Active Preoperative Anemia Management in Patients Undergoing Cardiac Surgery

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.

Inclusion Criteria:

- between the age of 18 and 80 years old

- diagnosed with preoperative anemia, defined as hemoglobin <13.0 grams per deciliter
(g/dL)

- scheduled for elective cardiac surgery (CABG, valve, or CABG/valve), including both
first time and repeat procedures

- documented negative pregnancy test within 7 days prior to the procedure for females of
child-bearing potential

- a written informed consent prior to any procedure, using a form that is approved by
the UT Southwestern Institutional Review Board

- agreement to be compliant

Exclusion Criteria:

- uncontrolled hypertension (defined as systolic pressure greater than 180 millimeters
of mercury (mmHg), diastolic pressure greater than 100mmHg, not adequately controlled
by anti-hypertensive therapy at the time of procedure)

- current renal failure on dialysis or serum creatinine >3.0 milligrams per deciliter
(mg/dL)

- unstable angina (defined by chest pain and EKG changes indicating ischemia at rest)

- thromboembolism within the past year

- current active primary or metastatic malignancy or history of myeloid malignancy

- seizures within the past year

- history of stroke within the last 6 months

- patients who have platelet count lower than 50,000 per cubic millimeter (mm3) or
coagulation abnormality

- sepsis or bacteremia defined by positive blood culture

- patients who have known hypersensitivity to EPO or any of its components

- patients who have known hypersensitivity to Feraheme or any of its components

- patients who refuse blood transfusion, (i.e. Jehovah's Witnesses)

- pregnant or breast feeding

- patients who are unable to provide informed consent or who has inability to understand
or corporate with study procedure