Exercise capacity and haemodynamics in patients with sickle cell disease with pulmonary hypertension treated with bosentan: results of the ASSET studies

Abstract

Doppler-defined pulmonary hypertension (PH) in sickle cell disease (SCD) is associated with 40% mortality at 40 months. To assess the effect of bosentan in SCD-PH, two randomized, double-blind, placebo-controlled, 16-week studies were initiated. Safety concerns are particularly relevant in SCD due to comorbid conditions. ASSET-1 and -2 enrolled patients with pulmonary arterial hypertension (PAH) and pulmonary venous hypertension (PH), respectively. Haemodynamics and 6-min walk distance (6MWD) were obtained at baseline and week 16. The studies were terminated due to slow site initiation and patient enrolment (n = 26). Bosentan appeared to be well tolerated. Although sample sizes were limited, in ASSET-1 at baseline, 6MWD correlated with cardiac output (CO; P = 0.006) with non-significant inverse correlations between 6MWD and pulmonary vascular resistance (PVR; P = 0.07) and between 6MWD and right atrial pressure (P = 0.08). In ASSET-2 at baseline, there was a non-significant correlation between 6MWD and CO (P = 0.06). Due to limited sample sizes, efficacy endpoints were not analysed. However, in both studies, non-significant increases in CO were observed with bosentan compared to placebo. Similarly, non-significant decreases in PVR were observed with bosentan. Limited data in SCD-PH suggest that a low 6MWD predicts a low CO. Standard-dose bosentan appears to be well tolerated. Further investigation is warranted. Clinicaltrials.gov registration numbers NCT00310830, NCT00313196, NCT00360087.

Conflict of interest statement

Disclosures: RJ Barst, RL Benza, KK Mubarak, R Naeije, N Sood, KI Ataga and PS Swerdlow have received consultancy fees and research grant funding from Actelion Pharmaceuticals Ltd. M T Gladwin and R Machado received grant support in the form of a Clinical Trials Agreement between the National Institutes of Health and Actelion Pharmaceuticals Ltd. O Castro is a paid consultant at the National Heart, Lung, and Blood Institute. M Hildesheim has no conflicts to disclose.

Figures

Fig 1. ASSET-1 and ASSET-2 Study Design

Patients in both ASSET-1 and ASSET-2 were screened and randomized 1:1 to bosentan or matching placebo based upon inclusion/exclusion criteria. After 4 weeks, bosentan dose was increased from 62Æ5 mg b.i.d. to 125 mg b.i.d with a placebo dummy up-titration. At the end of 16 weeks of study drug, patients had the option to enter into the ASSET-3 open-label study.

Fig 2. Patient Disposition

The number of patients from each study that completed each protocol phase.

Fig 3. ASSET-1 Baseline Measurement Correlations

6-minute walk distance (6MWD) and haemodynamic parameter correlations (Spearman’s rank correlation coefficients and P values).

Fig 3. ASSET-1 Baseline Measurement Correlations

6-minute walk distance (6MWD) and haemodynamic parameter correlations (Spearman’s rank correlation coefficients and P values).

Fig 3. ASSET-1 Baseline Measurement Correlations

6-minute walk distance (6MWD) and haemodynamic parameter correlations (Spearman’s rank correlation coefficients and P values).

Fig 4. ASSET-2 Baseline Measurement Correlations

6-minute walk distance (6MWD) and haemodynamic parameter correlations (Spearman’s rank correlation coefficients and P values).

Fig 4. ASSET-2 Baseline Measurement Correlations

6-minute walk distance (6MWD) and haemodynamic parameter correlations (Spearman’s rank correlation coefficients and P values).

Fig 5. Changes in 6-Minute Walk Distances (6MWDs)

Changes from baseline to Week 16 are shown for all patients in ASSET-1 and ASSET-2. Black bars indicate median 6MWD values.

Fig 5. Changes in 6-Minute Walk Distances (6MWDs)

Changes from baseline to Week 16 are shown for all patients in ASSET-1 and ASSET-2. Black bars indicate median 6MWD values.

Fig 5. Changes in 6-Minute Walk Distances (6MWDs)

Changes from baseline to Week 16 are shown for all patients in ASSET-1 and ASSET-2. Black bars indicate median 6MWD values.

Fig 5. Changes in 6-Minute Walk Distances (6MWDs)

Changes from baseline to Week 16 are shown for all patients in ASSET-1 and ASSET-2. Black bars indicate median 6MWD values.

Fig 6. Changes in Pulmonary Vascular Resistance (PVR)

Changes from baseline to Week 16 are shown for all patients in ASSET-1 and ASSET-2. Black bars indicate median PVR values.

Fig 6. Changes in Pulmonary Vascular Resistance (PVR)

Changes from baseline to Week 16 are shown for all patients in ASSET-1 and ASSET-2. Black bars indicate median PVR values.

Fig 6. Changes in Pulmonary Vascular Resistance (PVR)

Changes from baseline to Week 16 are shown for all patients in ASSET-1 and ASSET-2. Black bars indicate median PVR values.

Fig 6. Changes in Pulmonary Vascular Resistance (PVR)

Changes from baseline to Week 16 are shown for all patients in ASSET-1 and ASSET-2. Black bars indicate median PVR values.