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

Coronary Artery Disease Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01768585
• Other study ID #: HomRate04_2012
• Status: Recruiting
• Phase: Phase 4
• First received: January 11, 2013
• Last updated: January 14, 2013
• Start date: December 2012
• Est. completion date: December 2014

Study information

• Verified date: January 2013
• Source: University Hospital, Saarland
• Contact: Florian Custodis, MD
• Phone: 0049-6841-1623000
• Email: Florian.Custodis[@]uks.eu
• Is FDA regulated: No
• Health authority: Germany: Ethics CommissionGermany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: December 2014
• Est. primary completion date: December 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 90 Years

Eligibility

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

Study Design

Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Diagnostic

Related Conditions & MeSH terms

• Arteriosclerosis
• Coronary Arteriosclerosis
• Coronary Artery Disease
• Coronary Disease
• Heart Diseases
• Myocardial Ischemia

Intervention

Drug:
• Ivabradine
Please see description of Intervention Arm
• Placebo

Locations

Country	Name	City	State
Germany	University Hospital, Saarland	Homburg	Saarland

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Saarland	Saarland University

Country where clinical trial is conducted

Germany, 

References & Publications (7)

Beere PA, Glagov S, Zarins CK. Retarding effect of lowered heart rate on coronary atherosclerosis. Science. 1984 Oct 12;226(4671):180-2. — View 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. Review. — View Citation

Custodis F, Baumhäkel M, Schlimmer N, List F, Gensch C, Böhm 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. — View Citation

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):432-40. doi: 10.1159/000339547. Epub 2012 Jul 3. — View Citation

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 Dec 7;56(24):1973-83. doi: 10.1016/j.jacc.2010.09.014. Review. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Aortic distensibility (MRI), pulse wave velocity (SphygmoCor®), flow-mediated dilatation (A. brachialis)		Decembre 2014	No
Secondary	Biomarkers (inflammation, oxidative stress)		Decembre 2014	No