CSP #599 - Transfusion Trigger After Operations in High Cardiac Risk Patients (TOP)
Phase: NA
Conditions: Myocardial Infarction, Coronary Revascularization, Acute Renal Failure
Sponsor: VA Office of Research and Development

VA Central IRB
Effective Date:
January 8, 2025
ClinicalTrials.gov Identifier:  NCT03229941

Table of Contents
I.
INTRODUCTION AND BACKGROUND......................................................................................................3
II.
PRELIMINARY RESEARCH.......................................................................................................................5
III.
SIGNIFICANCE AND RELEVANCE TO VETERANS.......................................................................................9
IV.
STUDY OBJECTIVES................................................................................................................................9
A.
PRIMARY OBJECTIVE...........................................................................................................................................9
B.
SECONDARY OBJECTIVES....................................................................................................................................10
C.
TERTIARY OBJECTIVE.........................................................................................................................................10
V.
STUDY OUTCOME MEASURES..............................................................................................................11
A.
PRIMARY OUTCOME..........................................................................................................................................11
B.
SECONDARY OUTCOMES....................................................................................................................................11
C.
TERTIARY OUTCOMES........................................................................................................................................12
VI.
SUMMARY OF STUDY DESIGN..............................................................................................................12
VII.
PARTICIPANT POPULATION..................................................................................................................14
A.
INCLUSION CRITERIA..........................................................................................................................................14
B.
EXCLUSION CRITERIA.........................................................................................................................................15
C.
RECRUITMENT..................................................................................................................................................16
VIII.
HUMAN RIGHTS ISSUES AND INFORMED CONSENT..............................................................................18
IX.
EVALUATION PROCEDURES..................................................................................................................19
A.
SCREENING......................................................................................................................................................19
B.
RANDOMIZATION..............................................................................................................................................19
C.
PARTICIPANT ASSESSMENTS................................................................................................................................19
1.
Baseline Assessment..................................................................................................................................20
2.
Follow-up Assessment...............................................................................................................................21
D.
MISSED VISITS AND TERMINATION.......................................................................................................................22
1.
Missed Visits..............................................................................................................................................22
2.
Termination...............................................................................................................................................22
X.
TRANSFUSION STRATEGIES..................................................................................................................23
A.
LIBERAL GROUP (TRANSFUSION TRIGGER: HB < 10 GM/DL)......................................................................................23
B.
RESTRICTIVE GROUP (TRANSFUSION TRIGGER: HB < 7 GM/DL)..................................................................................23
XI.
MONITORING AND REPORTING SERIOUS ADVERSE EVENTS..................................................................25
A.
IMPORTANCE OF SERIOUS ADVERSE EVENT REPORTING...........................................................................................25
B.
ROLE OF THE LOCAL SITE INVESTIGATOR IN SERIOUS ADVERSE EVENT MONITORING.....................................................25
C.
DEFINITIONS....................................................................................................................................................26
1.
Serious Adverse Event...............................................................................................................................26
2.
Relatedness................................................................................................................................................26
D.
COLLECTION OF SAFETY INFORMATION.................................................................................................................27
1.
Expedited Reporting of Serious Adverse Events.......................................................................................27
2.
SAE Follow-up Reporting...........................................................................................................................27
E.
RISKS TO PARTICIPANT.......................................................................................................................................28
F.
BENEFITS FOR STUDY.........................................................................................................................................29
XII.
QUALITY CONTROL PROCEDURES.........................................................................................................29
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A.
STANDARDIZATION/VALIDATION OF MEASUREMENTS..............................................................................................29
B.
PARTICIPANT MANAGEMENT..............................................................................................................................30
C.
PROTOCOL VIOLATIONS.....................................................................................................................................30
D.
PLANS TO BE IMPLEMENTED IF RECRUITMENT GOALS ARE NOT MET............................................................................30
E.
SITE PERFORMANCE MONITORING.......................................................................................................................31
XIII.
DATA MANAGEMENT..........................................................................................................................33
A.
DATA COLLECTION AND DATA ENTRY...................................................................................................................33
B.
ARCHIVING STUDY DATA....................................................................................................................................34
XIV.
DATA SECURITY PLANS.........................................................................................................................34
XV.
GOOD CLINICAL PRACTICES..................................................................................................................36
A.
GOOD CLINICAL PRACTICES (GCP).......................................................................................................................36
B.
GCP TRAINING................................................................................................................................................36
C.
SUMMARY OF MONITORING AND AUDITING PLANS................................................................................................37
XVI.
BIOSTATISTICAL CONSIDERATIONS.......................................................................................................37
A.
EXPECTED TREATMENT EFFECTS..........................................................................................................................37
B.
SAMPLE SIZE CALCULATION AND POWER ANALYSIS.................................................................................................37
C.
DURATION OF STUDY AND NUMBER OF PARTICIPATING SITES...................................................................................38
D.
FEASIBILITY PHASE............................................................................................................................................38
E.
DATA ANALYSIS PLAN........................................................................................................................................39
1.
Analysis Populations..................................................................................................................................39
2.
Primary endpoint analysis.........................................................................................................................40
3.
Secondary endpoint analyses....................................................................................................................40
4.
Tertiary endpoint analyses........................................................................................................................41
5.
Other analyses...........................................................................................................................................41
F.
CRITERIA FOR STUDY TERMINATION.....................................................................................................................43
G.
HANDLING OF MISSING DATA.............................................................................................................................43
H.
REPORTING OF ANY DEVIATIONS FROM THE ORIGINAL STATISTICAL PLAN....................................................................44
XVII.
STUDY ORGANIZATION AND ADMINISTRATION...................................................................................44
A.
REQUIREMENTS FOR PARTICIPATING MEDICAL CENTERS...........................................................................................44
B.
STUDY MANAGEMENT.......................................................................................................................................45
C.
MONITORING OF THE STUDY..............................................................................................................................46
1.
Monitoring bodies.....................................................................................................................................46
D.
MONITORING DATA QUALITY AND PROTOCOL ADHERENCE........................................................................................48
E.
MONITORING OF SAFETY, EFFICACY AND FUTILITY....................................................................................................49
XVIII.
PUBLICATIONS.....................................................................................................................................49
A.
PUBLICATION OF RESEARCH RESULTS....................................................................................................................49
B.
PLANNED PUBLICATIONS....................................................................................................................................50
XIX.
REFERENCES........................................................................................................................................51
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I.
INTRODUCTION AND BACKGROUND
Blood is an indispensable product in modern medical practice.1 Red blood cells (RBC) replace 
intravascular volume, improve oxygen delivery to tissues in situations of hemorrhage, and 
anemia2 and consist one of the few treatments that adequately restore tissue oxygenation and 
maintain life when oxygen demand exceeds supply.3,4 Since the decision of blood transfusion is 
primarily guided by the physiologic need to provide a critical mass of oxygen carriers to assure 
that metabolic processes proceed uninterrupted, a physiologic test would be ideal to assist with 
clinical decision-making. Unfortunately, such a test has not been discovered yet. The lack of 
sophisticated physiologically driven transfusion algorithms has led to the development of the 
“transfusion trigger” concept, which dictates that a specific level of hemoglobin (Hb) should be 
used to guide transfusion decisions. Historically, the widely accepted clinical standard has been 
to transfuse patients when the Hb level drops below 10gm/dl or the hematocrit falls below 30%. 
This “10/30 rule” was first proposed by Adams and Lundy in 1942 and served as RBC 
transfusion guide for decades4,5, under the premise that a minimal RBC mass is critical to assure 
adequate oxygenation and avoid adverse cardiac events and death.  
Blood is a finite resource whose collection depends on the availability of donors and its 
processing is costly and time consuming.1,6,7,8,9,10-12 Therefore, clinicians sought to determine the 
safety of more restrictive blood transfusion strategies. In the first trial that challenged the 10/30 
transfusion dogma, Hebert et al.13 studied the impact of transfusion strategy in the ICU setting. 
The authors demonstrated that a restrictive transfusion strategy that accepted Hb as low as 
7gm/dl did not have an adverse impact on survival when compared to a liberal strategy under 
which patients were transfused at trigger Hb < 10 gm/dl. Although a post-hoc analysis14 of this 
trial that included a subset of patients with known ischemic heart disease demonstrated a trend 
for increased mortality in the restrictive transfusion group, this trial clearly indicated that 
restrictive transfusion could be safely practiced in some clinical settings.  
