The Role of Chronotropic Incompetence in Heart Failure With Normal Ejection Fraction (HFNEF)

NCT02354573 | Completed DMC

• 1 other identifier: 11/SC/0009
• Study Type: interventional
• Target: 121
• Locations: 1 country
• Sites: 1

Brief Summary

What is heart failure with normal ejection fraction? The heart contracts (pumps) and relaxes with each heartbeat. In some people with heart failure, the heart contracts normally but there is reduced relaxation of the heart. As a result, people notice a feeling of breathlessness, ankle swelling and fatigue especially on exertion. The investigators feel that patients with reduced or impaired relaxation of the heart have less heart filling time and poor energy utilisation during exercise. Therefore, the investigators are conducting a study to more thoroughly understand the disease condition by giving a drug called ivabradine to reduce the heart rate and hence to increase the heart filling time in these patients.

Conditions

Heart Failure

Outcome Measures

Primary Outcomes (1)

• Change in VO2max measured by CPEX

  After 2 weeks of intervention

Secondary Outcomes (3)

• Doppler derived E/e'

  After 2 weeks of intervention

• BNP (Brain natriuretic peptide)

  After 2 weeks of intervention

• Minnesota Living with Heart Failure Questionnaire (MLHFQ)

  After 2 weeks of intervention

Study Arms (2)

Active arm

ACTIVE COMPARATOR

All subjects will receive Ivabradine 7.5mg twice daily for 2 weeks in a double-blind randomized crossover design.

Drug: Ivabradine

Placebo arm

PLACEBO COMPARATOR

All subjects will receive matching placebo tablets twice daily for 2 weeks in a double-blind randomized crossover design.

Drug: Ivabradine

Interventions

Ivabradine DRUG

All subjects will receive Ivabradine 7.5mg twice daily for 2 weeks in a double-blind randomized crossover design.

Also known as: Procoralan

Active arm; Placebo arm

Eligibility Criteria

• Age: 60 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participant who is willing and able to give informed consent for participation in the study.
• Male or Female, aged 60 years and over (Group 1, Oxford).
• Patients diagnosed with HFNEF by ESC criteria and have peak V02 ≤ 85% with a cardiac pattern of exercise limitation during CPEX (Group 1, Oxford).
• Hypertensive controls aged 65 and over without HFNEF and with peak V02 \> 90% (Group 2, Aberdeen)
• Able to perform exercise testing.

You may not qualify if:

• The participant may not enter the study if ANY of the following apply:
• LVEF \<50%
• Inability to tolerate MRI scanning (claustrophobia, inability to lie flat)
• Contraindications to CMR imaging (implantable devices or other metal implants, internal cardioverter-defibrillator, cranial aneurysm clips, metallic ocular foreign bodies, hypersensitivity to gadolinium)
• Presence of other significant concomitant diseases such as ischaemic, valvular, pericardial heart disease or cardiomyopathy.
• Presence of asthma (contraindication to adenosine)
• Presence of 2nd or 3rd degree AV block (contraindications to ivabradine and adenosine)
• Presence of sick sinus syndrome
• Presence of atrial fibrillation
• Significant bradycardia (HR \<60 per minute).
• Objective evidence of lung disease on formal lung function testing
• Female participant who is pregnant, lactating or planning pregnancy during the course of the study
• Unable to perform exercise testing
• Patient who is in terminally ill or is inappropriate for medication
• Known hypersensitivity to Ivabradine or adenosine

Sponsors & Collaborators

• University of Oxford: lead
• University of Aberdeen: collaborator

Study Sites (1)

Univesrtity of Oxford, John Radcliffe Hospital

Oxford, OX3 9DU, United Kingdom

Location

Related Publications (19)

• 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.

  PMID: 16855265 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.

  PMID: 16855266 BACKGROUND

• De Keulenaer GW, Brutsaert DL. The heart failure spectrum: time for a phenotype-oriented approach. Circulation. 2009 Jun 23;119(24):3044-6. doi: 10.1161/CIRCULATIONAHA.109.870006. Epub 2009 Jun 8. No abstract available.

  PMID: 19506105 BACKGROUND

• Zile MR, Baicu CF, Gaasch WH. Diastolic heart failure--abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med. 2004 May 6;350(19):1953-9. doi: 10.1056/NEJMoa032566.

  PMID: 15128895 BACKGROUND

• Westermann D, Kasner M, Steendijk P, Spillmann F, Riad A, Weitmann K, Hoffmann W, Poller W, Pauschinger M, Schultheiss HP, Tschope C. Role of left ventricular stiffness in heart failure with normal ejection fraction. Circulation. 2008 Apr 22;117(16):2051-60. doi: 10.1161/CIRCULATIONAHA.107.716886. Epub 2008 Apr 14.

  PMID: 18413502 BACKGROUND

• Yip GW, Frenneaux M, Sanderson JE. Heart failure with a normal ejection fraction: new developments. Heart. 2009 Oct;95(19):1549-52. doi: 10.1136/hrt.2009.176222. Epub 2009 Jul 29. No abstract available.

  PMID: 19643767 BACKGROUND

• Kindermann M, Reil JC, Pieske B, van Veldhuisen DJ, Bohm M. Heart failure with normal left ventricular ejection fraction: what is the evidence? Trends Cardiovasc Med. 2008 Nov;18(8):280-92. doi: 10.1016/j.tcm.2008.12.003.

