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

Division of Pulmonary and Critical Care Medicine, University of California, San Diego, CA, USA.
The Lancet (Impact Factor: 39.21). 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Pulmonary hypertension (PH) is associated with significant morbidity and mortality. While the advent of disease-modifying therapies in the treatment of PH has dramatically increased the life expectancy of these patients, they remain at high risk for perioperative complications. Outcome studies suggest that patients with PH undergoing non-cardiac surgery have higher morbidity and mortality than those without, independent of severity. Despite these risks, more and more of these patients are presenting for non-cardiac surgery. Patients with rheumatologic disorders in particular often have pulmonary arterial hypertension (PAH), a group that is associated with a poorer prognosis. Yet, these patients invariably develop debilitating joint diseases and not uncommonly present for elective surgery. Preoperatively, patients with PH should be appropriately risk stratified based on functional class, etiology, exercise capacity, pulmonary hemodynamics, and the risk of surgery. If the risks and benefits assessment proves favorable, they should undergo optimization prior to surgery, with any chronic therapy continuing without cessation through the perioperative period. A multidisciplinary approach involving all intraoperative physicians is imperative to forming a safe intraoperative plan based on the inherent physiology underlying the patient's disease. Finally, because complications in this patient population often occur postoperatively, patients should be monitored in an appropriate setting with a goal of preventing right ventricular dysfunction. In this review article, we focus on the evaluation, risk stratification, and optimization of patients with PH undergoing non-cardiac surgery.
    Current Rheumatology Reports 03/2015; 17(3):490. DOI:10.1007/s11926-014-0490-z · 2.45 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The pulmonary endothelium represents a heterogeneous cell monolayer covering the luminal surface of the entire lung vasculature. As such, this cell layer lies at a critical interface between the blood, airways, and lung parenchyma, and must act as a selective barrier between these diverse compartments. Lung endothelial cells are able to produce and secrete mediators, display surface receptor, and cellular adhesion molecules, and metabolize circulating hormones to influence vasomotor tone, both local and systemic inflammation, and coagulation functions. In this review, we will explore the role of the pulmonary endothelium in each of these systems, highlighting key regulatory functions of the pulmonary endothelial cell, as well as novel aspects of the pulmonary endothelium in contrast to the systemic cell type. The interactions between pulmonary endothelial cells and both leukocytes and platelets will be discussed in detail, and wherever possible, elements of endothelial control over physiological and pathophysiological processes will be examined. © 2015 American Physiological Society. Compr Physiol 5: 531-559, 2015.
    03/2015; 5(2-2):531-559. DOI:10.1002/cphy.c140024
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pulmonary hypertension (PH) is a common complication of chronic obstructive pulmonary disease (COPD) without effective drugs to treat. We conducted a systematic review and meta-analysis in order to evaluate whether PH specific therapies were effective for stable COPD patients. Data were extracted from PubMed, Cochrane Central Register of Controlled Trials and China Knowledge Resource Integrated Database. Randomized controlled trials (RCTs) with PH specific therapy treated more than 4 weeks in COPD were selected. The main outcome was exercise capacity; meanwhile pulmonary arterial pressure (PAP), hypoxemia and health related life quality were also measured. We included nine trials involving 365 subjects, among which two were treated with bosentan and seven with sildenafil. The study time varied from 4 weeks to 18 months and mostly it was 12 weeks. In a pooled analysis of nine trials, exercise capacity of COPD patients was improved by PH-specific therapy [mean difference (MD) 66.39 m, 95% confidence intervals (CI): 59.44-73.34]. COPD with severe PH (mean PAP >35 mmHg by right heart catheterization or systolic PAP >50 mmHg by echocardiography) improved the exercise capacity (MD 67.24 m, 95% CI: 60.26-74.23), but COPD without PH at rest did not (MD -9.24 m, 95% CI: -75.08 to 56.31). Meanwhile PAP was decreased (MD -9.02 mmHg, 95% CI: -10.71 to -7.34 mmHg). Although hypoxemia and life quality were not improved, the dyspnea was alleviated or at least not aggravated (Borg dyspnea index, MD -0.86, 95% CI: -1.86 to 0.14). In conclusion, PH specific drugs (especially sildenafil) could improve exercise capacity and decrease PAP in COPD patients with severe PH.
    03/2015; 7(3):309-19. DOI:10.3978/j.issn.2072-1439.2015.02.08

Full-text (2 Sources)

Available from
May 23, 2014