Since then other randomized trials have examined the impact of transfusion strategy on specific 
patient populations using various combinations of restrictive and liberal thresholds. A trial in 
patients undergoing cardiac surgery15 (transfusion thresholds at hematocrit < 24% vs. hematocrit 
< 30%) not only demonstrated that a restrictive strategy is safe, but also that the number of units 
of blood transfused was an independent predictor of mortality, as well as respiratory, cardiac, 
renal, and infectious complications. Obviously, generalizing these findings to other patient 
populations and surgical scenarios is not straightforward, as the patient population was either 
free of coronary artery disease, or had their diseased coronary arteries surgically bypassed during 
the index operation. In patients undergoing hip replacement,16 transfusion trigger at Hb < 8 vs. 
Hb < 10 gm/dl did not adversely affect death or the ability to walk independently at 60 days after 
randomization. Results were similar in patients with septic shock17 who were treated in ICU 
setting and were randomized to transfusion trigger of Hb < 7 vs. Hb < 9 gm/dl. At 90 days post-
randomization the mortality was 43% vs. 45% for the restrictive and liberal group respectively 
(p=0.44), suggesting that a restrictive transfusion strategy is well tolerated in this patient 
population. Of note, only half of the patients in this trial underwent any type of surgery, and less 
than 15% had a history of underlying cardiovascular disease, a limitation acknowledged by the 
authors. Finally, the restrictive transfusion strategy was shown to be superior in patients with 
acute upper gastrointestinal bleeding who were assigned to thresholds of Hb < 7 vs. Hb < 9 
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gm/dl.18 At six weeks, patients in the restrictive arm were more likely to be alive (95 vs. 91%, p 
= 0.02), and less likely to rebleed (10% vs. 16%, p=0.01) or have in-hospital complications (40% 
vs. 48%, p=0.02).
The findings of these trials, combined with the increasing RBC processing-related cost and the 
rising demand for blood services have created a major paradigm shift in transfusion strategies 
over the past several years. Published guidelines2,19-21 and health policy statements22 place a lot of 
emphasis on the need for restrictive transfusion thresholds in a variety of clinical settings; at the 
same time, the guidelines acknowledge21 that a substantial area of uncertainty remains and 
concerns the patients with underlying cardiovascular disease, a population that is more likely 
than any other to be extremely sensitive to transfusion thresholds. Data on these high cardiac risk 
patients remain scarce, coming mainly from small trials and secondary analyses. Bush et al.23 
conducted a randomized trial of 99 patients undergoing major vascular reconstruction in order to 
evaluate a restrictive (trigger at Hb < 9gm/dl) vs. a liberal (trigger at Hb < 10gm/dl) transfusion 
strategy. These authors found equal morbidity and mortality (16% and 8% respectively) between 
the treatment groups. However, a subgroup analysis between an “anemic” group of patients who 
actually drop their postoperative Hb below 9 and the liberal group demonstrated trends for 
increased event rate in the restrictive arm (cardiac morbidity 23 vs. 14% and mortality 10 vs. 8% 
at 30 days for the anemic and liberal group respectively). In a separate study24, 110 patients with 
acute coronary syndrome or stable angina who had Hb < 10 gm/dl were randomized to liberal 
(trigger at Hb < 10 gm/dl) or restrictive (trigger at Hb < 8 gm/dl or signs and symptoms of 
anemia) strategies. The primary endpoint (death, myocardial infarction or unscheduled 
revascularization within 30 days after randomization) occurred in 10.9% vs. 25.5% of patients in 
the liberal and restrictive group respectively (p = 0.076). More interestingly, mortality was 
substantially higher in the restrictive group (13% vs. 1.8%, p = 0.032).  In the recently published 
TITRe2 trial, Murphy et al.25 randomized 2007 patients undergoing cardiac surgery to a liberal 
(trigger Hb < 9 gm/dl) or a restrictive (trigger Hb < 7.5 mg/dl) transfusion arm. The primary 
endpoint (a composite of a serious infection or an ischemic event at 90 days after randomization) 
was not different between the two groups (35.1% vs. 33.0%, p=0.30). Analysis of the secondary 
outcomes, however, demonstrated that mortality at 90 days was more likely in the restrictive 
group (4.2% vs. 2.6%, p=0.045). The authors did not perform adjustment for multiple 
comparisons, and it still possible that the above finding is due to chance. However, a 69% 
relative risk difference in mortality favoring the liberal group is difficult to ignore, and 
underscores the urgent need for clarity on transfusion strategies in patients with underlying 
cardiovascular disease. 
Taken together the above data in patients at high risk for adverse cardiac events raise serious 
concerns regarding the appropriateness of a restrictive transfusion strategy in this patient 
population. This uncertainty regarding transfusion thresholds is anything but trivial. In the 
United States one out of two males and one out of three females older than 40 years of age will 
develop ischemic heart disease (IHD) during their lifetime.26 Approximately every minute an 
American dies from a coronary event, making IHD the leading cause of mortality in this 
country.26 Since the fundamental pathophysiologic mechanism underlying coronary events is an 
imbalance between oxygen supply and demand, optimizing the oxygen carrying capacity of the 
blood is critical for these patients. As the world is progressively moving towards more restrictive 
transfusion standards, the unanswered question of transfusion thresholds in high cardiac risk 
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patients has created a knowledge gap that requires urgent attention. Published guidelines have 
made clinicians hesitant to transfuse these patients under a liberal strategy in order to minimize 
risks associated with a treatment the patient may not really need; on the other hand, the studies 
summarized above provide preliminary evidence that extrapolating transfusion strategies from 
other patient populations to individuals at high risk for coronary events is actually causing harm. 
Given the magnitude of IHD as health care problem, this uncertainty creates a critical patient 
safety issue. 
In order to address this knowledge gap, we propose a randomized trial to compare two 
transfusion strategies in high cardiac risk patients undergoing vascular and general surgery 
operations. The study cohort will include patients with known history of IHD, or patients with 
history of peripheral arterial disease (PAD). PAD is a well-known marker of IHD and 
myocardial infarction represents the leading cause of mortality after PAD-related operations.27 
Furthermore, and unlike the patients undergoing cardiac surgery operations who have been 
included in published trials, patients in the proposed study will not have their coronary artery 
lesions routinely repaired during or prior to the index operation, and therefore their risk of 
cardiac events postoperatively will remain at least as high as it was preoperatively.
II.
PRELIMINARY RESEARCH
a) The study proponent has performed a propensity score matched analysis of participants 
undergoing elective open surgical intervention for PAD.28 The primary objective of this study 
was to assess the independent effects of nadir postoperative Hb (nHb) level and transfusion on a 
composite outcome of death or acute coronary syndrome (ACS) up to 30 days postoperatively. 
Secondary endpoints included perioperative wound and respiratory complications; and death or 
adverse cardiac events during an average follow-up of 24 months. A total of 1074 PAD-related 
operations were examined. In light of reports indicating a harmful effect of blood transfusion on 
mortality and cardiac outcomes, the analysis was adjusted for units of PRBCs transfused prior to 
the occurrence of any of the events that consisted of components of the composite outcome. 
Level of statistical significance in this study was set at alpha 0.0125 to account for the four 
comparisons performed when assessing the primary endpoint (two exposures tested against two 
individual outcomes).
TABLE 1: Effect of Nadir Hb and Units of Blood Transfused on a Composite Endpoint of
Death, or ACS
Variable
Odds Ratio
Standard Error
P-Value
95% Confidence Interval
Nadir Hb < 10gm/dl
Reference
Reference
Reference
Reference
Nadir Hb  10gm/dl
0.62
0.17
0.120
0.33-1.14
Transfusion units
1.11
0.05
0.025
 1.01-1.22  
Univariate analysis in this study demonstrated a relative protective but not statistically significant 
effect of nHb >10gm/dl on the composite endpoint of death or ACS (OR: 0.68, 95% CI: 0.54 to 
1.19, p=0.12). On the multivariable model that included as predictors both nHb and units of 
blood transfused, nHb>10gm/dl was again seen to have a relative protective effect on the 
composite endpoint, although again this difference did not reach statistical significance. (OR: 
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0.62, 95% CI: 0.33 to 1.14, p=0.12, Table 1).  An intriguing observation of this study was that 
the event rate for the composite endpoint of death or ACS at 30 days was nearly 50% higher in 
the restrictive transfusion group (6.0% vs. 9.3%, Pearson’s chi square test 0.052 on univariate 
analysis). After appropriate risk adjustment using propensity score matching this difference 
turned out to not be of statistical significance; however, the possibility remained that, in this 
patient population, a conservative transfusion strategy had a harmful effect that this 
observational study was simply too underpowered to conclusively demonstrate.   
b) To address this possible power issue, Kougias et al conducted a larger single institution 
study29 with primary endpoint a composite of all-cause mortality, MI (defined according to the 
Third Universal Definition of MI), acute renal failure (defined as acute kidney injury stage 3 per 
RIFLE criteria), stroke, or coronary revascularization within 90 days after the index intervention. 
