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Study to Investigate the Effect of Heart Rate Reduction With Ivabradine on Vascular Elastic Properties and Endothelial Function in Patients With Stable Coronary Heart Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01768585
Recruitment Status : Unknown
Verified January 2013 by University Hospital, Saarland.
Recruitment status was:  Recruiting
First Posted : January 15, 2013
Last Update Posted : January 15, 2013
Saarland University
Information provided by (Responsible Party):
University Hospital, Saarland

Brief Summary:
This study investigates whether chronic heart rate reduction with ivabradine (Procoralan®, Servier, France) affects aortic compliance and endothelial function in patients with chronic stable coronary artery disease.

Condition or disease Intervention/treatment Phase
Coronary Artery Disease Coronary Arteriosclerosis Drug: Ivabradine Drug: Placebo Phase 4

Detailed Description:

Experimental and clinical data suggest that sustained elevation of heart rate contributes to the pathogenesis of vascular disease (1, 2). In animal studies accelerated heart rate is associated with signalling events leading to vascular oxidative stress, endothelial dysfunction and acceleration of atherogenesis (3). The underlying mechanisms are only partially understood and appear to correlate with mechanic properties such as reduction of vascular compliance. Heart rate reduction by I(f)-channel inhibition with ivabradine (Procoralan®, Servier, France) attenuates oxidative stress, improves endothelial function and reduces the formation of atherosclerotic plaques in mice models of lipid-induced atherosclerosis (1, 4).

Aortic stiffness is a consequence of arterial aging and vascular risk factors and determinates cardiovascular mortality (5). Heart rate depending repetitive pulsations appear to induce fatigue and fracture of elastin lamellae of central arteries. As a result the vessel stiffens and pulse wave reflections return earlier to the heart. In consequence aortic pressure rises and pulsations of flow extend further into smaller vessels of organs (notably the brain and kidney). Stiffening leads to increased left ventricular (LV) load with hypertrophy, decreased capacity for myocardial perfusion, and increased hemodynamic stresses on small arterial vessels.

Several experimental investigations revealed an interaction between heart rate and vascular compliance demonstrating a positive association between increased heart rate and arterial stiffness (6). Recent experimental data suggest that heart rate reduction by ivabradine (Procoralan®, Servier, France) significantly improves aortic distensibility in cholesterol fed ApoE -/- mice measured by MRI technique (7). While a benefit of pharmacological heart rate reduction on vascular outcomes was observed in animal studies, prospective clinical data are limited and evidence determining whether chronic modulation of heart rate can improve vascular function and compliance in patients with chronic stable coronary artery disease is needed.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Diagnostic
Official Title: A Randomised, Placebo Controlled, Double Blind, Cross-over, Single Center Clinical Study to Investigate the Effect of Heart Rate Reduction With Ivabradine on Vascular Elastic Properties and Endothelial Function in Patients With Stable Coronary Heart Disease
Study Start Date : December 2012
Estimated Primary Completion Date : December 2014
Estimated Study Completion Date : December 2014

Resource links provided by the National Library of Medicine

Drug Information available for: Ivabradine

Arm Intervention/treatment
Active Comparator: Ivabradine
Drug: Ivabradine bid administration of 7.5mg ivabradine Other Name: Procoralan, I(f)-inhibitor
Drug: Ivabradine
Please see description of Intervention Arm
Other Name: Procoralan

Placebo Comparator: Placebo
Drug: Placebo bid placebo Other Name: Placebo control
Drug: Placebo

Primary Outcome Measures :
  1. Aortic distensibility (MRI), pulse wave velocity (SphygmoCor®), flow-mediated dilatation (A. brachialis) [ Time Frame: Decembre 2014 ]

Secondary Outcome Measures :
  1. Biomarkers (inflammation, oxidative stress) [ Time Frame: Decembre 2014 ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Age > 18 years old
  • Resting heart rate ≥ 70 bpm
  • Sinus rhythm
  • Chronic stable coronary artery disease (CAD)
  • Coronary artery disease proven by coronary angiography
  • Written informed consent to participate in the study

Exclusion Criteria:

  • Acute coronary syndrome
  • CAD treated best by surgical coronary bypass
  • Stroke/TIA
  • Resting heart rate < 70 bpm
  • Indwelling pacemaker or AICD
  • Severe valvular heart disease
  • Any other rhythm than sinus
  • Sick-Sinus-Syndrome, SA nodal block, >2nd degree atrio-ventricular block
  • Untreated arterial hypertension
  • Arterial hypotension (<90/50mmHg)
  • Severe hepatic failure
  • Heart failure (NYHA class III - IV)
  • Patient already treated with study drug
  • Symptomatic PAD
  • Known diabetes mellitus
  • Pre-menopausal women
  • Hypersensitivity against ivabradine or adjuvants
  • Coexisting drug treatment with Cytochrom P450 3A4-inhibitors

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01768585

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Contact: Florian Custodis, MD 0049-6841-1623000
Contact: Angelika Knoll 0049-6841-23412

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University Hospital, Saarland Recruiting
Homburg, Saarland, Germany, 66421
Contact: Florian Custodis, MD    0049-6841-1623000   
Contact: Angelika Knoll    0049-6841-1623412   
Principal Investigator: Ulrich Laufs, Prof. Dr.         
Sub-Investigator: Florian Custodis, MD         
Sponsors and Collaborators
University Hospital, Saarland
Saarland University
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Principal Investigator: Ulrich Laufs Saarland University Hospital


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Responsible Party: University Hospital, Saarland Identifier: NCT01768585     History of Changes
Other Study ID Numbers: HomRate04_2012
First Posted: January 15, 2013    Key Record Dates
Last Update Posted: January 15, 2013
Last Verified: January 2013
Additional relevant MeSH terms:
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Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Heart Diseases
Cardiovascular Diseases
Arterial Occlusive Diseases
Vascular Diseases