Red Cell Storage Duration and Outcomes in Cardiac Surgery
Phase: NA
Conditions: Blood Transfusion, Cardiac Surgery
Sponsor: The Cleveland Clinic

Amendment 8 
05/17/2010 
1 
 
 
 
Red Cell Storage Duration and Outcomes in Cardiac Surgery:  
A Randomized Controlled Trial 
 
Colleen Gorman Koch, MD, MS, FACC and Colleagues 
Departments of Cardiothoracic Anesthesia and Outcomes Research 
 
NCT 00458783 
 
Cleveland Clinic  
9500 Euclid Avenue 
Cleveland, Ohio  44195 
 
Tel: 216-445-7418 
Fax: 216-445-2536 
E-mail: kochc@ccf.org 
 
 
 
 
 
Currently RBC units that have been stored up to 42 days are available for transfusion. Increasing RBC 
storage duration has been shown to alter red cells by reducing oxygen availability, creating proinflammatory and 
immunomodulatory effects, as well as reducing red cell deformability, and aggregability. Prior observational 
investigations report variable results in terms of morbid outcomes related to increasing length of RBC storage.  
We propose a randomized blinded clinical trial with a maximum enrollment of 2840 adult cardiac surgical 
patients. Consecutive consenting patients who meet the inclusion criteria will be randomized to ‘age of blood’ less 
than two weeks or greater than 20 days shelf life for all of the units allocated to the patient. The trial uses a group 
sequential design with three internal interim analyses that examine group sequential boundaries of both efficacy 
and futility. The overall type I error rate is 0.05 and power is 85%. The study we propose will provide an 
appropriate level of evidence for determining whether increased storage duration is associated with increased 
morbidity. We estimate that it will take approximately 2-3 years to complete the enrollment and randomization.  

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Personnel 
 
Name 
Organization 
Role on Project 
Colleen Gorman Koch, MD, MS 
CCLMC-CWRU* 
Principal Investigator 
Daniel I. Sessler, MD 
CCLMC-CWRU 
Co-investigator,  
Eugene H. Blackstone, MD 
CCLMC-CWRU 
Co-investigator,  
Liang Li, PhD 
CCLMC-CWRU 
Principal statistician 
Norman Starr, MD 
CCLMC-CWRU 
Co-investigator,  
Cardiothoracic anesthesiologist 
Andra I. Duncan, MD 
CCLMC-CWRU 
Co-investigator,  
Cardiothoracic anesthesiologist 
Bruce Lytle, MD 
CCLMC-CWRU 
Co-investigator, cardiothoracic surgeon 
Joseph Sabik, MD 
CCLMC-CWRU 
Co-investigator, cardiothoracic surgeon 
Lars Svensson, MD 
CCLMC-CWRU 
Co-investigator, cardiothoracic surgeon 
Tomislav Mihaljevic, MD 
CCLMC-CWRU 
Co-investigator, cardiothoracic surgeon 
Gerry Hoeltge, MD 
CCLMC-CWRU 
Co-investigator, Laboratory medicine/ Clinical 
pathology 
Pricilla Figueroa, MD 
CCLMC-CWRU 
Co-investigator, Laboratory medicine/ Clinical 
pathology 
*Cleveland Clinic Lerner College of Medicine, Case Western Reserve University 
 
Executive Committee  
 
Name 
Role  
Colleen Koch, MD, MS 
Chair 
Andrea Kurz, MD 
Member  
Daniel I. Sessler, MD 
Member 
Liang Li, PhD 
Statistician, non-voting 
  

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A. Specific Aims 
 
 
During preservation, RBC undergo functional and structural changes. What is termed ‘storage lesion’ is 
an amalgamation of reversible and irreversible rheological changes that may begin in the second week of storage, 
progress with storage duration 1 and lead to reduced red cell function and viability following transfusion. 2  
Increasing length of storage of RBC units has been shown to reduce oxygen availability and create 
immunomodulatory and proinflammatory effects. 3 Depletion in 2,3-diphosphoglycerate with increased length of 
storage may adversely impact oxygen delivery to tissues via shifts the oxyhemoglobin dissociation curve.4  In 
addition, reductions in RBC deformability and aggregability have also been noted with increasing storage time. 3  
A number of observational investigations 5-10 have reported on the impact of length of storage of RBC and 
outcomes after transfusion of RBC. The clinical impact of storage-related changes associated with age of RBC 
has been inconsistent 5, 7, 9-14.  Prior investigations have been limited by small sample size 10, 15, heterogeneous 
patients 15 and an inability to adequately control for confounding factors related to outcomes 10. Additionally, 
many of their end-points lack sensitivity to detect differences in organ function in so much as they examine broad 
outcomes such as survival or length of stay. 16 Although there are well-documented changes in rheologic 
properties with increasing length of RBC storage 1, 2, 17, 18, it is unknown whether these changes contribute to 
adverse patient outcome following transfusion. Our objective was to determine whether length of RBC storage 
duration is associated with adverse morbid outcomes in a large cohort of patients undergoing cardiac surgery.  
Among patients who are transfused RBC units, we will randomize units to less than two weeks and greater than 
20 days storage.  
 
