Acute myocardial infarction (AMI) remains a major cause of morbidity and mortality despite current strategies for early reperfusion. Many patients die early during the course, and those who survive are at increased risk of death from adverse cardiac remodeling and heart failure (HF). Indeed, despite the improvement in AMI treatment and the reduction in early mortality, the incidence and prevalence of HF continue to rise to unprecedented rates. There is hence an urgent unmet need for additional treatments to prevent HF after AMI. IL-1 blockade may represent a completely novel approach for the prevention of HF potentially leading to improved quality of life, reduced hospitalizations, reduced costs, and ultimately improved long-term survival. The initial ischemic damage to the myocardium initiates an intense inflammatory response resulting in further damage and promoting cardiac dysfunction and HF. Interleukin-1 (IL-1) is the prototypical inflammatory cytokine involved in the tissue response to injury. In AMI, IL-1 activity is increased and amplifies the inflammatory response and induces cardiac cell death. Anakinra is a recombinant form of human IL-1 receptor antagonist (rhIL-1Ra) that is FDA approved for the treatment of rheumatoid arthritis and is highly effective in the treatment of several inflammatory diseases. We recently completed 2 pilot safety and feasibility studies, VCU-ART (n=10) and VCU-ART2 (n=30), in patients with acute ST-segment elevation myocardial infarction (STEMI), randomized 1:1 to anakinra 100 mg daily or placebo for 14 days. Anakinra was well tolerated and associated with very few adverse events. In the combined analysis of both trials, anakinra was associated with a significant reduction in inflammatory markers (-50%, P=0.01) and a trend toward reduced incidence of symptomatic HF at 3 months (5% vs 30%, P=0.035). We propose a randomized, double-blinded, multi-center, pilot study with two different anakinra regimens (twice daily vs daily) to determine the maximum effect of anakinra on the acute inflammatory response during STEMI and to estimate the effect of anakinra on the incidence of HF up to 12 months after STEMI. Although the current pilot study is likely not sufficiently powered to detect statistically signifiant differences in the mortality or rehospitalization rates, this study will provide an estimate of the potential effect, which could be then explored in a larger phase III clinical trial (as part of a R1 application).
Despite improvements in medical treatments, heart attacks remain the leading cause of death in the US and those who survive are at high risk of developing heart failure. We propose that the inflammatory response during a heart attack is a key determinant of heart failure. The current application will therefore evaluate the use of anakinra (recombinant human Interleukin-1 receptor antagonist) in patients with a severe heart attack to reduce the inflammatory response and prevent the future development of heart failure.
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|Van Tassell, Benjamin W; Lipinski, Michael J; Appleton, Darryn et al. (2018) Rationale and design of the Virginia Commonwealth University-Anakinra Remodeling Trial-3 (VCU-ART3): A randomized, placebo-controlled, double-blinded, multicenter study. Clin Cardiol 41:1004-1008|
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|Toldo, Stefano; Van Tassell, Benjamin W; Abbate, Antonio (2017) Interleukin-1 Blockade in Acute Myocardial Infarction and Heart Failure: Getting Closer and Closer. JACC Basic Transl Sci 2:431-433|