UCSF

The phase 4 COMPASS-3 study evaluated whether a singular endpoint produces clinically meaningful outcomes in patients with pulmonary arterial hypertension (PAH). The relationship between cardiac magnetic resonance imaging (cMRI)-derived parameters and right heart catheterization (RHC) measurements was also examined. In COMPASS-3 (ClinicalTrials.gov NCT00433329), 100 patients with PAH received bosentan monotherapy for 16 weeks. Patients continued monotherapy if their 6-min walk distance (6MWD) was ≥380 m, or otherwise received add-on sildenafil for an additional 12 weeks. 6MWD, RHC, and cMRI were performed at baseline, week 16, and week 28 (6MWD and cMRI). Baseline median 6MWD was 274 m and 82% of patients had WHO Functional Class III/IV. At week 16, 17% (n = 16) of remaining patients achieved the 6MWD threshold and 78 (83%) did not. In the intention-to-treat population, median 6MWD increased significantly relative to baseline (week 16 = 308 m; week 28 = 327 m; P < 0.001). At week 28, 9/16 (monotherapy) and 15/76 (20%; add-on sildenafil) patients met the target threshold. Baseline cMRI-derived and RHC-derived parameters showed moderate-to-strong correlations (e.g. right to left ventricular end-diastolic ratio [RVEDV:LVEDV] correlated strongly with pulmonary vascular resistance [r = +0.729, P < 0.0001]). cMRI-derived parameters predicted clinical worsening/decline (e.g. week 16 RVEDV:LVDEV [ P = 0.0172]). Time to clinical worsening/decline did not differ between patients based on 6MWD threshold achievement. No unexpected safety events were reported. A substantial proportion of patients failed to achieve the goal of 380 m, regardless of treatment. Several cMRI parameters predicted clinical worsening/decline and its non-invasive nature further supports its use in future clinical trials.