Promotion of Coronary Collateral Function by Ivabradine-Induced Bradycardia in Patients With Coronary Artery Disease
Condition: Coronary Artery Disease
MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Bradycardia
Study type: Interventional

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.
    

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.
    

Intervention name(s): Ivabradine; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): bid administration of 5mg ivabradine (max 7.5mg) aiming to reduce resting heart rate to 60/min; bid placebo
Other intervention name(s): Procoralan, I(f)-inhibitor; Placebo control
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Coronary Artery Disease; Stable; Coronary Collaterals; Therapeutic Collateral Promotion; Arteriogenesis; Bradycardia