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

The recruitment status of this study is unknown because the information has not been verified recently.
Verified March 2012 by University of Athens.
Recruitment status was  Active, not recruiting
Sponsor:
Information provided by (Responsible Party):
Ignatios Ikonomidis, University of Athens
ClinicalTrials.gov Identifier:
NCT01566201
First received: March 27, 2012
Last updated: March 28, 2012
Last verified: March 2012

March 27, 2012
March 28, 2012
March 2011
April 2012   (final data collection date for primary outcome measure)
Improvement in vascular and left ventricular function after anakinra [ Time Frame: 3 hours after treatment ] [ Designated as safety issue: No ]
Improvement in vascular and left ventricular function after administration of anakinra compared to placebo
Same as current
Complete list of historical versions of study NCT01566201 on ClinicalTrials.gov Archive Site
Reduction of nitrooxidative stress and apoptosis after anakinra treatment [ Time Frame: 3 hours after treatment ] [ Designated as safety issue: No ]
Same as current
Not Provided
Not Provided
 
Effects of Interleukin-1 Inhibition on Vascular and Left Ventricular Function in Rheumatoid Arthritis Patients With Coronary Artery Disease
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).

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

Interventional
Not Provided
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
  • Rheumatoid Arthritis
  • Coronary Artery Disease
  • Inflammation
  • Drug: anakinra
    Inhibition of Interleukin-1 activity by anakinra (Kineret®) 100mg od, sc injection
    Other Name: Kineret® (anakinra)
  • Drug: placebo
    water for injection
    Other Name: water for injection
  • Active Comparator: anakinra
    Intervention: Drug: anakinra
  • Placebo Comparator: placebo
    Intervention: Drug: placebo
Ikonomidis I, Tzortzis S, Andreadou I, Paraskevaidis I, Katseli C, Katsimbri P, Pavlidis G, Parissis J, Kremastinos D, Anastasiou-Nana M, Lekakis J. Increased benefit of interleukin-1 inhibition on vascular function, myocardial deformation, and twisting in patients with coronary artery disease and coexisting rheumatoid arthritis. Circ Cardiovasc Imaging. 2014 Jul;7(4):619-28. doi: 10.1161/CIRCIMAGING.113.001193. Epub 2014 Apr 29.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
80
June 2012
April 2012   (final data collection date for primary outcome measure)

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
Both
18 Years and older
Yes
Contact information is only displayed when the study is recruiting subjects
Greece
 
NCT01566201
RCT-RACAD-ATTIKON-01
Yes
Ignatios Ikonomidis, University of Athens
University of Athens
Not Provided
Principal Investigator: Ignatios Ikonomidis, MD 2nd Cardiology Department, University of Athens, Greece
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
University of Athens
March 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP