Novel approach to classifying patients with pulmonary arterial hypertension using cluster analysis

Pulmonary arterial hypertension (PAH) patients have distinct disease courses and responses to treatment, but current diagnostic and treatment schemes provide limited insight. We aimed to see if cluster analysis could distinguish clinical phenotypes in PAH. An unbiased cluster analysis was performed on 17 baseline clinical variables of PAH patients from the FREEDOM-M, FREEDOM-C, and FREEDOM-C2 randomized trials of oral treprostinil versus placebo. Participants were either treatment-naïve (FREEDOM-M) or on background therapy (FREEDOM-C, FREEDOM-C2). We tested for association of clusters with outcomes and interaction with respect to treatment. Primary outcome was 6-minute walking distance (6MWD) change. We included 966 participants with 12-week (FREEDOM-M) or 16-week (FREEDOM-C and FREEDOM-C2) follow-up. Four patient clusters were identified. Compared with Clusters 1 (n = 131) and 2 (n = 496), Clusters 3 (n = 246) and 4 (n = 93) patients were older, heavier, had worse baseline functional class, 6MWD, Borg Dyspnea Index, and fewer years since PAH diagnosis. Clusters also differed by PAH etiology and background therapies, but not gender or race. Mean treatment effect of oral treprostinil differed across Clusters 1-4 increased in a monotonic fashion (Cluster 1: 10.9 m; Cluster 2: 13.0 m; Cluster 3: 25.0 m; Cluster 4: 50.9 m; interaction P value = 0.048). We identified four distinct clusters of PAH patients based on common patient characteristics. Patients who were older, diagnosed with PAH for a shorter period, and had worse baseline symptoms and exercise capacity had the greatest response to oral treprostinil treatment.