Short-Term Application of Tocilizumab Following Myocardial Infarction
Condition: Myocardial Infarction
MeSH terms: Myocardial Infarction; Infarction
Study type: Interventional

Summary: 
      Introduction: Interleukin 6 (IL-6) is a cytokine that has a pro-inflammatory effect on the
      immune system. In acute MI IL-6 levels rapidly increase in response to ischemia and
      inflammation. Tocilizumab is a humanized monoclonal antibody against the interleukin-6
      receptor (IL-6R). The use of tocilizumab within the first 24 hours of admission for acute MI
      could reduce 30 day mortality.

      Methods: This randomized, placebo controlled trial will assign subjects within 24 hours of
      admission to treatment with either 162 mg of tocilizumab subcutaneously once or placebo in
      addition to usual pharmacologic and interventional standard of care for acute MI (ST segment
      elevation MI or non-ST segment elevation MI).

      Outcomes: The primary outcome is difference in 30 day (plus/minus 5 days) occurrence of major
      adverse cardiac events (as defined later in this protocol) between placebo and Tocilizumab
      treated groups. Secondary outcomes to be assessed include length of hospitalization,
      readmission rates by day 30, CRP levels at 0 hours, 24 hours, 48 hours, and 30 days following
      treatment, and safety of Tocilizumab with focus on rates of known side effects.
    

Detailed description: 
      Interleukin 6 (IL-6) is a cytokine that has a pro-inflammatory effect on the immune system.
      Cytokines are a broad and loose category of small proteins (~5-20 kDa) that are important in
      cell signaling - they are released by cells and affect the behavior of other cells, and
      sometimes the releasing cell itself. IL-6 is an important mediator of fever and of the acute
      phase response. IL-6 is responsible for stimulating acute phase protein synthesis as well as
      the production of neutrophils in the bone marrow. The acute-phase response is the detectable
      change in acute phase proteins, a class of proteins whose plasma concentrations increase or
      decrease in response to inflammation. IL-6 is secreted by T cells and macrophages to
      stimulate the immune response during infection and after trauma, especially burns or other
      tissue damage leading to inflammation. Smooth muscle cells in the tunica media of many blood
      vessels also produce IL-6 as a pro-inflammatory cytokine. IL-6 is capable of crossing the
      blood-brain barrier and triggering production of Prostaglandin E2 in the hypothalamus,
      thereby changing the body's temperature set point. In muscle and fatty tissue, IL-6
      stimulates energy mobilization that leads to increased body temperature. IL-6 can be secreted
      by macrophages in response to specific microbial molecules, referred to as
      pathogen-associated molecular patterns (PAMPs). IL-6 is also produced by adipocytes and is
      thought to be a reason why obese individuals have higher endogenous levels of CRP. IL-6
      signals through a cell-surface type I cytokine receptor complex consisting of the
      ligand-binding IL-6Rα chain (CD126) and the signal-transducing component gp130 (also called
      CD130). CD130 is the common signal transducer for several cytokines but the expression of
      CD126 is restricted to certain tissues. As IL-6 interacts with its receptor, it triggers the
      gp130 and IL-6R proteins to form a complex, thus activating the receptor. These complexes
      bring together the intracellular regions of gp130 to initiate a signal transduction cascade
      through certain transcription factors.

      Acute Myocardial Infarction (MI) occurs when myocardial ischemia, a diminished blood supply
      to the heart muscle, exceeds a critical threshold and overwhelms myocardial cellular repair
      mechanisms designed to maintain normal function. Ischemia at this critical threshold level
      for an extended period results in irreversible myocardial cell damage or death. A common
      clinical diagnostic classification scheme is based on electrocardiographic findings as a
      means of distinguishing between two types of acute MI, one that is marked by ST elevation
      (STEMI) and one that is not (NSTEMI). In acute MI IL-6 levels rapidly increase in response to
      ischemia and inflammation. In one study, plasma IL-6 levels were increased at all sampling
      points from admission to discharge in patients with acute MI as compared with IL-6 levels in
      controls. Cardiac catheterization did not influence plasma IL-6 levels. In another study,
      patients with acute MI demonstrated a peak in IL-6 levels on days 1 and 2 which then declined
      rapidly to lower, although not normalized, levels during hospitalization and at 6 and 12
      weeks. It has also been demonstrated that elevated levels of IL-6 are associated with worse
      outcomes in acute MI. In one study elevated IL-6 levels at day 1 and day 30 were independent
      predictors of adverse events. In another study, on univariante analyses, baseline IL-6 was
      related to death but not recurrent non-fatal acute coronary syndromes. Another study
      demonstrated significant correlations between increased IL-6 levels and impaired left
      ventricle systolic and diastolic function supportive of a role of IL-6 in post-infarction
      cardiac damage. This same group also demonstrated that an increased level of IL-6 in acute MI
      was an independent predictor of left ventricle systolic and diastolic dysfunction 6 months
      after MI.
    

Intervention name(s): Tocilizumab; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 162 mg subcutaneously once (vs. 0.9% normal saline placebo injection once in placebo arm); Saline injection
Other intervention name(s): Actemra
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment