Safety and Efficacy of Bosentan in Patients With Diastolic Heart Failure and Secondary Pulmonary Hypertension
Condition: Heart Failure, Diastolic; Hypertension, Pulmonary
MeSH terms: Hypertension, Pulmonary; Hypertension; Heart Failure; Heart Failure, Diastolic
Study type: Interventional
Phase: Phase 3

Summary: 
      Heart failure is a major medical and socioeconomic problem in western industrial countries,
      especially with aging populations. Heart failure with normal left ventricle systolic function
      (heart failure with preserved ejection fraction, HFPEF, heart failure with normal ejection
      fraction, HFNEF) are common causes of hospitalization mainly in the elderly population and
      are frequently associated with pulmonary hypertension. It is commonly seen, that patients
      with left heart disease and pulmonary hypertension with right ventricle dysfunction have a
      worse prognosis.

      The investigators hypothesize, that an additional treatment with Bosentan in this patients
      will improve their exercise capacity, symptoms, hemodynamics and quality of life.
    

Detailed description: 
      Heart Failure with preserved ejection fraction is with more than 50% of cases the most common
      form of heart failure. Typically patients are elderly women with arterial hypertension.
      Mortality, hospitalization rates due to heart failure and in-hospital complications do not
      differ significantly from patients with systolic heart failure. However there are some
      subgroups of HFPEF-patients with a worse prognosis, for example up to 30% of patients develop
      secondary pulmonary hypertension and thus right ventricle dysfunction. Increased
      right-ventricle systolic pressure is associated with increased mortality in patients with all
      forms of heart failure.

      There is a lack of evidence about HFPEF. Drugs for treating systolic heart failure showed no
      improvement in mortality and prognosis. Diuretics are just able to relieve symptoms. There
      are no clinical trials concerning HFPEF with secondary pulmonary hypertension.

      The endothelin system is not only activated in PAH, but also in pulmonary venous hypertension
      and congestive heart failure, where ET-1 levels rise with the severity of secondary pulmonary
      hypertension. Pulmonary congestion leads to endothelial dysfunction that results in increased
      levels of Endothelin-1 (ET-1).

      ET-1 is a potent vasoconstrictor. In pulmonary arterial vessels the ETA receptor is the
      predominant receptor (ratio of ETA to ET B = 9:1), which is responsible for vasoconstriction
      and remodeling of the pulmonal vasculature. In heart failure the ETA receptor is upregulated.
      Elevated plasma ET-1 levels correlate with pulmonary artery pressure (PAP), pulmonary
      vascular resistance (PVR) and inversely with peak exercise capacity.

      Recent clinical and laboratory findings indicate comparable pathophysiological mechanisms in
      pulmonary hypertension secondary to left ventricular dysfunction and pulmonary arterial
      hypertension. Yet, despite an expanding application in pulmonary artery hypertension,
      according to current opinion, the oral dual endothelin (ETA/ETB) antagonist bosentan is not
      indicated for PVH caused by left ventricle / left atrial pressure overload and preserved
      systolic function. However, there are several studies which show some effects of pulmonary
      vessel dilating drugs in PAH and left ventricle dysfunction.
    

Intervention name(s): bosentan; placebo
Intervention type(s): Drug; Drug
Intervention description(s): 4 weeks of oral bosentan 62,5 mg b.i.d., followed by 8 weeks of 125 mg b.i.d.; placebo twice a day for 12 weeks
Other intervention name(s): Ro 47.0203
Intervention MeSH terms: Bosentan
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: HFNEF; HFPEF; Secondary Pulmonary Hypertension; Endothelin Receptor Blockade