Erythropoietin to Prevent Unnecessary Transfusions In Patients With Cyanotic CHD - A Prospective Control Trial

Erythropoietin to Prevent Unnecessary Transfusions In Patients With Cyanotic Congenital Heart Disease - A Prospective Randomized Control Trial

Cyanotic congenital cardiac patients require higher hemoglobin concentrations (red blood cell levels) for optimal oxygen delivery to the body. Prophylactic erythropoietin (EPO) and iron can prevent and/or decrease the amount of blood transfusions needed in this population. We seek to investigate if EPO and iron make a clinically significant difference in the number of transfusions given to these patients and the morbidity associated with it.

Study Overview

• Status: Terminated
• Conditions: Anemia; Congenital Heart Disease; Cyanotic Congenital Heart Disease; Cyanosis
• Intervention / Treatment: Drug: Iron; Drug: Epoetin Alfa and Iron

Detailed Description

Congenital heart disease occurs in about 1% of all live births. Cyanotic cardiac lesions in particular are at risk for significant mortality and morbidity because of their reduced ability to provide adequate oxygenation to the body and the brain. Many experts believe that to have adequate oxygen carrying capacity that these infants should ideally have a hemoglobin level greater than 13 g/dL. Many of these patients require blood transfusions prior to surgery to provide adequate oxygenation. The cause for this is likely multifactorial including normal neonatal physiology, frequent lab draws, and co-morbidities. Although rare, the morbidity due to transfusions can be devastating to this population including transmitted infections, transfusion reactions, extra hospitalizations, and antigen sensitization that would complicate heart transplant if needed.

There are centers in the United States that have developed protocols using erythropoietin to minimize blood product transfusions before and after surgery, also referred to as "bloodless surgery". There have been retrospective studies evaluating the success of these protocols, but there are no randomized controlled prospective studies that the investigators have studying the effects of erythropoietin effects in patients with cyanotic heart disease in regards to transfusion prevention.

Congenital cyanotic cardiac patients require higher hemoglobin concentrations for optimal oxygen delivery. Prophylactic erythropoietin can prevent and/or decrease the amount of blood transfusions needed prior to surgery. The researchers seek to investigate if erythropoietin makes a clinically significant difference in the number of transfusions given to these patients and the morbidity associated with it.

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 92123
      • Rady Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 month (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

• Newborns less than 4 weeks old at diagnosis
• Gestational age >34 weeks
• Birth weight 2.2-4kg
• Cyanotic heart disease who have had a surgical shunt or a catheterization intervention that is equivalent to a shunt (patent ductus arteriosus stent, right ventricular outflow tract stent).
• Baseline hematocrit to be below <40%.
• Completes at least 1 injection in the study by 8 weeks of age.

Exclusion Criteria

• Infants diagnosed at greater than 4 weeks of age
• Gestation <34 weeks
• Birth weight <2.2 kg or >4kg
• Hematocrit >40%
• Newborns with acyanotic heart disease

• Infants with significant co-morbidities:

  • Renal failure (Creatinine > 2 standard deviations above age adjusted norm)
  • Hepatic failure (elevated AST/ALT levels > 2 standard deviations above age adjusted norm
  • Hemolytic disease
  • Hemoglobinopathies (Sickle-cell disease, Thalassemias)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Control; Group II (non-treatment group): Patients in the treatment group will not receive any extra intervention outside of standard of care. They will receive iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization). They will be followed for 14 weeks.	Drug: Iron; Patients in the treatment group will not receive any extra intervention outside of standard of care. They will receive iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization). They will be followed for 14 weeks.; Other Names: No other name
Experimental: Epoetin alfa and iron supplements; Group I (treatment group): Patients in the treatment group will receive weekly EPO injections and iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization) They will be followed for 14 weeks.	Drug: Epoetin Alfa and Iron; Patients in the treatment group will receive weekly EPO injections and iron supplementation for 6 weeks starting before 8 weeks of age, 1 week after their first procedure (surgery or heart catheterization) They will be followed for 14 weeks.; Other Names: No other name

