Acute Myocardial Infarction, Heart Failure
Conditions
Keywords
Acute myocardial infarction, Heart Failure, Cardiac Remodeling
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.
Interventions
DRUGAnakinra
Anakinra 100 mg s.c. daily for 14 days
DRUGPlacebo
0.67 ml of NaCl 0.9% solution given subcutaneously daily for 14 days
Sponsors
American Heart Association
Virginia Commonwealth University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 110 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| 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 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 | — |
| Percentage of Patients in Each Group With Reverse Remodeling (Reduction in LVESVi >10%) | 10-14 weeks | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Anakinra Anakinra 100 mg injectable subcutaneously daily | 15 |
| Placebo 0.67 ml of NaCl 0.9% solution | 15 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 |
Baseline characteristics
| Characteristic | Placebo | Anakinra | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 4 Participants | 9 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 11 Participants | 21 Participants |
| Age, Continuous | 58 years STANDARD_DEVIATION 12 | 59 years STANDARD_DEVIATION 12 | 59 years STANDARD_DEVIATION 12 |
| Region of Enrollment United States | 15 participants | 15 participants | 30 participants |
| Sex: Female, Male Female | 2 Participants | 5 Participants | 7 Participants |
| Sex: Female, Male Male | 13 Participants | 10 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 15 | 8 / 15 |
| serious Total, serious adverse events | 4 / 15 | 6 / 15 |
Outcome results
Primary
Difference Between the Anakinra Arm and the Placebo Arm in Change in Left Ventricular End-systolic Volume Indices
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.
Time frame: 10-14 weeks minus baseline
Population: Applies only to subset of patients with magnetic resonance imaging (MRI) at baseline and 10-14 weeks.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anakinra | Difference Between the Anakinra Arm and the Placebo Arm in Change in Left Ventricular End-systolic Volume Indices | 1.5 mL/m2 |
| Placebo | Difference Between the Anakinra Arm and the Placebo Arm in Change in Left Ventricular End-systolic Volume Indices | 1.0 mL/m2 |
p-value: <0.05ANOVA
Secondary
Difference Between the 2 Arm in the Interval Change in Right Ventricular Ejection Fraction (RVEF)
Time frame: 10-14 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anakinra | Difference Between the 2 Arm in the Interval Change in Right Ventricular Ejection Fraction (RVEF) | 5 % (absolute change) |
| Placebo | Difference Between the 2 Arm in the Interval Change in Right Ventricular Ejection Fraction (RVEF) | 4 % (absolute change) |
p-value: >0.05ANOVA
Secondary
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
Time frame: 10-14 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anakinra | 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 | 2 % (absolute change) |
| Placebo | 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 | -2 % (absolute change) |
p-value: >0.05ANOVA
Secondary
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
Time frame: 10-14 weeks
Population: Applies only to subset of patients with magnetic resonance imaging (MRI) at baseline and 10-14 weeks.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anakinra | 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 | 3 mL/m2 |
| Placebo | 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 | -4 mL/m2 |
p-value: >0.05ANOVA
Secondary
Incidence of Heart Failure
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
Time frame: 10-14 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anakinra | Incidence of Heart Failure | 1 participants |
| Placebo | Incidence of Heart Failure | 4 participants |
p-value: <0.05Log Rank
Secondary
Median Difference Between the 2 Arms in the Peak Oxygen Consumption (VO2) at 10-14 Weeks
Time frame: 10-14 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anakinra | Median Difference Between the 2 Arms in the Peak Oxygen Consumption (VO2) at 10-14 Weeks | -1 ml*kg^-1*min^-1 |
| Placebo | Median Difference Between the 2 Arms in the Peak Oxygen Consumption (VO2) at 10-14 Weeks | 2.5 ml*kg^-1*min^-1 |
p-value: >0.05ANOVA
Secondary
