Effects of Interleukin-1 Inhibition on Vascular and Left Ventricular Function in Rheumatoid Arthritis Patients With Coronary Artery Disease

December 1, 2014 updated by: Ignatios Ikonomidis, University of Athens

The Effect of Inhibition of Interleukin-1 Activity on Vascular and Left Ventricular Function in Patients With Coronary Artery Disease and Coexistent Rheumatoid Arthritis

Inhibition of interleukin-1 (IL-1) activity in patients with RA without CAD ameliorates vascular and LV function. Moreover, data from species shows beneficial effect of this treatment on LV function after experimental myocardial infarction. The purpose of this study is to investigate whether anakinra, an IL-1 receptor antagonist, improves vascular and left ventricular (LV) function in patients with coronary artery disease (CAD) and coexistent rheumatoid arthritis (RA).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The inflammatory processes observed in patients with rheumatoid arthritis (RA) are strongly linked to enhanced interleukin-1 (IL-1) activity. Increased IL-1 activity causes myocardial cell damage and endothelial dysfunction. The adverse effects of IL-1 on myocardial and endothelial cells are mediated by an enhanced nitrooxidative stress and the promotion of apoptotic cardiomyocyte death through increased nitrooxidative stress and inflammation. Anakinra, a recombinant form of human IL-1 receptor antagonist, is commonly used for the treatment of RA. Experimental data indicates that administration of anakinra after acute myocardial infarction ameliorates cardiac remodeling by reducing cardiomyocyte apoptosis. Moreover, in our previous studies we have shown that treatment with anakinra reduces IL-1-mediated nitrooxidative stress and apoptotic markers leading to an improvement in Tissue Doppler and speckle tracking-derived parameters of left ventricular (LV) function in RA patients. However it has not been defined whether inhibition of IL-1 activity by anakinra shows beneficial effects on endothelial, coronary, arterial and LV systolic and diastolic function in patients with coronary artery disease (CAD).

For this purpose, we studied 60 patients with CAD and coexistent RA (American Rheumatism Association criteria) as well as 20 patients with RA and without CAD. All the above subjects had an inadequate response to disease modifying antirheumatic drugs (DMARDs) and corticosteroids and were going to initiate treatment with IL-1 activity inhibitor (anakinra). All patients were on treatment with statins and cardioactive medications respectively, for the last 6 months. In the 20 patients with only RA, the presence of CAD was excluded with a non-invasive test and/or a negative recent coronary arteriogram.

In a double-blind, placebo-controlled fashion, all patients were randomized to receive a single injection of anakinra(100 mg s.c.) or placebo. After 48-hours patients were crossed over to the alternate treatment (placebo or anakinra) and measurement of the examined markers was repeated. The 48h interval between the 2 consecutive studies was decided to secure a sufficient wash-out period of anakinra in accordance to the drug's half-life time.

Twenty asymptomatic subjects matched for age and sex as the RA patients and with a normal ECG, echocardiogram, and treadmill test were selected as healthy control subjects among subjects attending the cardiology outpatients' clinic.

At baseline in all RA subjects and controls as well as 3-hours after the single injection of anakinra in RA subjects, we assessed by means of echocardiography the following parameters a) the LV dimensions,fractional shortening and wall motion score index (WMSI) b) the systolic (Sm), early diastolic (Em) and late diastolic (Am) myocardial velocities of the mitral annulus by using of tissue Doppler (TDI) as well as the ratio of E wave of the mitral inflow measured by pulsed wave Doppler to the mean Em as an index of LV diastolic filling pressures c) the LV longitudinal, circumferential and radial strain and strain rate, as well as Global Longitudinal strain and Torsion using speckle tracking echocardiography d) the coronary flow reserve (CFR)after adenosine infusion to assess coronary vasomotor function e) the flow-mediated endothelial-dependent dilation of the brachial artery (FMD) to assess peripheral endothelial function f) the diameters of aorta at systole and diastole to calculate the aortic strain as an index of local aortic properties. At the same time periods, we measured in blood samples a) nitrotyrosine (NT), protein carbonyls (PC)and malondialdehyde(MDA)to assess nitrooxidative stress b)soluble Fas and Fas-ligand )to assess apoptosis c) interleukin-1b and tumor necrosis factor-a to assess inflammation

Study Type

Interventional

Enrollment (Actual)

80

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Greece
    • Attiki
      • Haidari, Athens, Attiki, Greece, 12462
        • "Attikon" University General Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients with rheumatoid arthritis and coexistent coronary artery disease or without CAD who had an inadequate response to disease modifying antirheumatic drugs (DMARDs) and corticosteroids and were going to initiate treatment with interleukin-1 inhibitor.

Exclusion Criteria:

  • Familiar hyperlipidemia
  • Diabetes mellitus
  • Chronic obstructive pulmonary disease or asthma, moderate or severe valvular heart disease, primary cardiomyopathies,malignant tumors

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: placebo
Drug: placebo
water for injection
Other Names:
  • water for injection
Active Comparator: anakinra
Drug: anakinra
Inhibition of Interleukin-1 activity by anakinra (Kineret®) 100mg od, sc injection
Other Names:
  • Kineret® (anakinra)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Improvement in vascular and left ventricular function after anakinra
Time Frame: 3 hours after treatment
Improvement in vascular and left ventricular function after administration of anakinra compared to placebo
3 hours after treatment

Secondary Outcome Measures

Outcome Measure
Time Frame
Reduction of nitrooxidative stress and apoptosis after anakinra treatment
Time Frame: 3 hours after treatment
3 hours after treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Athens

Investigators

  • Principal Investigator: Stavros Tzortzis, MD, 2nd Cardiology Department, University of Athens, Greece
  • Principal Investigator: John P. Lekakis, MD, 2nd Cardiology Department, University of Athens, Greece
  • Principal Investigator: Ioanna Andreadou, Dr, Department of Pharmaceutical Chemistry, University of Athens Medical School, Greece
  • Principal Investigator: Ioannis Paraskevaidis, MD, 2nd Cardiology Department, University of Athens, Greece
  • Principal Investigator: Maria Anastasiou-Nana, MD, 2nd Cardiology Department, University of Athens, Greece

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2011

Primary Completion (Actual)

April 1, 2012

Study Completion (Actual)

June 1, 2013

Study Registration Dates

First Submitted

March 27, 2012

First Submitted That Met QC Criteria

March 28, 2012

First Posted (Estimate)

March 29, 2012

Study Record Updates

Last Update Posted (Estimate)

December 3, 2014

Last Update Submitted That Met QC Criteria

December 1, 2014

Last Verified

December 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RCT-RACAD-ATTIKON-01

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Coronary Artery Disease

Clinical Trials on placebo

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Malta

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe