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Promotion of Coronary Collateral Function by Ivabradine-Induced Bradycardia in Patients With Coronary Artery Disease

This study is currently recruiting participants.
Verified December 2012 by University Hospital Inselspital, Berne
Sponsor:
Information provided by:
University Hospital Inselspital, Berne
ClinicalTrials.gov Identifier:
NCT01039389
First received: December 24, 2009
Last updated: December 18, 2012
Last verified: December 2012
History of Changes
  Purpose

The purpose of this study in patients with chronic stable coronary artery disease treatable by percutaneous coronary intervention (PCI) is to evaluate the long-term efficacy and safety of the orally taken selective I(f)-inhibitor Ivabradine (Procoralan®, Servier Switzerland) with regard to the promotion of collateral growth.


Condition Intervention
Coronary Artery Disease
 Drug: Ivabradine
Drug: Placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Promotion of Coronary Collateral Function by Ivabradine-Induced Bradycardia in Patients With Coronary Artery Disease

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by University Hospital Inselspital, Berne:

Primary Outcome Measures:
  • Collateral flow index (CFI) [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Myocardial blood flow (MBF) during hyperemia [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 80
Study Start Date: October 2009
Estimated Study Completion Date: December 2013
Estimated Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Collateral promotion; PCI after 6 months Drug: Ivabradine
bid administration of 5mg ivabradine (max 7.5mg) aiming to reduce resting heart rate to 60/min
Other Name: Procoralan, I(f)-inhibitor
Drug: Placebo
bid placebo
Other Name: Placebo control
Experimental: Collateral promotion; PCI at baseline Drug: Ivabradine
bid administration of 5mg ivabradine (max 7.5mg) aiming to reduce resting heart rate to 60/min
Other Name: Procoralan, I(f)-inhibitor
Drug: Placebo
bid placebo
Other Name: Placebo control

Detailed Description:

Coronary artery disease (CAD) is the leading cause of death in industrialized countries. Current therapies for restoration of coronary flow are percutaneous coronary intervention (PCI) or surgical revascularization. However, inherent to them are procedure-related risks and the fact that CAD progression is not prevented. Additionally, up to one fourth of all CAD patients are not amenable to standard revascularization therapies. Thus, there is a need for alternative therapies. Coronary collaterals as natural bypasses are anastomoses without an intervening capillary bed between portions of the same coronary artery or between different coronary arteries. The coronary collateral circulation is prevalent in humans and in CAD the amount of collateral flow is directly related to infarct size, all-cause- and cardiac mortality. Thus, the goal is to promote collateral function in the sense of prophylactic myocardial salvage.

Coronary (collateral) blood flow occurs almost entirely during diastole. Fluid shear stress (FSS) is the driving force in the formation, promotion and maintenance of collaterals (i.e. arteriogenesis). It is the product of blood viscosity and shear rate, the latter being the fluid velocity change between different fluid layers which is related to the fluid velocity at the endothelium. Prolongation of diastole via reduction of resting heart rate (RHR) is naturally equal to extension of shear stress at the endothelium. Bradycardia is likely to be the key factor for augmented collateral function: In several animal models, an inverse relation between heart rate and collateral function was found. We have recently confirmed this finding investigating collateral function measurements in normal coronary arteries of our patient population.

The fact that beta blockers depress contractility and unmask beta-adrenergic coronary vasoconstriction has prompted the development of selective I(f)-inhibitors. To date, ivabradine is the only clinically available specific inhibitor of the pacemaker current in the sinuatrial node (called "funny" current, because of permeability for mixed ions and activation by hyperpolarization instead of depolarization, I(f)). It acts as a pure heart rate lowering agent without affecting blood pressure, myocardial contractility, intra-cardiac conduction, or ventricular repolarization. In contrast to beta blockers or calcium channel blockers, it mimics physiological bradycardia and is therefore appropriate for the purpose of this study. By bradycardization in CAD, ischemia is targeted via reduction of myocardial oxygen demand and increase of oxygen supply without negative inotropic, coronary vasoconstrictive, or metabolic effects. In terms of anti-anginal efficacy, ivabradine has been found to be as effective as atenolol or amlodipine.

  Eligibility

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

Inclusion Criteria:

  1. Age > 18 years old
  2. 1- to 3-vessel stable coronary artery disease (CAD)
  3. At least 1 stenotic lesion suitable for PCI
  4. No Q-wave myocardial infarction in the area undergoing CFI measurement
  5. Written informed consent to participate in the study

Exclusion Criteria:

  1. Acute coronary syndrome
  2. CAD treated best by surgical coronary bypass
  3. Indications for BB treatment (heart failure, arrhythmias, <3months post-infarct)
  4. RHR <60/min without any treatment
  5. Sick sinus syndrome, sinuatrial block or >2nd degree atrio-ventricular block
  6. Atrial fibrillation
  7. Inherited or acquired long-QT syndrome
  8. Indwelling pacemaker
  9. Severe hepatic or renal failure (creatinine clearance <15ml/min)
  10. Hypersensitivity against ivabradine or adjuvants
  11. Pre-menopausal women
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01039389

Contacts
Contact: Michael Stoller, MD +41 31 632 8030 Michael.stoller@insel.ch
Contact: Christian Seiler, MD, Prof. +41 31 632 2111 christian.seiler@insel.ch

Locations
Switzerland
Bern University Hospital Recruiting
Bern, Switzerland
Contact: Michael Stoller, MD     +41 31 632 8030     Michael.stoller@insel.ch    
Principal Investigator: Christian Seiler, MD, Prof.            
Sub-Investigator: Tobias Traupe, MD            
Sub-Investigator: Stefano de Marchi, MD            
Sub-Investigator: Rolf Vogel, MD,PhD,Prof.            
Sub-Investigator: Steffen Gloekler, MD            
Sub-Investigator: Ahmed Khattab, MD            
Sponsors and Collaborators
University Hospital Inselspital, Berne
Investigators
Study Chair: Christian Seiler, MD, Prof. University Hospital Inselspital, Berne
Principal Investigator: Michael Stoller, MD University Hospital Inselspital, Berne
Principal Investigator: Tobias Traupe, MD University Hospital Inselspital, Berne
  More Information

Publications:

Responsible Party: Christian Seiler, MD, Professor and Co-Chairman of Cardiology, Department of Cardiology, University Hospital, CH-3010 Bern, Switzerland
ClinicalTrials.gov Identifier: NCT01039389     History of Changes
Other Study ID Numbers: 237/2008
Study First Received: December 24, 2009
Last Updated: December 18, 2012
Health Authority: Switzerland: Swissmedic

Keywords provided by University Hospital Inselspital, Berne:
Coronary Artery Disease
Stable
Coronary Collaterals
 Therapeutic Collateral Promotion
Arteriogenesis
Bradycardia

Additional relevant MeSH terms:
Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Bradycardia
Heart Diseases
Cardiovascular Diseases
 Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Arrhythmias, Cardiac
Pathologic Processes

ClinicalTrials.gov processed this record on May 21, 2013