Median Difference Between the 2 Arms in the Ratio of Minute Ventilation and Carbon Dioxide Production (VE/VCO2 Slope) at 10-14 Weeks
Time frame: 10-14 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anakinra | Median Difference Between the 2 Arms in the Ratio of Minute Ventilation and Carbon Dioxide Production (VE/VCO2 Slope) at 10-14 Weeks | -1 (no units; ratio of values) |
| Placebo | Median Difference Between the 2 Arms in the Ratio of Minute Ventilation and Carbon Dioxide Production (VE/VCO2 Slope) at 10-14 Weeks | -3 (no units; ratio of values) |
p-value: >0.05ANOVA
Secondary
Number of Adverse Events in Each Group
Time frame: 10-14 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anakinra | Number of Adverse Events in Each Group | 11 adverse events |
| Placebo | Number of Adverse Events in Each Group | 20 adverse events |
p-value: >0.05Chi-squared
Secondary
Number of Adverse Events Requiring Withdrawal in Each Group
Time frame: 10-14 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anakinra | Number of Adverse Events Requiring Withdrawal in Each Group | 2 adverse events |
| Placebo | Number of Adverse Events Requiring Withdrawal in Each Group | 2 adverse events |
p-value: >0.05Chi-squared
Secondary
Number of Deaths in Each Group
Time frame: 10-14 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anakinra | Number of Deaths in Each Group | 0 deaths |
| Placebo | Number of Deaths in Each Group | 1 deaths |
p-value: >0.05Chi-squared
Secondary
Percentage of Patients in Each Group With Adverse Remodeling (LVESVi Increase >10%)
Time frame: 10-14 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anakinra | Percentage of Patients in Each Group With Adverse Remodeling (LVESVi Increase >10%) | 45 % of participants |
| Placebo | Percentage of Patients in Each Group With Adverse Remodeling (LVESVi Increase >10%) | 29 % of participants |
p-value: >0.05Chi-squared
Secondary
Percentage of Patients in Each Group With Adverse Remodeling (LVESVi Increase >5%) Based Upon Cardiac Magnetic Resonance Imaging
Time frame: 10-14 weeks
Population: Applies only to subset of patients with magnetic resonance imaging (MRI) at baseline and 10-14 weeks.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anakinra | Percentage of Patients in Each Group With Adverse Remodeling (LVESVi Increase >5%) Based Upon Cardiac Magnetic Resonance Imaging | 55 % of participants |
| Placebo | Percentage of Patients in Each Group With Adverse Remodeling (LVESVi Increase >5%) Based Upon Cardiac Magnetic Resonance Imaging | 42 % of participants |
p-value: >0.05Chi-squared
Secondary
Percentage of Patients in Each Group With Left Ventricular Ejection Fraction Change >10%
Time frame: 10-14 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anakinra | Percentage of Patients in Each Group With Left Ventricular Ejection Fraction Change >10% | 27 % of participants |
| Placebo | Percentage of Patients in Each Group With Left Ventricular Ejection Fraction Change >10% | 0 % of participants |
p-value: >0.05Chi-squared
Secondary
Percentage of Patients in Each Group With Left Ventricular Ejection Fraction Change >5%
Time frame: 10-14 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anakinra | Percentage of Patients in Each Group With Left Ventricular Ejection Fraction Change >5% | 36 % of participants |
| Placebo | Percentage of Patients in Each Group With Left Ventricular Ejection Fraction Change >5% | 36 % of participants |
p-value: >0.05Chi-squared
Secondary
Percentage of Patients in Each Group With Reverse Remodeling (Reduction in LVESVi >10%)
Time frame: 10-14 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anakinra | Percentage of Patients in Each Group With Reverse Remodeling (Reduction in LVESVi >10%) | 27 % of participants |
| Placebo | Percentage of Patients in Each Group With Reverse Remodeling (Reduction in LVESVi >10%) | 36 % of participants |
p-value: >0.05Chi-squared
Secondary
Percentage of Patients in Each Group With Reverse Remodeling (Reduction in LVESVi >5%)
Time frame: 10-14 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Anakinra | Percentage of Patients in Each Group With Reverse Remodeling (Reduction in LVESVi >5%) | 45 % of participants |
| Placebo | Percentage of Patients in Each Group With Reverse Remodeling (Reduction in LVESVi >5%) | 43 % of participants |
p-value: >0.05Chi-squared