Early therapy failure in incident pulmonary arterial hypertension

Background Early clinical deterioration in incident pulmonary arterial hypertension (PAH) remains a major challenge despite contemporary combination therapy. Appropriate identification of patients at high risk of early life-threatening deterioration after treatment initiation (i.e. early treatment failure, ETF) may enable timely escalation to more aggressive therapeutic strategies. Purpose To investigate predictors of ETF in incident PAH and to assess their prognostic contribution beyond guideline-based risk stratification. Methods Incident Group 1 PAH patients from the multicentre FOCUS-PAH registry were analysed. ETF was defined as all-cause death or PAH-related hospitalization within 180 days of diagnosis. Patients without baseline PAH-specific therapy or with <180 days of potential follow-up in the absence of an event were excluded. Missing data were handled using multiple imputation by chained equations. Candidate predictors were screened by univariable logistic regression; variables with p<0.10 entered multivariable analysis after excluding collinear or conceptually overlapping covariates and those embedded in established risk tools. The final model was derived using backward elimination based on pooled Wald statistics, forcing age, sex, and the ESC/ERS three-strata risk score. A predefined subgroup analysis was performed in patients receiving upfront combination therapy. Results The study included 835 patients (mean age 58 ± 17 years; 64% female). ETF occurred in 60 patients (7.2%). In multivariable analysis, the ESC/ERS three-strata risk score was the strongest predictor of ETF (OR 3.25 per stratum increase; 95% CI 1.62–6.52; p=0.0009), together with age (OR 1.03 per year; 95% CI 1.01–1.05; p=0.0029) and tricuspid regurgitation severity (OR 1.51 per grade; 95% CI 1.06–2.16; p=0.0237). Among patients receiving upfront combination therapy (n=320, 38.3%), tricuspid regurgitation remained independently associated with ETF (OR 2.12; 95% CI 1.14–3.94; p=0.0185), whereas the ESC/ERS three-strata risk score did not. Conclusions In this large real-world cohort of incident PAH, ETF occurred in 7% of patients, attesting the complexity of these patients and the limitations of current therapeutic approaches. Beyond established risk stratification, TR severity identified patients at risk of very early deterioration, even under upfront combination therapy, suggesting a right-heart structural phenotype not fully captured by current guideline-based risk models.