Does Heme Oxygenase-1 Induction Ameliorate Cardiac Injury After Myocardial Infarction?
Condition: Acute Myocardial Infarction
MeSH terms: Myocardial Infarction; Acute Coronary Syndrome; Infarction
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Rationale: A safety and dose defining study in which the investigators hypothesize that in
      patients with acute coronary syndrome without ST-elevation (NSTEMI) treatment with heme
      arginate results in better clinical outcome by inducing the heme oxygenase-1 (HO-1) pathway.

      Objective: 1) Is induction of HO-1 and its degradation products, especially bilirubin, safe
      in patients with an acute coronary syndrome without ST-elevation; 2) What is the optimal
      effective dose to administer in patients with NSTEMI; 3) Are HO-1 and its degradation
      products endogenously activated in patients with acute coronary syndrome; 4) Does treatment
      with heme arginate result in a less cardiac damage; 5) Which other cardioprotecting pathways
      are activated by administration of heme arginate?

      Study population: Male and female patients with confirmed acute coronary syndrome without
      ST-elevation, between 18 - 80 yr old.

      Intervention: 10 patients receive a single administration of heme arginate (3 mg/kg),
      administered intravenously in 15 minutes directly after admission; 10 patients receive two
      administrations of heme arginate (3 mg/kg) on day 0 and 1; 10 patients receive three
      administrations of heme arginate (3 mg/kg) on day 0, 1 and 2 after admission, administered
      intravenously in 15 minutes. To determine endogenous levels of HO-1 and time course of HO-1
      activation after NSTEMI, blood is drawn and the same assays are performed in 15 patients with
      NSTEMI. As controls for the blood tests, blood is drawn and the same assays are performed in
      15 patients with non-typical angina pectoris in whom no cardiac disease could be detected
      from the investigators out-patient clinic.

      Main study parameters/endpoints: The primary endpoint is the incidence rate of adverse events
      between the three treated groups. This includes hemodynamic monitoring, rhythm monitoring and
      biochemical and hematological difference between the three treated groups. Secondary
      endpoints are the differences from baseline between heme arginate treated groups in activity
      of the HO-1 pathway, including, but not limited to, HO-1 activity, free heme, bilirubin
      (direct and indirect) levels, serum ferritin, and carbon monoxide (CO). Furthermore,
      differences between heme arginate treated groups on NTproBNP, CK-MB and Troponin T and
      difference between heme arginate treated subjects in LVEF measured by echocardiography, 3 and
      7 days and 6 months after NSTEMI.
    

Detailed description: 
      The interventional part of this study is a single centre safety and dose defining pilot study
      in which patients are allocated to heme arginate infusion for 1 day (hem-1d), heme arginate
      infusion for 2 days, or heme arginate infusion during 3 days (hem-3d) in consecutive order.
      So, the three patient groups consist of three intervention groups.

      Based upon the pharmacokinetic data in porphyria patients (3 mg/kg/day for 4-7 days), the
      investigators rationalize that 3 fixed doses of heme arginate will be the optimal dose to
      counter attack the acute phase after NSTEMI. Longer infusion of heme arginate seems at this
      moment not rational.

      The investigators will first administer in 10 patients 1 dose of heme arginate (hem-1d, day
      0) to assess safety. If safety is assured in the hem-1d group, 10 patients will receive two
      days of heme arginate infusion (day 0 and 1). After this group is completed and safety is
      assured, the third group (n = 10) will receive heme arginate infusion in three consecutive
      days after NSTEMI (day 0, 1 and 2 after admission).

