Abstract 2304: Clinical Deterioriation in WHO Functional Class II Patients with Pulmonary Arterial Hypertension - Results from EARLY, a Randomized, Double-Blind, Placebo-Controlled Trial
Purpose: Clinical worsening (CW) has been used as an endpoint in pulmonary arterial hypertension (PAH) trials to assess disease progression. In BREATHE-1, a trial with bosentan (BOS) in WHO functional class (FC) III/IV PAH patients (pts), CW was defined as the combined endpoint of: death, hospitalization for PAH, epoprostenol initiation, lung transplantation, premature discontinuation of treatment due to PAH worsening. In EARLY, the first trial to study FC II PAH pts exclusively, the definition of CW was adapted to assess disease progression in this less severely symptomatic population. A new endpoint, symptomatic progression of PAH, was included as one component of CW. We evaluated further its clinical relevance.
Methods: PAH pts ≥12 years (FC II) received BOS or placebo (PLC) double-blind for 6 months. CW was defined as death, hospitalization for PAH complications or symptomatic progression of PAH (new/worsening right heart failure, decrease from baseline in 6-minute walk distance (6MWD) in 2 consecutive tests (≥2 weeks apart) of ≥10%, or ≥5% with a ≥2-point increase in Borg dyspnea index.
Results: A total of 185 pts were enrolled (BOS, n=93; PLC, n=92). Baseline characteristics were similar between groups. Time to CW was significantly delayed in BOS-treated pts: Kaplan-Meier estimates of worsening (95%CI) at week 24: 3% (0,7) vs 11% (5,17), with a 77% reduction in hazard (p(log-rank)=0.0114). Three pts in the BOS group and 13 pts in the PLC group reached one endpoint of CW (BOS vs PLC, death: 1 pt vs 1 pt; hospitalization for PAH complications: 1 pt vs 3 pts). Symptomatic progression of PAH was seen in 1 pt in the BOS group vs 9 in the PLC group. Among these the clinical significance of progression was reinforced by an associated major reduction (>20%) in the 6MWD (when available) in 0/1 in the BOS vs 5/7 in the PLC group, by an increase in pulmonary vascular resistance (>20%) in 4/8 in the PLC group (not measured in the BOS group [1 pt]) and by a deterioration of ≥1 FC in 1/1 in the BOS and 6/8 in the PLC group, respectively.
Conclusions: The results suggest that inclusion of symptomatic progression of PAH as a component of the endpoint of CW is clinically relevant in mildly symptomatic PAH pts. This further supports the conclusion that BOS may delay time to CW in FC II pts.