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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 recruitment status of this study is unknown. The completion date has passed and the status has not been verified in more than two years.
Verified January 2013 by University Hospital, Saarland.
Recruitment status was:  Recruiting
Saarland University
Information provided by (Responsible Party):
University Hospital, Saarland Identifier:
First received: January 11, 2013
Last updated: January 14, 2013
Last verified: January 2013
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 Intervention Phase
Coronary Artery Disease Coronary Arteriosclerosis Drug: Ivabradine Drug: Placebo Phase 4

Study Type: Interventional
Study Design: 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

Resource links provided by NLM:

Further study details as provided by University Hospital, Saarland:

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

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

Estimated Enrollment: 50
Study Start Date: December 2012
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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.


Ages Eligible for Study:   18 Years to 90 Years   (Adult, Senior)
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
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01768585

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

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
Principal Investigator: Ulrich Laufs Saarland University Hospital
  More Information


Responsible Party: University Hospital, Saarland Identifier: NCT01768585     History of Changes
Other Study ID Numbers: HomRate04_2012
Study First Received: January 11, 2013
Last Updated: January 14, 2013

Additional relevant MeSH terms:
Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Heart Diseases
Cardiovascular Diseases
Arterial Occlusive Diseases
Vascular Diseases processed this record on September 21, 2017