Safety and Efficacy of Bosentan in Patients With Diastolic Heart Failure and Secondary Pulmonary Hypertension
Information source: University Teaching Hospital Hall in Tirol
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Heart Failure, Diastolic; Hypertension, Pulmonary
Intervention: bosentan (Drug); placebo (Drug)
Phase: Phase 3
Status: Completed
Sponsored by: University Teaching Hospital Hall in Tirol Official(s) and/or principal investigator(s): Wilhelm Grander, M.D., Principal Investigator, Affiliation: University Teaching Hospital Hall i.T.
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.
Clinical Details
Official title: Endothelin Receptor Blockade in Heart Failure With Diastolic Dysfunction and Pulmonary Hypertension
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Primary outcome: change in 6 minute waling distance after 12 weeks of bosentan (or placebo) treatment
Secondary outcome: change in 6 minute walking distance after 24 weeks (12 weeks bosentan or placebo treatment and 12 weeks follow-up)changes in hemodynamics assessed by echocardiography after 12 and 24 weeks time to clinical worsening after 12 and 24 weeks levels of NTpBNP, CRP and Endothelin-1 after 12 and 24 weeks Quality of Life assessment (SF-36 and Minnesota Living With Heart Failure Score) after 12 and 24 weeks Adverse event count after 12 and 24 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
Minimum age: 18 Years.
Maximum age: 75 Years.
Gender(s): Both.
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
Locations and Contacts
Hospital Hohenems, Hohenems 6845, Austria
Hospital Natters, Natters 6161, Austria
University Hospital Salzburg, Salzburg 5020, Austria
Hospital Mostviertel Waidhofen/Ybbs, Waidhofen, Lower Austria 3340, Austria
University Teaching Hospital Hall i.T., Hall i. T., Tyrol 6060, Austria
University Teaching Hospital of the Elisabethinen, Linz, Linz, Upper Austria 4010, Austria
Hospital Wels/Grieskirchen, Wels, Upper Austria 4600, Austria
Additional Information
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Starting date: January 2009
Last updated: June 27, 2014
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