An Open, Prospective, Randomized Study on the Efficacy of Iron Therapy Using Intravenous (IV) Iron Supplements Relative to Oral Iron Intake for Increasing Left Ventricular Systolic Function in Patients With Myocardial Infarction
Phase: NA
Conditions: Myocardial Infarction, Iron-deficiency
Sponsor: Kazan State Medical University

1 January 2022 
Study Protocol  
 
NCT05309499 
 
An Open, Prospective study on the Efficacy of iRon therapy using intravenous 
(IV) iron supplements relative to oral iron intake for increasing left ventriculAr 
systolic function in patients with Myocardial Infarction (OPERA-MI).  
 
 
 
Introduction  
Important cellular processes depend on iron and homeostasis of iron is well regulated.  
Furthermore, iron is essential for oxygen transport and storage, cardiac and skeletal muscle 
metabolism, energy production in the mitochondria, synthesis and degradation of proteins, lipids 
and ribonucleic acid, the correct functioning of immune and nervous systems [1]. Iron causes a 
protective effect in myocytes during hypoxia. Iron deficiency (ID) is more detrimental for the 
vitality of cardiomyocytes and skeletal myocytes during hypoxia, compared to iron excess [2]. ID 
directly affects function of the heart and leads to mitochondrial disfunction and adversely affects 
cardiomyocyte contractility and relaxation [3]. ID has been shown to be an independent predictor 
of poor outcomes, irrespective of the presence of anaemia, in patients with heart failure (HF) [4-
9].   
Negative impact of ID on the left ventricular (LV) function, quality of life and outcomes 
in patient with acute coronary syndrome (ACS) has been shown [10-14].  However, the effects of 
ID treatment in patient with myocardial infarction (MI) has not been well studied.   
Methods 
Proposed study uses an open-label prospective randomized single-center study approach. 
360 patients, with or without ID, hospitalized with MI are recruited at the Kazan city clinical 
hospital №7, which is the clinical base of Kazan State medical university. Patients with ID (n=240) 
are randomised (1:1) to either intravenous (i.v.) FCM or oral ferrous sulphate. Patients with normal 
iron status (n=120) are in the control group.  
The trial, which is conducted in strict compliance with Good Clinical Practice (GCP) and 
with the Declaration of Helsinki, was approved by the Local Ethics Committee.  

Study population. Male and female patients aged ≥18 years, hospitalised with MI and 
diagnosed according to Fourth Universal Definition of MI and Myocardial Injury (ESC 2018), 
with hypokinesia or akinesia in at least two connected LV segments according to 
echocardiography results obtained within the first 24 hours after myocardial infarction occurs, will 
be considered for participation. All patients who agreed to participate will be asked to provide 
written informed consent before any trial-related procedure is performed.  
Inclusion and exclusion criteria.  Inclusion/exclusion criteria are shown in Table 1 
Definition of MI.  MI is diagnosed according to Fourth Universal Definition of MI and 
Myocardial Injury (ESC 2018) when there is a rise and/or fall of cardiac troponin values (cTn) 
values with at least one value above the 99th percentile upper reference limit (URL) and at least 
one of the following signs: symptoms of myocardial ischaemia, new ischaemic ECG changes, 
development of pathological Q waves, imaging evidence of new loss of viable myocardium or 
new regional wall motion abnormality in a pattern consistent with an ischaemic aetiology [15]. 
Definition of ID.  ID is defined as serum ferritin <100 ng/mL (absolute ID) or 100 ng/mL 
≤ serum ferritin ≤299 ng/mL if transferrin saturation (TSAT) <20% (functional ID) [9]. 
Assessment of LV systolic function.  LV systolic function is assessed by transthoracic 
echocardiography with evaluation of Wall motion score index (WMSI) using 16-segment model 
[16]. 
Assessment of quality of life.  Quality of life is assessed using  the Kansas City 
Cardiomyopathy Questionnaire (KCCQ) [17] 
 
Screening. During screening all risks and benefits of participation are described to each 
patient who fit the chosen inclusion criteria. Each patient considered in the study will be provided 
2 copies of written consent and will receive one copy of the consent, in addition each patient will 
receive a form containing information about study participation. Anamnesis, physical 
examination, echocardiography, KCCQ, complete blood count (CBC), serum iron level, total iron 
binding capacity (TIBC), serum ferritin level, TSAT, alanine transaminase, aspartate 
transaminase, creatinine are performed at the screening visit within 24 hours after MI. The data of 
each study participant will bes entered into individual patient registration cards specially designed 
for each visit. 
Randomisation and study treatment dosing regimen. Patients with ID are randomised 
to either i.v. FCM or oral ferrous sulphate randomly with block randomizations. The FCM doses 
were determined using the patient’s screening visit body weight measurement and haemoglobin 
value (table 2).  Patients receives all doses during hospitalization accordance with the drug local 

labels. 100 mg of ferrous sulphate is administrated 2 times per day during hospitalization and 
continue within next 2 month.     
Study outcomes. The primary significant outcome is the decrease in WMSI value. The 
secondary outcome the composite of cardio-vascular (CV) mortality, non-fatal stroke, non-fatal 
MI, recurrent HF hospitalizations.   
Patient Assessments. All participants are observed for 12 months from the first visit after 
the admission to the study. Participants are evaluated in-person at 3-, 6-, and 12-month intervals 
with correction of treatment if necessary. Participants are also evaluated monthly through 
telephone consultation. Echocardiography with WMSI evaluation, KCCQ, CBC, serum iron level, 
TIBC, serum ferritin level, TSAT is perfumed during every physical evaluation visit. Primary and 
secondary outcomes are established during follow up period.    
 
Statistical analysis. Statistical data is analysed using standard methods of descriptive 
statistics. For categorical variables, summary tabulations of the number and percentage of subjects 
within each category of the corresponding parameterwill be presented. For continuous variables, 
the mean, median, standard deviation, first and third quartiles, and minimum and maximum values 
will be presented. Clinical-laboratory associations will be assessed as well as associations with 
outcomes (Kaplan-Meier subgroup survival curves). The level of significance to be used for tests 
will be 0.05.