  PMID: 19345315 BACKGROUND

• Phan TT, Abozguia K, Nallur Shivu G, Mahadevan G, Ahmed I, Williams L, Dwivedi G, Patel K, Steendijk P, Ashrafian H, Henning A, Frenneaux M. Heart failure with preserved ejection fraction is characterized by dynamic impairment of active relaxation and contraction of the left ventricle on exercise and associated with myocardial energy deficiency. J Am Coll Cardiol. 2009 Jul 28;54(5):402-9. doi: 10.1016/j.jacc.2009.05.012.

  PMID: 19628114 BACKGROUND

• Wachter R, Schmidt-Schweda S, Westermann D, Post H, Edelmann F, Kasner M, Luers C, Steendijk P, Hasenfuss G, Tschope C, Pieske B. Blunted frequency-dependent upregulation of cardiac output is related to impaired relaxation in diastolic heart failure. Eur Heart J. 2009 Dec;30(24):3027-36. doi: 10.1093/eurheartj/ehp341.

  PMID: 19720638 BACKGROUND

• Bergstrom A, Andersson B, Edner M, Nylander E, Persson H, Dahlstrom U. Effect of carvedilol on diastolic function in patients with diastolic heart failure and preserved systolic function. Results of the Swedish Doppler-echocardiographic study (SWEDIC). Eur J Heart Fail. 2004 Jun;6(4):453-61. doi: 10.1016/j.ejheart.2004.02.003.

  PMID: 15182771 BACKGROUND

• Liu CP, Ting CT, Lawrence W, Maughan WL, Chang MS, Kass DA. Diminished contractile response to increased heart rate in intact human left ventricular hypertrophy. Systolic versus diastolic determinants. Circulation. 1993 Oct;88(4 Pt 1):1893-906. doi: 10.1161/01.cir.88.4.1893.

  PMID: 8403335 BACKGROUND

• Fox K, Ford I, Steg PG, Tendera M, Ferrari R; BEAUTIFUL Investigators. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet. 2008 Sep 6;372(9641):807-16. doi: 10.1016/S0140-6736(08)61170-8. Epub 2008 Aug 29.

  PMID: 18757088 BACKGROUND

• Shivu GN, Abozguia K, Phan TT, Ahmed I, Henning A, Frenneaux M. (31)P magnetic resonance spectroscopy to measure in vivo cardiac energetics in normal myocardium and hypertrophic cardiomyopathy: Experiences at 3T. Eur J Radiol. 2010 Feb;73(2):255-9. doi: 10.1016/j.ejrad.2008.10.018. Epub 2008 Dec 3.

  PMID: 19056193 BACKGROUND

• Ommen SR, Nishimura RA, Appleton CP, Miller FA, Oh JK, Redfield MM, Tajik AJ. Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: A comparative simultaneous Doppler-catheterization study. Circulation. 2000 Oct 10;102(15):1788-94. doi: 10.1161/01.cir.102.15.1788.

  PMID: 11023933 BACKGROUND

• Pennell DJ, Sechtem UP, Higgins CB, Manning WJ, Pohost GM, Rademakers FE, van Rossum AC, Shaw LJ, Yucel EK; European Society of cardiology; Soceity for Cardiovascular Magnetic Resonance. Clinical indications for cardiovascular magnetic resonance (CMR): Consensus Panel report. J Cardiovasc Magn Reson. 2004;6(4):727-65. doi: 10.1081/jcmr-200038581. No abstract available.

  PMID: 15646878 BACKGROUND

• Hudsmith LE, Neubauer S. Magnetic resonance spectroscopy in myocardial disease. JACC Cardiovasc Imaging. 2009 Jan;2(1):87-96. doi: 10.1016/j.jcmg.2008.08.005.

  PMID: 19356540 BACKGROUND

• Scardovi AB, Coletta C, De Maria R, Perna S, Aspromonte N, Feola M, Rosso G, Greggi M, Ceci V. The cardiopulmonary exercise test is safe and reliable in elderly patients with chronic heart failure. J Cardiovasc Med (Hagerstown). 2007 Aug;8(8):608-12. doi: 10.2459/01.JCM.0000281698.53983.4e.

  PMID: 17667032 BACKGROUND

• Bacharach SL, Green MV, Borer JS, Hyde JE, Farkas SP, Johnston GS. Left-ventricular peak ejection rate, filling rate, and ejection fraction--frame rate requirements at rest and exercise: concise communication. J Nucl Med. 1979 Mar;20(3):189-93.

  PMID: 24180035 BACKGROUND

• Pal N, Sivaswamy N, Mahmod M, Yavari A, Rudd A, Singh S, Dawson DK, Francis JM, Dwight JS, Watkins H, Neubauer S, Frenneaux M, Ashrafian H. Effect of Selective Heart Rate Slowing in Heart Failure With Preserved Ejection Fraction. Circulation. 2015 Nov 3;132(18):1719-25. doi: 10.1161/CIRCULATIONAHA.115.017119. Epub 2015 Sep 2.

  PMID: 26338956 DERIVED

MeSH Terms

Conditions

Heart Failure

Interventions

Ivabradine

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Houman Ashrafian, MRCP

  University of Oxford

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 29, 2015
• First Posted: February 3, 2015
• Study Start: December 1, 2011
• Primary Completion: January 1, 2014
• Study Completion: January 1, 2014
• Last Updated: February 4, 2015

Record last verified: 2013-08

Locations

GB (1)