Effects of the Ivabradine on Reduction of Inflammatory Markers in Patients With Acute Coronary Syndrome

Randomised, Double-blind, Placebo-controlled Trial of IVabradine in Patients With Acute Coronary Syndrome: Effects of the If Current Inhibitor Ivabradine or rEduction of Inflammation maRkers in Patients With Acute Coronary Syndrome

The purpose of this study is to investigate whether a pure heart rate-lowering agent (Ivabradine) reduces vascular inflammatory stress in patients with acute coronary syndromes

Study Overview

• Status: Completed
• Conditions: Acute Coronary Syndromes
• Intervention / Treatment: Drug: Placebo; Drug: Ivabradine

Detailed Description

The activation of inflammatory pathways plays an important contributory role in coronary plaque instability and subsequent rupture, which can lead to the development of acute coronary syndromes. Elevated levels of serum inflammatory markers such as high-sensitivity C-reactive protein (hs-CRP) represent independent risk factors for further cardiovascular events. Raised resting heart rate (HR) has been shown to be associated with cardiovascular events. Ivabradine is a new HR-reducing agent, which has demonstrated antianginal and anti-ischemic properties in patients with stable angina. In an atherosclerosis model, selective HR reduction with ivabradine has been shown to decrease markers of vascular oxidative stress, to improve endothelial function, and to reduce atherosclerotic plaque formation. We hypothesized that the addition of ivabradine to standard medical therapy has a beneficial effect on markers of inflammatory stress in acute coronary syndrome patients.

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 4

Contacts and Locations

Study Locations

• Spain
  • Santa Cruz De Tenerife
    • La Laguna, Santa Cruz De Tenerife, Spain, 38320
      • Hospital Universitario de Canarias

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female.
2. Age > 18 years.

3. Ischemic symptoms suspected to represent a non-ST segment elevation acute coronary syndrome defined as:

   Clinical history consistent with new onset, or a worsening pattern, of characteristic ischemic chest pain occuring at rest or with minimal exertion (lasting longer than 10 min) and planned to be managed with an early invasive strategy with intention to perform a percutaneous coronary intervention as early as possible and not later than 72 hours of randomization, and at least one of the following:

   1. ECG changes compatible with new ischemia (ST depression of at least 1 mm or transient ST elevation or ST elevation of <1 mm or T wave inversion >3 mm in at least 2 contiguous leads; or
   2. Already elevated cardiac enzymes (eg, CK-MB) or biomarkers (troponin I or T) above the upper limit of normal.
4. Patients should be in sinus rhythm with a resting HR of > 60 beats per minute on a resting standard 12-lead ECG.
5. Written informed consent obtained.

Exclusion Criteria:

1. Patients unlikely to cooperate in the study or with inability or unwillingness to give informed consent.
2. Pregnant or breast-feeding women or women of childbearing potential.
3. Patients with recent (< 6 months) myocardial infarction or coronary revascularization or with a history of stroke or cerebral transient ischemic attack within the preceding 3 months or scheduled for revascularization (percutaneous coronary intervention and coronary artery bypass graft).

4. Patients with at least 1 of the following criteria:

   • Implanted pacemaker or implantable cardioverter defibrillator.
   • Valvular disease likely to require surgery within the next 2 years.
   • Sick sinus syndrome, sinoatrial block, congenital long QT syndrome, complete atrioventricular block.
   • Expectation of death from other illness during the course of the trial.
   • Known severe liver or renal disease.
   • Requiring or likely to require the following medications: macrolide antibiotics, cyclosporin, gestodene, antiretroviral drugs or azole antifungals such as ketoconazole or with known hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
5. Patients with systemic or cardiac inflammatory processes with the exception of atherosclerosis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo	Drug: Placebo; Eligible patients will be randomized to 1 of the 2 treatment arms, namely, double-blind ivabradine, or placebo, after hospital admission (at 48 hours). The starting dose of ivabradine will be 5 mg (or matching placebo) twice daily in all patients. Patients receiving 5 mg twice daily (or matching placebo) 1 week after the inclusion with a resting HR of ≥60 beats per minute will receive the target dose of 7.5 mg twice daily (or matching placebo).
ACTIVE_COMPARATOR: Ivabradine	Drug: Ivabradine; Eligible patients will be randomized to 1 of the 2 treatment arms, namely, double-blind ivabradine, or placebo, after hospital admission (at 48 hours). The starting dose of ivabradine will be 5 mg (or matching placebo) twice daily in all patients. Patients receiving 5 mg twice daily (or matching placebo) 1 week after the inclusion with a resting HR of ≥60 beats per minute will receive the target dose of 7.5 mg twice daily (or matching placebo).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Whether initiation of ivabradine therapy in patients with acute coronary syndromes immediately after hospital admission decreases high-sensitivity C-reactive protein.	day 4 and day 30

Secondary Outcome Measures

Outcome Measure	Time Frame
Whether initiation of ivabradine therapy decreases the occurrence of ischemic events (death, nonfatal myocardial infarction, unstable angina, urgent revascularization, cardiac arrest) in patients with acute coronary syndromes.	day 30, 90, 180 and 360

Collaborators and Investigators

• Sponsor: Hospital Universitario de Canarias

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 1, 2009
• Primary Completion (ACTUAL): April 1, 2011
• Study Completion (ACTUAL): September 7, 2011

Study Registration Dates

• First Submitted: December 25, 2008
• First Submitted That Met QC Criteria: December 26, 2008
• First Posted (ESTIMATE): December 29, 2008

Study Record Updates

• Last Update Posted (ACTUAL): August 11, 2020
• Last Update Submitted That Met QC Criteria: August 7, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: Inflammation; Atherosclerosis; Ivabradine; C-reactive protein; Acute coronary syndrome.
• Additional Relevant MeSH Terms: Pathologic Processes; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Disease; Syndrome; Acute Coronary Syndrome
• Other Study ID Numbers: Riviera/09