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Randomized Controlled Trial
. 2010 May;149(3):426-35.
doi: 10.1111/j.1365-2141.2010.08097.x. Epub 2010 Feb 17.

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

Robyn J Barst  1 , Kamal K Mubarak, Roberto F Machado, Kenneth I Ataga, Raymond L Benza, Oswaldo Castro, Robert Naeije, Namita Sood, Paul S Swerdlow, Mariana Hildesheim, Mark T Gladwin; ASSET study group*
Collaborators, Affiliations
Randomized Controlled Trial

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

Robyn J Barst et al. Br J Haematol. 2010 May.

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.

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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
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
Fig 2. Patient Disposition
The number of patients from each study that completed each protocol phase.
Fig 3
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
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
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
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
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
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
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
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
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
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
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
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
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.
See this image and copyright information in PMC

References

    1. Anthi A, Machado RF, Jison ML, Taveira-Dasilva AM, Rubin LJ, Hunter L, Hunter CJ, Coles W, Nichols J, Avila NA, Sachdev V, Chen CC, Gladwin MT. Hemodynamic and functional assessment of patients with sickle cell disease and pulmonary hypertension. Am J Respir Crit Care Med. 2007;175:1272–1279. - PMC - PubMed
    1. Ataga KI, Sood N, De Gent G, Kelly E, Henderson AG, Jones S, Strayhorn D, Lail A, Lieff S, Orringer EP. Pulmonary hypertension in sickle cell disease. Am J Med. 2004;117:665–669. - PubMed
    1. Ataga KI, Moore CG, Jones S, Olajide O, Strayhorn D, Hinderliter A, Orringer EP. Pulmonary hypertension in patients with sickle cell disease: a longitudinal study. Br J Haematol. 2006;134:109–115. - PubMed
    1. Barst RJ, Rich S, Widlitz A, Horn EM, McLaughlin V, McFarlin J. Clinical efficacy of sitaxsentan, an endothelin-A receptor antagonist, in patients with pulmonary arterial hypertension: open-label pilot study. Chest. 2002;121:1860–1868. - PubMed
    1. Castro O, Hoque M, Brown BD. Pulmonary hypertension in sickle cell disease: cardiac catheterization results and survival. Blood. 2003;101:1257–1261. - PubMed

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