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

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.

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.

• 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 after 6 months
  Interventions:

  • Drug: Ivabradine
  • Drug: Placebo
• Experimental: Collateral promotion; PCI at baseline
  Interventions:

  • Drug: Ivabradine
  • Drug: Placebo

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• DiFrancesco D, Camm JA. Heart rate lowering by specific and selective I(f) current inhibition with ivabradine: a new therapeutic perspective in cardiovascular disease. Drugs. 2004;64(16):1757-65. Review.
• Meier P, Gloekler S, de Marchi SF, Indermuehle A, Rutz T, Traupe T, Steck H, Vogel R, Seiler C. Myocardial salvage through coronary collateral growth by granulocyte colony-stimulating factor in chronic coronary artery disease: a controlled randomized trial. Circulation. 2009 Oct 6;120(14):1355-63. Epub 2009 Sep 21.
• Meier P, Gloekler S, Zbinden R, Beckh S, de Marchi SF, Zbinden S, Wustmann K, Billinger M, Vogel R, Cook S, Wenaweser P, Togni M, Windecker S, Meier B, Seiler C. Beneficial effect of recruitable collaterals: a 10-year follow-up study in patients with stable coronary artery disease undergoing quantitative collateral measurements. Circulation. 2007 Aug 28;116(9):975-83. Epub 2007 Aug 6.

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