In this new analysis a total of 2509 PAD-related operations were included. The composite 
endpoint occurred in 28.7% of patients with nadir Hb between 6-9gm/dl and 12.1% of patients 
with nadir Hb >9 gm/dl (p<0.001). Increasing nadir postoperative Hb demonstrated a strong 
curvilinear relationship with the composite outcome (OR 0.72, 95% CI: 0.74 to 0.85). Patients at 
higher baseline cardiac risk (as captured by Revised Cardiac Risk Index -RCRI) were at higher 
risk for the composite outcome across all ranges of postoperative nadir Hb; RCRI class II (OR: 
1.8, 95% CI: 1.29 to 2.40), class III (OR: 2.07, 95% CI: 1.45 to 2.94), and class IV (OR: 2.38, 
95% CI: 1.58 to 3.49) were associated with progressively increasing odds of the CE compared to 
RCRI class I. (Figure 1). 
FIGURE 1. Probability of the Composite Endpoint at Various Levels of the Postoperative 
Nadir Hb – Single institution data
0
.1
.2
.3
.4
Probability
6
8
10
12
14
Nadir Hb (gm/dl)
RCRI:I
RCRI:II
RCRI: III
RCRI:IV
Predicted Probability of Composite Endpoint vs. Nadir Hb
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c) In light of these single institution results, the principal proponent and members of the planning 
committee conducted a large multicenter observational study with objective to assess the impact 
of postoperative anemia on patients at high risk for cardiac events who underwent major 
Vascular and General Surgery operations throughout the VA system between January 2000 and 
December 2014. Data from the Corporate Data Warehouse (CDW) database was used for this 
purpose. Patients who underwent operations for peripheral arterial disease (operative vascular 
bypass or major amputation) or elective (non-ruptured) aneurysm repair (either open or 
endovascular) were identified using Current Procedural Terminology (CPT) codes. Similarly, we 
identified patients who underwent the following General Surgery operations: open 
cholecystectomy or other complex biliary reconstruction, splenectomy, small bowel resection, 
colon  resection, rectal resection, transabdominal esophagectomy, or open ventral hernia repair. 
We collected data on preoperative and postoperative hemoglobin, creatinine, and troponin levels. 
The CDW database includes a time stamp that indicates the time of blood specimen was 
collected from the patient, along with the numerical result of the blood test. This greatly 
facilitated the precise assessment of the temporal relationship between time of operation, anemia, 
and creatinine or troponin elevation. In order to assess baseline comorbidities we accessed data 
on outpatient visits that had occurred prior to the time of the index operation. We assumed that a 
patient suffered from a particular comorbidity only when that comorbidity was entered as reason 
for the outpatient visit in at least two separate occasions that took place prior to the operative 
intervention. ICD-9 diagnostic codes were used for comorbidity identification. 
The main outcome of this analysis was defined a-priori to be the same with the one of the 
proposed trial, and consisted of a composite of all-cause mortality, MI, acute renal failure, 
coronary revascularization (either percutaneous coronary intervention or open coronary artery 
bypass), or stroke, within 90 days from the index operation. Mortality was defined as death from 
any cause and was ascertained from the Vital Status patient file. MI was defined as a serum 
troponin I of at least 1ng/ml that was upwards trending in patients who either a) did not have 
elevated troponin preoperatively, or b) did not have any preoperative troponin I check. Clinicians 
do not routinely order postoperative troponin; thus, we assumed that that test was requested in 
patients with either EKG findings or symptomatology suggestive of MI, satisfying the Third 
Universal Definition. Although the 99th percentile upper reference limit of troponin I is 0.06 
ng/ml or less for most assays used, we employed a more conservative cutoff of 1ng/ml to 
minimize overestimation of the endpoint by patients who might have had mild troponin elevation 
from non-ischemic causes. Acute renal failure was defined as acute kidney injury (AKI) stage 3 
according to RIFLE criteria (serum creatinine at least > x3 of baseline, or serum creatinine > 4 
mg/dl and rise > 0.5 from baseline). The creatinine value just prior to the date of the index 
operation was considered as baseline for those calculations. Urine output criteria are also 
included in the RIFLE classification; however, urine output cannot be reliably determined from a 
database review, and for this reason our assessment of AKI stage 3 from this analysis may have 
been conservative. Coronary revascularization was ascertained using appropriate CPT codes for 
either percutaneous or open coronary interventions. Finally, we attempted to identify 
postoperative stroke using the ICD-9 code 997.5; however, this return no events. Unlike the rest 
of the outcomes, extracting reliable stroke rates from the CDW database is not straightforward. 
Furthermore, single institution data have shown the 90 day stroke rate after vascular 
interventions to be low (approximately 1%), which is possibly why the database query returned 
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no events. We stratified the patients as being high risk for cardiac events if they had history of 
IHD, peripheral artery disease (PAD), or underwent a PAD-related operation. We ultimately 
collected information on 171,357 patients who underwent the target operations and were 
included in our analysis. 
FIGURE 2. Probability of the Composite Endpoint at Various Levels of the Postoperative 
Nadir Hb – Multicenter data
Similarly to the single institutional analysis, a strong association was seen between increasing 
values of nadir postoperative Hb and freedom from the composite endpoint (OR: 0.566, 95% CI: 
0.561 to 0.57, Figure 2). From the initial patient pool, 38,153 patients were at high risk for 
cardiac events and dropped their nadir postoperative Hemoglobin in the early postoperative 
period below 10 gm/dl, conditions that would make them eligible for the proposed trial. In this 
high cardiac risk patient population, the composite outcome occurred in almost 30% of patients 
with nadir Hb between 6-9 gm/dl (a subset that will represent the restrictive transfusion arm in 
the proposed study) and in 15% of patients with nadir Hb between 9-10 gm/dl (a subset that will 
represent the liberal transfusion arm in the proposed trial). Event rates for the composite and 
individual endpoints are summarized in TABLE 2 below: 
TABLE 2.  Composite Event Rates and Individual Event Rates among Veterans at High 
Cardiac Risks after a Surgical Procedure
Nadir Hb
Composite 
Endpoint
Death
MI
ARF
Coronary Revascularization
6-9 gm/dl
29.5%
15.3%
11.0
%
11.1%
0.4%
9-10 gm/dl
15.0%
6.9%
6.2%
4.1%
0.3%
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III.
SIGNIFICANCE AND RELEVANCE TO VETERANS
The proposed trial is uniquely positioned to address the knowledge gap of appropriate 
postoperative transfusion thresholds in high cardiac risk patients. Given the high prevalence of 
IHD and the potentially devastating clinical consequences of inappropriate transfusion strategy 
selection, identifying the optimal transfusion strategy for this patient population is critical for 
patient safety. If the proposed trial demonstrates that the liberal strategy is superior, then 
outcomes in patients at high cardiac risk will improve, as clear guidance will be provided to 
clinicians that restrictive policies are not appropriate for this patient population. Conversely, if 
the restrictive strategy proves to be safe in these patients who represent a subset that is the least 
likely to benefit from such a strategy, then a well-informed and generalizable statement 
supporting restrictive blood transfusion strategy in practically every patient population can be 
made. This will result in policy changes that will reduce unnecessary transfusions, and 
transfusion-related complications and cost. Therefore, the proposed trial is well positioned to 
have substantial clinical and policy implications nationally and internationally regardless of its 
outcome. 
Optimizing transfusion thresholds in high cardiac risk patients is highly relevant to the VA and 
its mission. Veteran patients are older and have higher incidence of cardiovascular disease than 
the general US population.30 Furthermore, the cardiovascular risk profile of Veterans has been 
shown to deteriorate over time, with increasing rates of diabetes, obesity, and left main coronary 
artery disease.31 As a result, IHD is highly prevalent in the VA system, where it represents the 
leading cause of mortality and third leading cause of hospitalization.32,33 For these reasons, 
optimizing transfusion thresholds in high cardiac risk patients will have a particular impact 
among Veteran patients.
IV.
STUDY OBJECTIVES 
The goal of the proposed study is to determine whether a liberal transfusion strategy (transfusion 
trigger at Hb < 10 gm/dl) in Veterans at high cardiac risk who undergo major open vascular and 
general surgery operations is associated with decreased risk of adverse postoperative outcomes 
compared to a restrictive transfusion strategy (transfusion trigger at Hb < 7 gm/dl). 
A.
Primary Objective
Objective 1:  To examine the effect of transfusion strategies on a composite endpoint of all-
cause post-randomization mortality, myocardial infarction (MI), coronary 
revascularization, acute renal failure, or post-randomization stroke in Veterans at high 
cardiac risk undergoing open surgical interventions
Hypothesis 1:  A significantly smaller proportion of participants receiving blood under a liberal 
transfusion strategy will experience the composite compared to participants under restrictive 
transfusion strategy at 90 days after randomization.
 
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B.
Secondary Objectives
Objective 1:  To examine the effect of transfusion strategies on post-randomization 
infectious complications.
Hypothesis 1:  A smaller proportion of participants receiving blood under a liberal transfusion 
strategy will experience post-randomization infectious complications compared to participants 
under restrictive transfusion strategy at 90 days after randomization.
Objective 2:  To examine the effect of transfusion strategies on post-randomization cardiac 
complications other than MI.   
Hypothesis 2: A smaller proportion of participants receiving blood under a liberal transfusion 
strategy will experience post-randomization cardiac complications other than MI compared to 
participants under restrictive transfusion strategy at 90 days after randomization.
Objective 3:  To examine the effect of transfusion strategies on all-cause mortality during 
the one year post-randomization follow-up.
Hypothesis 3: A smaller proportion of participants receiving blood under a liberal transfusion 
strategy will die from any cause compared to participants under restrictive transfusion strategy 
during one year follow-up after randomization.
Objective 4:  To examine the effect of transfusion strategies on a composite endpoint of all-
cause post-randomization mortality, MI, coronary revascularization, acute renal failure, or 
post-randomization stroke at 30 days after randomization.
Hypothesis 4: A smaller proportion of participants receiving blood under a liberal transfusion 
strategy will experience the composite endpoint compared to participants under restrictive 
transfusion strategy at 30 days after randomization.
Objective 5: To examine the effect of transfusion strategies on the length of hospital stay
Hypothesis 5: Liberal transfusion strategy will lead to a shorter length of hospital stay. 
C.
Tertiary Objective
Objective:  To examine the effect of transfusion strategies on the components of the 
primary endpoint.
Hypotheses:  A smaller proportion of participants receiving blood under a liberal transfusion 
strategy will experience post-randomization death from any cause, MI, coronary 
revascularization, acute renal failure, or post-randomization stroke, compared to participants 
under restrictive transfusion strategy at 90 days after randomization.
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V.
STUDY OUTCOME MEASURES
A.
Primary Outcome 
The primary outcome is defined as a composite endpoint of all-cause post-randomization 
mortality, myocardial infarction (MI), coronary revascularization, acute renal failure, or post-
randomization ischemic stroke up to 90 days after randomization. 
MI will be defined using the Third Universal Definition of Myocardial Infarction.34 (Please see 
Appendix I.)
Acute renal failure will be defined as Acute Kidney Injury stage III according to RIFLE criteria: 
Serum creatinine rise greater than 3 times that of baseline creatinine; or if baseline serum 
creatinine is greater than 4 mg/dl, then rise more than 0.5 mg/dl compared to baseline; or urine 
output less than 0.3ml/Kg/hr for 24 hours; or anuria for 12 hours. Baseline creatinine will be 
considered the creatinine upon admission prior to the index operation. The above urine output 
criteria will be only used for patients who are in the ICU and have precise monitoring of their 
urinary output. For patients on the surgical floor only serum creatinine changes will be used for 
assessment of this endpoint. 
Coronary revascularization will be defined as a coronary artery bypass graft, or percutaneous 
coronary intervention (either angioplasty or stenting).
Stroke will be defined as new unilateral neurological deficit that lasts for more than 24 hours, 
and is confirmed by a brain imaging modality (either computed tomography or magnetic 
resonance imaging study) demonstrating new brain infarct. 
B.
Secondary Outcomes 
Outcome 1: A composite endpoint of post-randomization infectious complications at 90 days 
post-randomization: Infectious complications will include wound infections, pneumonia, and 
sepsis.
Wound infection will be defined according to the Centers for Disease Control and Prevention 
(CDC) guidelines as a) positive wound culture, or b) drainage of pus from a wound, or c) 
suspicion of wound infection that was drained operatively.
Pneumonia will be defined according to the CDC definition as chest radiograph or imaging with 
new or progressive infiltrate, consolidation, cavitation, or pleural effusion and any of the 
following: new onset of purulent sputum or change in character of sputum, or organism isolated 
from blood culture, trans-tracheal aspirate, bronchial brushings, or biopsy.  
Sepsis will be defined as a combination of two of the following systemic inflammatory response 
syndrome (SIRS) criteria, plus suspected or present source of infection. SIRS criteria will 
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include the following: temperature greater than 38C, heart rate greater than 90 beats/min, WBC > 
12,000 or < 4,000, or > 10% bands.
Outcome 2: A composite endpoint of cardiac complications (other than MI) at 90 days post-
randomization: Cardiac complications will include new cardiac arrhythmias that necessitate new 
treatment, new or worsening congestive heart failure (CHF), and cardiac arrest not leading to 
death.
The diagnosis of cardiac arrhythmias will be based on EKG findings. Only arrhythmias that 
result in initiation of new treatment regimen (to include medications, implantable devices, or 
surgical intervention) during hospitalization will be recorded.
CHF will require at least one of the following symptoms or signs new or worsening: dyspnea at 
rest, orthopnea, or paroxysmal nocturnal dyspnea and radiological evidence of heart failure or 
worsening heart failure and increase/initiation of established treatment.  
Cardiac arrest will be defined as the cessation of cardiac pump function activity that results in 
loss of consciousness and absence of circulating blood flow as evidenced by absent carotid pulse. 
Only episodes of cardiac arrest that are reversed will be collected under this endpoint. If they are 
not reversed the event will be categorized as death. 
Outcome 3:  All-cause mortality at 1 year after randomization. 
We will determine vital status by telephoning participants after hospital discharge, by searching 
the electronic medical record and the VHA Death Ascertainment File (DAF).  
Outcome 4:  A composite endpoint of all-cause mortality, MI, coronary revascularization, acute 
renal failure, or post-randomization ischemic stroke at 30 days after randomization.
Outcome 5:  Length of hospital stay. 
C.
Tertiary Outcomes  
We will examine individual rates of the outcomes that consist of individual components of the 
primary endpoint.
VI.
SUMMARY OF STUDY DESIGN
The study is a parallel, single-blind, controlled, superiority trial in which participants will be 
randomized to a restrictive or a liberal transfusion group. This study will randomize 1520 
Veterans at 15 VA Medical Centers.  The total recruitment period will be approximately 4 years 
which will be followed by a 3 month active and 9 month passive follow-up period.  The duration 
of the study will be approximately 5 years.   Consent for the study will be obtained prior to the 
index surgical intervention at the clinic visit or, in case of inpatients, at the hospital ward pre- or 
postoperatively. Randomization will be performed via a central telephone randomization system 
once the participant has a confirmed Hb < 10gm/dl. Active follow up will be up to three months 
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after randomization. Passive follow up will be from 3 months to one year after randomization. 
The study flow is shown in FIGURE 3. There will be no blinding at the treating physician level; 
however the participants and the Endpoint Committee will be unaware of group allocation. 
Follow up forms will be filled out during two postoperative clinic visits that will be after the 30th  
and 90th  post-randomization days. Participants who cannot make the clinic visits will be assessed 
by phone call follow-up, during which they will be asked specific questions to ascertain whether 
signs or symptoms related to any of the endpoints have developed. In addition, the electronic 
medical record, will be assessed to collect relevant information. If a participant gets re-admitted 
at any time after discharge and within 90 days after randomization, the electronic medical record 
will be examined for the presence of any of the diagnoses that consist part of either the primary 
or any other endpoints. If the participant has been admitted to a non-VA facility, a full copy of 
hospital records from that admission will be obtained and assessed for the presence of any of the 
outcomes. History and physical, consultation notes and progress notes will all be reviewed. 
