Does Heme Oxygenase-1 Induction Ameliorate Cardiac Injury After Myocardial Infarction? — HAEM  

Acute Myocardial Infarction Clinical Trial

Official title: A Safety and Efficacy Study to Evaluate Intravenous Heme Arginate Infusion in Patients With an Acute Coronary Syndrome Without ST-elevation (NSTEMI)

Status Completed

Clinical Trial 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.

Clinical Trial 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. ;

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Coronary Syndrome
• Acute Myocardial Infarction
• Infarction
• Myocardial Infarction

• NCT number: NCT00483587
• Study type: Interventional
• Source: University Medical Center Groningen
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: July 2007
• Completion date: February 2010