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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00820352
Recruitment Status : Completed
First Posted : January 12, 2009
Last Update Posted : June 30, 2014
Information provided by (Responsible Party):
Wilhelm Grander, M.D., University Teaching Hospital Hall in Tirol

Brief 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.

Condition or disease Intervention/treatment Phase
Heart Failure, Diastolic Hypertension, Pulmonary Drug: bosentan Drug: placebo Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Endothelin Receptor Blockade in Heart Failure With Diastolic Dysfunction and Pulmonary Hypertension
Study Start Date : January 2009
Actual Primary Completion Date : June 2014
Actual Study Completion Date : June 2014

Resource links provided by the National Library of Medicine

Drug Information available for: Bosentan

Arm Intervention/treatment
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 Name: Ro 47.0203

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

Primary Outcome Measures :
  1. change in 6 minute waling distance after 12 weeks of bosentan (or placebo) treatment [ Time Frame: 12 weeks ]

Secondary Outcome Measures :
  1. change in 6 minute walking distance after 24 weeks (12 weeks bosentan or placebo treatment and 12 weeks follow-up) [ Time Frame: 24 weeks ]
  2. changes in hemodynamics assessed by echocardiography after 12 and 24 weeks [ Time Frame: 24 weeks ]
  3. time to clinical worsening after 12 and 24 weeks [ Time Frame: 24 weeks ]
  4. levels of NTpBNP, CRP and Endothelin-1 after 12 and 24 weeks [ Time Frame: 24 weeks ]
  5. Quality of Life assessment (SF-36 and Minnesota Living With Heart Failure Score) after 12 and 24 weeks [ Time Frame: 24 weeks ]
  6. Adverse event count after 12 and 24 weeks [ Time Frame: 24 weeks ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00820352

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Hospital Mostviertel Waidhofen/Ybbs
Waidhofen, Lower Austria, Austria, 3340
University Teaching Hospital Hall i.T.
Hall i. T., Tyrol, Austria, 6060
University Teaching Hospital of the Elisabethinen, Linz
Linz, Upper Austria, Austria, 4010
Hospital Wels/Grieskirchen
Wels, Upper Austria, Austria, 4600
Hospital Hohenems
Hohenems, Austria, 6845
Hospital Natters
Natters, Austria, 6161
University Hospital Salzburg
Salzburg, Austria, 5020
Sponsors and Collaborators
University Teaching Hospital Hall in Tirol
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Principal Investigator: Wilhelm Grander, M.D. University Teaching Hospital Hall i.T.

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Responsible Party: Wilhelm Grander, M.D., principal investigator, University Teaching Hospital Hall in Tirol Identifier: NCT00820352    
Other Study ID Numbers: BO-001
EUDRACT Number: 2008-005514-40
First Posted: January 12, 2009    Key Record Dates
Last Update Posted: June 30, 2014
Last Verified: June 2014
Keywords provided by Wilhelm Grander, M.D., University Teaching Hospital Hall in Tirol:
Secondary Pulmonary Hypertension
Endothelin Receptor Blockade
Additional relevant MeSH terms:
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Hypertension, Pulmonary
Heart Failure
Heart Failure, Diastolic
Vascular Diseases
Cardiovascular Diseases
Heart Diseases
Lung Diseases
Respiratory Tract Diseases
Antihypertensive Agents
Endothelin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action