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

Sponsor

University Hospital Inselspital, Berne (Other)

Overall Status

Completed

CT.gov ID

NCT01039389

Collaborator

(none)

Enrollment

Location

Arms

Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
Coronary Artery Disease	Drug: Ivabradine Drug: Placebo	N/A

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

43 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Oct 1, 2009

Actual Primary Completion Date :

Mar 1, 2013

Actual Study Completion Date :

Mar 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
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 Names: Procoralan, I(f)-inhibitor Drug: Placebo bid placebo Other Names: 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 Names: Procoralan, I(f)-inhibitor Drug: Placebo bid placebo Other Names: Placebo control

Arm

Intervention/Treatment

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 Names:

Procoralan, I(f)-inhibitor

Drug: Placebo

bid placebo

Other Names:

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 Names:

Procoralan, I(f)-inhibitor

Drug: Placebo

bid placebo

Other Names:

Placebo control

Outcome Measures

Primary Outcome Measures

Collateral flow index (CFI) [6 months]

Secondary Outcome Measures

Myocardial blood flow (MBF) during hyperemia [6 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 90 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Exclusion Criteria:

Acute coronary syndrome
CAD treated best by surgical coronary bypass
Indications for BB treatment (heart failure, arrhythmias, <3months post-infarct)
RHR <60/min without any treatment
Sick sinus syndrome, sinuatrial block or >2nd degree atrio-ventricular block
Atrial fibrillation
Inherited or acquired long-QT syndrome
Indwelling pacemaker
Severe hepatic or renal failure (creatinine clearance <15ml/min)
Hypersensitivity against ivabradine or adjuvants
Pre-menopausal women

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Bern University Hospital	Bern		Switzerland

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