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

Coronary Artery Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01039389
• Other study ID #: 237/2008
• Status: Completed
• Phase: N/A
• First received: December 24, 2009
• Last updated: July 11, 2013
• Start date: October 2009
• Est. completion date: March 2013

Study information

• Verified date: July 2013
• Source: University Hospital Inselspital, Berne
• Contact: n/a
• Is FDA regulated: No
• Health authority: Switzerland: Swissmedic
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 43
• Est. completion date: March 2013
• Est. primary completion date: March 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 90 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Bradycardia
• Coronary Artery Disease
• Coronary Disease
• Myocardial Ischemia

Intervention

Drug:
• Ivabradine
bid administration of 5mg ivabradine (max 7.5mg) aiming to reduce resting heart rate to 60/min
• Placebo
bid placebo

Locations

Country	Name	City	State
Switzerland	Bern University Hospital	Bern

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital Inselspital, Berne

Country where clinical trial is conducted

Switzerland, 

References & Publications (4)

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. — View Citation

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. doi: 10.1161/CIRCULATIONAHA.109.866269. Epub 2009 Sep 21. — View Citation

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. — View Citation

Patel SR, Breall JA, Diver DJ, Gersh BJ, Levy AP. Bradycardia is associated with development of coronary collateral vessels in humans. Coron Artery Dis. 2000 Sep;11(6):467-72. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Collateral flow index (CFI)		6 months	Yes
Secondary	Myocardial blood flow (MBF) during hyperemia		6 months	No

External Links

•   Information for patients