Cluster analysis identifies novel real-world lung disease-pulmonary hypertension subphenotypes: implications for treatment response

• Published in: ERJ open research Vol. 10; no. 3; p. 959
• Main Authors: Johnson, Shelsey W, Wang, Rui-Sheng, Winter, Michael R, Gillmeyer, Kari R, Zeder, Katarina, Klings, Elizabeth S, Goldstein, Ronald H, Wiener, Renda Soylemez, Maron, Bradley A
• Format: Journal Article
• Language: English
• Published: England European Respiratory Society 01.05.2024
• Subjects: Original s
• ISSN: 2312-0541; 2312-0541
• DOI: 10.1183/23120541.00959-2023

Clinical trials repurposing pulmonary arterial hypertension (PAH) therapies to patients with lung disease- or hypoxia-pulmonary hypertension (PH) (classified as World Health Organization Group 3 PH) have failed to show a consistent benefit. However, Group 3 PH clinical heterogeneity suggests robust phenotyping may inform detection of treatment-responsive subgroups. We hypothesised that cluster analysis would identify subphenotypes with differential responses to oral PAH therapy. Two k-means analyses were performed on a national cohort of US veterans with Group 3 PH; an inclusive model (I) of all treated patients (n=196) and a haemodynamic model (H) limited to patients with right heart catheterisations (n=112). The primary outcome was organ failure or all-cause mortality by cluster. An exploratory analysis evaluated within-cluster treatment effects. Three distinct clusters of Group 3 PH patients were identified. In the inclusive model (C1 n=43, 21.9%; C2 n=102, 52.0%; C3 n=51, 26.0%), lung disease and spirometry drove cluster assignment. By contrast, in the haemodynamic model (C1 n=44, 39.3%; C2 n=43, 38.4%; C3 n=25, 22.3%), right heart catheterisation data surpassed the importance of lung disease and spirometry. In the haemodynamic model, compared to C3 , C1 experienced the greatest hazard for respiratory failure or death (HR 6.1, 95% CI 3.2-11.8). In an exploratory analysis, cluster determined treatment response (p=0.006). Conclusions regarding within-cluster treatment responses were limited by significant differences between select variables in the treated and untreated groups. Cluster analysis identifies novel real-world subphenotypes of Group 3 PH patients with distinct clinical trajectories. Future studies may consider this methodological approach to identify subgroups of heterogeneous patients that may be responsive to existing pulmonary vasodilatory therapies.