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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Wilhelm Grander, M.D., University Teaching Hospital Hall in Tirol
ClinicalTrials.gov Identifier:
NCT00820352
First received: January 8, 2009
Last updated: June 27, 2014
Last verified: June 2014
  Purpose

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 Phase
Heart Failure, Diastolic
Hypertension, Pulmonary
Drug: bosentan
Drug: placebo
Phase 3

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 ]

Enrollment: 20
Study Start Date: January 2009
Study Completion Date: June 2014
Primary Completion Date: June 2014 (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.

  Eligibility

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

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00820352

Locations
Austria
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
Investigators
Principal Investigator: Wilhelm Grander, M.D. University Teaching Hospital Hall i.T.
  More Information

Publications:

Responsible Party: Wilhelm Grander, M.D., principal investigator, University Teaching Hospital Hall in Tirol
ClinicalTrials.gov Identifier: NCT00820352     History of Changes
Other Study ID Numbers: BO-001, EUDRACT Number: 2008-005514-40
Study First Received: January 8, 2009
Last Updated: June 27, 2014
Health Authority: Austria: Agency for Health and Food Safety

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

Additional relevant MeSH terms:
Hypertension
Heart Failure
Hypertension, Pulmonary
Heart Failure, Diastolic
Vascular Diseases
Cardiovascular Diseases
Heart Diseases
Lung Diseases
Respiratory Tract Diseases
Bosentan
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 18, 2014