 
Our primary aim is to determine whether length of storage of RBC is related to postoperative morbid 
outcomes.  
 
 
The purpose of a RBC transfusion is to increase tissue oxygenation, thereby reducing tissue oxygen debt. 
During storage progressive morphological and biochemical changes occur to the RBC product which may 
contribute to a reduction in microvascular tissue flow and contribute to tissue hypoxia.19-23 The observed increase 
in complications in transfused patients could be related, in part, to older RBC units contributing to reductions in 
local tissue oxygenation. After RBC transfusion, an increase of hemoglobin levels is readily observed, but the 
effect of RBC transfusion on tissue oxygenation is rarely measured. Therefore, a quantitative evaluation of the 
effectiveness of stored RBC in increasing tissue oxygenation is required to assess the risk of complications related 
to tissue oxygenation and storage duration of the RBC units transfused. 
 
 

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B. Background and Significance: 
 
Effect of RBC Storage Time 
 
 
Considerable evidence suggests that transfusions increase the risk of serious complications and mortality 
in both cardiac surgical patients 24-31 and in critically ill patients.32-34 But evidence also suggests that, within the 
transfused population, risk of complications increases when administered blood has been stored for long periods 
of time.5, 6, 9, 15, 35 Blood banks, including ours, generally provide clinicians with the oldest matched units to 
minimize the number that expire. Under American Red Cross guidelines, packed red cells can be stored up to 42 
days. It is well established that storage provokes a progressive degradation in erythrocyte shape and 
deformability, beginning after about two weeks.1, 2, 17, 18 However, the clinical importance of transfusing older 
versus younger red cells remains unclear with some studies identifying adverse consequences 5, 6, 9, 15, 35  and others 
not.12, 16, 36, 37 Raat and colleagues19 reported that among 74,084 units of RBC transfused, more than one-third were 
units transfused with storage durations greater than 3 weeks. Among patients with type AB negative, up to 68.4% 
of units transfused were greater than 3 weeks storage duration.19  
 
During preservation, RBC undergo a series of reversible and irreversible functional and structural 
changes. A number of investigators have demonstrated storage-induced decreases in RBC deformability that may 
contribute to decreased microvascular flow, local hypoxia and posttransfusion complications. 17 1 Changes in 
erythrocytes with storage time include depletion of 2,3-diphosphoglycerate 4 which may result in a leftward shift 
of the oxyhemoglobin dissociation curve and adversely impact oxygen delivery to the tissues. Reductions in red 
cell deformability, adhesiveness and aggregability have also been noted with increasing storage time. 3 22 
Hemorrheological changes in stored blood may begin in the second week of storage and progress during the rest 
of the storage period. 1 23 Furthermore, storage time progressively reduces levels of nitric oxide 38 and reductions 
in adenosine triphosphate  (likely correlating with reduced post-transfusion survival). Recent work by Stamler and 
colleagues 21demonstrated impaired vasodilatory response to hypoxia secondary to reductions in nitric oxide 
bioactivity with storage duration.21  In an animal model, Rigamonti and colleagues 20 recently demonstrated 
differences in cerebral tissue oxygen delivery with fresh vs. older blood. Fresh blood demonstrated improved 
cerebral oxygen delivery as compared to stored blood.20   Others 14 1 2 17 have described progressive time-related 
alterations in erythrocyte shape and deformability beginning as early as 2 weeks duration and progressing 
throughout storage. Recent work by Anniss and colleagues 39 demonstrated that increased RBC storage duration 
was associated with an increase in the number and strength of adhesion of RBC to the vascular endothelium. Of 
note, the authors comment that these findings are of importance as increased adhesion of RBC to the vascular 
endothelium can reduce tissue oxygen delivery due to a reduction in local tissue blood flow.39, 40 
 
 
Mynster and colleagues 6 reported transfusion of blood stored > 21 days was associated with an increased 
risk for postoperative infectious complications in patients undergoing surgery for rectal cancer.  Leal-Noval et al 
9examined the influence of RBC storage time on postsurgical morbidity in cardiac surgery patients. Outcomes 
were prolonged ICU stay, or mechanical ventilation time or perioperative MI, and sepsis. Prolonged storage was 
not related to an increase in morbidity but storage beyond 28 days was related to an increase in nosocomial 
pneumonia. 9 Purdy et al 35 reported an increased mortality associated with age of blood transfused in septic ICU 
patients. Positive correlation between mortality in severe sepsis and age of non-leukoreduced RBC units 
transfused. The median age of RBC transfused to survivors was 17 days compared with 25 days for non survivors.  
Others 14 1 2 17   have described progressive time-related alterations in erythrocyte shape and deformability 
beginning as early as 2 weeks duration and progressing throughout storage.  Kirkpatrick 18 and colleagues 
similarly reported markedly abnormal flow and biochemical properties of blood cells in stored bank blood and 
salvaged blood. While some of the storage related changes in RBC are reversible such as restoration of 2,3 DPG, 
it has been reported that that recovery of 2,3 DPG may be at 50-70% of normal at 24 hours post RBC 
transfusion.41, 42  
 
Marik and colleagues,13 were unable to demonstrate improved systemic oxygen uptake as measured by 
indirect calorimetry for up to 6 hours following RBC transfusion. In addition, they found an inverse association 
between the changes in gastric intramucosal pH and the age of the transfused blood for patients who received 
RBC stored >15 days. Furthermore, patients receiving old RBC developed evidence of splanchnic ischemia.  The 
authors postulated that the poorly deformable transfused RBC caused microcirculatory occlusion in some organs, 
potentially contributing to tissue ischemia. While RBC physiology is restored with time following transfusion, the 

Amendment 8 
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authors could not demonstrate time-dependent changes in systemic oxygen uptake for up to 6 hours post 
transfusion. 13  
 
Zallen and colleagues reported that the age of red blood cells was an independent predictor of multiple 
organ failure. 5   Similarly, in a small investigation of 61 trauma patients, Offner and colleagues, 15 reported that 
transfusion of older blood was associated with increased infection following major traumatic injury. The authors 
15 commented on the laboratory work of Silliman and colleagues 43, 44 describing the significant priming of the 
nicotinamide adenine dinucleotide phosphate oxidase system after 2 weeks storage, reaching a peak at the shelf 
life of the RBC units and thought to be primarily due to accumulation of proinflammatory lipids. 45 
 
 
 
 
There are however, investigations that do not report adverse effects of RBC storage time as reflected by 
similar measurements of tissue oxygenation 7, 8. Vamvakas and colleagues 12 reported no increase in postoperative 
morbidity (as defined by length of intensive care unit stay, length of hospital stay and length of postoperative 
ventilation) with length of storage in 268 patients undergoing cardiac surgery.  Walsh and colleagues 7 examined 
the effect of RBC storage time on regional and global indexes of tissue oxygenation in anemic critically ill 
patients in a randomized double-blind study in 22 patients. They reported that transfusion of RBC to euvolemic, 
anemic critically ill patients had no clinically significant adverse effects on gastric tonometry or global indexes of 
tissue oxygenation. 7  Interestingly, there were also unable to demonstrate a beneficial effect of RBC transfusion 
on indexes of tissue hypoxia when hemoglobin concentration was increased from 8-9 to 9-11, even when fresh 
RBC were transfused.7  van de Watering and colleagues 16 did not report an impact with increasing storage time of 
RBC units on 30-day survival, and ICU and hospital length of stay end-points. In a small investigation, Weiskopf 
and colleagues 37 reported that both fresh and stored blood were similarly efficacious in reversing anemia-induced 
brain oxygen deficits.37 A recent investigation by Yap and colleagues36 reported similar clinical outcomes for 
RBC units of varying storage duration in 670 cardiac surgical patients. The investigation was limited due to an 
inability to separately analyze patients receiving exclusively fresh vs. older RBC units; the impact of patients 
receiving an admixture of RBC units with varying storage duration is unknown. In addition, the sample size and 
number of outcome events was limited.36  
 
Ho et al 3 recently highlighted RBC storage duration and the relationship to the efficacy of transfusion. 
Their review examined the clinical evidence for benefit/harm of RBC transfusions and possible adverse effects 
associated with changes in RBC storage.3 The authors concluded that clinical effects beyond post-transfusion 
viability are uncertain, but a growing body of evidence suggests that the storage lesions may reduce tissue oxygen 
availability, have proinflammatory and immunomodulatory effects and influence morbidity.  
 
From preliminary data on approximately 6000 cardiac surgical patients in our institution, we report that 
increasing RBC storage duration is associated with increased risk for morbid outcomes following cardiac surgery. 
Hospital death, intubation morbidity, renal failure, sepsis, multisystem organ failure and composite outcome were 
higher in the group with increasing RBC storage duration. We are also aware of the strong and incrementally 
increased risk for morbid outcomes associated with each unit of RBC transfused 24-26. 
 
 
 
 
 
C. Preliminary Studies 
 
 
Recent work46  from our institution demonstrated a significant risk-adjusted impact of RBC transfusion on 
in-hospital mortality, pulmonary, cardiac, renal, infectious and neurological morbidity in over 11,963 isolated 
CABG patients. Transfusion was the single factor most reliably associated with increased risk for these morbid 
events. Figure 1 displays the unadjusted relationship between units of RBC transfused, platelet transfusion and 
morbidity and mortality outcomes. As the number of units of RBC transfused is increased, so is the risk for every 
postoperative adverse outcome. Figure 2 displays a Forrest plot of unadjusted and adjusted odds ratios and their 
confidence limits for the seven postoperative morbid outcomes.  
 

Amendment 8 
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6 
 
 
Figure 1.  
 
Unadjusted morbid outcomes and 
RBC, and platelet transfusion. 
(Solid lines depict patients who 
received platelet transfusions per 
unit of RBC transfused; Dashed 
lines represent those patients who 
only received RBC units).  
 
 
 
 
 
 
Figure 2.  
 
Forrest plot displays adjusted and 
unadjusted odds ratios and their 
confidence limits for 7 
postoperative morbid outcomes.  
 
 
 
 
 
 
In a separate investigation 25 , we demonstrated the association between RBC transfusion and an increased 
early (within 6 months after surgery) and late hazard (out to 10 years) for death. We examined the incremental 
influence of perioperative RBC transfusion and component therapy on long-term survival after isolated coronary 
artery bypass grafting after controlling for the effects of demographics, comorbidity, operative factors and the 
early hazard for death. Approximately half of the 10,289 patients received at least 1 unit of RBC in the 
perioperative period. Survival among transfused patients was significantly reduced compared to those who did not 
receive a RBC transfusion. Figure 3. The hazard for death displayed a more influential early impact of RBC 
transfusion out to 6 months postoperatively. While the late hazard for death was less, the association was 
remained statistically significantly different from those who did not receive RBC transfusion throughout the 
follow-up period. Risk-adjusted reduction in survival for both early and late phases were (0.34 +/- 0.02, P <.0001) 
and late phases (0.074 +/- 0.016, P <0.0001). 
 

Amendment 8 
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Figure 3.   
 
(A). Hazard function by transfusion status. The 
curves display the non-proportionality with an 
increased early risk for red blood cell (RBC) 
transfusion, and a reduced late risk after 6 
months throughout the entire follow-up period. 
Note increasing units of RBC is associated with 
an increased hazard for death.  
 
(B). Survival by transfusion for the entire 
follow-up period by transfusion status. 
Increasing units of RBC are associated with 
incremental decrement in survival (black, no 
blood transfusion; green, 1 unit RBC; yellow, 2 
units RBC; blue, 3-5 units RBC and red >/= 6 
units of RBC) 
 
 
 
 
Patient centered outcomes are important measures of assessing the success of an operative procedure. We 
examined 47 the impact of perioperative RBC transfusion in 7,321 cardiac surgical patients with the use of the 
Duke Activity Status Index (DASI). Functional recovery after cardiac surgery was significantly reduced in 
patients who received RBC transfusions perioperatively, even after adjustments for baseline DASI, preoperative 
clinical status, comorbidities, hematopoietic system measurements, laboratory values, operative factors, surgical 
procedure and postoperative morbid events. Figure 4 displays the follow-up DASI scores for those who received 
and did not receive perioperative RBC transfusions. Figure 5 displays the empirical probabilities of five grouped 
follow-up DASI groups at each RBC by platelets (yes/no) usage. As the number of RBC units increases, more 
patients were in the lowest DASI score group (0-34.7) and fewer achieved the highest DASI score group (58.2). 
The predicted probability of achieving the highest follow-up DASI by increasing age and transfusion status is 
shown in figure 6. The predicted probability of achieving the highest follow-up DASI category decreases with 
increasing age and is further decreased with the addition of a blood transfusion.  
 
 
Figure 4.  
 
Mirrored histogram displays nominally 6-
month follow-up Duke Activity Status Index 
score according to whether red blood cells had 
been transfused. (Blue bars=no blood 
transfusion; red bars=red blood cell 
transfusion).  
 

Amendment 8 
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8 
 
Figure 5.  
 
Empirical probabilities of five grouped follow-
up DASI groups at each PRBC by platelets 
(yes/no) usage. The solid lines denote with 
platelet usage; the dashed lines represent no 
platelet usage. Patient representation in lowest 
functional category (black) increases with 
increasing RBC units administered.  
 
 
Figure 6.   
Relationship between increasing age, recipient 
of RBC units (solid black line) or not (gray 
line) and the probability of being in the highest 
follow-up DASI functional category (58.2) 
based on a low risk patient and the equation 
represented in table 1 below. The dotted lines 
represent the 95% confidence limits.  
 
 
 
 
We recently tested the hypothesis that RBC transfusion increases the risk of postoperative atrial 
fibrillation in cardiac surgical patients via modulating inflammation. In 5841 patients we were able to demonstrate 
that transfusion of RBC in the ICU was associated with a statistically significant increased risk for the 
development of new onset postoperative atrial fibrillation, odds ratio per unit transfused 1.18, confidence limits 
1.14, 1.23, P<0.0001.26  
 
 

Amendment 8 
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Figure 7.  
  
Predicted probability for 
developing new onset 
postoperative atrial fibrillation 
by red blood cell units 
transfused and preoperative 
statin therapy for a low risk 
patient undergoing valve 
surgery. As the number of red 
cell units transfused increases, 
the probability of developing 
atrial fibrillation also 
increases. Preoperative statin 
therapy ameliorates the impact 
of red cell transfusion on new 
onset postoperative atrial 
fibrillation.  
 
 
 
 
 
In addition, we have recently examined length of RBC storage duration on morbid outcomes from 
approximately 6000 transfused cardiac surgery patients from the Cleveland Clinic Heart Center. There were 2872 
patients who received exclusively RBC units <14 days and 3130 patients received units that were exclusively >14 
days storage duration. Morbid outcomes were prospectively collected on every patient. The blood bank was 
blinded to patient clinical status and specific operative procedure when assigning RBC units of particular storage 
duration. The allocation could be considered ‘random’ as is reflected by an even distribution for a majority 
demographics, comorbidity, and operative factors among the 2 groups.  Patients whose RBC unit storage duration 
was >14 days verus <14 days had a higher incidence of in-hospital mortality: 1.7% versus 2.8%, P=0.004; 
intubation morbidity: 9.7% vs 5.6%, P<0.001; renal failure: 2.7% vs 1.6%, P=0.003; septicemia / sepsis: 4.0% vs 
2.8%, P=0.010; multisystem organ failure: 0.73% vs 0.24%, P=0.007; and adverse composite outcome: 26% vs 
22%, P=0.001, respectively. From a multivariable logistic regression model on composite adverse outcome the 
maximum age of RBC units was significantly related to the composite outcome as was increasing number RBC 
units transfused and other important demographic variables and comorbidity. Figure 8.  

