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
Primary Purpose
Coronary Artery Disease, Coronary Arteriosclerosis
Status
Unknown status
Phase
Phase 4
Locations
Germany
Study Type
Interventional
Intervention
Ivabradine
Placebo
Sponsored by
About this trial
This is an interventional diagnostic trial for Coronary Artery Disease
Eligibility 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
Sites / Locations
- University Hospital, SaarlandRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Active Comparator
Placebo Comparator
Arm Label
Ivabradine
Placebo
Arm Description
Drug: Ivabradine bid administration of 7.5mg ivabradine Other Name: Procoralan, I(f)-inhibitor
Drug: Placebo bid placebo Other Name: Placebo control
Outcomes
Primary Outcome Measures
Aortic distensibility (MRI), pulse wave velocity (SphygmoCor®), flow-mediated dilatation (A. brachialis)
Secondary Outcome Measures
Biomarkers (inflammation, oxidative stress)
Full Information
NCT ID
NCT01768585
First Posted
January 11, 2013
Last Updated
January 14, 2013
Sponsor
University Hospital, Saarland
Collaborators
Universität des Saarlandes
1. Study Identification
Unique Protocol Identification Number
NCT01768585
Brief Title
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
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 Type
Interventional
2. Study Status
Record Verification Date
January 2013
Overall Recruitment Status
Unknown status
Study Start Date
December 2012 (undefined)
Primary Completion Date
December 2014 (Anticipated)
Study Completion Date
December 2014 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Saarland
Collaborators
Universität des Saarlandes
4. Oversight
Data Monitoring Committee
No
5. Study Description
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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Coronary Artery Disease, Coronary Arteriosclerosis
7. Study Design
Primary Purpose
Diagnostic
Study Phase
Phase 4
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
50 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Ivabradine
Arm Type
Active Comparator
Arm Description
Drug: Ivabradine bid administration of 7.5mg ivabradine Other Name: Procoralan, I(f)-inhibitor
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Drug: Placebo bid placebo Other Name: Placebo control
Intervention Type
Drug
Intervention Name(s)
Ivabradine
Other Intervention Name(s)
Procoralan
Intervention Description
Please see description of Intervention Arm
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Aortic distensibility (MRI), pulse wave velocity (SphygmoCor®), flow-mediated dilatation (A. brachialis)
Time Frame
Decembre 2014
Secondary Outcome Measure Information:
Title
Biomarkers (inflammation, oxidative stress)
Time Frame
Decembre 2014
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
90 Years
Accepts Healthy Volunteers
No
Eligibility 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Florian Custodis, MD
Phone
0049-6841-1623000
Email
Florian.Custodis@uks.eu
First Name & Middle Initial & Last Name or Official Title & Degree
Angelika Knoll
Phone
0049-6841-23412
Email
Angelika.Knoll@uks.eu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ulrich Laufs
Organizational Affiliation
Saarland University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital, Saarland
City
Homburg
State/Province
Saarland
ZIP/Postal Code
66421
Country
Germany
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Florian Custodis, MD
Phone
0049-6841-1623000
Email
Florian.Custodis@uks.eu
First Name & Middle Initial & Last Name & Degree
Angelika Knoll
Phone
0049-6841-1623412
Email
Angelika.Knoll@uks.eu
First Name & Middle Initial & Last Name & Degree
Ulrich Laufs, Prof. Dr.
First Name & Middle Initial & Last Name & Degree
Florian Custodis, MD
12. IPD Sharing Statement
Citations:
PubMed Identifier
18443241
Citation
Custodis F, Baumhakel M, Schlimmer N, List F, Gensch C, Bohm M, Laufs U. Heart rate reduction by ivabradine reduces oxidative stress, improves endothelial function, and prevents atherosclerosis in apolipoprotein E-deficient mice. Circulation. 2008 May 6;117(18):2377-87. doi: 10.1161/CIRCULATIONAHA.107.746537. Epub 2008 Apr 28.
Results Reference
background
PubMed Identifier
6484569
Citation
Beere PA, Glagov S, Zarins CK. Retarding effect of lowered heart rate on coronary atherosclerosis. Science. 1984 Oct 12;226(4671):180-2. doi: 10.1126/science.6484569.
Results Reference
background
PubMed Identifier
21126638
Citation
Custodis F, Schirmer SH, Baumhakel M, Heusch G, Bohm M, Laufs U. Vascular pathophysiology in response to increased heart rate. J Am Coll Cardiol. 2010 Dec 7;56(24):1973-83. doi: 10.1016/j.jacc.2010.09.014.
Results Reference
background
PubMed Identifier
20033269
Citation
Noels H, Weber C. Fractalkine as an important target of aspirin in the prevention of atherogenesis : Editorial to: "Aspirin inhibits fractalkine expression in atherosclerotic plaques and reduces atherosclerosis in ApoE gene knockout mice" by H. Liu et al. Cardiovasc Drugs Ther. 2010 Feb;24(1):1-3. doi: 10.1007/s10557-009-6213-4. No abstract available.
Results Reference
background
PubMed Identifier
21453829
Citation
Cavalcante JL, Lima JA, Redheuil A, Al-Mallah MH. Aortic stiffness: current understanding and future directions. J Am Coll Cardiol. 2011 Apr 5;57(14):1511-22. doi: 10.1016/j.jacc.2010.12.017.
Results Reference
background
PubMed Identifier
8818929
Citation
Mangoni AA, Mircoli L, Giannattasio C, Ferrari AU, Mancia G. Heart rate-dependence of arterial distensibility in vivo. J Hypertens. 1996 Jul;14(7):897-901. doi: 10.1097/00004872-199607000-00013.
Results Reference
background
PubMed Identifier
22759927
Citation
Custodis F, Fries P, Muller A, Stamm C, Grube M, Kroemer HK, Bohm M, Laufs U. Heart rate reduction by ivabradine improves aortic compliance in apolipoprotein E-deficient mice. J Vasc Res. 2012;49(5):432-40. doi: 10.1159/000339547. Epub 2012 Jul 3.
Results Reference
background
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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
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