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

Abstract

Clinical trials repurposing pulmonary arterial hypertension (PAH) therapies to patients with lung disease- or hypoxia-pulmonary hypertension (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 hypothesized that cluster analysis would identify sub-phenotypes with differential responses to oral PAH therapy.Two k-means analyses were performed on a national cohort of U.S. Veterans with Group 3 PH; an inclusive model (I) of all treated patients (n=196) and a hemodynamic model (H) limited to patients with right heart catheterisations (RHC) (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” (C1I=43, 21.9%; C2I=102, 52.0%; C3I=51, 26.0%) lung disease and spirometry drove cluster assignment whereas RHC data surpassed the importance of these variables in the hemodynamic model (C1H=44, 39.3%; C2H=43, 38.4%; C3H=25, 22.3%). In the hemodynamic model, compared to C3H, C1Hexperienced 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 sub-phenotypes of Group 3 PH patients with distinct clinical trajectories. Future studies may consider this methodologic approach to identify subgroups of heterogeneous patients that may be responsive to existing pulmonary vasodilatory therapies.