Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: A randomised placebo-controlled study

Duke University, Durham, North Carolina, United States
The Lancet (Impact Factor: 45.22). 10/2001; 358(9288):1119-23. DOI: 10.1016/S0140-6736(01)06250-X
Source: PubMed

ABSTRACT Endothelin 1, a powerful endogenous vasoconstrictor and mitogen, might be a cause of pulmonary hypertension. We describe the efficacy and safety of bosentan, a dual endothelin-receptor antagonist that can be taken orally, in patients with severe pulmonary hypertension.
In this double-blind, placebo-controlled study, 32 patients with pulmonary hypertension (primary or associated with scleroderma) were randomly assigned to bosentan (62.5mg taken twice daily for 4 weeks then 125 mg twice daily) or placebo for a minimum of 12 weeks. The primary endpoint was change in exercise capacity. Secondary endpoints included changes in cardiopulmonary haemodynamics, Borg dyspnoea index, WHO functional class, and withdrawal due to clinical worsening. Analysis was by intention to treat.
In patients given bosentan, the distance walked in 6 min improved by 70 m at 12 weeks compared with baseline, whereas it worsened by 6 m in those on placebo (difference 76 m [95% CI 12-139], p=0.021). The improvement was maintained for at least 20 weeks. The cardiac index was 1.0 L min(-1) m(-2) (95% CI 0.6-1.4, p<0.0001) greater in patients given bosentan than in those given placebo. Pulmonary vascular resistance decreased by 223 dyn s cm(-)(5) with bosentan, but increased by 191 dyn s cm(-5) with placebo (difference -415 [-608 to -221], p=0.0002). Patients given bosentan had a reduced Borg dyspnoea index and an improved WHO functional class. All three withdrawals from clinical worsening were in the placebo group (p=0.033). The number and nature of adverse events did not differ between the two groups.
Bosentan increases exercise capacity and improves haemodynamics in patients with pulmonary hypertension, suggesting that endothelin has an important role in pulmonary hypertension.

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Available from: Victor F Tapson, Aug 25, 2015
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    • "Sildenafil improves exercise capacity and reduces PAP [6]. Bosentan reduces PAP and improves exercise capacity as well as functional class in patients with PAH [7] [8]. A combination of a PDE-5 inhibitor and endothelin-1 receptor antagonist is standard therapy for advanced PAH [9]. "
    Pharmacology & Pharmacy 12/2013; 04(07):542-548. DOI:10.4236/pp.2013.47078
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    • "The currently used parameters are far from perfect, especially in young children with PAH. The World Health Organization functional class (WHO-functional class) and 6-minute walk distance (6-MWD) are recognized as valuable prognostic parameters that are recommended to be used in goal-oriented treatment strategies in adult PAH-patients [4] [5] [6] [7]. "
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    ABSTRACT: BACKGROUND: There is a need for reliable prognostic parameters in pulmonary arterial hypertension (PAH), especially in children. Pulsatile components of the right ventricular afterload, represented by pulmonary arterial compliance (PACi) and pulmonary stroke volume (PSVi), may provide important additional prognostic information to conventional static haemodynamic parameters. The aim of this study was to determine the prognostic value of PACi and PSVi in paediatric PAH. METHODS: Right heart catheterization data of 52 consecutive paediatric idiopathic/hereditary PAH and PAH associated with congenital heart disease patients with full haemodynamic evaluation seen at the Dutch national referral centre for paediatric pulmonary hypertension between 1993 and 2010 were reviewed. A control group was composed of patients with normal pulmonary vascular resistance. PSVi and PACi were calculated and tested for predictive value for transplant-free survival. RESULTS: PAH patients had significantly lower PSVi and PACi compared to control patients. PSVi and PACi were lower in patients with higher WHO-functional class compared to those with lower functional classes. Higher PSVi, PACi and mSAP and lower mPAP/mSAP and heart rate were associated with improved survival, independent from WHO-functional class and PAH-targeted therapy. In multivariate analyses PSVi, heart rate and mSAP emerged as the strongest haemodynamic predictors of survival. The effect of vasodilator challenge on the haemodynamic variables did not provide additional prognostic information. CONCLUSIONS: The parameters of both the pulsatile and static pulmonary circulations are strong independent predictors for transplant-free survival, and therefore can be of complementary value in assessing disease severity, predicting survival and guiding treatment in paediatric PAH.
    International journal of cardiology 01/2013; 168(2):1370-7. DOI:10.1016/j.ijcard.2012.12.080 · 6.18 Impact Factor
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    • " shown previously ( Aldashev et al . , 2002 ) . Taken into account that ET - 1 plays an important role in high altitude - related illness , we decided to investigate the effect of dual ET receptors blocker on PAP in highlanders with HAPH . Bosentan is known to reduce PAP , and improve ex - ercise capacity and quality of life in patients with PAH ( Channick et al . , 2001 ; Rubin et al . , 2002 ) . Modesti and co - authors demonstrated that bosentan effectively attenuates hypoxic pulmonary vasoconstriction in healthy subjects dur - ing acclimatization to high altitude , but was also associated with reduction of urinary volume and free water clearance ( Modesti et al . , 2006 ) . In another study , a sing"
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    ABSTRACT: Abstract Kojonazarov, Baktybek, Jainagul Isakova, Baktybek Imanov, Nurmira Sovkhozova, Talantbek Sooronbaev, Takeshi Ishizaki, and Almaz A. Aldashev. Bosentan reduces pulmonary artery pressure in high altitude residents. High Alt Med Biol. 13:217-223, 2012.-Endothelin-1 (ET-1) plays a critical role in the regulation of pulmonary vascular tone. The aim of this study was to investigate the role of ET-1 in the pathogenesis of high altitude pulmonary arterial hypertension (HAPH). Methods: Pulmonary artery pressure (PAP) was measured by echocardiography in permanent residents of the Kyrgyz Republic (3200-4000 m above sea level) both before and 3 h after a single oral dose of ET receptor antagonist, bosentan (125 mg). Plasma ET-1 levels were measured by ELISA assay. Genomic DNA was extracted from peripheral blood samples and the frequency of -3a and -4a alleles of the ET-1 gene determined by PCR. Results: Plasma ET-1 in HAPH highlanders was significantly higher than in healthy subjects (7.05±2.35 vs. 4.65±1.65 pg/ml, p<0.002). After the treatment with 125 mg bosentan, systolic PAP decreased from 46±1.9 to 37±2.2 mm Hg (p<0.01), and pulmonary artery acceleration time (PAAT) increased from 0.086±0.001 to 0.098±0.001 sec (p<0.001). The frequency of the -4a allele was significantly higher in HAPH patients compared to healthy highlanders (0.43 vs. 0.3, χ(2)=4.3, p=0.03). Conclusion: Increased ET-1 levels play an important role in development of HAPH.
    High altitude medicine & biology 09/2012; 13(3):217-23. DOI:10.1089/ham.2011.1107 · 1.82 Impact Factor
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