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10 
 
 
 
 
 
 
Figure 8. 
Predicted 
survival 
of 
an 
intermediate-risk 
patient 
with 
different maximum age of blood (1 
day, 15 days, 30 days, and 42 days). 
This nomogram displays the “dose-
response” 
relationship 
between 
maximum age of blood and survival, 
adjusting 
for 
other 
relevant 
confounding factors. Maximum age 
of blood groups: 1 day = orange; 15 
days = red; 30 days = blue and 42 
days= black.  
 

Amendment 8 
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11 
 
D. Research Design and Methods: 
 
 
We propose to provide an appropriate level of evidence for determining whether increasing length of 
storage of RBC impacts morbid outcomes following cardiac surgery.  We plan to study a large and diverse 
population so our results will be generalizable to most adults undergoing cardiac surgery. 
 
 
Our aim is to determine whether length of red cell storage is related to adverse perioperative outcomes. 
 
Setting and Population 
 
 
Cleveland Clinic Heart Center is a large tertiary care center and is among the busiest cardiac surgical 
centers in the US. Our annual volume over the last 5 years for coronary artery bypass grafting, and valve 
procedures has been between 3500-3790 surgeries. Transfusion of RBC currently occurs in approximately 40-
50% of these patients. 
 
Inclusion Criteria 
 
 
All primary and reoperative adult cardiac surgical patients undergoing cardiopulmonary bypass for 
coronary artery bypass grafting, coronary artery bypass grafting with a valve procedure, isolated valve procedures 
and ascending aortic aneurysm or dissection repair alone or combined with CABG and valve procedures.  
 
 
Exclusion criteria:  
 
 
Age less than 18 years, descending thoracic aortic aneurysm repairs, left or right ventricular assist 
devices, and those unwilling to receive blood for religious reasons (Jehovah Witness).  
 
Protocol 
 
 
Our primary aim is to determine whether increased length of storage of RBC is related to adverse 
perioperative outcomes.  
 
Study Intervention 
 
 
Consecutive consenting patients who meet the inclusion criteria will be randomized to ‘age of blood’ less 
than two weeks or greater than 20 days shelf life for all of the units allocated to the patient.  Red blood cell and 
component transfusion will follow management decisions of the care team. Adherence to the treatment protocol 
will be required for the patients in the operating room, intensive care unit and postoperatively until discharge from 
the hospital.  Good clinical judgment supersedes the protocol.    
 
Measurements 
 
Baseline Information: 
 
 
Baseline demographics, laboratory values, comorbidity, surgical procedure, operative variables, and 
postoperative morbid events are contained in Appendix 1. (CRF).These variables are routinely prospectively 
collected by the Departments of Cardiothoracic Anesthesia and Thoracic and Cardiovascular Surgery 
Cardiovascular Information Registries. These research registries have been approved by the institutional Internal 
Review Board for research purposes.  Individual patient consent has been waived. Anesthesia automated record 
keeping system (ARKS) currently stores all hemodynamic information, intraoperative medication usage, arterial 
blood gas analyses, amount of crystalloid administered, time, number and identification number for RBC units 
transfused. Component blood product use and urine output are also automatically recorded and stored within the 
automated system.  

Amendment 8 
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12 
 
 
Primary Outcome  
 
 
Major and minor composite outcomes are defined by the Society of Thoracic Surgeons (STS) definitions 
for postoperative events www.sts.org.  Major serious composite outcomes include in-hospital death, myocardial 
infarction, asystole, ventricular tachycardia or fibrillation, tamponade, femoral or aortic dissection, renal failure, 
sepsis, respiratory insufficiency, pulmonary embolism, pneumonia, cerebral vascular accident, coma, 
gastrointestinal morbidity, deep sternal wound infection, multisystem organ failure, acute limb ischemia, return to 
the operating room for any one of the following: graft occlusion, valve dysfunction, or bleeding. Two additional 
major outcome variables prolonged postoperative ventilation and occurrence of atrial fibrillation occur with 
greater frequency and will be considered separately from the other major composite outcomes.  Minor composite 
postoperative morbid outcomes include urinary tract infection, superficial wound and leg harvest infection, 
complete heart block and transient stroke. These outcome measures are routinely collected as part of a data 
harvest for the STS database.  Length of intensive care unit and hospital stay will also be examined. Appendix 1 
(CRF). While considered as an expected outcome for the investigation, death and prolonged hospital length of 
stay will be collected as serious adverse events and reported as outlined by IRB guidelines. Other expected 
outcome events are not considered as SAE however will be reported at the annual renewal date.  
 
