Conditions: Anemia Cardiovascular Disease
Keywords: Active preoperative anemia management Erythrocyte transfusion RBC transfusion Red cell transfusion Transfusion in cardiac surgery Anemia treatment with erythropoietin Anemic cardiac surgery patients Erythrocyte stimulating agent (ESA) Iron deficiency anemia EPO Feraheme
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 5
Healthy volunteers: no

Brief summary:
Anemia which is a decreased blood count or lower than normal hemoglobin (hgb), is a major health problem for patients having heart surgery. Hemoglobin is the part of our blood that carries oxygen from the lungs to the rest of the body. Anemia that is present before surgery, called preoperative anemia, is a risk factor for an increased chance of morbidity (illness) and/or mortality (death) after heart surgery. It is also an important indicator of blood transfusion necessity. Recent clinical research investigations done to study preoperative anemia suggest a blood transfusion can damage the immune system (the system that protects us from disease) which can lead to infection, organ dysfunction (especially of the heart, kidney, brain), prolonged hospital stays, as well as increased supplies, resources and cost in surgical patients. Comprehensive anemia management can reduce or eliminate the need for blood transfusions and provide better outcomes after surgery. Therefore, controlling anemia before surgery is extremely important, and could be a lifesaving measure.

This pilot, feasibility study is being done for several reasons. First of all, it will test the the safety and effectiveness of using a short-course of two medications, erythropoietin (EPO) and Feraheme (iron given intravenously \[IV\]), to increase hemoglobin levels in order to improve preoperative anemia, reduce transfusions and lower postoperative complications in anemic patients undergoing heart surgery. Secondly, findings will be used to design a large randomized controlled trial (RCT). The RCT will establish a protocol to actively manage anemia before surgery, thus reducing transfusions during surgery and improving recovery afterwards. It will also help identify valuable information regarding what needs to be done for timely completion of the planned RCT.

EPO is a medication approved by the Food and Drug Administration (FDA) used to treat anemia in patients with certain conditions in order to reduce blood transfusions. And although approved for use during surgery, it has not been FDA approved for use in cardiac (heart) or vascular (blood vessels, including veins and arteries) surgery. Common side effects include nausea, vomiting, itching, headache, injection site pain, chills, deep vein thrombosis (blood clot), cough, and changes in blood pressure (BP). Feraheme is an iron replacement product approved for the treatment of low iron anemia in adult patients. It may cause serious allergic reactions, including anaphylaxis (severe, whole body allergic reaction), as well as low BP and excessive iron storage.

Patients meeting all eligibility requirements that consent to participate will be randomized into the study. Randomization is being placed by chance (like a flip of a coin) into one of two study groups, the treatment group or the control group. There is an equal chance of being placed into either group, which will be done by a computer.

1. The Treatment Group will receive a 300 unit (U) per kilogram (kg) injection of EPO and a 510 milligram (mg) IV infusion of Feraheme 7-28 days before the day of surgery. And again 1-7 days before the day of surgery, a second dose of both of these medications will be given. The third dose, of EPO only, will be administered 2 days after surgery. Before initiating a dose or giving a subsequent dose, laboratory parameters will be measured to assess the hemoglobin level and response to the medication. If blood values increase too rapidly or are too high, the meds will not be started or, if already dosed, they will not be given again.
2. The Control Group will receive no preoperative intervention for anemia unless lab results show iron deficiency anemia. The control group will be screened for the presence of iron deficiency anemia by evaluating blood laboratory values drawn during the baseline or preoperative visit. If lab results indicate iron deficiency anemia, over-the-counter oral iron will be recommended, to take until the day of surgery. In doing so, patients may benefit by potentially reducing the need for blood transfusions.

Data will be collected from all participants from the preoperative visits throughout the admission, including lab results, medications, vital signs, information about the procedure, transfusions, and any problems or adverse events.

Detailed description:
Anemia and transfusion are independent predictors of morbidity and mortality in the cardiac surgical patient population. Even so, active preoperative anemia management is not currently the standard of care at our institution. Cost associated with erythrocyte transfusions at University of Texas Southwestern (UTSW) University Hospitals exceeds twenty million dollars annually, not including costs associated with treatment of known complications of red cell transfusions (renal insufficiency, respiratory failure, infection and prolonged length of stay, etc). Fifty percent of our cardiac surgical population suffer from preoperative anemia and 79% of these patients will receive one or more red blood cell (RBC) transfusions. In contrast, the incidence of RBC transfusion was only 35% in those without preoperative anemia in the calendar year 2011-12.

The mechanism of injury in patients with preoperative anemia is either the duration/intensity of the anemia exposure and resultant organ ischemia, or the harmful effects of erythrocyte transfusion(s) itself. Active preoperative anemia management is a strategy that attempts to minimize both of these events, and in doing so, exert an additive or possibly synergistic effect on improving clinical outcomes. A randomized controlled trial utilizing a standardized transfusion strategy is a necessary step in determining if increases in preoperative hemoglobin lead to improved outcomes. A pilot, feasibility study is the first essential step in insuring the adequacy of future trials designed to answer this important question.

The APART study is being conducted to test the safety and efficacy of using a short-course (1-4 weeks) of EPO plus Feraheme to increase erythrocyte mass. The findings will be used to guide the design of a randomized, controlled trial (RCT) that examines the effects of active preoperative anemia management on erythrocyte transfusion and clinical outcomes. The RCT will test the hypothesis that a short-course (1-4 weeks) of EPO plus Feraheme is superior to the standard of care (SOC) at reducing transfusion and improving outcomes in anemic patients scheduled for cardiac surgery. Means and standard deviations derived from pilot data on changes in hemoglobin levels, reticulocyte counts and differences in erythrocyte transfusions and clinical outcomes will be analyzed for possible use in sample size calculations for the larger RCT. This pilot will also provide information in determining logistics for timely completion of the RCT, and will also address data collection, data management, adherence to the study protocol, transfusion and surveillance strategies and classification of clinical outcomes and adverse events.

Pilot Study Specific Aims Include:

1. To determine the proportion of patients who fulfill all the eligibility criteria for the study and agree to be part of a randomized trial of short-course EPO plus supplemental Feraheme (up to 3 doses given over a 1-4 week interval prior to surgery) vs. standard of care management in patients scheduled for coronary bypass grafting (CABG), valve surgery, or CABG/valve surgery.
2. To determine the adherence of patients and health care team to the procedures included in the study protocol (scheduled appointments, surveillance and transfusion strategies).
3. To determine the increase in hemoglobin levels and reticulocyte counts following a short-course of EPO plus supplemental Feraheme over a 1-4 week interval prior to the date of surgery vs. standard of care management in patients scheduled for CABG, valve, or CABG/valve surgery.
4. To assess differences in the proportion of patients receiving erythrocyte transfusions and number of blood products utilized (RBC, platelets and plasma) in the peri- and post-operative periods for those receiving a short-course of EPO plus supplemental Feraheme vs. standard of care management in patients scheduled for CABG, valve or CABG/valve surgery.
5. To determine the frequency and intensity of pre-defined clinical outcomes (mortality, major cardiac, renal, neurological events \[associated with anemia\] and infection) in the peri- and post-operative periods for those receiving a short-course of EPO plus Feraheme vs. standard of care management in patients scheduled for CABG, valve, or CABG/valve surgery.

Differences in hemoglobin levels and reticulocyte counts from baseline to the day of surgery and postop day (POD) 5, proportion of patients receiving transfusions and number of blood products utilized and the pre-defined clinical events will be assessed between the two groups. Each patient will be enrolled in the study up to 28 days before the day of surgery and for up to 30 days following the day of surgery. This pilot, feasibility study will enroll 50 subjects (25 per group). Both groups will have detailed clinical data and biological specimens collected.

