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

June 27, 2014 updated by: Wilhelm Grander, M.D., University Teaching Hospital Hall in Tirol

Endothelin Receptor Blockade in Heart Failure With Diastolic Dysfunction and Pulmonary Hypertension

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

20

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Austria
      • Hohenems, Austria, 6845
        • Hospital Hohenems
      • Natters, Austria, 6161
        • Hospital Natters
      • Salzburg, Austria, 5020
        • University Hospital Salzburg
    • Lower Austria
      • Waidhofen, Lower Austria, Austria, 3340
        • Hospital Mostviertel Waidhofen/Ybbs
    • Tyrol
      • Hall i. T., Tyrol, Austria, 6060
        • University Teaching Hospital Hall i.T.
    • Upper Austria
      • Linz, Upper Austria, Austria, 4010
        • University Teaching Hospital of the Elisabethinen, Linz
      • Wels, Upper Austria, Austria, 4600
        • Hospital Wels/Grieskirchen

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / 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 Names:
  • 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
change in 6 minute waling distance after 12 weeks of bosentan (or placebo) treatment
Time Frame: 12 weeks
12 weeks

Secondary Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Teaching Hospital Hall in Tirol

Investigators

  • Principal Investigator: Wilhelm Grander, M.D., University Teaching Hospital Hall i.T.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2009

Primary Completion (Actual)

June 1, 2014

Study Completion (Actual)

June 1, 2014

Study Registration Dates

First Submitted

January 8, 2009

First Submitted That Met QC Criteria

January 9, 2009

First Posted (Estimate)

January 12, 2009

Study Record Updates

Last Update Posted (Estimate)

June 30, 2014

Last Update Submitted That Met QC Criteria

June 27, 2014

Last Verified

June 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • BO-001
  • EUDRACT Number: 2008-005514-40

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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