Furthermore, particular attention will be paid to laboratory reports for troponin, creatinine,  CK-
MB (if available), and WBC levels, reports of cardiac echograms, radiology reports, and results 
of cultures (blood, wound, sputum). Participant agreement for release of information to the study 
personnel for all postoperative hospital visits that occur within 90 days after randomization will 
be obtained as part of the original consent form. 
Assessment of one year mortality will be performed as part of a passive follow up performed by 
the Chairman’s office via examination of the electronic medical record, follow up phone calls, 
and search of national databases documenting mortality. 
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FIGURE 3:  Study Flow
VII.
PARTICIPANT POPULATION
All Veterans who are scheduled to undergo vascular or general surgery at a VAMC will be 
invited to participate in this trial. The inclusion and exclusion criteria are outlined below.
A.
Inclusion Criteria
1)
Male and female Veterans older than 18 years of age who have postoperative Hb < 
10gm/dl within 15 days after the index operation
2)
Patients undergo an operation in either one of the three following categories 
a.
Veterans who undergo PAD – related operations including but not limited to 
the following:  aortobifemoral or aortobiiliac bypass, open abdominal aortic 
aneurysm repair with simultaneous repair of aortoiliac occlusive disease, 
visceral bypass,  iliofemoral bypass, femoral bypass or endarterectomy, 
infrainguinal bypass; thromboembolectomy; supra-aortic trunk bypass or 
endarterectomy, carotid endarterectomy, and major lower extremity 
amputations (transfemoral, through the knee, or transtibial)
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b. Veterans with past medical history of ischemic stroke/TIA of likely carotid 
origin, or history of IHD (defined as known prior MI, EKG findings consistent 
with prior MI, prior percutaneous coronary intervention, prior coronary artery 
bypass surgery, history of angina for which the patient is currently receiving 
treatment, or stress test indicating myocardial ischemia), or history of PAD 
(defined as prior intervention for PAD or ABIs < 0.9) who undergo the 
following General Surgery operations: Open cholecystectomy or other open 
complex biliary reconstruction (such as open common bile duct exploration 
for stones, reconstruction as part of oncologic operations such as palliative 
pancreatic cancer procedures), open or laparoscopic small bowel resection, 
pancreatectomy, colon resection, colostomies (reversals and takedowns), 
intestinal anastomosis takedown and revision, rectal resection, splenectomy, 
transhiatal esophagectomy, liver resection, gastric operations (resections or 
repairs), gastric bypasses, adrenalectomy, major diaphragmatic hiatal hernia 
repair, Nissen fundoplications, and ventral hernia repair
c.
Veterans with past medical history of ischemic stroke/TIA of likely carotid 
origin, or history of IHD, or history of PAD (defined as prior intervention for 
PAD or ABIs < 0.9) who undergo the following Vascular Surgery operations: 
Open aneurysm repair (including but not limited to carotid, subclavian, 
abdominal aortic, iliac, femoral, or popliteal aneurysms); and complex 
endovascular aneurysm repair (defined as fenestrated endograft, or endograft 
with need for iliac conduit, or endovascular aneurysm repair with 
simultaneous femoral artery reconstruction or bypass). Subclavian/vertebral 
bypasses and transpositions are eligible with a history of PAD/IHD/ischemic 
stroke. 
Patients undergoing the above procedures will be included in the study regardless of their 
preoperative Hb level, and regardless of preoperative or intraoperative transfusion they 
might have received. For non-compressible arteries and patients with diabetes, toe 
pressures (<60 mm Hg) may be used to identify prevalence of PAD. 
B.
 Exclusion Criteria
1)
Veteran unable to consent
2)
Veteran unwilling to follow protocol (such as Jehovah’s witnesses)
3)
Veteran with known history of hereditary anemias such as Thalassemia or Sickle 
cell disease
4)
Veteran with known history of hereditary bleeding disorders, such as factor VIII or 
factor IX deficiency
5)
Veteran with prior history of adverse reaction to blood administration, such as 
fever, rash, or hemolysis
6)
Veteran does not speak or understand English
7)
Veteran hemodynamically unstable (systolic blood pressure <90 and heart rate >100 
that persists for at least 30 minutes) or in cardiogenic shock for > 48 hours after the 
index procedure
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8)
Veterans participating in another interventional trial
9)
Pregnancy in female Veterans
10)    Veteran is a prisoner or in custody of law enforcement
11)
Prior randomization in the CSP#599
12)
Patients who are known to have tested positive for COVID-19 and have not 
recovered prior to consent will not be consented. Any participant who is known to 
have a positive COVID-19 test during the screening process and has not recovered 
will be excluded prior to randomization.
Recovery from COVID-19 is defined as a patient who is asymptomatic (per local 
preoperative clearance policies) and at least 10 days post a positive test. 
Note: Patients may be screened, consented, and randomized once recovered, if not 
previously randomized. Veterans who test positive after randomization but before 
discharge must be terminated for study ineligibility. Veterans who test positive 
after randomization and after discharge from the index admission, may continue to 
participate in the study as long as follow up is completed remotely. 
C.
Recruitment 
The site coordinator along with the local site investigator (LSI) will be primarily responsible for 
identifying each potential participant scheduled for an open surgical procedure.  At the beginning 
of the study, vascular and general surgeons performing the operations of interest at a VAMC will 
be personally contacted by the Site coordinator to discuss logistical and procedural issues related 
to recruitment.  Surgeons (both vascular and general surgeons) have been contacted in 15 
primary and 8 back up VAMCs and have confirmed interest in participation in the study. 
The methods to identify and recruit Veterans with a proposed surgical procedure will be as 
follows; a) for outpatients seen in the clinic, any physician (resident or attending) can explain the 
study to the participant in collaboration with the LSIs, Site Coordinator, Research Assistant, and 
study team, check the participant’s eligibility for the study and notify the site coordinator to 
obtain informed consent at the time consent is obtained for surgery. Participants will be given up 
to 2 days to decide whether or not they would like to participate in this study. Participants will 
receive a signed and dated copy of the informed consent (10-1086) and a signed and dated copy 
of the HIPAA authorization.  To optimize recruitment, the site coordinator will maintain a list of 
outpatient preoperative clinics in which Veterans undergoing the operations of interest are seen, 
and will review with physicians who staff those clinics, the inclusion and exclusion criteria for 
the study. Furthermore, the site coordinator will be present during clinic hours in order to 
provide immediate feedback and answer questions with respect to study eligibility; b) for 
inpatients, any physician can explain the study in collaboration with the LSIs, Site Coordinator, 
Research Assistant, and study team,  check the participant’s eligibility for the study and notify 
the site coordinator to obtain consent. To assure that no participants are lost, the site coordinator 
will review the surgery schedule two days ahead of time to assure that all eligible inpatients 
scheduled for an open operation have been approached and the study has been discussed with 
them. If unable to obtain consent preoperatively for any reason, participants can be approached 
postoperatively, provided they are able to provide informed consent. Post-operative consent must 
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be completed within 48 hours of the procedure; if the procedure was completed on a Friday, 
consent may be obtained the following Monday for a 72-hr. consent window.
To assess feasibility of this study within the VHA system, we estimated volume for the 
operations of interest by a) querying the Corporate Data Warehouse (CDW) VA database using 
ICD-9 and CPT codes, and b) conducting a survey of possible Site Investigators in individual 
participating VAMCs who have confirmed interest in participating in the trial. 
a) According to the VA CDW database that tracks operative interventions using ICD-9 and CPT 
codes, the average number of Veterans who had vascular and general surgeries from 2011-2014 
were 9,154 per year among 15 VA medical centers who have agreed to participate in the 
proposed trial. For four-year recruitment time, we project that Veterans who will have the 
surgical interventions of interest will be over 36,616.  We estimated that 14,646 of the Veterans 
who undergo the operations of interest have high cardiac risk (approximately 40%).This 
assumption is based on our review of the CDW database that included approximately 171,000 
patients as described on page 5. Among these high cardiac risk Veterans, we assume that 7,323 
(50%) will agree to be randomized to the study (agreement to randomization has been 
approximately 70% in other published trials on the topic; we prefer to err towards a more 
conservative side). Of these consented Veterans, 4,027 (55%) will drop their postoperative Hb 
level below the threshold of 10 gm/dl to be eligible for randomization (this assumption is again 
based on the CDW data analysis described on page 5). Among those who have Hb level below 
10 gm/dl, 10% are assumed to fall under the exclusion criteria (approximately 403), which will 
yield over 3,624 eligible Veterans available for randomization; while the targeted sample size is 
1,520 participants (Figure 3).  Simply, according to the above estimations, approximately 10% 
(40% 50% 55%90%) of the Veterans who undergo the operations of interest will be 
eventually randomized. Put it differently, in the sites that have already agreed to participate in 
the trial an average of 610 operations per facility per year can be expected. In the proposed 
scenario 10% of these Veterans will be ultimately randomized then we anticipate recruiting 61 
Veterans per site per year (or 5 Veterans available per site per month). 
b) In addition to the above analysis, we have conducted a survey of the possible Site 
Investigators in these 15 facilities that have expressed interest in participating in the trial, as well 
as in 8 additional facilities that will serve as back up sites. These Site Investigators are surgery 
section leaders and have been selected on the basis of clinical experience (80% of them have 
been in practice for more than 10 years), and also experience with prior CSP studies (65% of 
these Site Investigators have in the past participated in a CSP trial). According to the survey, 
vascular surgeons estimate that on average 3.5 vascular surgery patients per month per facility 
can be recruited, whereas general surgeons estimate that on average 3 general surgery patients 
per month will be recruited. This represents a minimum of 6 patients per month available for 
recruitment, an estimate fairly close to the results of the CDW database analysis. 