Visits and Procedures:

* Screening: Patients undergoing cardiac surgery (CABG, valve, CABG/valve) with anemia will be identified in advance of their operations. Basic features of patient medical and surgical histories (i.e. age, gender, type of surgery) will be screened. If eligible for the study based on the inclusion/exclusion criteria, they will be consented into the study.
* Baseline Visit: Data on demographics, lab results, vital signs, medical history, current medications, height/weight will be reviewed and recorded. Randomization by computer will be done and the patient will receive the 1st dose of study drugs, as assigned, then monitored for any serious reactions (chest pain, dyspnea, seizures, severe headache, fever, nausea, vomiting, diarrhea, increase in BP). Control group patients with evidence of iron-deficiency by laboratory criteria will be advised to initiate supplementation with a non-prescription, over-the-counter oral iron preparation (ferrous sulfate 325 mg, three times a day is commonly used) to be taken until the planned surgical operation.
* Pre-op Visit: Patients will receive the 2nd dose of study drugs as assigned. Vital signs (heart rate, BP, oxygen saturation, temperature) will be recorded before and after drug administration, then monitored for any serious adverse events; SOC lab results; reticulocyte count, troponin, creatine kinase-myocardial band (CK-MB) samples will be collected.
* Day of Surgery: Patient vital signs (BP, electrocardiogram \[EKG\], etc) will be monitored as part of standard of care. Reticulocyte count, iron panel (includes transferrin, ferritin, total iron binding capacity, iron level) samples will be collected. SOC lab results, record of transfusions, estimated blood loss, adverse events will be monitored/recorded.
* POD 2: Troponin, CK-MB, Rotem (Rotational thromboelastometry) samples will be collected. Patients will receive study drug, as assigned, then monitored for serious events.
* POD 1-7: Vital signs (BP, EKG, etc) will be monitored; SOC lab results, record of transfusions, and adverse events will be monitored/recorded. Estimated blood loss will be recorded on POD 1 and 2 only.
* Other lab to be collected: POD 1 - reticulocyte count, iron panel, troponin, CK-MB; POD 2 - troponin, CK-MB, Rotem; POD 5 - reticulocyte count, iron panel, aspartate transaminase/alanine transaminase (AST/ALT); POD 7 - complete blood count (CBC), reticulocyte count, creatinine; POD 14 or discharge (whichever comes first) - CBC, creatinine.

Transfusion Strategy: Erythrocyte transfusion is permitted during cardiopulmonary bypass, during surgery and afterwards per protocol, when criteria is met. Red cell transfusions should be given one unit at a time with measurement of the pre- and post-transfusion hemoglobin levels along with physiologic parameters used to assess adequacy of organ perfusion. A consensus for transfusion thresholds was established among anesthesiologists, perfusionists and surgeons in our practice. The transfusion thresholds implemented in this protocol reflects our current "standard of care;" a threshold at which clinicians generally believe the benefits of erythrocyte transfusion outweigh the risks. Adherence to the transfusion strategy will be recorded by the research nurse and protocol deviations will be discussed with the attending physician of record and a member of the clinical research team. However, research staff will not order nor prohibit erythrocyte transfusions. This will be left to the discretion of the treating physician(s) if he/she deems it clinically necessary. Following randomization, patient's charts will be clearly labeled to indicate participation in the study protocol.

Surveillance Strategy: The decision to initiate and continue administering doses of EPO is based on evidence accrued from randomized controlled trials and clinical practice guidelines provided by multiple sub-specialty and international societies. Substantial heterogeneity exists in factors that could be included in a surveillance strategy to minimize the risk of a thrombotic event in this setting; with no one strategy proven to be superior. The surveillance strategy included in this protocol derives from, what we believe to be, the most current safety analyses of perioperative EPO use reflected in the literature. Implementing such surveillance methods are intended to minimize the possibly rare but potentially life-threatening adverse events. Risk factors considered in our surveillance strategy include: evidence of unstable angina or myocardial infarction, recent thrombotic event, hemoglobin levels associated with a higher risk of a myocardial event, excessive thrombocytosis or laboratory evidence of a hypercoagulable postoperative state. EPO dosing will be stratified based on patient risk (degree of perioperative anemia), type of procedure (CABG vs. valve) and laboratory data (hgb, Rotem). All doses will be given per surveillance guidelines.

Primary End Point: The primary objective is to assess the enrollment rate and adherence to the dosing protocol and surveillance strategies. We define successful adherence as adherence to dosing in more than 90% of patients for more than 90% of the doses deemed appropriate by the surveillance strategy. Secondary outcomes will include changes in hemoglobin levels and reticulocyte counts within the two groups from baseline to the day of surgery and POD 5, number of RBC units transfused, frequency of pre-specified clinical outcomes and incidence of adverse events in each of the study groups. Data from this pilot study will be used for the power analysis and design of the larger RCT.

Adverse events (AEs) are events that involve physiological, social, or psychological harm to subjects or risks of harm to additional subjects or others. AEs include expected and unexpected harmful effects, and unexpected risks of an interaction or an intervention. AEs may be caused by: the test article or test procedure, other aspects of the interaction or intervention, the subject's underlying condition, or the subject's concurrent standard treatment. AEs may be definitely related, probably related, possibly related, unlikely to be related, or definitely not related to the research. We will report all adverse events and other reportable incidences to the Institutional Review Board (IRB) per reporting guidelines. Any adverse event will be documented of that event including a description, subject number, date, outcome, and follow-up.

The primary safety endpoints of the study are the incidence of adverse events associated with the use of the study medications. These include: hypersensitivity (e.g. pruritis, rash, and urticaria), hypertension, hypotension, bleeding, nausea, vomiting, injection site pain, deep venous thrombosis or other thrombotic complications. Surveillance for these adverse events will be conducted by direct observation (during drug administration), daily bedside visits by the research nurse for the first 7 postoperative days, review of the patients medical record and listing any of these complications in the Society of Thoracic Surgery (STS) database. The definition of a stroke, myocardial infarction (MI), mesenteric artery occlusion or peripheral vascular event will be based on STS criteria. Any event resulting in death from time of initial drug administration to hospital discharge will be recorded.

The Principal Investigator, along with the Secondary Investigators, will be responsible for the monitoring, reviewing and analyses of study data. This will be done quarterly unless an issue requires immediate attention or if a recurrent pattern develops into a need for a more frequent review. An interim analysis will be done at 50% enrollment by the principal and secondary investigators.

Arms:
arm 1: Patients in the treatment group will receive a subcutaneous injection of EPO 300U/kg at the Baseline visit, the Preoperative visit and on POD 2; and an infusion of Feraheme 510mg at the Baseline visit and the Preoperative visit. arm 2: The control group will receive no preoperative intervention for anemia. The exception being iron deficiency anemia found during baseline. If laboratory values indicate iron deficiency, oral iron will be recommended to take until surgery.

Interventions: intervention 1: EPO intervention 2: Feraheme
Intervention descriptions: intervention 1: The treatment group will receive up to three doses of EPO 300U/kg. The first dose of study medication will be administered up to 28 days before the day of surgery and the second will be administered 1-7 days before the day of surgery. These first two doses will be given at least 7 days apart. A third dose may be administered two days following surgery. All 3 doses will be administered per surveillance strategy guidelines. intervention 2: Supplementation with Feraheme, 510mg delivered as an IV infusion, will be given following the first two preoperative doses of EPO.

Protocol document:
Prot_SAP_000.pdf: 
Official title: Active Preoperative Anemia Management to Reduce 
Erythrocyte Transfusion in Patients undergoing Cardiac Surgery 
(APART): A Feasibility Propensity-Matched Study 
 
NCT number:  NCT02189889 
 
Document date: Version 6, May 13, 2019 
 


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Active Preoperative Anemia Management to Reduce Erythrocyte 
Transfusion in Patients undergoing Cardiac Surgery (APART):  
A Feasibility Propensity-Matched Study 
 
UT Southwestern  
Department of Anesthesiology 
 And Pain Management  
 
Principal Investigator: Philip E. Greilich, M.D. 
 
 
Version 6, February 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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I. INTRODUCTION AND PURPOSE: 
Every year, over 600,000 open-heart operations are performed in the United States alone. Preoperative 
anemia is highly prevalent in this population of patients. A recent study involving over 4,800 patients 
undergoing coronary artery bypass grafting (CABG) at 70 institutions worldwide revealed that greater 
than 30% of patients fulfilled the World Health Organization criteria for anemia in the preoperative period.1 
A recent review of this topic reported that preoperative anemia may exceed 50% in some institutions.2  
This is particularly concerning given that several large risk-adjusted, retrospective and observational 
studies have demonstrated that preoperative anemia is associated with a two-fold increase in morbidity 
and mortality in this patient population1,3,4-5 The vast majority of patients undergoing cardiac surgery 
require cardiopulmonary bypass (CPB). The average drop in hemoglobin concentration (from 
preoperative levels to nadir) in these patients is between 4-6g/dL.51 Preoperative anemia, combined with 
significant, acute blood loss (750mls - 2,000mLs) and the hemodilution (30-40%) associated with CPB 
frequently leads to hemoglobin levels that result in insufficient oxygen delivery (DO2) and organ 
dysfunction.3,6-7 
 
Anemia and transfusion are independent predictors of morbidity and mortality in this patient population. 
Preoperative anemia is the single most important predictor of perioperative erythrocyte transfusion.8 
Karkouti et al. demonstrated that approximately 80% of patients with preoperative anemia received at 
least one erythrocyte transfusions while undergoing cardiac surgery.3  While open cardiac surgeries 
represent only  1% of the 48 million in-patient surgeries performed annually in the U.S., this small 
population of patients consumes over 20% of the red blood cell supply in U.S. blood banks.3,9  Of those 
transfused, over 50% receive ≤3 units of red blood cells.10  Whereas transmission of infectious disease 
has been a historic concern, we now realize that adverse outcomes are more commonly the result of 
immunomodulation, hypoxia, and free radical induced injury.11,12  Studies have repeatedly demonstrated 
that even low-volume erythrocyte transfusions (1-3 units) can significantly increase the risk of acute renal 
injury, infection, and pulmonary dysfunction following cardiac surgery.1-3,8,9  Reduction and possible 
elimination of RBC transfusion is now recognized as one of the most significant modifiable risk factors 
leading to these adverse events.   
 
