Iron Intravenous Therapy in Reducing the Burden of Severe Arrhythmias in Heart Failure With Reduced Ejection Fraction (RESAFE)

An Open Label,Single-center, Non-interventional Prospective Study to Determine the Efficacy of Iron Therapy Using Intravenous Ferric Carboxymaltose and Its Effect in Reducing Arrhythmic Events in Participants With Iron Deficiency and HFrEF

An open label,single-center, non-interventional prospective study with the aim on investigating the effect of intravenous ferric carboxymaltose in restoring iron status and reducing the risk of severe arrhythmic events in participants with iron deficiency and a reduced ejection fraction (HFrEF).

Study Overview

• Status: Active, not recruiting
• Conditions: Arrhythmias, Cardiac; Heart Failure With Reduced Ejection Fraction; Ferric Carboxymaltose
• Intervention / Treatment: Drug: Ferric carboxymaltose

Detailed Description

Patients with HFrEF already scheduled to receive IV FCM to treat iron deficiency will be included in this registry trial. These patients undergo clinical examination, echocardiography, blood testing, 6-minute walking testing, cardiopulmonary exercise testing, cardiac implantable device interrogation, 24-hour Holter monitoring and quality of life quantification as part of standard clinical practice. This database will be extracted from clinical databases and stored on a separate, registry database. The study will examine the effect of IV FCM on patients' iron stores, arrhythmic burden, hospitalizations and clinical, echocardiographic, exercise-testing-derived and biological markers of disease severity such as 6-minute walking distance, peak VO2 consumption, LVEF and LV global longitudinal strain and NT-proBNP.

• Study Type: Observational
• Enrollment (Actual): 106

Contacts and Locations

Study Locations

• Greece
  • Macedonia
    • Thessaloníki, Macedonia, Greece, GR54642
      • Hippokration General Hospital of Thessaloniki, Third Department of Cardiology (Aristotle University of Thessaloniki)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients with heart failure and reduced ejection fraction, cardiac implantable electronic devices and iron deficiency visiting the outpatient HF clinic of the Third Department of Cardiology AUTh

Description

Inclusion Criteria:

• Diagnosis of HFrEF (LVEF≤40%)
• Implanted cardiac implantable electronic device with at least 3 months of recorded arrhythmic history
• Patient is scheduled to receive IV ferric carboxymaltose to treat diagnosed iron deficiency

Exclusion Criteria:

• Myocardial infarction, acute heart failure or life-threatening arrhythmias in the preceding 15 days
• Autoimmune disorders, cancer or other diseases other than heart failure that significantly affect patients' life expectancy, appetite and emotional status
• Known allergic reaction to ferric carboxymaltose.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Participants; HFrEF patients undergoing iron therapy with intravenous carboxymaltose (FCM). FCM administered dosage as per clinical routine. FCM administration is repeated no sooner than 3 months than last therapy, based on repeat ferritin and transferrin saturation levels.	Drug: Ferric carboxymaltose; Intravenous ferric carboxymaltose for the treatment of iron deficiency in HFrEF as per 2016 European Society of Cardiology Heart Failure guidelines.; Other Names: Ferinject