Despite those estimates, we take a more conservative approach to assume that on average each 
participating site will recruit approximately 3 patients per month.  Target sample size is 1,520 
Veterans. The enrollment period will be approximately four years based on 15 sites and 3 
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participants/month/site rate of enrollment (starting with eight sites for the first year and adding 
the remaining seven sites on the second year).  In total,  4,560 participants will be consented; we 
estimate that 1,520 participants will be eventually randomized. In each site, the number of 
participants enrolled annually will not exceed 250. We estimate that 102 participants per site will 
be randomized. It is possible that some sites with higher surgical volumes will randomize more 
than 102 participants. This is acceptable. 
Depending on study progress and recruitment, if only one service (vascular or general) of a high 
surgical volume VA Medical Center is interested in participating, the site may be included in the 
trial.
c) During the first year, eight sites including three Network of Dedicated Enrollment sites 
(NODES) will be launched. This will enable the study Executive Committee to monitor the 
recruitment rates at these sites during the first year of the study’s conduct. If the recruitment rates 
at these sites do not meet the expected rate (3 participants/site/month), measures will be taken by 
the study leadership to ensure meeting the recruitment target as follows: a) Targeted intervention 
and surgeon education will be performed if changes in a specific site’s human resources are 
thought to be the reason for poor recruitment (e.g. if new surgeons have arrived and are not 
supportive of the study); b) Site’s overall surgical volume will be reassessed and if a substantial 
decline is seen, one out of eight available back up sites will be chosen to replace 
underperforming sites; c) In the unlikely event that poor recruitment is an issue for multiple sites, 
the patient population will be expanded to include high cardiac risk patients who undergo major 
orthopedic operations, such as knee and hip replacement, and major open fracture repair. 
VIII.
HUMAN RIGHTS ISSUES AND INFORMED CONSENT
CSP follows the principles of medical research involving human participants as outlined in the 
Declaration of Helsinki.  
Informed consent will be obtained from all CSP study participants prior to participation in this 
study.  Informed consent requires that the participant understand and agree to the study 
procedures, treatments, and risks.  The participant will be explained the voluntary nature of 
participation in the research study and can withdraw from participation without penalty at any 
time.  It will be communicated that current treatment, future medical care, and benefits will not 
be dependent on participation in the research.  The participant must have sufficient time to read 
and discuss the informed consent document prior to signing.  
The process of informed consent must occur verbally with the study participant.  In discussion of 
the consent form with the participant, the investigator (or other study personnel identified in this 
protocol to conduct the informed consent process) may provide additional details beyond those 
contained in the consent form.  Additional information may not represent any significant 
additions, deletions, or modifications to the information in the informed consent document.  The 
research participant will be provided with a paper signed and dated copy of the consent form and 
any supplementary materials to read and review prior to consent.  
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The informed consent document will contain all elements as outlined in VHA Handbook 1200.05 
as required by the Common Rule, and will meet the requirements of 21 CFR 50.25. The consent 
will be documented on VA Form 10-1086 Research Consent Form.  The VA CIRB or other IRB 
of record for the study will approve the consent form prior to its use.  
An IRB approved most current version of the informed consent must be signed and dated by the 
study participant and the person obtaining the informed consent.  The original signed and dated 
informed consent document will be placed in the investigator’s research file.  Copies of the 
signed and dated informed consent document will be provided to the participant at the time of 
consent and to the CSPCC per instructions in the Operations Manual. 
The informed consent process will be documented in a detailed progress note prior to study 
participation.    
A separate written HIPAA authorization for the use of individually identifiable health 
information must be signed by the research participant unless a waiver for HIPAA authorization 
has been granted by the VA Central IRB or IRB of record for the research.
Data will be retained after the end of the study as per VA and IRB regulations.   
IX.
EVALUATION PROCEDURES
A.
Screening 
The Site Study Coordinator will be primarily responsible for identifying each Veteran scheduled 
for an open surgery at the clinic. Each site will obtain a waiver of informed consent/HIPAA for 
pre-screening purposes from the VA Central IRB. 
B.
Randomization
After an eligible participant provides informed consent, the study staff will complete all sections 
of the pre-randomization forms except for the postoperative Hb measurements. The clinical site 
coordinator will be responsible for tracking the postoperative Hb levels and identifying 
participants whose Hb level is below 10 gm/dl and therefore eligible for randomization. iStat 
hemoglobin values may not be used as the basis for randomization/transfusion decisions. The 
CSPCC staff will prepare randomization schedules for each clinical site participating in the 
study.  The study randomization to either liberal or restrictive transfusion policy will be done by 
an Interactive Touchtone Telephone Randomization System (ITTRS). A stratified block 
randomization scheme will be used to randomize participants in the two transfusion groups.  The 
stratifying factors are clinical site and revised cardiac risk index (RCRI) class. Following 
participant randomization, clinical data and transfusion records will be obtained by the study 
team.
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C.
Participant Assessments
1.
Baseline Assessment
Baseline assessments will be collected the time between identification of an eligible participant 
and either randomization or 15 days after surgery (or until discharge, whatever comes first) 
including revised cardiac risk index (RCRI), patient history, hemoglobin level, EKG diagnosis, 
troponin, serum creatinine, albumin, and patient clinical status. Data collected during this period 
is used primarily for monitoring recruitment and randomization status. We will maintain the 
information of all identified potential participants. This will be accomplished by completing the 
screening form for every participant presenting to the clinical site for eligible operations 
including those who are excluded from the study for any reason.  Following is a list of 
assessments that we plan on collecting:
Screening Record:  To compare patient screened (but not randomized) to patient randomized in 
this study, a comprehensive screening assessment will be completed for all potentially eligible 
subjects scheduled to receive an open surgery procedure at a participating center by the Study 
Coordinator.
Demographic: The clinical site coordinator will collect demographic and participant information. 
The demographic information will include participant’s age, gender, race, marital status, etc.
Clinical Data:  The site coordinator will also collect clinical data using information from the 
medical record and consult with the surgeon as needed. These will include height, weight, last 
preoperative serum Hb, albumin, blood pressure, and history of comorbidities, including 
coronary artery disease, end-stage renal disease, chronic obstructive pulmonary disease, 
hyperlipidemia, diabetes mellitus, and hypertension. 
To assure that MI or acute renal failure have not occurred prior to the time of randomization the 
patient’s chart will be reviewed for Troponin, EKG, and serum creatinine. If these values are 
available in the 24 hrs. prior to randomization, they will not be collected again. If unavailable 
within this period, EKG, serum creatinine, and troponin data will be  collected within 24 hours 
from the time of randomization. If available at the institution, CK-MB will also be collected (not 
required).  
We will also collect information on prior history of MI, coronary artery bypass, and stent 
placement. Furthermore, intraoperative assessments will be collected during the surgical 
procedure, such as type of operation, amount of intraoperative blood loss, intraoperative 
transfusion, amount and type of fluids administered, and length of the operation.
Lab, transfusion, EKG ordering procedures: Once the participant is randomized, a study team 
member should enter a CPRS note indicating (1) randomization arm, (2) lab/EKG collection 
schedule, and (3) transfusion regimen. When possible, the lab, EKG, and transfusion orders 
should be placed by a study team member. If verbal lab or transfusion orders are given by the 
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LSI to a resident or nurse, the order should be co-signed by the LSI according to the local 
facility’s standard operating procedure. If the co-sign option is unavailable under Orders, the LSI 
or study team member must enter a CPRS note after the order has been placed indicating that the 
order was placed by resident/nurse at the LSI’s request. If the note is entered by a study team 
member, the note must be co-signed by the LSI. 
