Safety and Efficacy of Bosentan in Patients With Diastolic Heart Failure and Secondary Pulmonary Hypertension
NCT ID: NCT00820352
Last Updated: 2014-06-30
Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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Recruitment Status
COMPLETED
Clinical Phase
PHASE3
Total Enrollment
20 participants
Study Classification
INTERVENTIONAL
Study Start Date
2009-01-31
Study Completion Date
2014-06-30
Brief Summary
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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.
The investigators hypothesize, that an additional treatment with Bosentan in this patients will improve their exercise capacity, symptoms, hemodynamics and quality of life.
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Detailed Description
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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.
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.
Conditions
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Heart Failure, Diastolic
Hypertension, Pulmonary
Study Design
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Allocation Method
RANDOMIZED
Intervention Model
PARALLEL
Primary Study Purpose
TREATMENT
Blinding Strategy
QUADRUPLE
Participants
Caregivers
Investigators
Outcome Assessors
Study Groups
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bosentan
Patients in this arm receive bosentan twice a day for 12 weeks
Group Type
ACTIVE_COMPARATOR
bosentan
Intervention Type
DRUG
4 weeks of oral bosentan 62,5 mg b.i.d., followed by 8 weeks of 125 mg b.i.d.
placebo
patients in this arm receive 12 placebo twice a day for 12 weeks
Group Type
PLACEBO_COMPARATOR
placebo
Intervention Type
DRUG
placebo twice a day for 12 weeks
Interventions
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bosentan
4 weeks of oral bosentan 62,5 mg b.i.d., followed by 8 weeks of 125 mg b.i.d.
Intervention Type
DRUG
placebo
placebo twice a day for 12 weeks
Intervention Type
DRUG
Other Intervention Names
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Ro 47.0203
Eligibility Criteria
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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
* 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
* 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
Minimum Eligible Age
18 Years
Maximum Eligible Age
75 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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University Teaching Hospital Hall in Tirol
OTHER
Sponsor Role
lead
Responsible Party
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Wilhelm Grander, M.D.
principal investigator
Responsibility Role
PRINCIPAL_INVESTIGATOR
Principal Investigators
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Wilhelm Grander, M.D.
Role: PRINCIPAL_INVESTIGATOR
University Teaching Hospital Hall i.T.
Locations
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Hospital Mostviertel Waidhofen/Ybbs
Waidhofen an der Thaya, Lower Austria, Austria
Site Status
University Teaching Hospital Hall i.T.
Hall I. T., Tyrol, Austria
Site Status
University Teaching Hospital of the Elisabethinen, Linz
Linz, Upper Austria, Austria
Site Status
Hospital Wels/Grieskirchen
Wels, Upper Austria, Austria
Site Status
Hospital Hohenems
Hohenems, , Austria
Site Status
Hospital Natters
Natters, , Austria
Site Status
University Hospital Salzburg
Salzburg, , Austria
Site Status
Countries
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Austria
References
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Kjaergaard J, Akkan D, Iversen KK, Kjoller E, Kober L, Torp-Pedersen C, Hassager C. Prognostic importance of pulmonary hypertension in patients with heart failure. Am J Cardiol. 2007 Apr 15;99(8):1146-50. doi: 10.1016/j.amjcard.2006.11.052. Epub 2007 Mar 8.
Reference Type
BACKGROUND
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. doi: 10.1056/NEJMoa052256.
Reference Type
BACKGROUND
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. No abstract available.
Reference Type
BACKGROUND
Sanderson JE. Heart failure with a normal ejection fraction. Heart. 2007 Feb;93(2):155-8. doi: 10.1136/hrt.2005.074187. Epub 2005 Dec 30.
Reference Type
BACKGROUND
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.
Reference Type
BACKGROUND
Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, Gong Y, Liu PP. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med. 2006 Jul 20;355(3):260-9. doi: 10.1056/NEJMoa051530.
Reference Type
BACKGROUND
Bursi F, Weston SA, Redfield MM, Jacobsen SJ, Pakhomov S, Nkomo VT, Meverden RA, Roger VL. Systolic and diastolic heart failure in the community. JAMA. 2006 Nov 8;296(18):2209-16. doi: 10.1001/jama.296.18.2209.
