat, but only 1 of 8 patients who received placebo, showed a > 30-m improvement in 6MWD (P > .05). No significant adverse events associated with riociguat occurred.

Interpretation

Over the 1 year of the study, riociguat was effective in preventing clinical worsening and improving exercise capacity in patients with SAPH.

Section snippets

Methods

This was a multicenter trial of patients older than 18 years with a diagnosis of sarcoidosis14 and SAPH confirmed by right heart catheterization. For this study, the diagnosis of SAPH required a pulmonary artery (PA) pressure mean of ≥ 25 mm Hg and a PA occlusion pressure of ≤ 15 mm Hg,15 in accordance with the reports from the PH 5th World Symposium.16 Patients with mean PA pressure of 21 to 24 mm Hg were not included in this study. Patients with known postcapillary or pulmonary venoocclusive

Results

A total of 17 patients from four centers provided written consent for participation in the study. One patient was a screening failure, and the remaining 16 patients (eight in each arm) were randomized (Fig 1).24 All 16 patients were receiving riociguat at a dose of 2.5 mg three times daily or the placebo equivalent by week 12. One patient in the riociguat arm did not comply, was withdrawn from the study after 3 months of therapy, and completed the end-of-study visit. Table 1 summarizes the

Discussion

In this double-blind, placebo-controlled trial, we found that 48 weeks of riociguat therapy was associated with a significant delay in TCW compared with placebo. Our TCW used predefined criteria, including death, transplantation, hospitalization for progression of disease, or decrease in 6 MWD of > 50 m. In this study, all the TCW events were heralded by a > 50-m decrease in 6MWD.

The approval of most medications for the treatment of PAH have relied on surrogate markers as end points, including

Interpretation

In conclusion, this small 1-year double-blind placebo-controlled randomized controlled trial of riociguat in SAPH demonstrated significant improvement in 6MWD and a prolonged TCW for riociguat compared with placebo. This supports the implementation of a larger phase 3 clinical trial of riociguat for this specific indication with a number of lessons to be learned from this small study in the design of any such future program.

Acknowledgments

Author contributions: R. P. B. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis, including and especially any adverse effects. R. P. B., O. A. S., R. G., P. J. E., J. I. S., E. E. L., F. F. R., J. Z., and S. D. N. contributed substantially to the study design, data analysis and interpretation, and the writing of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the

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    FUNDING/SUPPORT: This study was supported by an investigational grant from Bayer Pharmaceuticals and the National Institutes of Health [Grant 2UL1TR001425-05A1].

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