The mechanism of injury in patients with preoperative anemia is either the duration/intensity of the 
anemia exposure (and resultant organ ischemia) or the harmful effects of erythrocyte transfusion(s) itself. 
Active preoperative anemia management is a strategy that attempts to minimize both of these events, 
and in doing so, exert an additive or possibly synergistic effect on improving clinical outcomes. A 
randomized controlled trial utilizing a standardized transfusion strategy is sorely needed to determine if 
increases in preoperative hemoglobin lead to improved outcomes. Conducting a feasibility propensity-
matched study is an essential step for insuring the adequacy of future trials designed to answer this 
important question.   


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The use of erythropoietin (EPO) is one method for optimizing hematopoiesis especially in those with 
preoperative anemia. In fact, evidence-based practice guidelines currently recommend selective, short-
term, preoperative use of EPO plus supplemental iron to optimize erythropoiesis and to reduce 
erythrocyte transfusions in the perioperative setting.13-15   The “Blood Conservation in Cardiac Surgery”  
guideline, updated in 2011, states “it is reasonable to use preoperative EPO plus iron, given several days 
before cardiac operation, to increase red cell mass in patients with preoperative anemia (AHA class IIA 
recommendation; level of evidence B)”.14 This recommendation is based on six randomized trials (810 
subjects) that used an ultra-short course of EPO (<5 days) in patients scheduled for cardiac surgery. 
Wide adoption of these recommendations has been, however, very slow. Significant limitations in 
previous work include:  
  1) insufficient treatment duration/dosing to increase red blood cell mass enough to avoid more than 1U  
       of red blood cells15-18;  
  2) widely variable and inadequate dosing (dose, frequency, route of administration) of supplemental iron 
       for an optimal erythrocytic response; and  
  3) a need for a simple and safe method to administer and monitor EPO plus iron in anemic patients 
       scheduled for cardiac surgery.   
 
We therefore propose a feasibility propensity-matched study to test the safety and efficacy of using a 
short- course (1-4 weeks) of EPO plus intravenous (IV) iron to increase erythrocyte mass. The findings 
from this study will be used to design a phase II/III randomized, controlled trial to determine if a similar 
treatment (EPO + IV iron) can significantly reduce erythrocyte transfusion and postoperative 
complications in anemic patients undergoing cardiac surgery. 
 
Aims in this pilot feasibility study are as follows: 
 
• 
Specific Aim 1: Among patients scheduled to undergoing elective coronary artery bypass graft 
surgery (CABG), valve repair or replacement surgery (valve), or CABG/valve at UTSW University 
Hospital, to determine the proportion of patients who fulfill all the eligibility criteria for the study 
and agree to be part of a propensity-matched study of short-course EPO (up to 3 doses given 
over a 1-4 week interval prior to surgery and a postoperative dose 2-4 days following surgery) 
plus supplemental IV iron (2 doses)  vs. untreated matched patients scheduled for CABG, valve, 
or CABG/valve surgery. 
 
• 
Specific Aim 2: To determine the adherence of patients and health care team to the procedures 
included in the study protocol (scheduled appointments, surveillance and transfusion strategies).  
  
• 
Specific Aim 3: To determine the increase in hemoglobin levels and reticulocyte count following a 


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short-course of EPO plus supplemental IV iron vs. standard of care management in matched 
patients scheduled for CABG, valve, or CABG/valve surgery. 
 
• 
Specific Aim 4: To assess differences in the proportion of patients receiving erythrocyte 
transfusions and number of blood products utilized (RBC, platelets and plasma) in the peri- and 
post-operative periods for those receiving a short-course of EPO plus supplemental IV iron vs. 
standard of care management in matched patients scheduled for CABG, valve, or CABG/valve 
surgery. 
 
• 
Specific Aim 5: To determine the frequency and intensity of pre-defined clinical outcomes 
(mortality, major cardiac, renal, neurological events [associated with anemia] and infection) in 
those receiving a short-course of EPO plus supplemental IV iron vs. standard of care 
management in matched patients scheduled for CABG, valve, or CABG/valve surgery. 
 
II. BACKGROUND: 
Active preoperative anemia management is not currently the standard of care at our institution. Cost 
associated with erythrocyte transfusions at UT Southwestern University Hospitals exceeds $20M dollars 
annually. This figure does not include costs associated with treatment of known complications of red 
blood cells transfusions (renal insufficiency, respiratory failure, infection and prolonged length of stay, 
etc).19-20 Fifty percent (50%) of our cardiac surgical population suffers from preoperative anemia and 
seventy-nine (79%) of these patients will receive one or more erythrocyte transfusions. In contrast, the 
incidence of erythrocyte transfusion was only 35% in those without preoperative anemia in CY2011-12.   
 
 
The goal of active preoperative anemia management is to restore red blood cell mass and reduce 
complications associated with anemia and erythrocyte transfusion. The use of erythrocyte stimulating 
agents (ESAs) has been effective in increasing hemoglobin levels and reducing red blood cell transfusion 
requirements in a variety of settings. Although commonly used to treat anemia in patients with chronic 
renal failure and certain types of cancers, short-term pre- and peri-operative use of EPO is one strategy 
for addressing the high prevalence of anemia (20%-50%) in the aging surgical population.  The safety 
and efficacy of recombinant human EPO use in orthopedic21-23 and gynecological surgeries24-25 are well-
documented. Dosing and duration have generally been EPO 600U/kg once weekly for a total of four 
weeks. No differences in the incidence of adverse events have been demonstrated between the 
treatment and control groups in these studies.   
 
Six randomized controlled trials have been published  using EPO in the setting of cardiac surgery.15-18,21,26  
Those receiving EPO demonstrated a greater increase in hemoglobin concentration on the day of surgery 
(1.4g/dL - 2.1g/dL; compared to baseline; p <0.05)17-18  with fewer erythrocyte transfusions (1U vs. 2U; p 


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< 0.01) compared to placebo controls.18  These regimens were ultra-short in duration (≤5 days) and in 
some studies included a postoperative dose.15,17,26  No differences in adverse events were noted in the 
810 subjects enrolled in these studies. However, none of these studies were sufficiently powered to 
detect either differences in clinical outcome or safety. As such, the beneficial effects of an ultra-short 
course of EPO remain uncertain. Studies from the orthopedic surgery literature suggest that longer 
treatment intervals will likely be required to increase red blood cell mass to a level capable of reducing 
erythrocyte transfusions to the degree needed to detect an independent effect on clinical outcome. 
Prolonged use of these agents (EPO, darbepoetin) in patients with cardiovascular disease and heart 
failure have been shown to be safe.27,28  The Study of Anemia in Heart Failure Trial (STAMINA-HeFT), the 
largest of these multicenter, randomized, controlled trials, demonstrated that darbepoetin was effective in 
raising the hemoglobin levels (1.8g/dL vs. 0.3g/dL; p<0.001) without increasing the risk of ischemic 
complications.28  In fact, a trend towards lowering the risk of morbidity and mortality was observed in the 
162 subjects enrolled in the treatment group.  
 
Overuse of EPO in patients undergoing cardiac surgery needs to be monitored. A study by D’Ambra et 
al.15 demonstrated that aggressive dosing of this agent in non-anemic patients could be problematic. 
Given its potential to contribute to a pro-thrombotic phenotype in some individuals, even its short-term 
use in patients with unstable angina is discouraged by the cardiac surgery practice guidelines.14 Its black 
box warning for chronic use in patients with end stage renal disease with cardiovascular disease is also 
intended to minimize the risk of a thrombotic event. The package insert for darbepoetin also recommends 
holding scheduled doses should the rise in hemoglobin level exceed 1g/dL per week based on an 
anaylsis of their safety data.29-30 The creation of a surveillance strategy is one method to increase the 
safety of EPO use by monitoring patient characteristics that may present an increased risk of a thrombotic 
event in this clinical setting.  This strategy could include:  
  1) limit use to those with preoperative anemia;  
  2) hold scheduled doses in those with hemoglobin thresholds deemed to be safe;  
  3) limit the duration of treatment or total number of doses;  
  4) administer treatments in close proximity to the scheduled surgical date; and  
  5) hold post-operative doses in patients with laboratory evidence of a hypercoagulable state.    
 
