Highlight
– Riociguat treatment in early pulmonary vascular disease (PVD) significantly reduced pulmonary vascular resistance (PVR) compared to placebo over 24 weeks.
– The trial was conducted in a predominantly female cohort with connective tissue disease-associated pulmonary arterial hypertension (PAH).
– Secondary endpoints and exploratory outcomes showed trends but no statistically significant improvements.
– Riociguat was well tolerated with no serious treatment-related adverse events reported.
Study Background
Pulmonary arterial hypertension (PAH) is a progressive vascular disorder characterized by increased pulmonary vascular resistance leading to right heart failure and premature death. Despite advances in PAH therapies targeting vasodilation and vascular remodeling, most clinical trials have focused on patients with established moderate-to-severe disease. Early-stage pulmonary vascular disease (PVD), identified by mildly elevated mean pulmonary arterial pressure (mPAP) and modest pulmonary vascular resistance (PVR) elevations, remains understudied despite the potential that early intervention could halt or slow disease progression and improve long-term outcomes.
Riociguat, a soluble guanylate cyclase stimulator, enhances nitric oxide signaling to induce vasodilation and has proven efficacy in established PAH. However, its efficacy and safety profile in early PVD have not been systematically explored. This trial aimed to evaluate riociguat’s effects on hemodynamic and functional parameters in patients with early PVD, including those with PAH associated with connective tissue diseases, a group at particular risk for disease progression and morbidity.
Study Design and Methods
This prospective, multicenter, double-blind, placebo-controlled phase IIa trial enrolled adults with early pulmonary vascular disease defined by two hemodynamic criteria: (1) mPAP ≥25 mmHg with PVR between ≥2 and <3 Wood Units (WU), or (2) mPAP 21 to <25 mmHg with PVR ≥2 WU. These thresholds represent a borderline or mildly elevated pulmonary pressure and resistance indicative of early pathological changes.
Eligible participants were randomized 1:1 to receive riociguat or placebo for 24 weeks. The primary efficacy endpoint was the change in PVR from baseline to week 24, as measured by right heart catheterization, reflecting direct assessment of pulmonary vascular load. Secondary endpoints, evaluated in a hierarchical manner, included changes in cardiac index (a measure of heart pumping efficiency), total pulmonary resistance, diffusing capacity of the lung for carbon monoxide (DLCO), six-minute walking distance (6MWD), WHO functional class, and quality of life (QoL) metrics. Additional exploratory biomarkers and parameters were also documented to explore potential mechanisms and broader clinical impacts. Safety data were collected throughout the study period.
Key Findings
Among 261 patients pre-screened, 35 met strict eligibility and were randomized, with a high predominance of females (97%) and an average age of 65.5 years. Most patients (77.1%) had connective tissue disease-associated PAH—reflecting a high-risk subgroup often underrepresented in early intervention trials. Thirty-two participants completed the trial.
Primary Endpoint: Riociguat produced a statistically significant reduction in PVR compared to placebo. Mean change in PVR was -0.73 ± 0.67 WU for riociguat versus -0.02 ± 0.67 WU for placebo, corresponding to a 27% placebo-adjusted reduction (p=0.043). This finding suggests riociguat effectively reduces pulmonary vascular load in early disease stages.
Secondary Endpoints: No statistically significant differences were observed in cardiac index, total pulmonary resistance, DLCO, 6MWD, WHO functional class, or QoL between treatment arms at 24 weeks. However, the limited sample size and relatively preserved functional status at baseline may have constrained the ability to detect changes.
Exploratory Outcomes: Cardiac output trended towards improvement with riociguat (mean change 0.35 ± 0.86 L/min vs. -0.19 ± 0.75 L/min for placebo; p=0.084), indicating a possible favorable hemodynamic effect worth further investigation.
Safety: Riociguat was well tolerated with only mild to moderate adverse events reported. No serious adverse events were considered related to treatment, supporting the safety profile in this early-stage population.
Expert Commentary
This phase IIa trial provides important preliminary evidence supporting the safety and efficacy of riociguat in early pulmonary vascular disease, particularly in a cohort dominated by connective tissue disease-associated PAH. The achieved reduction in PVR is clinically relevant as increased PVR is a key determinant of right ventricular afterload and disease progression.
Nevertheless, the study has limitations that temper conclusions. The small cohort size limits statistical power for secondary endpoints and exploration of clinical outcomes. The predominance of older females with connective tissue disease may restrict generalizability to other etiologies of PVD or PAH. Moreover, the 24-week treatment duration may be insufficient to appreciate functional improvements or changes in quality of life.
These results align biologically with riociguat’s mechanism targeting soluble guanylate cyclase, improving nitric oxide signaling and vasodilation in early pulmonary vascular remodeling. Early intervention in PVD could potentially modify disease trajectory, but future larger-scale, longer-term studies are needed to confirm these benefits and establish clinical outcome improvements.
Conclusion
The ESRA phase IIa trial demonstrates that riociguat is a safe therapeutic option that significantly decreases pulmonary vascular resistance in patients with early pulmonary vascular disease, primarily in connective tissue disease-associated PAH. While secondary functional and quality of life measures did not show significant changes, the trend in hemodynamic improvements supports further investigation. Early-stage intervention with riociguat may represent a promising approach to alter pulmonary vascular pathophysiology. Larger randomized controlled trials are needed to confirm clinical benefits and inform treatment guidelines in early PVD management.
Funding and Clinical Trial Registration
The study is registered on ClinicalTrials.gov under identifier NCT05339087. No specific funding details are provided in the source abstract.
References
1. Xanthouli P, Benjamin N, Coghlan G, et al. Efficacy and safety of riociguat in early pulmonary vascular disease (ESRA): a prospective, multicenter, randomized, double-blind, placebo-controlled phase IIa trial. Chest. 2026 Jul 15. PMID: 42457022.
2. Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2023;61(1):2200724.
3. Galiè N, Komócsi A, Barbera JA, et al. Riociguat for the treatment of pulmonary arterial hypertension: a review of clinical evidence. Eur Respir Rev. 2019;28(154):190036.
4. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension. Circulation. 2009;119(16):2250–2294.
