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

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2013 by University Hospital, Saarland
Sponsor:
Collaborator:
Saarland University
Information provided by (Responsible Party):
University Hospital, Saarland
ClinicalTrials.gov Identifier:
NCT01768585
First received: January 11, 2013
Last updated: January 14, 2013
Last verified: January 2013
  Purpose

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: Double Blind (Subject, Caregiver, 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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Biomarkers (inflammation, oxidative stress) [ Time Frame: Decembre 2014 ] [ Designated as safety issue: No ]

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.

  Eligibility

Ages Eligible for Study:   18 Years to 90 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 ClinicalTrials.gov identifier: NCT01768585

Contacts
Contact: Florian Custodis, MD 0049-6841-1623000 Florian.Custodis@uks.eu
Contact: Angelika Knoll 0049-6841-23412 Angelika.Knoll@uks.eu

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

Publications:
Custodis F, Schirmer SH, Baumhäkel M, Heusch G, Böhm M, Laufs U. Vascular pathophysiology in response to increased heart rate. J Am Coll Cardiol 2010; 56(24):1973-1983.
Cavalcante JL, Lima JA, Redheuil A, Al-Mallah MH. Aortic stiffness: current understanding and future directions. J Am Coll Cardiol 2011; 57(14):1511-1522.
Custodis F, Fries P, Müller A, Stamm C, Grube M, Kroemer HK, Böhm M, Laufs U. Heart rate reduction by ivabradine improves aortic compliance in apolipoprotein e-deficient mice. J Vasc Res 2012; 49(5):432-440.

Responsible Party: University Hospital, Saarland
ClinicalTrials.gov Identifier: NCT01768585     History of Changes
Other Study ID Numbers: HomRate04_2012
Study First Received: January 11, 2013
Last Updated: January 14, 2013
Health Authority: Germany: Ethics Commission
Germany: Federal Institute for Drugs and Medical Devices

Additional relevant MeSH terms:
Heart Diseases
Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Arteriosclerosis
Atherosclerosis
Cardiovascular Diseases
Arterial Occlusive Diseases
Vascular Diseases

ClinicalTrials.gov processed this record on September 30, 2014