Iron is an essential co-factor for erythropoiesis. Absolute or functional iron deficiency is a common reason 
for an inadequate erythropoietic response to acute anemia and EPO therapy. Intravenous iron 
administration is the most reliable method for insuring this vital co-factor is not the rate-limiting step in 
restoring red cell mass with EPO.4,15 Although iron supplementation alone has been effective in restoring 
red blood cell mass and decreasing erythrocyte transfusion in non-cardiac surgery,4 this finding has not 
been demonstrated in cardiac surgery where blood loss is generally higher.31 
 


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Randomized controlled trials designed to test the hypothesis that active preoperative anemia 
management improves clinical outcomes have been called for by numerous large, observational trials, but 
to date have not been performed.   This feasibilitypropensity-matched study builds upon the safety record 
that ultra-short duration (≤5 days) EPO use in cardiac surgery by extending the duration of treatment to 1-
4 weeks and including supplemental IV iron in the treatment group. The design of this study includes 
transfusion and surveillance strategies to minimize the confounding influence of overuse of either 
erythrocyte transfusions and/or EPO on clinical outcomes.      
 
 
III. CONCISE SUMMARY OF PROJECT  
Research Design and Methods: 
Propensity score matching (PSM) is a statistical matching technique that attempts to estimate the effect of 
a treatment or other intervention by accounting for the covariates that predict receiving the treatment. 
PSM attempts to reduce the bias due to confounding variables that could be found in an estimate of the 
treatment effect obtained from simply comparing outcomes among units that received the treatment 
versus those that did not. This feasibility propensity-matched study is being conducted to guide the 
design of a future randomized, controlled trial (RCT) that examines the effects of active preoperative 
anemia management on erythrocyte transfusion and clinical outcomes. The RCT will test the hypothesis 
that a short-course (1-4 weeks) of EPO plus IV iron is superior to the standard of care at reducing 
erythrocyte transfusion and improving outcomes in anemic patients scheduled for cardiac surgery. Means 
and standard deviations derived from pilot data on changes in hemoglobin levels, reticulocyte count and 
differences in erythrocyte transfusion and clinical outcomes will be analyzed for possible use in sample 
size calculations for the larger RCT. This study will also provide valuable information in determining 
whether the addition of other clinical sites with similar patient populations will be needed in order to help 
recruit patients for timely completion of the RCT. In addition, the study will provide important information 
on issues related to data collection, data management, adherence to the study protocol, transfusion and 
surveillance strategies and classification of clinical outcomes and adverse events.  
 
Anemic patients scheduled to undergo CABG, valve, or CABG/valve surgeries will be considered for the 
study. Patients who fulfill all the inclusion/exclusion criteria will be asked to participate in the study. The 
proportion of screen failures and eligible patients who refuse to participate will be recorded using a screen 
failure log. Patients who agree to be in the study and sign an informed consent form will be sequentially 
enrolled into the treatment group.  The treatment group will receive up to three doses of EPO 300U/kg.  
The first dose of study medication will be administered up to 28 days before the day of surgery and the 
second will be administered 1-7 days before the day of surgery. These first two doses will be given at 
least 7 days apart. A third dose may be administered two to four days following surgery. All 3 doses will 
be administered subcutaneously and per surveillance strategy guidelines. In addition, supplementation 


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with IV iron (feraheme; 510mg delivered per IV infusion over a minimum of 15 minutes) will be given 
following the first two preoperative doses of EPO.  
 
Differences in hemoglobin levels and reticulocyte counts from baseline to the day of surgery (preop to 
POD#0) and postoperative day five (POD#5), proportion of patients receiving erythrocyte transfusions 
and number of blood products (RBC, platelets and plasma) utilized and pre-defined clinical events 
(mortality, major cardiac, renal, neurological events [associated with anemia] and infection) will be 
assessed in all treated participants. Each patient will be enrolled in the study up to 28 days before the day 
of surgery and for up to 30 days following the day of surgery. This feasibility propensity-matched study 
will sequentially enroll 23 more treatment subjects to total 25. The propensity-matching control group will 
be comprised of 25 total “like” patients for comparison. The source of the data for the control group will be 
the Society of Thoracic Surgery (STS) Database, an institutional registry.  
  
Study medications: 
1. EPO (Procrit®; Janssen Biotech, Inc; Horsham, PA) is a medication that promotes erythropoiesis 
and is indicated for the reduction of allogeneic erythrocyte transfusions in patients undergoing 
elective noncardiac, nonvascular surgery.29, 30, 32 Native EPO is a 165 amino acid glycoprotein 
hormone that binds to the EPO receptor on erythroid progenitor cells to induce intracellular 
signaling that inhibits apoptosis important to erythroid differentiation. EPO differs only slightly 
(protein moiety) from its native form. EPO may be administered intravenously, intraperitoneally or 
subcutaneously. Subcutaneous administration results in peak concentrations at about 18 hours. 
The bioavailability of subcutaneous EPO is about 20 to 30% and detectable serum concentrations 
are still present 4 days after administration. Remarkably, little is known of the mechanism in 
which either endogenous EPO or recombinant human EPO is metabolized. About 3 to 10% of 
EPO is excreted unchanged in the urine. In common with other glycoproteins, the carbohydrate 
residues which constitute 40% of its molecular size are essential for maintaining the stability of 
EPO in circulation. The most common serious adverse effects are hypertension, bleeding and 
thrombotic events. Caution is advised with chronic (over 2-3 months) administration in patients 
who are at high risk for thromboembolic events.  Relatively short-duration (<1 month) 
administration, however, has demonstrated a promising safety profile.16-18 No significant 
differences in adverse events related to EPO administration have been reported in the literature 
for over fifteen years.16-18,21   
  
2. Intravenous Iron supplement (FerahemeTM AMAG Pharmaceuticals, Inc, MA): Feraheme injection 
is an IV iron indicated for the treatment of iron deficiency anemia in adult patients with chronic 
kidney disease.33 Feraheme consists of a super-paramagnetic iron oxide coated with a 
carbohydrate shell, which helps to isolate the bioactive iron from plasma components. The iron is 


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released within vesicles in the macrophages of the reticuloendothelial system, and the iron 
subsequently enters the intracellular storage iron pool (e.g., ferritin) or is transferred to plasma 
transferrin. Feraheme exhibits a dose-dependent elimination from plasma with a half-life of 
approximately 15 hours in humans. The clearance decreases by increasing the dose of 
feraheme. Volume of distribution is consistent with plasma volume, and the mean maximum 
observed plasma concentration and half-life increases with dose. 
 
 
Transfusion Strategy: 
Retrospective analyses in cardiac surgery demonstrate increased morbidity and mortality with 
intraoperative hemoglobin between 5.0g/dL to 8.0g/dL (Hct 15-24%) and postoperative hemoglobin 
>11g/dL (Hct >34%).6,12,14,34 In addition, two recent RCT35-36 demonstrated no clear advantage of using a 
transfusion threshold >8g/dL unless patients are experiencing symptoms of anemia, rapid blood loss or 
life-threatening circulatory shock.  Lower transfusion threshold appears justified during CPB because 
metabolic demands are reduced during anesthesia and CPB. Hematocrits as low as 22% during CPB 
have been shown to be well-tolerated.37-38 In fact, transfusing patients with hematocrits >22% during CPB 
have been associated with increases in adverse events (especially in low- and moderate-risk sub-
groups).34,39 
  
A consensus for transfusion thresholds was established among anesthesiologists, perfusionists and 
surgeons in our practice. The transfusion thresholds implemented in this protocol reflects our current 
“standard of care;” a threshold at which clinicians generally believe the benefits of erythrocyte transfusion 
outweigh the risks. Adherence to the transfusion strategy will be recorded by the research nurse and 
protocol deviations will be discussed with the attending physician of record and a member of the clinical 
research team.  However, research staff will not order nor prohibit erythrocyte transfusions. This will be 
left to the discretion of the treating physician(s) if he/she deems it clinically necessary. Following 
randomization, patient’s charts will be clearly labeled to indicate participation in the study protocol. 
 
Erythrocyte transfusion is permitted during CPB if:  
• 
Hemoglobin <6.0g/dL;   
• 
Hemoglobin between 6.0g/dL and 8.0g/dL if the patient 
 is considered high-risk by:  
 EuroScore or Higgins Score ≥6 and ≥10, respectively  
 age >75yrs 
 history of stroke or TIA or baseline cognitive dysfunction or dementia 
 incomplete revascularization 
 demonstrates signs of inadequate organ perfusion despite MAP ≥60mmHg or CPB flows 
of ≥2.5L/kg/m2 evidenced by  


P a g e  | 9 
 
 myocardial ischemia (by EKG or TEE) despite an adequate MAP  
 mixed venous oxygen saturation (Sv02) <60% 
 unable to separate from CPB despite adequate doses of inotropic/pressor support 
 
Erythrocyte transfusion is permitted intra- and post-operatively if:  
• 
Hemoglobin <8.0g/dL 
• 
Hemoglobin between 8.0g/dL and 9.5g/dL, if the patient 
 is experiencing rapid blood loss (≥300mLs/hr) 
 is experiencing signs/symptoms of anemia evidence by  
 tachycardia and/or hypotension (MAP <60mHg for >10mins) unresponsive to 
adequate volume replacement alone 
 escalating doses of 2 or more inotropic / pressor agents (i.e. EPI/NE ≥0.03 
mcg/kg/min) 
 is experiencing signs/symptoms of inadequate oxygen delivery or circulatory shock 
 cardiac index <2.0L/min/m2 
 mixed venous/central venous oxygen saturation (Sv02)/Scv02) ≤60% 
 base deficit >6.0mEq/L in absence of renal failure 
 urine output <0.5mL/kg/hr 
 is considered high-risk by EuroScore or Higgins Score (≥6 and ≥10, respectively)  
• 
If the patient does not demonstrate any of the signs/symptoms above, yet the physician still 
believes an erythrocyte transfusion is warranted, he/she will be asked to provide a justification 
that will be recorded and classified.  
 