 
2.
Follow-up Assessment 
Follow-up assessments will be collected after participants are discharged from the hospital 
including 30- day and 90-day active follow-up assessments and one-year passive follow-up 
assessment.
a)
Thirty Day Follow-up
Participants will be given an appointment for a clinic visit within one week after the 30 
post-randomization day. Questions regarding symptoms related to MI, other cardiac 
events, stroke, pneumonia, and wound infection will be asked.  If a participant has a 
readmission prior to the 30 day post-randomization time point, then the electronic 
medical record, will be reviewed to determine whether the reason for admission includes 
any of the complications that consist of the primary or other study endpoints, such as 
coronary revascularization or acute renal failure. If the participant has been admitted to a 
non-VA hospital, then complete records from this admission will be obtained from that 
hospital to document the reason for admission and whether any of the study endpoints 
have been developed which led to the readmission. The hospital records obtained will 
include History and Physical, all consultations, procedures, laboratory values, fluid 
cultures, copies of EKG and Echocardiography reports, as well as reports from all 
imaging studies performed, catheterization laboratory reports and operating room reports. 
To assure access to these records, release of information forms will have to be signed by 
the participant as part of the initial informed consent process. If the participant does not 
present for the follow up within two weeks from the anticipated appointment time, an 
electronic medical record review and phone call follow-up will be performed and focused 
questions will be asked, to identify the occurrence of any of the endpoints. Questions 
about interval readmission will also be asked at the follow up visit/call.
b)
Ninety Day Follow-up
 Participants will be given a clinic appointment within two weeks after the 90th post-
randomization day. Questions regarding symptoms related to cardiac events, stroke, 
infectious complications will be asked as described above for the 30-day post-
randomization follow up. If participants are unable to make the clinic visit within two 
weeks of the assigned appointment then an electronic medical record review and phone 
call follow-up will be performed as described above. Readmissions since previous 
follow-up will also be investigated with similar series of actions as with the 30 day post-
randomization follow-up. Pertinent laboratory values (creatinine, troponin), EKG results, 
cardiac catheterization reports and operating room reports since the previous visit will be 
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reviewed in the electronic medical record to ascertain the presence of coronary 
revascularization, stroke, MI, or acute renal failure. 
c)
One Year Follow-up 
This will be follow up performed by trained staff from the Chair’s office who will call all 
study participants at twelve months after randomization to ascertain vital status. The 
CSPCC will generate listings of participants due for follow-up which will be sent to the 
Chairman’s personnel responsible for conducting the telephone interviews.  Follow-up 
data will be obtained by study staff.  This removes the need for personal identifying 
information to be maintained at the individual sites or the CSPCC and helps to protect 
participant confidentiality. Furthermore, chart reviews using the CAPRI/VistaWeb/JLV 
system will be performed as a participant’s death and the date of death are typically 
documented in the electronic medical record. Access to the national electronic health 
record will be requested. The VHA Death Ascertainment File (DAF) will be used to 
assess the one year vital status of those participants discharged alive from the hospital for 
whom vital status cannot be determined. Social Security number will be used to obtain 
the patient identifier PatientICN, which will be necessary for linkage to the DAF. We will 
request DAF data for all participants that have been randomized in the study.  All 
additional deaths identified through the DAF will be reported by study staff to the 
CSPCC staff in an electronic file.
D.
Missed Visits and Termination 
1.
Missed Visits 
If the subject fails to present to the clinic for follow-up visit, the site coordinator at the site will 
call the participant within 10 days to inquire about the reason for the missed visit and to 
reschedule the participant’s appointment as soon as possible.  If the participant still refuses to 
come for a clinic visit, the site coordinator will complete as much of the assessment as possible 
on the phone and using information from the electronic medical records. We anticipate issues 
with no-show for clinic visits to be minimal, as standard of care entails that participants need to 
present for frequent clinic visits after the major operations included in this study. Missed visits 
will be documented. The Site Coordinator will maintain a phone log that will include date, time, 
phone number called, reason for the missed visit, rescheduled date of clinic appointment, and/or 
reason for visit refusal. 
2.
Termination 
The active follow up period for study purposes will be up to 90 days after randomization. If the 
participant refuses to continue participation during active follow up, his or her participation in 
the study will be  be terminated. All participants who complete the active follow-up phase of the 
study will be followed up to one year by the Chair’s Office to assess mortality using a 
combination of phone call follow-up, search of the DAF, or electronic medical record 
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assessment. If a participant declines to participate in long term follow up then one year mortality 
data for this participant will not be collected. Given that the one year follow up is passive and 
does not involve any participant action we do not anticipate this to become a major issue.  
X.
TRANSFUSION STRATEGIES
Participants will be randomized to a liberal (transfuse if Hb <10 gm/dl) or restrictive (transfuse if 
Hb <7gm/dl) transfusion groups. Transfusion will be administered in order to maintain Hb just 
above the aforementioned thresholds for the index hospital stay or up to 30 days after 
randomization, whatever comes first. A participant must be randomized within 24-hrs of the first 
postoperative Hb falling below 10 gm/dl. It is strongly recommended that the transfusion 
treatment is initiated as soon as possible after and no longer than 24 hours from identifying a 
protocol-required transfusion Hb threshold.Transfusions will be administered according to the 
following scheme.
A.
 Liberal group (transfusion trigger: Hb < 10 gm/dl)
i.
If Hb < 7.5 gm/dl transfuse three units PRBCs, then check Hb. Based on the 
return Hb value, follow the transfusion protocol (steps i, ii, or iii) until Hb > 10. 
ii.
If 7.5  Hb < 8.5 gm/dl transfuse two units PRBCs, then check Hb. Based on the 
return Hb value, follow the transfusion protocol (steps i, ii, or iii) until Hb > 10.
iii.
If Hb ≥ 8.5 gm/dl transfuse one unit PRBCs, then check Hb. Based on the return 
Hb value, follow the transfusion protocol (steps i, ii, or iii) until Hb > 10.  
B.
Restrictive group (transfusion trigger: Hb < 7 gm/dl)
i.
If Hb < 5.5 gm/dl transfuse of two units PRBCs, then check Hb. Based on the 
return Hb value, follow the transfusion protocol (steps i, or ii) until Hb > 7. 
ii.
If 5.5 < Hb < 7 gm/dl transfuse one unit PRBCs, then check Hb. Based on the 
return Hb value, follow the transfusion protocol (steps i, or ii) until Hb > 7.
If during the course of the initial transfusions, any routine, non-protocol required hemoglobin 
check shows that Hb is past the target threshold prior to administering the total number of units 
indicated by the protocol, transfusion may be stopped. (example: participant assigned to the 
Liberal arm and has Hb less than 7.5 is, per protocol, to receive three units of PRBCs. If after the 
second unit, a Hb check reveals Hb greater than or equal to 10, then a third unit of PRBC is not 
necessary.)
For Hb values that are suspected to be incorrect (i.e., artificially low or high in the context of the 
participant’s clinical setting), order a repeat Hb within 6 hrs. of last lab to confirm values prior to 
initiating transfusion. 
A participant in either group may be transfused at any time without an Hb level if there is 
evidence of rapid bleeding (e.g. brisk gastrointestinal bleeding or suspected intraabdominal 
bleeding after major aortic repair) and the physician believes emergency transfusion is needed. 
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Furthermore, if a participant develops signs or symptoms of a possible transfusion reaction, 
which are estimated to occur in approximately 1% of transfused patients, the transfusion will be 
stopped immediately and hospital policies must be followed with respect to reporting of blood 
transfusions and obtaining any applicable required blood and/or urine specimens for hospital 
testing. The transfusion strategy protocol may be reinstituted with a different unit of blood after 
the participant’s condition has stabilized or if it is determined that the participant’s signs or 
symptoms were probably not related to a possible blood transfusion. In the uncommon event that 
more than ¾ of a unit of blood is transfused prior to halting of the transfusion, then the ¾ of a 
unit may be considered a full unit of blood. A different unit of blood need not be transfused to 
fulfill the initial 1 unit requirement. The transfusion protocol may be continued as required. 
