Infl uence Of Age In The Assessment Of Therapeutic Response In Patients With Pulmonary Arterial Hypertension

Background in patients with pulmonary arterial hypertension (PAH) current European guidelines recommend achieving a low-risk profile, primarily based on World Health Organization functional class (WHO-FC), 6-minute walk distance (6MWD), and natriuretic peptides (BNP/NT-proBNP). However, these non-invasive parameters are influenced by age. We investigated the impact of age on treatment response and evaluated the prognostic role of haemodynamic-based risk assessments. Methods treatment-naïve PAH patients from a single-centre registry were included, stratified by age. Clinical, functional, and haemodynamics were assessed at baseline and after initial PAH-targeted therapy. Prognostic discrimination was performed using non-invasive (ESC/ERS 4-strata, REVEAL Lite 2) and haemodynamic-based risk models (including a purely haemodynamic - RHC - risk tool and its combination with WHO-FC, 6MWD, and BNP/NT-proBNP - COMPERA-RHC) with Cox regression and c-statistics. Results 794 PAH patients were enrolled. Elderly individuals exhibited worse WHO-FC (WHO-FC III/IV: 84% vs 63%, p-value <0.001), higher BNP/NT-proBNP levels (intermediate-high/high values: 65% vs 46%, p-value <0.001), and shorter 6MWD (312 m vs 424 m, p-value <0.001), despite lower right ventricular (RV) afterload (mean pulmonary arterial pressure: 44 mmHg vs 56 mmHg, p-value <0.001; pulmonary vascular resistance: 9.1 WU vs 11.6 WU, p-value <0.001; pulmonary arterial compliance 1.08 ml/mmHg vs 0.94 ml/mmHg, p-value= 0.013; pulmonary arterial elastance 1.47 mmHg/ml vs 1.83 mmHg/ml, p-value <0.001), likely due to comorbidities and worse RV function. In older patients, non-invasive risk tools overestimated RHC risk tool severity and demonstrated a reduced prognostic accuracy, comparable to RHC risk tool (ESC/ERS 4-strata c-index 0.65, REVEAL Lite 2 c-index 0.66, RHC-risk tool c-index 0.66). In patients >65 years reaching a low-risk haemodynamic profile, non-invasive risk tools were of no added prognostic value [ESC/ERS 4-strata HR (95% CI) 1.53 (0.99-2.36); p-value 0.056, REVEAL Lite 2 HR (95% CI) 1.30 (0.84-2.01); p-value 0.240]. Conversely, haemodynamics provided independent prognostic information in patients younger than 44 years (ESC/ERS 4-strata c-index 0.68, REVEAL Lite 2 c-index 0.68, RHC-risk tool c-index 0.73). Conclusions haemodynamics is less influenced by age than non-invasive risk assessment and is of added prognostic value to non-invasive assessment in younger patients. Achieving a low-risk haemodynamic profile can be a valid therapeutic target when non-invasive criteria are not met in patients >65 years.