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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

Related publications:

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Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006 Jul 20;355(3):251-9.

Shah SJ, Gheorghiade M. Heart failure with preserved ejection fraction: treat now by treating comorbidities. JAMA. 2008 Jul 23;300(4):431-3. doi: 10.1001/jama.300.4.431.

Sanderson JE. Heart failure with a normal ejection fraction. Heart. 2007 Feb;93(2):155-8. Epub 2005 Dec 30. Review.

Yip GW, Wang M, Wang T, Chan S, Fung JW, Yeung L, Yip T, Lau ST, Lau CP, Tang MO, Yu CM, Sanderson JE. The Hong Kong diastolic heart failure study: a randomised controlled trial of diuretics, irbesartan and ramipril on quality of life, exercise capacity, left ventricular global and regional function in heart failure with a normal ejection fraction. Heart. 2008 May;94(5):573-80. doi: 10.1136/hrt.2007.117978. Epub 2008 Jan 20.

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Sitbon O, Badesch DB, Channick RN, Frost A, Robbins IM, Simonneau G, Tapson VF, Rubin LJ. Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary arterial hypertension: a 1-year follow-up study. Chest. 2003 Jul;124(1):247-54.

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Starting date: January 2009
Last updated: June 27, 2014

Page last updated: August 23, 2015

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