Erythrocyte transfusions should be given one unit at a time with measurement of the pre- and post-
transfusion hemoglobin levels along with physiologic parameters used to assess adequacy of organ 
perfusion. 
 
Surveillance Strategy for ESA Dosing: 
The decision to initiate and continue administering doses of EPO is based on evidence accrued from 
randomized controlled trials and clinical practice guidelines provided by multiple sub-specialty and 
international societies.14,40-41 Substantial heterogeneity exists in factors that could be included in a 
surveillance strategy to minimize the risk of a thrombotic event in this setting; with no one strategy proven 
to be superior.  The surveillance strategy included in this protocol derives from, what we believe to be, the 
most current safety analyses of perioperative EPO use reflected in the literature. Implementing such 
surveillance methods are intended to minimize the possibly rare but potentially life-threatening adverse 
events. Risk factors considered in our surveillance strategy include: evidence of unstable angina or 
myocardial infarction, recent thrombotic event, hemoglobin levels associated with a higher risk of a 


P a g e  | 10 
 
myocardial event, excessive thrombocytosis (platelet count >300 x103/μL) or laboratory evidence of a 
hypercoagulable postoperative state.   
 
EPO dosing will be stratified based on patient risk (degree of perioperative anemia), type of procedure 
(CABG vs. valve) and laboratory data (Hb, RoTEM: MCF) in the following manner:  
 
Initial dosing/Re-dosing of EPO plus IV iron (Prior to Surgical Procedure): 
Therapy or a dose will NOT be administered in patients under the following conditions: 
• 
Patients scheduled for a CABG procedure with Hb concentration ≥12.5g/dL  
• 
Patients scheduled for a cardiac valve procedure with Hb concentrations ≥13.5g/dL 
• 
Rate of rise in Hb level that exceeds 1g/dL in past 7 days (and not secondary to erythrocyte 
transfusion)a 
• 
Evidence of any new or evolving symptoms or signs suggesting the presence of myocardial 
ischemia, including chest pain, EKG changes, or elevation of laboratory cardiac biochemical (CK-
MB, Troponin) 
• 
Average of three diastolic blood pressures (over 1hr) >100mmHg despite scheduled anti-
hypertensive therapy.   
a Rationale:  The original label for EPO29-30 included a warning regarding the risk of exacerbation of hypertension with 
hematocrit increases exceeding 4 percentage points (corresponding to increases in the hemoglobin concentration of 
approximately 1.3 g per deciliter) within a 2-week period. During a review of the marketing application, an association was 
found between rates of increase in the hemoglobin level exceeding 1g/dL per 2-week period and the risk of cardiovascular 
and thromboembolic events. This observation provided the basis for a warning on the package insert for darbepoetin 
regarding excessive rates of increase in hemoglobin concentrations.  
 
Continuation of Dosing of EPO (Post-Operative Administration) 
Postoperative therapy will NOT be administered in patients under the following conditions: 
• 
Hb concentration >10.0g/dL (both CABG and valve procedures) b 
• 
Rotational Thromboelastogram (RoTEM) measurement of Maximum Clot Firmness (MCF) 
>70mm (RoTEM to be performed during procedure and 2-4 days after surgery, prior to re-
dosing). 
• 
Evidence of any new or evolving symptoms or signs suggesting the presence of myocardial 
ischemia, including chest pain, EKG changes, or elevation of laboratory cardiac biomarkers (CK-
MB, Troponin) that have failed to have a decreasing trend 
• 
Average of three diastolic blood pressures (over 1hr) >100mmHg despite scheduled anti-
hypertensive therapy.   
b Rationale: A multi-center study in over 2,000 CABG patients by Spiess et al.12 demonstrated that hematocrit >34% 
(11.3g/dL) upon entry in the ICU was the single greatest predictor of myocardial infarction following surgery. Furthermore, 
according to the labeling for EPO targeting higher hemoglobin (13 to 14g/dL) compared to a lower range (9 to 11.3g/dL) 
increased the risk of death, myocardial infarction, stroke, and thrombotic events in patients with CKD.29-30  


P a g e  | 11 
 
Screening for Potential Participants:   A HIPAA waiver was obtained to allow the research team to screen 
the medical records of patients scheduled for CABG, valve or CABG/valve surgery at UTSW University 
Hospital eligible for participation in this study. At the initial consultation with the cardiothoracic service or 
through Patient Blood Management Clinic, patients who fulfill the initial entry criteria for the study will be 
invited to participate in this propensity-matched study for patients with “low preoperative blood counts (or 
anemia)”. Patients who agree to be part of the study will be approached by members of the research 
team, who will explain the protocol in detail and will ask the patient to sign a written informed consent. 
Patients that become aware of the trial via the UT Southwestern clinical research website, will be referred 
directly to the clinical research nurse to answer all their questions and be encouraged to discuss possible 
participation with their surgeon during their next appointment.               
 
 
Baseline Research Visit (7-28 days before day of surgery): 
 
• 
Patients will be asked to sign the informed consent and HIPAA forms should they decide to 
proceed with the study. 
• 
Patients will be escorted from the cardiothoracic surgery clinic by a member of the clinical 
research team or asked to come to the UTSW Patient Blood Management Clinic, Zale Lipshy 
University Hospital at 6201 Harry Hines Blvd.  
• 
Data on demographics, vital signs, medical history, current medications, height, and weight will 
be recorded. 
• 
We will review all available lab results. 
• 
The patient will be enrolled into the treatment group.  
• 
Treatment group patients will receive a single subcutaneous injection of EPO 300U/kg and an IV 
iron infusion of 510mg. Vital signs including heart rate, blood pressure, oxygen saturation, and 
temperature will be recorded before, during, and after drug administration.  
• 
Patient will be monitored for any serious reactions during drug administration and for at least 30 
minutes following each infusion. Serious reactions include anaphylaxis, chest pain, dyspnea, 
seizures, severe headache, fever, nausea, vomiting, and diarrhea, an increase in blood pressure 
greater than 20mmHg above baseline systolic, systolic BP greater than 180mmHg and/or 
diastolic BP greater than 100mmHg, hypotension. 
• 
The visit will last approximately 1.5 hours. 
 
Pre-op Visit (1-7 days before surgery) 
• 
Patients in the treatment group will be seen again in a Patient Blood Management infusion room 
to receive a single subcutaneous injection of EPO 300U/kg and a 2nd IV iron infusion of 510mg, if 
iron reserves are believed to be inadequate (for a major hemorrhage) based on the result from 
the baseline iron panel and per Surveillance Strategy guidelines.   


P a g e  | 12 
 
• 
Vitals signs, including heart rate, blood pressure, oxygen saturation, and temperature will be 
recorded before, during, and after drug administration. 
• 
Patient will be monitored for any serious reactions (anaphylaxis, chest pain, dyspnea, seizures, 
severe headache, fever, nausea, vomiting, and diarrhea, an increase in blood pressure greater 
than 20mmHg above baseline systolic, systolic BP greater than 180mmHg and/or diastolic BP 
greater than 100mmHg, hypotension). 
• 
Approximately 8mLs of blood will be drawn to obtain troponinT/CK-MB and reticulocyte count. 
• 
The visit will last approximately 1 hour. 
 
Day of Surgery 
• 
We will monitor the patient’s vitals (blood pressure, EKG, etc) as part of standard care. 
• 
Approximately 8mLs of blood will be drawn to obtain hemoglobin concentration and reticulocyte 
count. 
 
Post-Operative Dose 
• 
Approximately 3mLs of blood will be drawn for a rotational thromboelastogram (RoTEM) 
measurement prior to redosing. 
• 
Patients in the treatment group will receive a single subcutaneous injection of EPO 300U/kg two 
to four days following surgery, if they meet criteria as described in the surveillance plan. 
• 
Vitals signs, including heart rate, blood pressure, oxygen saturation, and temperature will be 
recorded before and after injection. 
• 
Patient will be monitored for any serious reactions (chest pain, dyspnea, seizures, severe 
headache, fever, nausea, vomiting, and diarrhea, an increase in blood pressure greater than 
20mmHg above baseline systolic, systolic BP greater than 180mmHg and/or diastolic BP greater 
than 100mmHg). 
 
Post-Operative Days #5, #7, #14 
• 
On Day #5 approximately 8mLs of blood will be drawn to obtain a reticulocyte count, iron panel, 
AST/ALT. 
• 
On Day #7 approximately 8mLs of blood will be drawn to obtain a reticulocyte count, CBC and 
creatinine (unless done as SOC). 
• 
On Day #14 or at discharge approximately 6mLs of blood will be drawn to obtain a CBC and 
creatinine (unless done as SOC). 
 
 
Clinical Outcomes 
The primary objective is to assess the enrollment rate and adherence to the dosing protocol and 


P a g e  | 13 
 
surveillance strategies. We define successful adherence as adhering to dosing in ≥90% of patients for 
≥90% of the doses deemed appropriate by the surveillance strategy. Secondary outcomes will include:  
  1) changes in hemoglobin levels and reticulocyte counts within the two groups from baseline to the day 
       of surgery (preop to POD#0) and POD#5;  
  2) proportion of patients receiving erythrocyte transfusions and number of blood products (RBC, 
       platelets and plasma) utilized;  
  3) incidence of pre-defined clinical events (mortality, major cardiac, renal, neurological events 
       [associated with anemia] and infection) in each of the study groups. 
 These events will include myocardial infarction, prolonged low-output state, stroke, encephalopathy, 
duration of mechanical ventilation, renal insufficiency, and mortality and dialysis dependence at 30 days 
or discharge.  Data from this feasibility study will be used for the power analysis and design of the larger 
RCT. 
 
Clinical events will be defined using the following criteria: Society of Thoracic Surgery (STS)42 for 
stroke/transient ischemic attack (TIA), coma/encephalopathy, myocardial infarction (MI), prolonged 
ventilation, reoperation for bleeding or graft occlusion/revision, postoperative venous thrombosis, 
thromboembolic event, deep venous thrombosis and pulmonary embolism; RIFLE43-44 for acute renal 
injury (AKI), National Healthcare Safety Network (NHSN)45 for surgical site infections (SSI); Surgenor SD 
et al.46 for low output heart failure (LOHF); any life-threatening events (i.e., subject was at substantial risk 
of dying at the time of the adverse event) and in-hospital or 30-day mortality based on observation. 
Outcome data will be collected via contact with primary physician, public record review or by a follow-up 
telephone call by the research nurse. 
 
The cost of erythrocyte transfusions, EPO plus iron, direct hospital costs and direct margins associated 
with the care of those randomized in this pilot study will be recorded for future analysis of resource 
utilization. The duration of operating room time, intensive care unit and hospital length of stay will be 
collected. The total cost of erythrocyte transfusion will be based on four times the acquisition cost 
($1,200.00)47 The cost of EPO and IV iron will be calculated based on recommended manufacturer 
suggested retail price at the time of publication and will include activity based costs of administering these 
treatments based on the protocol outlined in this study.        
 
 
 
 
 
 


P a g e  | 14 
 
IV. STUDY PROCEDURES: 
Time Line of Pilot Study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Supplementation with intravenous iron (feraheme; 510mg delivered as an IV infusion) will only be 
administered following the first two preoperative doses of EPO (shown in diagram).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiothoracic 
clinic  
Screen for 
eligibility and 
consent  
Baseline visit: 
7-28d before surgery 
1st dose of study med:  
EPO+ IV Iron 
Preop visit:  1-7d  
before surgery 
2nd dose of study med: 
EPO + IV Iron 
Day of surgery = POD 0 
POD1 
30d F/U 
POD4 
POD5 
POD2 
POD 3 
3rd dose of study med:  
EPO only, given 2-4d after 
surgery 


P a g e  | 15 
 
Consort Diagram of Pilot Study: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
        Cardiac surgery                                                                              Cardiac Surgery 
 
 
 
 
 
 
 
 
 
 
Patients scheduled for CABG, valve, or 
CABG/valve surgery 
(N=50) 
 Inclusion Criteria 
1. Between age 18 and 80 years old 
2. Scheduled for elective CABG, valve, 
or CABG/valve surgery 
3. Hemoglobin level <13mg/dL 
4. Surgery scheduled at least 7 days 
after clinic visit 
5. Ability to provide informed consent 
 
          Serial Enrollment 
Exclusion criteria   
1. 
Uncontrolled 
hypertension 
2. 
Renal failure, Cr >3 
3. 
Unstable angina 
4. 
H/O thromboembolism 
within the last year 
5. 
H/O drug abuse 
6. 
Seizures within last 6 
months 
7. 
Current active 
malignant disease or 
H/O hematologic 
malignancies 
8. 
Stroke within the past 6 
months 
9. 
Current sepsis or 
bacteremia 
10. Platelet count of lower 
than 50,000/mm3 or 
coagulation abnormality 
11. Hypersensitivity to 
study medications 
12. Refuse to receive 
transfusion 
 
              Treatment group (N=25) 
EPO 300U/kg administered 7-28d preop, 1-7d 
preop, and 2-4d after surgery  
 
Feraheme 510mg administered after 1st two 
doses of EPO 
                Propensity-matching group (N=25) 
 
Standard of care 
             Treatment group 
 
Data collection  
 
Number of patients withdrawn (N)= 
 Propensity-matching group 
 
Data collection  
 
Number of patients withdrawn (N)= 
 
Data Analysis 
 


P a g e  | 16 
 
Table 1.  SUBJECT SCHEDULE OF EVENTS  
Test/evaluation 
& collected/required 
forms 
 7-28d 
PreOp 
 1-7d 
PreOp 
 
POD0 
PreOp 
 
 
POD0 
PostOp 
 
 
POD
1 
 
POD
2 
 
POD 
5 
POD 
7 
POD  
14 
Inclusion & exclusion criteria 
X 
 
 
 
 
 
 
 
 
Informed consent/HIPAA 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical History/Meds 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body mass index 
X 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ASA  
X 
 
 
 
 
 
 
 
 
Laboratory  
 
 
 
 
 
 
 
 
 
  CBC  
S 
S 
S 
S 
S 
S 
S 
S 
S/X 
  Reticulocyte Count 
S 
X 
 
X 
S 
 
X 
X 
 
  Iron panel** 
S 
 
X 
 
S 
 
X 
 
 
  Creatinine 
S 
S 
S 
S 
S 
S 
S 
S 
S/X 
  Troponin T/CK-MB 
 
X 
 
S 
S 
S/X 
 
 
 
  AST/ALT 
 
S 
 
 
S 
 
X 
 
 
Rotational Thromboelastogram 
(Rotem)+ 
 
 
 
S 
 
X 
 
 
 
  12-lead EKG 
S 
S 
S 
S 
S 
S 
S 
S 
 
 
 
 
 
 
 
 
 
 
 
Record of Erythrocyte 
transfusion 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Estimated blood loss 
 
 
 
X 
X 
X 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Survey 
X 
 
 
 
 
 
 
 
 
Protocol Compliance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
S = Standard of Care laboratory tests routinely ordered per ICU care team 
X = Not routinely ordered laboratory tests; obtained for research purpose only. 
*Will obtain hemoglobin and creatinine on POD14 or before hospital discharge (whichever event occurs first) 
**Iron panel includes ferritin, TIBC, iron, transferrin 
+ Will obtain RoTEM EXTEM 2-4 days after surgery 
 
Adverse events and survival will be reviewed at the time of hospital discharge and 30d following surgery.     
 
 
V. SUBSTUDY PROCEDURES 
Our study does not include any sub-studies.  
 
VI. CRITERIA FOR INCLUSION OF SUBJECTS: 
The inclusion criteria of subjects are as follows: 
1. The subject must be between the age of 18 and 80 years old. 
2. The subject must be diagnosed with preoperative anemia, defined as hemoglobin <13.0g/dL. 
3. The subject must be scheduled for elective cardiac surgery (CABG, valve, or CABG/valve), 
including both first time and repeat procedures. 
4. Female subjects of child bearing potential must have a documented negative pregnancy test 
within 7 days prior to the procedure.  


P a g e  | 17 
 
5. The subject must sign a written informed consent prior to the procedure, using a form that is 
approved by the UT Southwestern Institutional Review Board. 
6. The subject must agree to be compliant and return for all follow-up visits.  
 
VII. CRITERIA FOR EXCLUSION OF SUBJECTS: 
The subjects will be excluded if they meet any one of the following criteria: 
1. Uncontrolled hypertension (defined as systolic pressure greater than 180mmHg, diastolic 
pressure greater than 100mmHg, not adequately controlled by anti-hypertensive therapy at the 
time of procedure). 
2. Current renal failure on dialysis or serum creatinine [Cr]>3.0mg/dL. 1 
3. Unstable angina (defined by chest pain and ECG changes indicating ischemia at rest). 
4. Thromboembolism within the past year. 
5. Current active primary or metastatic malignancy or history of myeloid malignancy. 
6. Seizures within the past year. 
7. History of stroke within the last 6 months. 
8. Patients who have platelet count lower than 50,000/mm3 or coagulation abnormality. 
9.  Sepsis or bacteremia defined by positive blood culture. 
10. Patients who have known hypersensitivity to EPO or any of its components. 
11. Patients who have known hypersensitivity to Feraheme or any of its components. 
12. Patients who refuse blood transfusion, (i.e. Jehovah's Witnesses). 
13. Pregnant or breast feeding. 
14. Patients who are unable to provide informed consent or who has inability to understand or 
corporate with study procedure. 
 
