ST Segment Elevation Acute Myocardial Infarction
Conditions
Keywords
acute myocardial infarction
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.
Interventions
DRUGAnakinra
100 mg daily subcutaneous injection for 14 days
DRUGPlacebo
0.67 ml of NaCl 0.9% subcutaneously daily for 14 days
Sponsors
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 No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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. | 10-14 weeks |
Other
| Measure | Time frame |
|---|---|
| Difference Between the 2 Arms in the Incidence of Significant Cardiac Arrhythmias in the Acute Phase | 48 hours |
| Difference Between the 2 Arms in Change in the Number of Circulating Endothelial Progenitor Cells From Baseline to Follow up Exam | 10-14 weeks |
| 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 | 10-14 weeks |
| Difference Between the 2 Arms in Change in Serum BNP Levels, C-reactive Protein, and Hemoglobin A1c% From Baseline to Follow up | 10-14 weeks |
| Difference Between the 2 Arms in Change in Oxygen Uptake Kinetics From Baseline to Follow up Exam at Submaximal Cardiopulmonary Exercise Test | 10-14 weeks |
| 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 | 10-14 weeks |
| 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 | 10-14 weeks |
| 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 | 10-14 weeks |
Countries
United States
Participant flow
Recruitment details
Enrollment started in November 2008. During the first 4 months, 33 patients admitted with STEMI were screened and 10 patients were enrolled. One patient withdrew consent to the study on day 2 prior to all assessment and was excluded. The Institutional Review Board then approved enrollment of an additional patient who was enrolled in May 2009.
Participants by arm
| Arm | Count |
|---|---|
| Anakinra Anakinra 100 mg given daily by subcutaneous injection for 14 days | 5 |
| Placebo 0.67 ml of NaCl 0.9% solution | 5 |
| Total | 10 |
Baseline characteristics
| Characteristic | Placebo | Anakinra | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 5 Participants | 10 Participants |
| Age, Continuous | 52 years STANDARD_DEVIATION 15 | 45 years STANDARD_DEVIATION 13 | 48 years STANDARD_DEVIATION 13 |
| Region of Enrollment United States | 5 participants | 5 participants | 10 participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 5 Participants | 3 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 5 | 0 / 5 |
| serious Total, serious adverse events | 2 / 5 | 4 / 5 |
Outcome results
Primary
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.
Time frame: 10-14 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anakinra | 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. | -3.2 mL/m2 |
| Placebo | 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. | 2.0 mL/m2 |
p-value: 0.033ANOVA
Other Pre-specified
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
Time frame: 10-14 weeks
Other Pre-specified
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
Time frame: 10-14 weeks
Other Pre-specified
Difference Between the 2 Arms in Change in Oxygen Uptake Kinetics From Baseline to Follow up Exam at Submaximal Cardiopulmonary Exercise Test
Time frame: 10-14 weeks
Other Pre-specified
Difference Between the 2 Arms in Change in Serum BNP Levels, C-reactive Protein, and Hemoglobin A1c% From Baseline to Follow up
Time frame: 10-14 weeks
Other Pre-specified
Difference Between the 2 Arms in Change in the Number of Circulating Endothelial Progenitor Cells From Baseline to Follow up Exam
Time frame: 10-14 weeks
Other Pre-specified
Difference Between the 2 Arms in the Incidence of Significant Cardiac Arrhythmias in the Acute Phase
Time frame: 48 hours
Other Pre-specified
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
Time frame: 10-14 weeks
Other Pre-specified
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
Time frame: 10-14 weeks