Statistical Analysis Plan 
 
 
This trial is a single center, two-arm parallel design with two interventions: newer blood versus older 
blood. Patients randomized to the newer blood group will receive blood units that have been stored less than or 
equal to 14 days; patients randomized to the older blood group will receive blood units that have been stored more 
than or equal to 20 days. The primary outcome is a binary composite outcome composed of major and minor 
postoperative morbid events defined by STS definitions. The secondary outcomes include prolonged 
postoperative ventilation and occurrence of atrial fibrillation, length of intensive care unit and length of hospital 
stay. These outcomes will be assessed by research assistants blinded to the treatment assignment. All the 
outcomes are short-term endpoints that can be ascertained within a few weeks after the operation, which makes it 
possible to do sequential monitoring. The randomized groups will be descriptively compared on all baseline 
variables using summary statistics such as mean and standard deviation, median and quartiles or frequency and 
percent, as appropriate. No two-sample tests on baseline variables are necessary, but those that are believed to be 
strongly correlated with the outcomes will be included in the covariate adjustment in the primary and secondary 
analyses. The level of statistical significance used in the primary analysis will be 0.05, and all tests in the primary 
and secondary analyses are two-tailed. The statistical analysis will be performed using SAS 9.1 (SAS Institute, 
Cary, NC).  
 
 
If a patient meets the inclusion criteria and gives consent, he/she could potentially be randomized in the 
trial. Before the start of surgery, the research coordinator responsible for randomization will check the 
randomization list and determine that person’s randomization allocation. The coordinator will then contact the 
blood bank and check whether there are adequate type-matched newer or older blood units available for that 
patient. Occasionally, there is short of supply of newer or older blood for a certain blood type. If the Blood Bank 
can not ensure that the patient receive only the kind of blood he/she is randomized to receive, that patient will be 
taken out of the trial and not randomized. We expect that this failure of randomization occurs infrequently, and it 
more likely occurs to patients with rare blood types. Since there is no evidence for an interaction between rare 
blood types and age of blood, this practice is not expected to introduce bias to the study. Another situation that 
may cause failure of randomization is that the patient may not need any transfusion for the entire hospital stay as 
determined by the surgeon. In that case the patient will also be taken out of the trial at hospital discharge. We 
expect that about 40-50% patients will not need any transfusion. This is a special kind of drop-out after 
randomization. However, since the dropping out is not related to the treatment assignment, we do not believe it 
will introduce bias to the study, and the two treatment arms will still be balanced.  
 
 
The primary analysis is a two-sided chi-square test comparing the two treatment groups on the rate of 
composite outcome, based on the intent-to-treat (ITT) principal. The 95% confidence interval of the rate of 

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composite outcome will be calculated for the two treatment groups, and for the treatment effect which is 
quantified by the odds ratio.  
 
 
We will test the interaction between the treatment groups and the recipients’ blood type, and donors’ 
blood type. In this way, we may identify subgroups more sensitive to the treatment. Although pre-specified, we 
will interpret the estimated interactions and their statistical significance with much caution due to multiplicity and 
they are not the primary analysis or focus. Our assessment of interactions will be viewed as exploratory and 
hypothesis generating.  
 
 
 
Sample Size Calculation and Sequential Monitoring 
 
 
The sample size calculation is based on the primary analysis, which is a Chi-squared test comparing the 
proportion of composite outcome between the two randomized groups. We estimate that the unadjusted odds ratio 
of the composite outcome between older and newer blood groups is 1.21 (25.9% vs. 22.4%). The adjusted odds 
ratio is 1.16 (95% confidence interval 1.01-1.33). That result was from a comparison between age of blood less 
than 14 days versus more than 14 days. For this trial we expect a bigger effect because we define the older group 
as age of blood being longer than 20 days instead of 14 days. Therefore, for this sample size calculation we 
assume the odds ratio is 1.3. The overall proportion of composite outcome is estimated to be roughly around 30% 
in an observational data set from CVIR. These two assumptions lead to the estimated composite event rate of the 
newer blood group being 27.3% and that of the older blood group being 32.7%. If we set the type I error to be 
0.05 and power to be 0.85, the study would need to enroll 1328 transfused patients per treatment arm, for a total 
of 2656 patients with equal assignment. The total sample size could increase to 4810 transfused patients if the 
odds ratio is 1.2 (32% vs. 28%), and it becomes 1600 if the odds ratio is 1.4 (33.5% vs. 26.5%).  
 
 
We plan on three interim analyses at 25%, 50%, 75% of the accrual, plus the final analysis. Our 
calculations of group sequential boundaries assume non-binding stopping rules and account for monitoring both 
the null (efficacy) and alternative hypothesis (futility). We use the gamma family spending function with gamma 
= -4 for efficacy and gamma = -2 for futility, which is between Pocock and O’Brien-Fleming approaches Figure 
9. We are thus spending beta somewhat faster than the alpha during the trial, allowing for early termination if 
there is little treatment group difference. The stopping boundaries are shown in Figure 10 (on the scale of Z-
statistic of two-sample proportions test) and Table 1 (on the P value scale). The total sample size has to be 
modified up a bit (n=2838) in order to properly account for the interim looks. Note that this is the maximum 
sample size for this study. Because the group sequential design makes it possible to terminate the study early for 
either efficacy or futility, the expected sample size is 2004 if the null hypothesis of no difference is true and it is 
2063 if the alternative hypothesis (27.3% vs. 32.7%) is true.   
 
