Long-Term Effect of Endothelin Receptor Antagonism With Bosentan on the Morbidity and Mortality of Patients With Severe Chronic Heart Failure

Abstract

Bosentan did not improve the clinical course or natural history of patients with severe chronic heart failure and but caused early and important fluid retention.

Pulmonary hypertension associated with left heart disease: Updated Recommendations of the Cologne Consensus Conference 2018

“…Based on these data, patients with IpcPH should not be treated with targeted PAH medications, especially not sildenafil. Likewise, vasoactive therapies did not prove effective in patients with HF and no PH [60,91,96,98,99].…”

“…Moreover, there are numerous examples of neutral studies in this area [2,3,8]. Recent examples include the ENABLE and MELODY-1 studies, showing that the two ERAs bosentan and macitentan failed to improve clinical measures or outcome in patients with HFrEF or HFpEF, respectively, and in both studies ERA therapy was associated with an increased occurrence of fluid retention [91,92]. In addition, the SIOVAC trial has shown that the use of sildenafil was associated with an increased risk of clinical deterioration and worse outcome versus placebo in patients with PH after VHD intervention (aortic, mitral, or tricuspid) [93], thus indicating that such therapies may even be harmful in the context of LHD.…”

Macitentan in pulmonary hypertension due to left ventricular dysfunction

“…A number of therapies used to treat PAH, mainly those targeting the nitric oxide and endothelin pathways, have been evaluated in studies of patients with HF and PH-LHD [7][8][9][12][13][14][15][16][17][18][19]. However, results have been inconsistent; although some studies have reported improvements in exercise tolerance, functional capacity and clinical status [18,19], others have failed to show statistical or clinically significant improvements [7,9]. Moreover, early worsening of HF in studies of ERAs has led to safety concerns regarding the development of oedema during treatment [6,7].…”

“…However, results have been inconsistent; although some studies have reported improvements in exercise tolerance, functional capacity and clinical status [18,19], others have failed to show statistical or clinically significant improvements [7,9]. Moreover, early worsening of HF in studies of ERAs has led to safety concerns regarding the development of oedema during treatment [6,7].…”

“…In patients with HF, plasma endothelin-1 levels are elevated and are associated with increased pulmonary pressure [5] and a greater risk of mortality [6]. Based on this observation, endothelin receptor antagonists (ERAs) have been evaluated as a potential treatment option for HF; a potential benefit has not been demonstrated, possibly because of a high incidence of premature study withdrawal caused by early excess fluid retention and worsening HF [7][8][9]. However, to date, no study has stratified patients according to the presence and severity of PH-LHD.…”