VIII. SOURCES OF RESEARCH MATERIAL 
Data will be obtained from the patient's medical records EPIC and the Society of Thoracic Surgery (STS) 
database entries. Laboratory tests for reticulocyte count and additional serum ferritin, cardiac biomarkers, 
serum creatinine, thromboelastographic and liver transaminase measurements will be obtained 
specifically for research purposes. Other tests conducted (e.g. hemoglobin concentration, creatinine, 
EKG) will be part of standard of care (see Table 1 for details regarding standard of care and for research 
only).  
 
IX. RECRUITMENT METHODS AND CONSENTING PROCESS 
Potential subjects will be patients of the cardiothoracic surgeons. Patients fulfilling the entry criteria will be 
evaluated by their surgeon and invited to participate if none of the exclusion criteria are present and they 
are judged to be appropriate for the trial. Each patient will be asked if they are willing to speak with the 
research nurse and learn more about the study.  If interested, the surgeon or their nurse, will notify the 


P a g e  | 18 
 
clinical research nurse to discuss the details of the study either on the same day, by phone at another 
time, or by scheduling another appointment at their earliest convenience. Patients will be given an 
information pamphlet about the study.  
 
The research nurse will provide a full description of the study to the patient and answer any questions that 
the patient might have. In order to minimize potential for undue influence or coercion, a section explaining 
the voluntary nature of the study will be included in the informed consent. The research nurse will also 
inform the patients that taking part in the study is entirely voluntary. The patient may decide not to endure 
the study and they may leave this study at any time. Choosing not to participate or leaving the study will 
not result in any punishment or loss of benefits to which they are entitled.  The patient’s decision will not 
affect his or her routine medical treatment and the relationship with those treating the patients or the 
study staff.  Once patients have gained a full understanding of their rights and responsibilities and all 
pertinent aspects of the study, those who wish to participate in the study will be asked to sign an informed 
consent and a form for Authorization for Use and Disclosure of Health Information for Research Purposes 
(HIPAA). The patient's protected health information created or received for the purpose of this study is 
protected under HIPAA. Patient information will remain confidential unless the patient gives his or her 
permission to share it with others, or if the researchers are required by law to release it. Specific 
measures to protect the confidentiality and privacy of the patient are detailed in Section 11, “Procedures 
to Maintain Confidentiality" in the protocol. We do not request a waiver of informed consent, and we will 
not recruit vulnerable population in the study. 
 
 
A copy of the consent form will be given to the patient for their review. Consented patients will be given 
the option of receiving their initial dose of study medication during the same visit, if appropriate, or 
scheduled at another appointment (7-28 days before their date of surgery) that either coincides with other 
hospital appointments or necessitates a separate research visit.  
 
X. POTENTIAL RISKS 
Risks associated with collection of blood for laboratory tests: 
The total amount of blood collected for this study (if the blood tests have not been done as part of the 
routine care), will not exceed 8mLs per day.   The blood sample will be drawn from a venous or arterial 
catheter, which will be placed in the operating room for routine care. If the IV access from which blood 
samples can be drawn has already been removed, blood will be drawn from an arm vein.      
 
 
Risks associated with administration of medications: 
Erythropoeitin: The safety of using EPO in an acute, perioperative setting has been well established in 
several meta-analyses.1,4-5 The dosing schedule in this study is consistent with phase I and phase II 
human clinical trials19-20 as well as multicenter clinical trials assessing the optimal and effective dosing of 


P a g e  | 19 
 
EPO. The package insert for EPO does not recommend its use in patients undergoing cardiovascular 
surgery given the lack of sufficient safety and efficacy data; hence its use in this study would be 
considered “off-label”. As with all erythropoietic therapies, EPO may increase the risk of cardiovascular 
events, including death. In clinical trials, the most common adverse reactions, encountered in over 5% of 
EPO-treated perioperative patients, include nausea, vomiting, pruritis, headache, injection site pain, chills, 
deep vein thrombosis (DVT), cough, and hypertension.  Due to the increased thrombotic risk in the 
perioperative period, DVT prophylaxis is recommended in all surgical patients receiving EPO.29-30 
Thrombo-prophylaxis in the cardiac surgery consists of sequential compression device, anticoagulation 
following valve surgery and aspirin following CABG surgery.      
 
 
Because clinical trials have been conducted under widely varying conditions, adverse reaction rates 
observed in clinical trials of EPO may not reflect rates observed in our study. The black-box warning 
issued by the FDA for chronic use of erythrocyte stimulating agents in patients with end stage renal 
disease (ESRD) and cardiovascular disease (for increased risk of thrombotic and cardiovascular events) 
has been challenged by more recent publications outlining differences in the safety profile for short-term 
use in the perioperative setting. It is important to understand the differences in our patient population 
when comparing the adverse events listed on the package insert for this drug. First, the majority of 
adverse events reported by EPO clinical trials have been in chronic renal failure patients and in cancer 
patients receiving chemotherapy, whom we exclude from our study. Second, our protocol is a short-term 
(1-4 weeks) in patients experiencing moderate-to-high levels of acute hemorrhage (750mLs-1,500mLs). 
Third, all of the patients in our study will be anemic; thus the likelihood of having a hematocrit at a level 
likely to result in a thrombotic complications following CABG surgery is unlikely. Erythrocyte stimulating 
agents have been used in clinical practice at our institution for over 2 years and increases in the rates of 
seizure, thrombotic events, pure red blood cell dysplasia, or serious allergic reactions have not been 
observed in patients receiving these medications. The only side effect that has been observed is 
hypertension. In our study, treatment will be held in patients with blood pressure above 180/100mmHg.  
 
Only one study in the cardiac surgery population has reported an uneven distribution of adverse events 
and mortality in the EPO-treated versus placebo group (6% vs. 0%, respectively)15 Although the author of 
the study concluded there were no differences in adverse events between EPO and placebo-treated 
patients, an uneven distribution of mortality between the groups cannot be ruled out to any degree of 
certainty.  Remarkably, given the small cohort size of this study, the probability is only 0.229 that, indeed, 
a statistically significant difference (p<0.05) exists between the EPO versus placebo treated groups.48 Of 
note, an aggressive perioperative dosing regimen was utilized in the protocol of this study and the 
majority of these patients did not have preoperative anemia. In contrast, the remaining clinical trials, 
conducted over the past decade, have enrolled anemic patients and have failed to demonstrate a 
negative safety signal. More specifically, these trials found no observed difference in mortality, thrombotic 


P a g e  | 20 
 
events, or serious adverse events associated with perioperative EPO use.16-18  
 
This study protocol builds upon the safety profile established with using an ultra-short (<5 days) duration 
regimen recommended in the current practice guideline for cardiac surgery.17-18,23,29,30 This study extends 
the dosing interval to 1-4 weeks in anemic patients using a well-established dosing regimen (300U/kg per 
dose).29-30 Our risk:benefit  assessment took into consideration that almost 80% of our patients with 
preoperative anemia have received erythrocyte transfusions in the past. The use of a novel surveillance 
strategy in our study provides additional safety measures to further minimize the risk of a thrombotic 
event.  
 
Feraheme is an iron replacement product indicated for the treatment of iron deficiency anemia in adult 
patients with chronic kidney disease (CKD). It may cause serious hypersensitivity reactions, including 
anaphylaxis and/or anaphylactic reactions. In clinical cases,46 serious hypersensitivity was reported in 
0.2% (3/1,726) subjects. Other adverse reactions potentially associated with hypersensitivity (e.g. 
pruritus, rash, urticaria, or wheezing) were reported in 3.7% (63/1726) of these subjects. Hypotension 
may follow feraheme administration. In clinical studies, hypotension was reported in 1.9% (33/1726) 
subjects, including 3 patients with serious hypotensive reactions. Excessive therapy with parenteral iron 
can lead to excess storage of iron with the possibility of iatrogenic hemosiderosis (a form of iron overload 
disorder). Administration of feraheme may transiently affect the diagnostic ability of MR imaging. 
Alteration of MR imaging studies may persist for up to 3 months following the last feraheme dose. In CKD 
patients, adverse reactions to feraheme reported in ≤1% of patients are nausea, dizziness, hypotension, 
peripheral edema, headache, edema, vomiting, abdominal pain, chest pain, cough, pruritus, pyrexia, back 
pain, muscle spasms, dyspnea, and rash. 
 
