Clinical trial NCT00789724: Anakinra to Prevent Post-infarction Remodeling
Official title: Recombinant Human Interleukin-1 Receptor Antagonist, Anakinra, to Prevent Post-infarction Remodeling: the Virginia Commonwealth University Anakinra Remodeling Trial (VCU-ART)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: ST Segment Elevation Acute Myocardial Infarction
Keywords: acute myocardial infarction
Lead sponsor: Virginia Commonwealth University
Sponsor class: OTHER
First posted: 2008-11-13
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Thousands of patients die daily from early and late complications of a heart attack (acute myocardial infarction, AMI). Patients surviving AMI remain at high risk of death from adverse cardiac remodeling (dysfunction and enlargement of the heart) leading to heart failure (weakening of the heart).

Current interventions proven to reduce adverse remodeling and progression to heart failure include early reperfusion (restoring blood flow to the heart muscle) and long-term use of medicines that block the effects of hormones (such as angiotensin II, norepinephrine and aldosterone) involved in adverse remodeling. Despite these treatments, however, many patients continue to develop heart failure within 1 year of AMI. These patients are at very high risk of death.

Numerous changes occur in the hearts of patients after AMI that lead to adverse remodeling. Ischemia (lack of oxygen) and infarction (cell damage) lead to increased interleukin-1 (IL-1) production in the heart. IL-1 plays a critical role in adverse cardiac remodeling by coordinating the inflammatory pathway (leading to wound healing) and apoptotic pathway (leading to cell death).

In opposition to IL-1 activity, the human body produces a natural IL-1 receptor antagonist that blocks the effects of IL-1. The drug form of this IL-1 receptor antagonist (anakinra) is currently FDA approved for the treatment of rheumatoid arthritis, an inflammatory disease characterized by excessive IL-1 activity. Experimental studies show that anakinra is able to prevent cardiac remodeling and improve survival in mice after AMI.

We hypothesize that anakinra will show similar benefits in human patients by preventing adverse remodeling and heart failure after AMI.


Eligibility criteria: Inclusion Criteria:

* Age \>18 years
* Acute (\<24 hours) onset of chest pain
* New or presumably new ST elevation on ECG
* Planned coronary angiography for percutaneous revascularization

Exclusion Criteria:

* Inability to give informed consent
* Late presentation (\>24 hours)
* Unsuccessful revascularization or urgent coronary bypass surgery
* Hemodynamic instability
* End-stage congestive heart failure (AHA/ACC stage C/D, NYHA class IV)
* Preexisting severe LV dysfunction (LVEF\<20%) or severe valvular disease
* Severe asthma
* Pregnancy ( pre-enrollment pregnancy test)
* Contraindications to cardiac MRI or cardiac angiography
* Severe coagulopathy (INR\>2.0, Platelet count\<50,000/mm3)
* Severe renal insufficiency (creatinine clearance \<30 ml/min/m2)
* Recent (\<14 days) use of anti-inflammatory drugs (NSAIDS excluded)
* Chronic inflammatory disease

Primary outcomes:
measure: Difference Between the Anakinra Arm and Placebo Arm in Change in End-systolic Volume Indices From Baseline to Follow up Exam 10-14 Weeks Later at Cardiac Magnetic Resonance Imaging.
timeFrame: 10-14 weeks
Secondary outcomes:
Other outcomes:
measure: Difference Between the 2 Arms in the Percentage of Patients With Any of the Following : a) End-systolic or End-diastolic Volume Index Increase >10%; b) Ejection Fraction Decrease >10%; c) E/E'>15 at Follow up
timeFrame: 10-14 weeks
measure: Difference Between the 2 Arms in Change in the Number of Circulating Endothelial Progenitor Cells From Baseline to Follow up Exam
timeFrame: 10-14 weeks
measure: Difference Between the 2 Arms in Change in Serum BNP Levels, C-reactive Protein, and Hemoglobin A1c% From Baseline to Follow up
timeFrame: 10-14 weeks
measure: Difference Between the 2 Arms in the Incidence of Significant Cardiac Arrhythmias in the Acute Phase
timeFrame: 48 hours
measure: Difference Between the 2 Arms in the Number of Adverse Effects Including a) All Events; b) All Events Requiring Unblinding of the Treatment; c) All Events Requiring Early Termination of the Intervention
timeFrame: 10-14 weeks
measure: Difference Between the 2 Arms in Change in Oxygen Uptake Kinetics From Baseline to Follow up Exam at Submaximal Cardiopulmonary Exercise Test
timeFrame: 10-14 weeks
measure: Difference Between the 2 Arms in Change in E/E' Ratios and Myocardial Performance (Tei) Indices From Baseline to Follow up Exam at Transthoracic Echo-color-Doppler Cardiac Exam
timeFrame: 10-14 weeks
measure: Difference Between the 2 Arms in Change in End-diastolic Volume Indices and Ejection Fraction Values From Baseline to Follow up Exam at Cardiac Magnetic Resonance Imaging
timeFrame: 10-14 weeks
Locations:
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
Study officials:
affiliation: Virginia Commonwealth University
name: Antonio Abbate, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Del Buono MG, Damonte JI, Chiabrando JG, Markley R, Turlington J, Trankle CR, Kang L, Biondi-Zoccai G, Van Tassell BW, Abbate A. Effect of IL-1 Blockade With Anakinra on Heart Failure Outcomes in Patients With Anterior Versus Nonanterior ST Elevation Myocardial Infarction. J Cardiovasc Pharmacol. 2022 Jun 1;79(6):774-780. doi: 10.1097/FJC.0000000000001240.
citation: Abbate A, Kontos MC, Abouzaki NA, Melchior RD, Thomas C, Van Tassell BW, Oddi C, Carbone S, Trankle CR, Roberts CS, Mueller GH, Gambill ML, Christopher S, Markley R, Vetrovec GW, Dinarello CA, Biondi-Zoccai G. Comparative safety of interleukin-1 blockade with anakinra in patients with ST-segment elevation acute myocardial infarction (from the VCU-ART and VCU-ART2 pilot studies). Am J Cardiol. 2015 Feb 1;115(3):288-92. doi: 10.1016/j.amjcard.2014.11.003. Epub 2014 Nov 13.