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

Hypertension, Pulmonary Clinical Trial

— BADDHY  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00820352
• Other study ID #: BO-001
• Secondary ID: EUDRACT Number:
• Status: Completed
• Phase: Phase 3
• First received: January 8, 2009
• Last updated: June 27, 2014
• Start date: January 2009
• Est. completion date: June 2014

Study information

• Verified date: June 2014
• Source: University Teaching Hospital Hall in Tirol
• Contact: n/a
• Is FDA regulated: No
• Health authority: Austria: Agency for Health and Food Safety
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: June 2014
• Est. primary completion date: June 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure, Diastolic
• Hypertension
• Hypertension, Pulmonary

Intervention

Drug:
• bosentan
4 weeks of oral bosentan 62,5 mg b.i.d., followed by 8 weeks of 125 mg b.i.d.
• placebo
placebo twice a day for 12 weeks

Locations

Country	Name	City	State
Austria	University Teaching Hospital Hall i.T.	Hall i. T.	Tyrol
Austria	Hospital Hohenems	Hohenems
Austria	University Teaching Hospital of the Elisabethinen, Linz	Linz	Upper Austria
Austria	Hospital Natters	Natters
Austria	University Hospital Salzburg	Salzburg
Austria	Hospital Mostviertel Waidhofen/Ybbs	Waidhofen	Lower Austria
Austria	Hospital Wels/Grieskirchen	Wels	Upper Austria

Sponsors (1)

Lead Sponsor	Collaborator
University Teaching Hospital Hall in Tirol

Country where clinical trial is conducted

Austria, 

References & Publications (20)

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. — View Citation

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. — View Citation

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. — View Citation

Cowburn PJ, Cleland JG. Endothelin antagonists for chronic heart failure: do they have a role? Eur Heart J. 2001 Oct;22(19):1772-84. Review. — View Citation

Galiè 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. Epub 2006 Jun 26. — View Citation

Galié N, Manes A, Branzi A. The endothelin system in pulmonary arterial hypertension. Cardiovasc Res. 2004 Feb 1;61(2):227-37. Review. — View Citation

Kjaergaard J, Akkan D, Iversen KK, Kjoller E, Køber 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. Epub 2007 Mar 8. — View Citation

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. Epub 2007 Sep 4. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

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. Erratum in: N Engl J Med 2002 Apr 18;346(16):1258. — View Citation

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

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. — View Citation

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. — View Citation

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. — View Citation

Tribouilloy C, Rusinaru D, Mahjoub H, Soulière V, Lévy 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. Epub 2007 Dec 22. — View Citation

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. — View Citation

Zolk O, Quattek J, Sitzler G, Schrader T, Nickenig G, Schnabel P, Shimada K, Takahashi M, Böhm M. Expression of endothelin-1, endothelin-converting enzyme, and endothelin receptors in chronic heart failure. Circulation. 1999 Apr 27;99(16):2118-23. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	change in 6 minute waling distance after 12 weeks of bosentan (or placebo) treatment		12 weeks	No
Secondary	change in 6 minute walking distance after 24 weeks (12 weeks bosentan or placebo treatment and 12 weeks follow-up)		24 weeks	No
Secondary	changes in hemodynamics assessed by echocardiography after 12 and 24 weeks		24 weeks	No
Secondary	time to clinical worsening after 12 and 24 weeks		24 weeks	No
Secondary	levels of NTpBNP, CRP and Endothelin-1 after 12 and 24 weeks		24 weeks	No
Secondary	Quality of Life assessment (SF-36 and Minnesota Living With Heart Failure Score) after 12 and 24 weeks		24 weeks	No
Secondary	Adverse event count after 12 and 24 weeks		24 weeks	Yes