 
Table 1. Stopping boundaries on the P value scale and probabilities of crossing the boundaries (H0: there is 
no difference in the proportions of composite outcome between the treatment groups; H1: there is a 
difference) 
P value threshold 
Interim 1 
(n=708) 
Interim 2 
(n=1418) 
Interim 3 
(n=2128) 
Final 
(n=2838) 
To reject H0, p must be less than or equal to 
0.0016 
0.0048 
0.0147 
0.044 
To reject H1, p must be larger than or equal 
to 
0.9478 
0.7128 
0.2424 
Boundary crossing probability under H0 
0.054 
0.271 
0.472 
0.203* 
Boundary crossing probability under H1 
0.071 
0.251 
0.376 
0.302* 
* Probability of reaching the final analysis without early boundary crossing 
 
 
We assume stable enrollment (uniform accrual) during the trial. Based on the number of cardiac surgeries 
conducted at the Cleveland Clinic each year, we estimate that it may take 2-3 years to complete the enrollment. 
The clinical endpoint can usually be determined within 30 days after the operation. Therefore, the interim/final 

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14 
analyses will be performed at six months, one year, one and half year, and two year. The probabilities of crossing 
(at least one) boundary at each interim looks are calculated in Table 1. The stopping rules presented here will be 
used for reference by the Data Safety Monitoring Board to make decisions.  
 
 
In summary, we recommend that the study enroll a maximum of 2840 patients, with 1420 patients in each 
treatment arm in order to achieve 0.05 type I error and 0.85 power. The enrollment could take 2-3 years. The 
sample size and grouping sequential boundary calculations were performed using NCSS-PASS 
(www.NCSS.com) and East 5.0 (Cytel Inc.).  
 
 
 
 
 
 
 
Figure 9. Alpha (blue) and 
beta (red) spending 
functions used in the 
calculation of group 
sequential boundaries. The 
beta (futility) is spent 
faster than alpha 
(efficacy), allowing for 
early termination is there is 
little difference between 
the treatment groups. 
 
 

Amendment 8 
05/17/2010 
15 
Figure 10. Grouping 
sequential boundaries 
for efficacy (extremes) 
and futility (middle). If 
the test statistic 
(normalized difference 
of two proportions) 
crosses the boundaries 
and enters into the 
purple or pink areas, 
we may terminate the 
trial with claim of 
either efficacy or 
futility.  
 
 
Strengths, Limitations and Significance 
 
Strengths 
 
 
Cleveland Clinic Heart Center is among one of the largest cardiac surgical programs in the United States. 
Our procedural volume coupled with the research infrastructure at the Cleveland Clinic will allow for us to 
perform this study with sufficient power within a time frame of approximately 2-3 years. Our protocol will 
provide evidence-based medical guidelines for red cell storage duration.  
 
 
Significance 
 
 
Blood is a limited resource and should our findings indicate that older blood is detrimental, current blood 
inventory management strategies may need to be reconsidered. For example, ‘first in, first out’ (FIFO) is presently 
considered the responsible approach to managing a limited blood supply. The FIFO approach releases older red 
cell units first to prevent outdating of inventory and minimize the patient-care and financial impact of lost 
inventory.  It may be that a ‘last in, first out’ (LIFO), which releases the newest red cell units first, is more 
feasible in terms of inventory management and patient outcome. However, to maximize use of "young" blood, 
mathematical modeling of blood supply, inventory, and utilization,48 and application of modern methods of 
dynamic optimization of resources, so successful in the business world, may be required. 49   
 
Data Management and Quality Assurance 
 
 
This investigation will be registered with Clinical Trials.Gov before the first patients are enrolled. An 
Executive Committee will be comprised of the experienced clinical trialists. The executive committee will 
evaluate overall results and adverse events from the proposal trial at six-month intervals, but more often if the 
Committee deems it necessary. It will be the responsibility of this committee to alert the IRB via letter to any 

Amendment 8 
05/17/2010 
16 
untoward toxicity in one of the study groups. This committee along with the IRB, will have authority to stop the 
study either because the hypotheses have been confirmed or denied, or because of adverse events are detected.   
 
 All interviewers will undergo training by our social worker, and must demonstrate a high level of 
proficiency before being certified to interview subjects. Procedures used to assure the integrity of data include: 
1) quarterly external audits by Outcomes Research staff; 2) data entry procedures following standard operating 
procedures (SOPs); and, 3) data queries and resolution processes following SOPs. Frequent interaction among 
members of the study Executive Committee (PI, co-investigators, consultants), RAs and others as necessary, will 
maintain overall quality assurance. They will meet or have conference calls at least quarterly throughout the data 
collection period, and as necessary thereafter.  
 
Hard-copy forms will be stored in locked cabinets within a secured area. To protect electronic records and 
files against loss, duplicate files will be maintained and on Division of Anesthesiology servers at the Cleveland 
Clinic. These servers are highly secured because they already contain much patient-related information and are 
backed up daily to tape which is maintained in a remote location. The system meets all applicable HIPAA Privacy 
and Security rules. Access to the database and backups are strictly monitored according to need.  
 