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Transfusions Needed	Prophylactic erythropoietin can prevent and/or decrease the amount of blood transfusions needed prior to surgery. We seek to investigate if erythropoietin makes a clinically significant difference in the number of transfusions given to these patients and the morbidity associated with it during the period in which the subjects will be active in the study (from baseline to 14 weeks post initial injection). The primary aim will be assessed when all subjects have completed week 14 or discontinue early.	First 4 months of life

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Oxygen Saturation	Often, cyanotic congenital heart defect neonates have prolonged initial hospital stays due to the inability to maintain acceptable oxygen saturations, and transition to adequate oral intake for appropriate weight gain. If the hospital stay is found to be shortened after starting erythropoietin, this may be of clinical and financial significance.	First 4 months of life
Number of Hospitalizations	The number of hospital readmissions (related to failure to thrive or cyanosis) may imply the overall clinical stability of a patient. Because these infants are at high risk for mortality at home, there are multiple reasons why they may be admitted to the hospital including clinically significant anemia which requires blood transfusions, poor weight gain, difficulty feeding, inadequate oxygen saturations, and illnesses. Each admission is stressful to the patient and their families. Having a normal hemoglobin level may have a role in preventing several of these factors, especially regarding failure to thrive or cyanosis.	First 4 months of life
Weight Gain	The secondary outcome of weight gain is appropriate in the setting of infants as this variable has been used to monitor the ability to thrive and meet the body's metabolic demands. It is well established in pediatrics that the neonate and infant should gain 15-30 grams per day for optimal growth. Infants who are cyanotic already have a deficiency in meeting their metabolic demands due to a reduced oxygen carrying capacity. This is further complicated in the instance of anemia. Thus, infants may have an increased ability to optimize weight gain in the setting of normal, stable hemoglobin levels which may be achieved with erythropoietin.	First 4 months of life
Time to Initial Discharge	If the hospital stay is found to be shortened after starting erythropoietin, this may be of clinical and financial significance.	First 4 months of life

Collaborators and Investigators

• Sponsor: University of California, San Diego
• Investigators: Principal Investigator: David K Werho, MD, University of California, San Diego/Rady Children's Hospital San Diego

Publications and helpful links

General Publications

• Donato H. Erythropoietin: an update on the therapeutic use in newborn infants and children. Expert Opin Pharmacother. 2005 May;6(5):723-34. doi: 10.1517/14656566.6.5.723.
• Fearon JA, Weinthal J. The use of recombinant erythropoietin in the reduction of blood transfusion rates in craniosynostosis repair in infants and children. Plast Reconstr Surg. 2002 Jun;109(7):2190-6. doi: 10.1097/00006534-200206000-00002.
• Maier RF, Obladen M, Muller-Hansen I, Kattner E, Merz U, Arlettaz R, Groneck P, Hammer H, Kossel H, Verellen G, Stock GJ, Lacaze-Masmonteil T, Claris O, Wagner M, Matis J, Gilberg F; European Multicenter Erythropoietin Beta Study Group. Early treatment with erythropoietin beta ameliorates anemia and reduces transfusion requirements in infants with birth weights below 1000 g. J Pediatr. 2002 Jul;141(1):8-15. doi: 10.1067/mpd.2002.124309.
• Richard S, Brion JP, Couck AM, Flament-Durand J. Accumulation of smooth endoplasmic reticulum in Alzheimer's disease: new morphological evidence of axoplasmic flow disturbances. J Submicrosc Cytol Pathol. 1989 Jul;21(3):461-7.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2016
• Primary Completion (Actual): June 1, 2020
• Study Completion (Actual): June 1, 2020

Study Registration Dates

• First Submitted: September 29, 2015
• First Submitted That Met QC Criteria: September 30, 2015
• First Posted (Estimate): October 1, 2015

Study Record Updates

• Last Update Posted (Actual): December 2, 2021
• Last Update Submitted That Met QC Criteria: November 3, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Keywords: Congenital Heart Disease; Transfusion; Erythropoetin; Cyanotic Heart Disease
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Diseases; Heart Defects, Congenital; Cyanosis; Physiological Effects of Drugs; Trace Elements; Micronutrients; Hematinics; Epoetin Alfa; Iron
• Other Study ID Numbers: 160871

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No