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hemoglobin	Measured in g/dL, will be aggregated to form a composite primary endpoint of hemoglobin ≥ 12g/dL, plasma ferritin ≥ 50 ng/mL and transferrin saturation > 20%	6 and 12 months
Ferritin	Measured in ng/mL, will be aggregated to form a composite primary endpoint of hemoglobin ≥ 12g/dL, plasma ferritin ≥ 50 ng/mL and transferrin saturation > 20%	6 and 12 months
Transferrin saturation	Measured as a percentage, will be aggregated to form a composite primary endpoint of hemoglobin ≥ 12g/dL, plasma ferritin ≥ 50 ng/mL and transferrin saturation > 20%	6 and 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HF-related hospitalizations	Hospitalizations due to acute-on-chronic heart failure or worsening heart failure (compared with 12 months preceding treatment)	6 and 12 months
N-terminal prohormone of brain natriuretic peptide (NT-proBNP)	NT-proBNP levels measured in serum (compared to baseline). NT-proBNP values are reported in pg/mL.	6 and 12 months
Kansas City Cardiomyopathy Questionnaire	HF-specific QoL quantified with the Kansas City Cardiomyopathy Questionnaire (compared to baseline). The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item self-administered questionnaire developed to independently measure the patient's perception of their health status. The questionnaire ranges from 0% (worst possible QoL) to 100% (best possible QoL)	6 and 12 months
EQ-5D-5L	General QoL is quantified with the EQ-5D-5L questionnaire (compared to baseline). EQ-5D-5L is a standardised measure of health-related quality of life. It contains a short descriptive system questionnaire and a visual analogue scale (EQ VAS). VAS ranges 0% to 100%.	6 and 12 months
Ventricular tachycardias recorded by cardiac implantable electronic device	Compared with 12 months preceding recruitment.	6 and 12 months
Non-sustained ventricular tachycardias recorded by cardiac implantable electronic device	Compared with 12 months preceding recruitment.	6 and 12 months
Appropriate therapies administered by cardiac implantable electronic device	Compared with 12 months preceding recruitment.	6 and 12 months
Appropriate atrial mode switch events recorded by cardiac implantable electronic device	Compared with 12 months preceding recruitment.	6 and 12 months
Non-sustained ventricular tachycardias recorded during 24-hour Holter monitoring	Compared with baseline.	6 and 12 months
Ventricular runs recorded during 24-hour Holter monitoring	Compared with baseline.	6 and 12 months
Ventricular triple premature complexes during 24-hour Holter monitoring	Compared with baseline.	6 and 12 months
Ventricular dual premature complexes during 24-hour Holter monitoring	Compared with baseline.	6 and 12 months
Ventricular premature complexes during 24-hour Holter monitoring	Compared with baseline.	6 and 12 months
Left ventricular end-diastolic volume index (LVEDVi)	Compared to baseline. Measured in mL/m^2.	6 and 12 months
Left ventricular ejection fraction (LVEF)	Compared to baseline. Measured as a percentage.	6 and 12 months
Left ventricular mass index (LVMi)	Compared to baseline. Measured in g/m^2.	6 and 12 months
Left ventricular global longitudinal strain (LV GLS)	Compared to baseline. Measured as a percentage.	6 and 12 months
Peak early diastolic tissue velocity (e')	Μeasured at the septal and lateral mitral annulus. Used to calculate E/e' ratio. Measured as m/s.	6 and 12 months
E-wave mitral inflow velocity (E)	Used to calculate E/e' ratio. Measured as m/s.	6 and 12 months
Right ventricular fractional area change (RV FAC)	Compared to baseline. Measured as a percentage.	6 and 12 months
6-minute walking distance (6MWD)	Distance recorded during six-minute walk testing. Measured in meters. Compared to baseline.	6 and 12 months
Maximal oxygen consumption (VO2 max)	Maximal oxygen consumption recorded during cardiopulmonary exercise testing. Measured in mL/kg/min. Compared to baseline.	6 and 12 months
Minute ventilation/carbon dioxide production slope (VE/VCO2 slope)	The VE/VCO2 slope recorded during cardiopulmonary exercise testing. Absolute unit. Compared to baseline.	6 and 12 months
End-tidal carbon dioxide at anaerobic threshold (etCO2-AT)	Recorded during cardiopulmonary exercise testing. Measured in mmHg. Compared to baseline.	6 and 12 months
Late potentials	Signal Averaged ECG (SAECG) enables the detection of late potentials. Specialist software automatically performs the detection of late potentials in patients' Holter monitor recordings.	6 and 12 months
Microvolt T-wave Alternans (TWA)	Specialist software quantifies microvolt TWA voltage in patients' Holter monitor recordings. microvolt TWA is measured in μV.	6 and 12 months
Heart rate turbulence (HRT)	Heart rate turbulence (HRT) is the baroreflex-mediated short-term oscillation of cardiac cycle lengths after spontaneous ventricular premature complexes. Specialist software detects abnormal HRT in patients' Holter monitor recordings. The existence of abnormal heart rate turbulence is a nominal variable.	6 and 12 months
Deceleration capacity	(Heart rate) deceleration capacity is a measurement of autonomic nerve regulation in heart failure. Specialist software quantifies deceleration capacity, which is measured in milliseconds (ms).	6 and 12 months

Collaborators and Investigators

• Sponsor: Aristotle University Of Thessaloniki
• Investigators: Principal Investigator: Vassilios P Vassilikos, PhD, Hippokration General Hospital of Thessaloniki, Third Department of Cardiology, AUThi

Study record dates

Study Major Dates

• Study Start (Actual): June 20, 2019
• Primary Completion (Anticipated): August 30, 2021
• Study Completion (Anticipated): September 30, 2021

Study Registration Dates

• First Submitted: July 5, 2021
• First Submitted That Met QC Criteria: July 13, 2021
• First Posted (Actual): July 23, 2021

Study Record Updates

• Last Update Posted (Actual): July 23, 2021
• Last Update Submitted That Met QC Criteria: July 13, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: heart failure; ferric carboxymaltose; arrhythmias
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Heart Failure; Arrhythmias, Cardiac
• Other Study ID Numbers: 219/12-3-19

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No