Clinical trial NCT01175018: Anakinra to Prevent Adverse Post-infarction Remodeling (2)
Official title: Anakinra to Prevent Adverse Post-infarction Remodeling (2)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Myocardial Infarction
Heart Failure
Keywords: Acute myocardial infarction
Heart Failure
Cardiac Remodeling
Lead sponsor: Virginia Commonwealth University
Sponsor class: OTHER
Collaborators: name: American Heart Association
First posted: 2010-08-04
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 110
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Difference Between the Anakinra Arm and the Placebo Arm in Change in Left Ventricular End-systolic Volume Indices
timeFrame: 10-14 weeks minus baseline
Secondary outcomes:
measure: 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
timeFrame: 10-14 weeks
measure: Percentage of Patients in Each Group With Reverse Remodeling (Reduction in LVESVi >5%)
timeFrame: 10-14 weeks
measure: Median Difference Between the 2 Arms in the Peak Oxygen Consumption (VO2) at 10-14 Weeks
timeFrame: 10-14 weeks
measure: Incidence of Heart Failure
timeFrame: 10-14 weeks
measure: Number of Adverse Events in Each Group
timeFrame: 10-14 weeks
measure: Difference Between the 2 Arm in the Interval Change in Right Ventricular Ejection Fraction (RVEF)
timeFrame: 10-14 weeks
measure: 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
timeFrame: 10-14 weeks
measure: Median Difference Between the 2 Arms in the Ratio of Minute Ventilation and Carbon Dioxide Production (VE/VCO2 Slope) at 10-14 Weeks
timeFrame: 10-14 weeks
measure: Percentage of Patients in Each Group With Reverse Remodeling (Reduction in LVESVi >10%)
timeFrame: 10-14 weeks
measure: Percentage of Patients in Each Group With Adverse Remodeling (LVESVi Increase >5%) Based Upon Cardiac Magnetic Resonance Imaging
timeFrame: 10-14 weeks
measure: Percentage of Patients in Each Group With Adverse Remodeling (LVESVi Increase >10%)
timeFrame: 10-14 weeks
measure: Percentage of Patients in Each Group With Left Ventricular Ejection Fraction Change >5%
timeFrame: 10-14 weeks
measure: Percentage of Patients in Each Group With Left Ventricular Ejection Fraction Change >10%
timeFrame: 10-14 weeks
measure: Number of Deaths in Each Group
timeFrame: 10-14 weeks
measure: Number of Adverse Events Requiring Withdrawal in Each Group
timeFrame: 10-14 weeks
Other outcomes:
Locations:
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
Study officials:
affiliation: Virginia Commonwealth University
name: Antonio Abbate, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Abbate A, Kontos MC, Grizzard JD, Biondi-Zoccai GG, Van Tassell BW, Robati R, Roach LM, Arena RA, Roberts CS, Varma A, Gelwix CC, Salloum FN, Hastillo A, Dinarello CA, Vetrovec GW; VCU-ART Investigators. Interleukin-1 blockade with anakinra to prevent adverse cardiac remodeling after acute myocardial infarction (Virginia Commonwealth University Anakinra Remodeling Trial [VCU-ART] Pilot study). Am J Cardiol. 2010 May 15;105(10):1371-1377.e1. doi: 10.1016/j.amjcard.2009.12.059. Epub 2010 Apr 2.
citation: Abbate A, Van Tassell BW, Biondi-Zoccai G, Kontos MC, Grizzard JD, Spillman DW, Oddi C, Roberts CS, Melchior RD, Mueller GH, Abouzaki NA, Rengel LR, Varma A, Gambill ML, Falcao RA, Voelkel NF, Dinarello CA, Vetrovec GW. Effects of interleukin-1 blockade with anakinra on adverse cardiac remodeling and heart failure after acute myocardial infarction [from the Virginia Commonwealth University-Anakinra Remodeling Trial (2) (VCU-ART2) pilot study]. Am J Cardiol. 2013 May 15;111(10):1394-400. doi: 10.1016/j.amjcard.2013.01.287. Epub 2013 Feb 27.
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.
citation: Sonnino C, Christopher S, Oddi C, Toldo S, Falcao RA, Melchior RD, Mueller GH, Abouzaki NA, Varma A, Gambill ML, Van Tassell BW, Dinarello CA, Abbate A. Leukocyte activity in patients with ST-segment elevation acute myocardial infarction treated with anakinra. Mol Med. 2014 Nov 18;20(1):486-9. doi: 10.2119/molmed.2014.00121.
citation: Falcao RA, Christopher S, Oddi C, Reznikov L, Grizzard JD, Abouzaki NA, Varma A, Van Tassell BW, Dinarello CA, Abbate A. Interleukin-10 in patients with ST-segment elevation myocardial infarction. Int J Cardiol. 2014 Mar 1;172(1):e6-8. doi: 10.1016/j.ijcard.2013.12.126. Epub 2014 Jan 5. No abstract available.