Dataset Information

Riociguat for pulmonary arterial hypertension associated with congenital heart disease.

ABSTRACT:

Objective

The Pulmonary Arterial hyperTENsion sGC-stimulator Trial-1 (PATENT-1) was a randomised, double-blind, placebo-controlled phase III trial evaluating riociguat in patients with pulmonary arterial hypertension (PAH). PATENT-2 was an open-label long-term extension to PATENT-1. Here, we explore the efficacy and safety of riociguat in the subgroup of patients with persistent/recurrent PAH after correction of congenital heart disease (PAH-CHD) from the PATENT studies.

Methods

In PATENT-1, patients received riociguat (maximum 2.5 or 1.5 mg three times daily) or placebo for 12 weeks; efficacy assessments included change from baseline to study end in 6-min walking distance (6MWD; primary), pulmonary vascular resistance (PVR), N-terminal of the prohormone of brain natriuretic peptide (NT-proBNP), WHO functional class (WHO FC) and time to clinical worsening. In PATENT-2, eligible patients from PATENT-1 received long-term riociguat (maximum 2.5 mg three times daily); the primary assessment was safety and tolerability. All PAH-CHD patients had a corrected cardiac defect.

Results

In PATENT-1, riociguat increased mean±SD 6MWD from baseline to week 12 by 39±60 m in patients with PAH-CHD versus 0±42 m for placebo. Riociguat also improved several secondary variables versus placebo, including PVR (-250±410 vs -66±632 dyn·s/cm(5)), NT-proBNP (-164±317 vs -46±697 pg/mL) and WHO FC (21%/79%/0% vs 8%/83%/8% improved/stabilised/worsened). One patient experienced clinical worsening (riociguat 1.5 mg group). Riociguat was well tolerated. In PATENT-2, riociguat showed sustained efficacy and tolerability in patients with PAH-CHD at 2 years.

Conclusions

Riociguat was well tolerated in patients with PAH-CHD and improved clinical outcomes including 6MWD, PVR, WHO FC and NT-proBNP.

Trial registration number

The clinical trials numbers are NCT00810693 for PATENT-1 and NCT00863681 for PATENT-2.

SUBMITTER: Rosenkranz S

PROVIDER: S-EPMC4680166 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: As the most common types of pulmonary arterial hypertension (PAH) in childhood, the similarities and differences in clinical characteristics and prognosis between idiopathic PAH (IPAH) and PAH associated with congenital heart disease (PAH-CHD) are not well-known. This study describes and compares clinical features of pediatric IPAH and PAH-CHD in a single center of China during an 11-year period and explores the prognostic factors. Methods: Twenty-five children with IPAH and 60 children with PAH-CHD, diagnosed in West China Second Hospital of Sichuan University from January 2008 to December 2018, were chosen as study objects. The follow-up deadline was June 2019, and the end-point was all-cause death. The baseline data, results of auxiliary examinations, treatment strategies, and follow-up outcomes were recorded and compared between IPAH and PAH-CHD patients to explore the similarities, differences, and prognostic factors. Results: The median diagnostic age for PAH-CHD patients was 2.3 years, which was younger than IPAH patients (7.3 years; p = 0.009). Sixty-eight percent of the IPAH patients presented with exercise-induced symptoms at initial diagnosis, whereas 58.3% of the PAH-CHD patients were asymptomatic (p < 0.001). Sixty percent of the IPAH patients were in World Health Organization-functional class (WHO-FC) III or IV, which was significantly worse than those of the PAH-CHD patients (p = 0.002). The incidence of ST-segment and T-wave (ST-T) change in children with IPAH (76.0%) was significantly higher than that (28.3%) in children with PAH-CHD (p < 0.001). Mean corpuscular volume (MCV), mean platelet volume (MPV), and platelet distribution width were larger in IPAH patients than those in PAH-CHD patients (p < 0.01). The 1-, 3-, and 5-year survival rates of IPAH and PAH-CHD patients were 53.5, 46.5, and 31.2% and 96.5, 93.1, and 77.6%, respectively (p < 0.05). WHO-FC III-IV [relative risk (RR) = 2.750, p = 0.008] and higher MPV (RR = 1.657, p = 0.006) predicted poor prognosis for pediatric PAH. Conclusion: We showed that there are more differences than similarities between IPAH and PAH-CHD patients in clinical characteristics. PAH-CHD patients have a better prognosis than IPAH patients. WHO-FC III-IV and higher MPV at initial diagnosis are independent risk factors for poor prognosis.

Project description:BackgroundDue to a special hemodynamic feature, pulmonary vascular disease in pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) has two stages: reversible and irreversible. So far, the mechanism involved in the transition from reversible to irreversible stage is elusive. Moreover, no recognized and reliable assessments to distinguish these two stages are available. Furthermore, we found that compared with control and reversible PAH, thrombospondin-4 (THBS4) was significantly upregulated in irreversible group by bioinformatic analysis. Hence, we further verify and investigate the expression and role of THBS4 in PAH-CHD.MethodsWe established the monocrotaline plus aorto-cava shunt-induced (MCT-AV) rat model. We measured the expression of THBS4 in lung tissues from MCT-AV rats. Double immunofluorescence staining of lung tissue for THBS4 and α-SMA (biomarker of smooth muscle cells) or vWF (biomarker of endothelial cells) to identify the location of THBS4 in the pulmonary artery. Primary pulmonary artery smooth muscle cells (PASMCs) were cultivated, identified, and used in this study. THBS4 was inhibited and overexpressed by siRNA and plasmid, respectively, to explore the effect of THBS4 on phenotype transformation, proliferation, apoptosis, and migration of PASMCs. The effect of THBS4 on pulmonary vascular remodeling was evaluated in vivo by adeno-associated virus which suppressed THBS4 expression. Circulating level of THBS4 in patients with PAH-CHD was measured by ELISA.ResultsTHBS4 was upregulated in the lung tissues of MCT-AV rats, and was further upregulated in severe pulmonary vascular lesions. And THBS4 was expressed mainly in PASMCs. When THBS4 was inhibited, contractile markers α-SMA and MYH11 were upregulated, while the proliferative marker PCNA was decreased, the endothelial-mensenchymal transition marker N-cad was downregulated, proapototic marker BAX was increased. Additionally, proliferation and migration of PASMCs was inhibited and apoptosis was increased. Conversely, THBS4 overexpression resulted in opposite effects. And the impact of THBS4 on PASMCs was probably achieved through the regulation of the PI3K/AKT pathway. THBS4 suppression attenuated pulmonary vascular remodeling. Furthermore, compared with patients with simple congenital heart disease and mild PAH-CHD, the circulating level of THBS4 was higher in patients with severe PAH-CHD.ConclusionsTHBS4 is a promising biomarker to distinguish reversible from irreversible PAH-CHD before repairing the shunt. THBS4 is a potential treatment target in PAH-CHD, especially in irreversible stage.