Safety and Efficacy of Bosentan in Patients With Diastolic Heart Failure and Secondary Pulmonary Hypertension (BADDHY)

The recruitment status of this study is unknown because the information has not been verified recently.
Verified June 2009 by University Teaching Hospital Hall in Tirol.
Recruitment status was  Recruiting
Information provided by:
University Teaching Hospital Hall in Tirol Identifier:
First received: January 8, 2009
Last updated: January 12, 2010
Last verified: June 2009

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.

Condition Intervention
Heart Failure, Diastolic
Hypertension, Pulmonary
Drug: bosentan
Drug: placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Endothelin Receptor Blockade in Heart Failure With Diastolic Dysfunction and Pulmonary Hypertension

Resource links provided by NLM:

Further study details as provided by University Teaching Hospital Hall in Tirol:

Primary Outcome Measures:
  • change in 6 minute waling distance after 12 weeks of bosentan (or placebo) treatment [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • change in 6 minute walking distance after 24 weeks (12 weeks bosentan or placebo treatment and 12 weeks follow-up) [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  • changes in hemodynamics assessed by echocardiography after 12 and 24 weeks [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  • time to clinical worsening after 12 and 24 weeks [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  • levels of NTpBNP, CRP and Endothelin-1 after 12 and 24 weeks [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  • Quality of Life assessment (SF-36 and Minnesota Living With Heart Failure Score) after 12 and 24 weeks [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
  • Adverse event count after 12 and 24 weeks [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 60
Study Start Date: January 2009
Estimated Study Completion Date: April 2011
Estimated Primary Completion Date: February 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: bosentan
Patients in this arm receive bosentan twice a day for 12 weeks
Drug: bosentan
4 weeks of oral bosentan 62,5 mg b.i.d., followed by 8 weeks of 125 mg b.i.d.
Other Names:
  • Ro 47.0203
  • bosentan
Placebo Comparator: placebo
patients in this arm receive 12 placebo twice a day for 12 weeks
Drug: placebo
placebo twice a day for 12 weeks

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.


Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Clinically signs or history of congestive heart failure NYHA II-III (Fatigue, dyspnea on exertion, lung crepitations, pulmonary edema, ankle and or lower leg swelling, jugular pressure enhancement, hepatomegaly)
  • Echocardiographic signs of diastolic dysfunction (heart failure with normal ejection fraction)
  • Right ventricle enlargement with pulmonary hypertension
  • 6 minute walking distance > 150 m < 400 m
  • Right Heart Catheterization: Mean PAP > 25 mmHg, PCWP > 15 mmHg

Echocardiographic requirements for definition of heart failure with normal ejection fraction

  • E/E` > 15, or
  • E/E` > 8 + NTpBNP > 220 pg/ml, or
  • E/E` > 8 + E:A < 0.5 + DT > 280 ms or
  • Ard-Ad > 30 ms or
  • atrial enlargement or
  • atrial fibrillation
  • NTpBNP > 220 pg/ml + combination
  • IVRT - IVRTm < 0 septal und lateral

Echocardiographic requirements for pulmonary hypertension and right ventricle dysfunction

  • RVEDD > 30 mm short axis parasternal, and
  • one of the following:

    • Tricuspid valve regurgitation velocity (TRV) > 3 m/s;
    • RV-annular systolic velocity < 10 cm/sec (TDI)
    • TAPSE < 18 mm

Exclusion Criteria:

  • Patients who are not on guideline conform treatments for cardiovascular disease.
  • Left ventricle systolic dysfunction (EF < 50 %), aortic stenosis with peak gradient (instantane) > 40 mm Hg,moderate and severe aortic insufficiency
  • moderate and severe mitral regurgitation,
  • acute coronary disease, stable coronary artery disease or peripheral vascular disease limiting exercise.
  • Other causes of pulmonary - artery - hypertension:

