Anakinra to Prevent Adverse Post-infarction Remodeling (2)

Phase 2

Completed

Conditions: Heart Failure
Acute Myocardial Infarction

Interventions: Drug: Placebo
Drug: Anakinra

Registration Number: NCT01175018

Lead Sponsor: Virginia Commonwealth University

Brief Summary: Acute myocardial infarction (AMI) remains a major cause of morbidity and mortality. Many patients die early during the course, and those who survive are at risk for dying late from adverse cardiac remodeling and heart failure.

The initial ischemic damage to the myocardium initiates an intense inflammatory response in promoting further cardiac dysfunction and heart failure. The investigators propose that an antiinflammatory strategy based on blockade of Interleukin-1 will quench the inflammatory response and lead to a more favorable cardiac remodeling process.

Detailed Description: Acute myocardial infarction (AMI) remains a major cause of morbidity and mortality. Many patients die early during the course, and those who survive are at risk for dying late from adverse cardiac remodeling and heart failure.

The initial ischemic damage to the myocardium initiates an intense inflammatory response in promoting further cardiac dysfunction and heart failure. Interleukin-1 (IL-1) is the prototypical inflammatory cytokine involved in the tissue response to injury. In the experimental model of large anterior wall AMI in the mouse, IL-1 blockade using anakinra, a recombinant human IL-1 receptor antagonist ameliorates cardiac remodeling and improves survival following AMI. Although the mouse AMI model is helpful in understanding the events leading to adverse post-infarction cardiac remodeling and heart failure, the exact role of IL-1 in patients with AMI has not been completely characterized. The investigators propose to address this question by studying patients presenting with ST-segment elevation AMI (STEMI). Such patients are at high risk for in-hospital and long-term mortality and display several markers of inflammation. The investigators hypothesize that IL-1 blockade in patients STEMI with will limit the acute inflammatory response and prevent adverse cardiac remodeling, heart failure, and related morbidity.

The investigators hypothesize that treatment with anakinra will lead to more favorable cardiac remodeling. Left ventricular end-systolic volume index (LVESVi) is the preferred clinical marker of adverse cardiac remodeling and a strong predictor of heart failure-related mortality in patients with STEMI, and will be used as primary endpoint of the study. The investigators propose that anakinra will reduce the change in LVESVi from baseline to 10-14 weeks after STEMI, and will prevent, at least in part, other changes in cardiac function and exercise tolerance associated with adverse cardiac remodeling and heart failure.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 30

Inclusion Criteria

Patients with STEMI will be asked to enroll according to the following inclusion criteria:
- age > 18 years,
- acute (<12 h) onset of chest pain associated with ST segment elevation (>2 mm) in 2 or more anatomically contiguous leads at ECG,
- and successful primary percutaneous coronary intervention.

Exclusion criteria:

inability to give informed consent,
late presentation (>12 h),
unsuccessful revascularization procedure,
hemodynamic instability including hypotension,
prior Q-wave AMI,
end-stage congestive heart failure (American Heart Association [AHA]/American College of Cardiology [ACC] class C-D, New York Heart Association IV), severe left ventricular dysfunction (EF<20%),
severe valvular heart disease,
pregnancy, dye allergy or contraindications to cardiac angiography and/or magnetic resonance imaging, coagulopathy (INR>1.5 or platelet count<50000/mm3),
recent (<14 days) use of anti-inflammatory drugs (not including NSAIDs),
chronic inflammatory disease (including but not limited to rheumatoid arthritis, systemic lupus erythematosus), and malignancy or any comorbidity limiting survival or conditions predicting inability to complete the study.

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	0.67 ml of sodium chloride (NaCl) 0.9% solution
Anakinra	Anakinra	Anakinra 100 mg injectable subcutaneously daily

Primary Outcome Measures

Name	Time	Method
Difference Between the Anakinra Arm and the Placebo Arm in Change in Left Ventricular End-systolic Volume Indices	10-14 weeks minus baseline	Change in n left ventricular end-systolic volume indices from baseline to follow up exam at cardiac magnetic resonance imaging comparing anakinra- and placebo-treated patients.

Secondary Outcome Measures

Name	Time	Method
Difference Between the Anakinra Arm and the Placebo Arm in Change in Left Ventricular End-diastolic Volume Indices From Baseline to Follow up Exam at Cardiac Magnetic Resonance Imaging	10-14 weeks
Percentage of Patients in Each Group With Reverse Remodeling (Reduction in LVESVi >5%)	10-14 weeks
Median Difference Between the 2 Arms in the Peak Oxygen Consumption (VO2) at 10-14 Weeks	10-14 weeks
Incidence of Heart Failure	10-14 weeks	Difference between the anakinra arm and the placebo arm in number of patients with a new diagnosis or admission to the hospital for heart failure
Number of Adverse Events in Each Group	10-14 weeks
Difference Between the 2 Arm in the Interval Change in Right Ventricular Ejection Fraction (RVEF)	10-14 weeks
Difference Between the Anakinra Arm and the Placebo Arm in Change in Left Ventricular Ejection Fraction Values From Baseline to Follow up Exam at Cardiac Magnetic Resonance Imaging	10-14 weeks
Median Difference Between the 2 Arms in the Ratio of Minute Ventilation and Carbon Dioxide Production (VE/VCO2 Slope) at 10-14 Weeks	10-14 weeks
Percentage of Patients in Each Group With Reverse Remodeling (Reduction in LVESVi >10%)	10-14 weeks
Percentage of Patients in Each Group With Adverse Remodeling (LVESVi Increase >5%) Based Upon Cardiac Magnetic Resonance Imaging	10-14 weeks
Percentage of Patients in Each Group With Adverse Remodeling (LVESVi Increase >10%)	10-14 weeks
Percentage of Patients in Each Group With Left Ventricular Ejection Fraction Change >5%	10-14 weeks
Percentage of Patients in Each Group With Left Ventricular Ejection Fraction Change >10%	10-14 weeks
Number of Deaths in Each Group	10-14 weeks
Number of Adverse Events Requiring Withdrawal in Each Group	10-14 weeks