Cluster Analysis Identifies Novel Real-world Lung Disease-pulmonary Hypertension Subphenotypes: Implications for Treatment Response

Overview

Journal ERJ Open Res

Specialty Pulmonary Medicine

Date 2024 May 21

PMID 38770008

Authors

Shelsey W Johnson

Rui-Sheng Wang

Michael R Winter

Kari R Gillmeyer

Katarina Zeder

Elizabeth S Klings

Ronald H Goldstein

Renda Soylemez Wiener

Bradley A Maron

Affiliations

Soon will be listed here.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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