      Heme arginate is considered safe in NSTEMI patients if no adverse events occur in the
      consecutive groups. To assess safety during the course of the study the following possible
      events are monitored:

        -  New onset of myocardial infarction with ST-elevation (STEMI);

        -  Cardiac decompensation;

        -  Sustained ventricular arrhythmia requiring defibrillation;

        -  All cause death;

        -  Drop of mean arterial blood pressure (MAP) of more than 20 mmHg (MAP is defined as 2 x
           diastolic blood pressure + 1 x systolic blood pressure divided by 3 (MAP = 2 x Pdias +
           Psys / 3));

        -  Eosinophilia (> 0.5 x 109/l) in combination with fever and/or rash and/or shivering or
           anaphylactic shock;

        -  Renal insufficiency (serum creatinine above 300 µmol/l);

        -  ASAT or ALAT are elevated to at least 3 times the upper limit of normal;

        -  Severe hematological abnormalities, defined as thrombocytopenia < 40 x 109/l,
           leucocytopenia < 2.0 x 109/l, or hemolytic anemia;

        -  Activated partial thromboplastin time (aPTT) elevated to at least 3 times the upper
           limit of normal;

        -  Severe bleeding, defined as requiring blood transfusion.

      In the event one of the above mentioned effects occur, the investigators will report this to
      the METC and deliberate before continuing the study. If, after deliberation with the METC,
      heme arginate turns out not to be safe in NSTEMI patients, the inclusion of patients will be
      terminated immediately and all patients who already received heme arginate will be followed
      thoroughly. The investigator will take care that all subjects are kept informed.

      After completion of each group the METC will be informed about the progress of the study.

      Regardless of allocation, all patients will receive care as usual according to
      national/international guidelines 79, 80.

      Patients with NSTEMI, admitted to the University Medical Center Groningen (UMCG), are asked
      to participate in the study and will sign informed consent. After signing consent, blood is
      drawn via venipuncture for baseline data.

      On day 0, 1, 2, 3, 7, and 180 after NSTEMI blood is drawn for additional measurements.
      Echocardiography is performed to determine left ventricular function, including left
      ventricular ejection fraction (LVEF), after 3 days, 7 days and 180 days. To assess the
      possible anti-hypertensive component of heme arginate treatment, 24 hour ambulatory blood
      pressure recordings will be conducted at day 7 and 6 months after NSTEMI.

      The following components of the heme pathway will be determined: free heme, hemoglobin,
      ferritin, carbon monoxide, heme oxygenase (HO)-1, biliverdin, and direct and non direct
      bilirubin. To monitor safety, the investigators will evaluate liver enzymes (ALAT, ASAT,
      γ-GT, AP, LDH), clotting times (INR, APTT, PT), electrolytes (Na, K, Cl, Mg) and furthermore
      regular hematology (Hb, Ht, thrombocytes) and chemistry (Blood Urea Nitrogen, Creatinine, CK,
      CK-MB, Troponin T, Brain Natriuretic Peptide, VEGF and Erythropoietin).

      All participants will also be asked for blood to assess DNA polymorphisms affecting HO-1
      activity, such as HO-1 polymorphisms, and for assessment of quality of endothelial progenitor
      cells (EPCs).

      Total number included patients into the interventional part of this study will be 30
      patients. Follow-up is completed 6 months after inclusion of the last patient. The
      investigators estimate inclusion will take approximately 6 months. The study duration
      therefore comes to a total of at least 12 months. The maximal duration of the study will be
      18 months, including analysis of the results.

      In addition, two groups of patients will be asked in the non-interventional part of this
      study:

        1. The investigators hypothesize that due to the acute coronary syndrome HO-1 is activated,
           but at too low levels to have clinical benefit. To determine the time course for HO-1
           activity and its degradation products after NSTEMI, the investigators will draw blood
           and perform all the same assays in 15 patients with NSTEMI as described above. It is not
           possible to use the same assays executed in the interventional part of this study, for
           heme arginate infusion will interfere with the outcomes.

        2. As healthy controls for the blood tests and to gain insight in normal levels of HO-1
           activity, the investigators will draw blood and do the same baseline assays in 15
           patients with non-typical angina pectoris in whom no cardiac disease could be detected
           from our out-patient clinic.

      All these patients will be asked to participate in the non-intervention part of this study,
      receive a separate information letter and will sign an informed consent form. If consent is
      given, blood is drawn via venipuncture.
    

Intervention name(s): Heme arginate
Intervention type(s): Drug
Intervention description(s): 1-3 x heme arginate infusion, in 30 minutes iv. Heme arginate is dissolved in 250 ml NACl.
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: NSTEMI; Acute coronary syndrome; Heme arginate; HO-1; Heme oxygenase-1