An initial training meeting before study enrollment and frequent meetings thereafter will ensure reliability 
and consistency in the use of diagnostic criteria and written standard operating procedures (SOPs). All data will 
be independently audited to confirm consistency among patient records, study data sheets and the main database. 
Data will be maintained on a custom-designed Filemaker or SQL relational database.  (CVIR, CTA Registry).  
 
Upon completion of the trial and publication of the main results which will be provided to PubMed 
Central, the master data set will be de-identified to meet HIPAA requirements. The resulting limited data set will 
be published on the Outcomes Research web site (www.or.org).  

 
 
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21 
Appendix 1. Case Report Form 
 
 
Table 1. Baseline Continuous Variables  
 
Demographics 
  Age at surgery (years) 
  Height (cm) 
  Weight (kg) 
  Body mass index (kg/m2) 
  Body surface area (m2) 
Preoperative Laboratory 
Values 
  Hematocrit (%) 
  Bilirubin (mg/dl) 
  Albumin (g/dl) 
  Blood urea nitrogen 
(mg/dl) 
  Serum creatinine (mg/dl) 
  Triglycerides (mg/dl) 
  High density lipoprotein 
cholesterol (mg/dl) 
  Low density lipoprotein 
cholesterol (mg/dl) 
  Red cell mass estimate (L) 
 

 
22 
 
 
Table 2. 
Baseline Categorical Variables  
 
Preoperative Cardiac Variables 
Myocardial infarction 
Cardiogenic shock 
Intra-Aortic balloon pump 
Emergency surgery 
Unstable angina 
Atrial fibrillation 
Left ventricular ejection fraction (EF) 
EF>60% 
EF=50-59% 
EF=46-49% 
EF=41-45% 
EF=35-40% 
EF<35% 
New York Heart Association functional class  
1 
2 
3 
4 
Reoperation number 0-3 
0 
1 
2 
3 
Coronary artery disease (>70%)  
Left circumflex disease 
Left main disease 
Left anterior descending disease 
Right coronary artery disease 
Preoperative Valve Pathology 
   Aortic valve regurgitation 
   Aortic valve stenosis 
   Mitral valve regurgitation 
Comorbidities 
Chronic obstructive pulmonary disease 
Smoking 
Hypertension 

 
23 
Diabetes: insulin dependent 
Diabetes: non-insulin dependent 
Stroke 
Peripheral vascular disease 
Renal disease 
Alcohol use 
Operative Factors 
Aortic Cross clamp time (minutes) 
 
Cardiopulmonary bypass time (minutes) 
Internal thoracic artery grafting use  
Procedure performed 
 
 
 
 
 
 
 
 
 
 
 
 

 
24 
Table 3. Outcome Variables as defined by Cleveland Clinic CTA and CVIR 
Postoperative 
Complications 
Hospital death 
Neurological Morbidity 
   Encephalopathy 
   Focal deficit 
   Global deficit 
Pulmonary Morbidity 
   ARDS 
   Aspiration pneumonia 
   Pneumonia 
   Pulmonary edema 
   Tracheostomy 
   Pulmonary embolus 
   Plural effusion 
   Hours on ventilator in 
intensive     care unit 
Renal Morbidity 
   Renal failure 
   Anuria 
   Renal protective 
dopamine  
Infectious Morbidity 
   Sternal wound infection 
   Mediastinitis 
   Septicemia/ sepsis 
   Endocarditis 
Cardiac Morbidity 
   Low cardiac output 
   Cardiac arrest 
   Atrial fibrillation 
   Myocardial infarction 
   Intra/Postop IABP 
   Anti-arrhythmics 
   Inotropic agents 
   Vasopressors 
 Multisystem organ 
failure 
Reoperation for bleeding 
/ tamponade 
 

 
25 
Table 4.  Outcome Variables as defined by STS data collection 
 
Mortality 
 
   Hospital death 
 
Neurologic Morbidity 
 
  Transient stroke 
 
   Coma 
 
   Cerebral vascular  accident 
 
Pulmonary Morbidity 
 
   Pneumonia 
 
   Pulmonary embolus 
 
   Respiratory insufficiency 
 
   Prolonged ventilation 
 
Renal Morbidity 
 
   Renal failure 
 
Infectious Morbidity 
 
   Deep Sternal wound infection 
 
   Septicemia/ sepsis 
 
   Septicemia 
 
   Superficial wound infection 
 
   Urinary tract infection 
 
   Leg harvest site infection 
 
Cardiac Morbidity 
 
   Atrial fibrillation 
 
   Myocardial infarction 
 
   Complete heart block 
 
   Ventricular tachycardia 
 
   Ventricular fibrillation 
 
   Asystole 
 
 Gastrointestinal Morbidity 
 
 Multisystem organ failure 
 
Return to operating room for 
bleeding / tamponade 
 
Reopen for graft occlusion, 
valve dysfunction, noncardiac 
reasons 
 
Aortic or femoral artery 
dissection 
 
Acute limb ischemia