Clinical and Hemodynamic Effects of Bosentan Dose Optimization in Symptomatic Heart Failure Patients with Severe Systolic Dysfunction, Associated with Secondary Pulmonary Hypertension – A Multi-Center Randomized Study

Abstract

Objective: Toevaluate the effects of bosentan on echo-derived hemodynamic measurements, and clinical variables in symptomatic heart failure (HF) patients. Method: Multi- center, double-blind, randomized (2:1), placebo-controlled study comparing bosentan (8–125 mg b.i.d.) to placebo in patients with New York Heart Association class IIIb–IV HF, left ventricular ejection fraction <35% and systolic pulmonary artery pressure (SPAP) >40 mm Hg. Primary and secondary endpoints were change from baseline to 20 weeks in SPAP and cardiac index, respectively. Safety endpoints were treatment emergent adverse events (AEs), change in body weight, hemoglobin, hematocrit, systolic blood pressure and diuretic use. Results: Ninety-four patients enrolled: 60 to bosentan, 34 to placebo. There was no significant difference between the 2 arms in SPAP change (0.1 ± 11.5 mm Hg , 95% confidence limit (CL) –5.4 to 5.2, p = 0.97), cardiac index shift (0.12 ± 0.45, 95% CL –0.09 to 0.33 , p = 0.24 ) or any of the other 22 echocardigraphic measurements obtained. Therapy-duration was longer in the placebo arm, while more patients in the bosentan arm experienced adverse and serious AEs. Conclusion: In HF patients with left ventricular dysfunction and secondary pulmonary hypertension, bosentan did not provide any measurable hemodynamic benefit, and was associated with more frequent AEs, requiring drug discontinuation.

Clinical and Hemodynamic Effects of Endothelin Receptor Antagonists in Patients With Heart Failure

“…Hence, the dose-dependent effect of ERA on the hemodynamics of HF patients and higher SVR which could hinder cardiac ejection may explain the negative effect on the cardiac index. 17,24) Our meta-analysis of hemodynamic variables also indicated that ERA could effectively reduce the PCWP and mPAP of HF patients. However, why did ERA fail to improve dyspnea and clinical outcomes, despite evidence of improved pulmonary hemodynamics?…”

“…After title and abstract screening, 2,972 were excluded and 40 potentially relevant articles were retrieved for full text evaluation. In the end, 25 were excluded (Supplementary Table I) and 15 2,9,11,[14][15][16][17][18][20][21][22][23][24][25][26] RCTs that met the predetermined criteria were included in the present study. Major characteristics of the included RCTs are summarized in the Table. In general, the 15 studies, covering a total of 3,624 patients, were published between 1998 and 2013.…”

Safety and tolerability of bosentan in the management of pulmonary arterial hypertension

“…In a recent double-blind, randomized study evaluating non-invasive (echocardiographic) parameters of hemodynamics in patients with pulmonary hypertension secondary to left ventricular dysfunction, bosentan did not improve any endpoint and was associated with more frequent adverse effects. 46 Similarly, bosentan was not benefi cial in patients with severe COPD. 47 These studies emphasize the importance of establishing the correct diagnosis prior to institution of any therapy for pulmonary arterial hypertension.…”

Who should be referred to a specialist pulmonary ­hypertension centre – a referrer’s guide

“…27,28 PH-specific therapy is therefore not licensed or funded for use in these patients and should only be considered within a trial setting.…”