Bosentan‐based, treat‐to‐target therapy in patients with pulmonary arterial hypertension: results from the COMPASS‐3 study

Abstract

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 ¼ 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 ¼ 308 m; week 28 ¼ 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 ¼ þ0.729, P < 0.0001]). cMRI-derived parameters predicted clinical worsening/decline (e.g. week 16 RVEDV:LVDEV [P ¼ 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.

Risk Assessment in Pulmonary Arterial Hypertension Patients: The Long and Short of it

“…47 Cardiac MRI-derived parameters, such as right ventricular and left ventricular volumes and ratios, mass, and ejection fraction correlate with traditional measures of functional status, including 6MWD, 46,48,49 hemodynamics, 50 and survival. [50][51][52][53][54] In addition, viewing MRI parameters in the context of other standard risk parameters may allow us a better spatial assessment of risk of the continuum of each individual factor ( Figure 6).…”

“…[50][51][52][53][54] In addition, viewing MRI parameters in the context of other standard risk parameters may allow us a better spatial assessment of risk of the continuum of each individual factor ( Figure 6). …”

The Use of Risk Assessment Tools and Prognostic Scores in Managing Patients with Pulmonary Arterial Hypertension

“…CMRI is being increasingly utilized as a clinical and research tool in PH. RV and LV end diastolic volume indices, RV mass index, RV stroke volume index, RVEF, and RV to LV ratios are all associated with other hemodynamic and functional surrogates of survival and importantly with survival itself in PAH [40-44]. Among these CMRI parameters, decrease in RVEF by 5% was the strongest predictor of mortality in PAH [45].…”

“…Lastly, viewing right and left ventricular morphometrics (RVEDV:LVEDV ratio) with hemodynamic parameters, particularly PVR, can add to the predictive value of each parameter individually (Fig. 3) [40].…”

Lessons from the COMPASS‐3 Study

“…Although a number of treatment goals have been described in PAH, 1 6-min walk distance (6MWD) has remained one of the most widely used measures in both PAH pivotal trials as well as in clinical practice. The Phase-4 multicenter COMPASS-3 study published in this issue of Pulmonary Circulation 2 sought to evaluate whether using a singular endpoint of 6MWD ≥ 380 m produced clinically meaningful outcomes in PAH. This study was conducted during 2007–2010, i.e.…”