There might be other side effects of the study medication that we cannot predict and possibly other side 
effects that are unknown at this time.  
 
Risk associated with timing of surgery   
The protocol is designed to result in no delay from the time when the patient is ready to schedule their 
surgical date to the day of surgery. The patient and treating physicians may elect to schedule surgery in a 
manner that would insure the full potential benefits of participation if deemed medically safe.   
 
Risks involved with loss of confidentiality: 
Any time information is collected there is a potential risk for loss of confidentiality. Every effort will be 
made to keep the patient's information confidential; however, this cannot be guaranteed.  
 
 


P a g e  | 21 
 
XI. SUBJECT SAFETY AND DATA MONITORING  
A. Adverse Events (AE): 
Adverse events are events that involve physiological, social, or psychological harm to subjects or risks of 
harm to additional subjects or others. AEs include expected and unexpected harmful effects, and 
unexpected risks of an interaction or an intervention.  AEs may be caused by:  the test article or test 
procedure, other aspects of the interaction or intervention, the subject's underlying condition, or the 
subject's concurrent standard treatment. AEs may be definitely related, probably related, possibly related, 
unlikely to be related, or definitely not related to the research.  
 
B. Method of Identifying, Recording, Monitoring and Reporting Adverse Events: 
We will report all adverse events and other reportable incidences and occurrences to the IRB per 
reporting guidelines.  Any adverse event will be documented of that event including a description, subject 
number, date, outcome, and follow-up.  
 
C. Safety Endpoints: 
The primary safety endpoints of the study are the incidence of adverse events associated with the use of 
the study medications.  These include: hypersensitivity (e.g. pruritis, rash, and urticaria), hypertension, 
hypotension, bleeding, nausea, vomiting, injection site pain, deep venous thrombosis or other thrombotic 
complications. Surveillance for these adverse events will be conducted by direct observation (during drug 
administration), daily bedside visits by the research nurse for the first 7 postoperative days, review of the 
patient’s medical record and listing any of these complication in the Society of Thoracic Surgery (STS) 
database. The definition of a stroke, myocardial infarction (MI), mesenteric artery occlusion or peripheral 
vascular event will be based on STS criteria.37 Any event resulting in death from time of initial drug 
administration to hospital discharge will be recorded.  
  
  
 
XII. PROCEDURES TO MAINTAIN CONFIDENTIALITY 
We will collect data from lab tests and EPIC, the electronic medical record.  
 
Raw data: We will remove personal identifying information of the patients from the raw data and replace 
them with coded IDs before data processing and analysis. Any materials containing personal identifying 
information will be stored in a locked cabinet in the principal investigator's office. After data entry, any 
materials containing personal identifying information will be promptly and securely returned to the 
principal investigator. Any materials with personal identifying information on them will be shredded before 
discard. 
 


P a g e  | 22 
 
Computer files:   Computer databases will contain only coded ID information. When computerized 
names and addresses are needed, they will be kept separate from other project data. All computer files 
will be password protected. We will destroy any computer disks with personal identifying information 
before discarding them. Personal identifying information will not be sent via e-mail. 
 
Release of Data sets and Analysis of results:  All data and information collected during this study will 
be considered confidential and remains the sole property of UTSW Medical Center. Data may be shared 
with AMAG Pharmaceuticals prior to any publications. All data used in the analysis and summary of this 
study will be anonymous, and without reference to specific subject names. Access to subject files will be 
limited to the Investigator, authorized clinical research staff and authorized Regulatory Authorities. 
  
The principal investigator must authorize any release of information about the analysis results of the 
project. However, the UTSW institutional review board or government agencies such as the U.S Food 
and Drug administration (FDA) may look at and/or copy the patient's medical records for research, quality 
assurance, and data analysis. 
 
XIII. POTENTIAL BENEFITS 
Study participants could potentially increase their red blood cell mass and iron stores before going into 
surgery.  Preoperative anemia is independently associated with a number of postoperative morbidities 
and mortality. Hence, the treatment has the potential to partially/completely correct preoperative anemia 
in patients undergoing cardiac surgery and lead to better postoperative outcomes. Anemia is also a major 
risk factor for allogeneic blood transfusion in the preoperative period. Transfusion has been demonstrated 
to be significantly associated with increased morbidity. These leading causes of transfusion-related 
morbidity and mortality are unrelated to viral transmission and include but not limited to changes in the 
immune system, which cause a stepwise increase in serious complications including postoperative 
infection, ventilator acquired pneumonia, central line sepsis, acute renal failure, cardiac events, and 
increased ICU and hospital length of stay. Thus, the treatment has the potential to reduce the transfusion 
requirement in these patients and improve postoperative outcome and decrease post-operative mortality. 
The study also has significant potential benefits to society. Transfusion is not only potentially hazardous 
for the individual patient, but it is also scarce and costly. Blood utilization in America is significantly higher 
than most Western countries and the gap is increasing. At this same time, the number of eligible donors 
has been declining because of a growing number of donor deferral criteria instituted to protect the blood 
supply.  This supply and demand mismatch means that blood banks now have to work harder to recruit 
donors and blood shortages will become more frequent, leading to interruptions in hospital operations and 
the cancellation of elective surgeries. The total cost of transfusing patients exceeds blood acquisition cost 
by five times or greater when labor, supplies, blood administration and transfusion-related adverse event 
costs are considered. Hence, by potentially reducing the transfusion requirement in patients undergoing 


P a g e  | 23 
 
cardiac surgery, the study has the potential to improve patient outcome, save lives, conserve a scarce 
resource, and also decrease the cost for hospitals.  
 
XIII. BIOSTATISTICS 
The analysis of this feasibility study will be mainly descriptive and will focus on confidence interval 
estimation. Results from hypothesis testing will be treated as preliminary and interpreted with caution, as 
no formal power calculations have been carried out. 
 
Analyses will be performed using parametric and nonparametric univariate and multivariate (where 
appropriate) statistical methods. Univariate distribution of all variables will initially be performed assessing 
their distribution with the use of scatter plots and histograms.  These results will be used as guidelines in 
the application of both univariate and multivariate techniques.  For descriptive purposes, continuous 
variables with normal distribution will be described using means, variance and standard deviations; 
otherwise, medians, interquartile and full ranges will be used. For variables showing distributions that are 
significantly away from normality, nonparametric statistical tests will be applied. Differences will be 
considered significant when P <.05. 
 
Dichotomous variables will be presented as percentages and analyzed using chi-square or Fisher’s exact 
tests as appropriate. Student t tests or Mann-Whitney U tests will be used to assess differences between 
independent continuous variables. The analysis of paired continuous variables (such as changes of 
hemoglobin level or reticulocyte counts from baseline to the day of surgery) will be performed with paired 
student t tests or Wilcoxon signed rank tests for normally or non-normally distributed variables, 
respectively. Multivariable regression techniques, including linear mixed models, will be used to analyze 
differences in continuous variables measured at several different points during the study between the 
groups (such as hemoglobin level, reticulocyte count, creatinine, etc.) accounting for the within-subject 
correlation of the data. All statistical analyses will be performed with SAS® software (Version # 9.3, SAS 
Institute Inc. Cary, NC).  
 
 
 
 
 
 
 
 
 
 


P a g e  | 24 
 
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Patient Questionnaire 
 
You have agreed to participate in a research study testing whether it is practical to treat 
preoperative anemia up to 30 days prior to cardiac surgery. We think that treating anemia prior to 
cardiac surgery will result in better outcomes, but before we can conduct a study big enough to 
test that idea we first need to perform a smaller study to see whether our approach is feasible. We 
are interested in obtaining feedback about how important the treatment of preoperative anemia is 
to you.  Answering the following questions will help physicians and hospitals understand your 
opinion of the approach being taken by this study.  
 
A. Strongly Agree       B. Agree       C. Neutral        D. Disagree       E. Strongly disagree 
 
1) I have concerns about receiving a blood transfusion. 
A        B        C        D         E 
 
2) I would be willing to receive subcutaneous and intravenous injections preoperatively 
(to treat my anemia) if it could save me 1-2 units of red blood cell transfusions during 
or after my surgery. 
A        B        C        D         E 
 
3) If it was considered to be medically safe by my cardiologist and surgeon, I would be 
willing to schedule my surgery up to 30 days after the decision to have surgery was 
made if this would decrease my chance of receiving a blood transfusion. 
A        B        C        D         E 
 
4) I would be willing to make 1-2 additional trips to UT Southwestern in order to 
receive treatment for my anemia. 
A        B        C        D         E 
 
5) The fact that UT Southwestern physicians are concerned about decreasing my chance 
of receiving blood transfusion(s) is important to me. 
A        B        C        D         E 
 
6) Knowing a hospital is committed to treating my anemia preoperatively to avoid blood 
transfusion(s) could influence my selection where to have my surgery performed. 
A        B        C        D         E