title: 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.
authors.affiliation: Department of Pediatric Cardiology, Columbia University, New York, NY, USA. robyn.barst@gmail.com
authors.forename: Robyn J
authors.initials: RJ
authors.lastname: Barst
authors.forename: Kamal K
authors.initials: KK
authors.lastname: Mubarak
authors.forename: Roberto F
authors.initials: RF
authors.lastname: Machado
authors.forename: Kenneth I
authors.initials: KI
authors.lastname: Ataga
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Benza
authors.forename: Oswaldo
authors.initials: O
authors.lastname: Castro
authors.forename: Robert
authors.initials: R
authors.lastname: Naeije
authors.forename: Namita
authors.initials: N
authors.lastname: Sood
authors.forename: Paul S
authors.initials: PS
authors.lastname: Swerdlow
authors.forename: Mariana
authors.initials: M
authors.lastname: Hildesheim
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
mesh_terms: D000328:Adult; D000755:Anemia, Sickle Cell / Q000150:complications* / Q000503:physiopathology; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000077300:Bosentan; D004311:Double-Blind Method; D005080:Exercise Test / Q000379:methods; D017079:Exercise Tolerance / Q000187:drug effects*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011651:Pulmonary Artery / Q000503:physiopathology; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use*; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D013449:Sulfonamides; D000077300:Bosentan