    • relevant obstructive ventilatory disease > grade II (lung functions tests)
    • collagen disease (Tests: MSCT and ANA, ANCA),
    • chronic thrombo- embolic pulmonary arterial hypertension (MSCT),
    • sleep disorder.
    • HIV, HCV, HBV infection.
    • Drug related PAH.
  • Orthopaedic disease, immobility, inability to perform 6MWT and cancer.
  • Liver disease Child-Pugh B and C, three fold above normal elevated liver enzymes,
  • anaemia Hb < 10 mg/dl,
  • other specific treatment of pulmonary arterial hypertension including other endothelin receptor blockers, phosphodiesterase inhibitors, prostaglandins and L-arginin
  • drug therapy with glibenclamide, rifampicin, tacrolimus, sirolimus, cyclosporine A
  • known adverse reactions to bosentan and
  • pregnancy and lactation
  Contacts and Locations
Please refer to this study by its identifier: NCT00820352

Contact: Bernhard Koller, M.D. +43 (0) 5223 502
Contact: Wilhelm Grander, M.D. +43 (0) 5223 502

Hospital Mostviertel Waidhofen/Ybbs Recruiting
Waidhofen, Lower Austria, Austria, 3340
Contact: Martin Gattermeier, Prim. M.D.    07442 9004 1810   
Principal Investigator: Martin Gattermeier, Prim. M.D.         
University Teaching Hospital Hall i.T. Recruiting
Hall I. T., Tyrol, Austria, 6060
Contact: Wilhelm Grander, M.D.    +43 (0) 5223 502   
Contact: Bernhard Koller, M.D.    +43 (0) 5223 502   
Principal Investigator: Wilhelm Grander, M.D.         
Sub-Investigator: Patrizia Eller, M.D.         
Sub-Investigator: Johannes Schwaiger, M.D.         
Sub-Investigator: Bernhard Koller, M.D.         
University Teaching Hospital of the Elisabethinen, Linz Recruiting
Linz, Upper Austria, Austria, 4010
Contact: Regina Steringer-Mascherbauer, M.D.    0732 7676 0   
Principal Investigator: Regina Steringer-Mascherbauer, M.D.         
Sub-Investigator: Christian Ebner, M.D.         
Hospital Wels/Grieskirchen Recruiting
Wels, Upper Austria, Austria, 4600
Contact: Thomas Weber, M.D.    07242 415 2215   
Principal Investigator: Thomas Weber, Doz. M.D.         
Sub-Investigator: Marcus Ammer, M.D.         
Hospital Hohenems Recruiting
Hohenems, Austria, 6845
Contact: Alexander Kopf, MD    0043 5576 703   
Principal Investigator: Alexander Kopf, MD         
Hospital Natters Recruiting
Natters, Austria, 6161
Contact: Christan Geltner, MD    0043 512 5408   
Principal Investigator: Christian Geltner, MD         
University Hospital Salzburg Recruiting
Salzburg, Austria, 5020
Contact: Jörg Eichinger, MD    0043 662 4482   
Principal Investigator: Jörg Eichinger, MD         
Sponsors and Collaborators
University Teaching Hospital Hall in Tirol
Principal Investigator: Wilhelm Grander, M.D. University Teaching Hospital Hall i.T.
  More Information


Responsible Party: Wilhelm Grander, M.D., University Teaching Hospital Hall i.T. Identifier: NCT00820352     History of Changes
Other Study ID Numbers: BO-001, EUDRACT Number: 2008-005514-40
Study First Received: January 8, 2009
Last Updated: January 12, 2010
Health Authority: Austria: Agency for Health and Food Safety

Keywords provided by University Teaching Hospital Hall in Tirol:
Secondary Pulmonary Hypertension
Endothelin Receptor Blockade

Additional relevant MeSH terms:
Hypertension, Pulmonary
Heart Failure
Heart Failure, Diastolic
Heart Diseases
Cardiovascular Diseases
Vascular Diseases
Lung Diseases
Respiratory Tract Diseases
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions processed this record on April 16, 2014