Reference Type
BACKGROUND
Tribouilloy C, Rusinaru D, Mahjoub H, Souliere V, Levy F, Peltier M, Slama M, Massy Z. Prognosis of heart failure with preserved ejection fraction: a 5 year prospective population-based study. Eur Heart J. 2008 Feb;29(3):339-47. doi: 10.1093/eurheartj/ehm554. Epub 2007 Dec 22.
Reference Type
BACKGROUND
Sweitzer NK, Lopatin M, Yancy CW, Mills RM, Stevenson LW. Comparison of clinical features and outcomes of patients hospitalized with heart failure and normal ejection fraction (> or =55%) versus those with mildly reduced (40% to 55%) and moderately to severely reduced (<40%) fractions. Am J Cardiol. 2008 Apr 15;101(8):1151-6. doi: 10.1016/j.amjcard.2007.12.014. Epub 2008 Feb 20.
Reference Type
BACKGROUND
Onishi K, Ohno M, Little WC, Cheng CP. Endogenous endothelin-1 depresses left ventricular systolic and diastolic performance in congestive heart failure. J Pharmacol Exp Ther. 1999 Mar;288(3):1214-22.
Reference Type
BACKGROUND
Moraes DL, Colucci WS, Givertz MM. Secondary pulmonary hypertension in chronic heart failure: the role of the endothelium in pathophysiology and management. Circulation. 2000 Oct 3;102(14):1718-23. doi: 10.1161/01.cir.102.14.1718.
Reference Type
BACKGROUND
Lewis GD, Shah R, Shahzad K, Camuso JM, Pappagianopoulos PP, Hung J, Tawakol A, Gerszten RE, Systrom DM, Bloch KD, Semigran MJ. Sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension. Circulation. 2007 Oct 2;116(14):1555-62. doi: 10.1161/CIRCULATIONAHA.107.716373. Epub 2007 Sep 4.
Reference Type
BACKGROUND
Galie N, Manes A, Branzi A. The endothelin system in pulmonary arterial hypertension. Cardiovasc Res. 2004 Feb 1;61(2):227-37. doi: 10.1016/j.cardiores.2003.11.026.
Reference Type
BACKGROUND
Cowburn PJ, Cleland JG. Endothelin antagonists for chronic heart failure: do they have a role? Eur Heart J. 2001 Oct;22(19):1772-84. doi: 10.1053/euhj.2000.2557. No abstract available.
Reference Type
BACKGROUND
Cowburn PJ, Cleland JG, McDonagh TA, McArthur JD, Dargie HJ, Morton JJ. Comparison of selective ET(A) and ET(B) receptor antagonists in patients with chronic heart failure. Eur J Heart Fail. 2005 Jan;7(1):37-42. doi: 10.1016/j.ejheart.2004.08.001.
Reference Type
BACKGROUND
Opitz CF, Ewert R, Kirch W, Pittrow D. Inhibition of endothelin receptors in the treatment of pulmonary arterial hypertension: does selectivity matter? Eur Heart J. 2008 Aug;29(16):1936-48. doi: 10.1093/eurheartj/ehn234. Epub 2008 Jun 17.
Reference Type
BACKGROUND
Galie N, Beghetti M, Gatzoulis MA, Granton J, Berger RM, Lauer A, Chiossi E, Landzberg M; Bosentan Randomized Trial of Endothelin Antagonist Therapy-5 (BREATHE-5) Investigators. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation. 2006 Jul 4;114(1):48-54. doi: 10.1161/CIRCULATIONAHA.106.630715. Epub 2006 Jun 26.
Reference Type
BACKGROUND
Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, Pulido T, Frost A, Roux S, Leconte I, Landzberg M, Simonneau G. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002 Mar 21;346(12):896-903. doi: 10.1056/NEJMoa012212.
Reference Type
BACKGROUND
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. doi: 10.1378/chest.124.1.247.
Reference Type
BACKGROUND
Zolk O, Quattek J, Sitzler G, Schrader T, Nickenig G, Schnabel P, Shimada K, Takahashi M, Bohm M. Expression of endothelin-1, endothelin-converting enzyme, and endothelin receptors in chronic heart failure. Circulation. 1999 Apr 27;99(16):2118-23. doi: 10.1161/01.cir.99.16.2118.
Reference Type
BACKGROUND
Other Identifiers
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EUDRACT Number: 2008-005514-40
Identifier Type: -
Identifier Source: secondary_id
BO-001
Identifier Type: -
Identifier Source: org_study_id
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