If a participant experiences a myocardial infarction after being randomized to the transfusion 
protocol, the site investigators may either continue the participant’s study assignment to the 
transfusion protocol or elect not to follow the participant’s assignment to the transfusion protocol 
without removing the participant from the study. It is recommended that these participants 
continue on the transfusion protocol if randomized to that treatment, but the decision will be 
made by the site investigator and the participant’s attending physician. This modification is made 
to reflect the lack of high level empirical evidence regarding the optimal transfusion threshold 
after patients experience a myocardial infarction. 
Immediately following randomization, study personnel will place a label on the participant’s 
room indicating that the patient is part of a transfusion study. The purpose of this label will be to 
remind housestaff that this is a study patient and that the Site Investigator needs to be contacted 
prior to making any transfusion decisions. The Site Investigator along with the Study 
Coordinator will be in charge of implementing the treatment protocol during work hours. On 
nights and weekends when Study Coordinator is not available then implementation of the 
protocol will be the responsibility of the Site Investigator(s). For patients who are in the 
Intensive Care Unit postoperatively special circumstances may arise, as care in ICU setting is 
sometimes provided by a group of intensivists in some hospitals. To facilitate study execution in 
these facilities, every effort will be made to designate an ICU attending surgeon as Site 
Investigator. If this is not feasible, then the intensivist team of physicians will be educated with 
respect to the study, and arrangements will be made for the Site Investigators to make the 
transfusion decisions in the randomized patients. 
Participant Hb, creatinine, and troponin levels will be collected on days 1, 2, 3, 4, and 7 post-
randomization or discharge (whatever is shortest). EKG will be performed on days 1 and 4 after 
randomization. If a participant is discharged prior to post-randomization day 4, EKG will be 
obtained at discharge. Results on Hb (standard of care/per transfusion protocol requirements), 
creatinine, troponin, and EKG performed at other time points will also be collected until 
discharge as supporting documentation for endpoint adjudication. If available at the institution, 
CK-MB will also be collected (not required).
Urine output will also be monitored in patients admitted to the Intensive Care Unit and it will be 
reviewed daily by the Study Coordinator. If the patient has anuria for more than 12 hours, or has 
urine output less than 0.3 ml/Kg/hr for more than 24 hours then the urine output will be 
documented as evidence for the development of ARF. 
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Hemoglobin and transfusion record: We will record the number of blood transfusions during the 
preoperative, intraoperative, and postoperative time periods. The protocol requires that Hb levels 
be measured on day of randomization, days 1,2,3, and 4 after randomization as well as on day 7 
if the participant remains in the hospital.  Hb measurements, performed as standard clinical 
practice, will also be recorded. The Site Coordinator will record information on a) preoperative, 
intra-operative, and postoperative transfusions, and b) Pre- and post-randomization Hb levels. 
Information on Hb levels and transfusions will be obtained by contacting the hospital laboratory 
directly or from the chart.  Information on transfusions will be obtained from the chart and the 
blood bank.  
XI.
MONITORING AND REPORTING SERIOUS ADVERSE EVENTS
A.
Importance of Serious Adverse Event Reporting
Timely and complete reporting of safety information assists study management in identifying 
any untoward medical occurrence, thereby allowing:  a) protection of safety of study 
participants, b) a greater understanding of the overall safety profile of the study treatments and 
therapeutic modalities, c) improvements in study design or procedures, and d) compliance with 
regulatory requirements. 
B.
Role of the Local Site Investigator in Serious Adverse Event Monitoring
The local site investigator, as well as other site personnel, shall be personally responsible for the 
following requirements:
1.
Closely monitoring all study participants for new SAEs;
2.
 Reviewing the accuracy and completeness of all SAEs reports; 
3.
Completion of all SAE case report forms as required by this protocol and further 
described in the study Operations Manual; 
4.
Complying with Cooperative Studies Program (CSP) policies for reporting SAEs;
5.
Knowing and complying with the VA Central IRB (CIRB) (accessible at  
http://www.research.va.gov/vacentralirb/) and VHA Handbook 1058.01 Research 
Reporting Compliance Requirements section 7.a, 7.b and 7.c (accessible at 
http://www1.va.gov/vhapublications/ViewPublication.asp?pub_ID=2463) reporting 
requirements for unanticipated problems. Education on the responsibility of site study 
staff at each participating site to know and comply with these requirements will be a 
component of the study kickoff meeting, reinforced at study annual meetings, and on 
periodic conference calls. Questions about managing or reporting of serious adverse 
events will be directly addressed by the Study Pharmacist at the CSPCRPCC, CSPCC 
or the Quality Assurance Nurse (QAN) at the CSPCC. These requirements, however, 
do not eliminate the need for investigators to report SAEs to the CSP Sponsor as per 
the study’s Operations Manual, and;
6.
Complying with local Research & Development Committee (R&DC) policies and 
CIRB of record policies for reporting SAEs; 
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7.
Closely monitoring research participants during their study participation at each 
follow-up visit for any new SAEs and for follow-up of previously reported SAEs
8.
Providing SAE follow-up information at least every 30 calendar days or sooner if 
new information becomes available until the SAE has resolved or is stable with no 
changes anticipated in the future.  
9.
Notifying the CIRB or record and local R&DC of safety issues reported to the 
investigator by the Study Sponsor (CSP).
C.
Definitions
1.
Serious Adverse Event
Serious adverse events are defined by the ICH for Clinical Safety Data Management (ICH-E2A), 
the Food and Drug Administration (21CFR312.32 and CSP Global SOP 3.6, as any untoward 
medical occurrence that:

Results in death, 

Is life threatening,

Requires inpatient hospitalization or prolongation of existing hospitalization,

Results in persistent or significant disability or incapacity,

Is a congenital anomaly/birth defect, or

Any other condition that, based upon medical judgment, may jeopardize the subject and 
require medical, surgical, behavioral, social or other intervention to prevent such an 
outcome.
2.
Relatedness
Relatedness involves an assessment of the degree of causality (attributability) between the study 
intervention and the event. Site investigators will be asked to provide an assessment of 
relatedness. The assessment provided by the site investigator is part of the information used by 
the sponsor to determine if the adverse event presents a patient safety concern and/or requires 
regulatory reporting. Pursuant to CSP Global SOP 3.6, a SAE is deemed to be associated with 
the use of a study drug/device if “there is a reasonable possibility that the experience may have 
been caused by the drug/device or by participation in the trial.” Thus, all SAEs with a reasonable 
causal relationship to the investigational treatment should be considered “possibly related” or 
“related.” A definite relationship does not need to be established but there must be some 
evidence to suggest a causal relationship between the investigational treatment and the adverse 
event (21 CFR 312.32). The following levels of relatedness will be used in this trial:

Not attributed to a study intervention 

Possibly attributed to a study intervention 

Attributed to a study intervention
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D.
Collection of Safety Information
Given the large number of comorbidities expected in the study population and the high-risk 
operative procedures these patients will be undergoing, it is anticipated that a large number of 
AEs will be observed, most of which will not be related to the study intervention. For this reason, 
the study will only collect reports of Serious Adverse Events (SAEs).
All SAEs, whether related or unrelated to the treatment interventions, will be recorded and 
reported in an expedited fashion. Assessment of relatedness for SAEs is described above.  
Unexpected serious adverse events that are attributed or possibly attributed to a study 
intervention will be managed as provided in CSP Global SOP 3.6. 
Directions on how to complete the Serious Adverse Event Form will be detailed in the 
Operations Manual. Sites are required to report each SAE to the Sponsor within 3 calendar days 
from the time the site investigator becomes aware of it. The PCC Study Pharmacist will complete 
a safety and regulatory review of all SAEs. All investigators will be notified of any new hazards 
or other trends involving patient safety as provided in Global SOP 5.3.
Active monitoring of reportable SAEs will begin as soon as randomization is complete and will 
end at 90 days after randomization or termination. The treatment plan includes follow-up 
outpatient visits of all participants for 3 months after randomization. 
1.
Expedited Reporting of Serious Adverse Events
All SAEs require prompt reporting to the CSP Coordinating Center and CSP Clinical Research 
Pharmacy Coordinating Center (CSPCRPCC) within 3 calendar days of the site investigator 
becoming aware of the event. The Pharmacist at the CSPCRPCC is responsible for evaluating all 
SAEs for participant safety concerns and/or regulatory reporting.  The Pharmacist will consult 
with the Chairman’s office during the review process, as necessary.  The CSPCPRCC maintains 
a database of serious events for evaluation, by using the Medical Dictionary for Regulatory 
Activities (MedDRA) for coding and trending.  Periodic summaries will be provided to the Data 
Monitoring Committee, the Study Chairman’s office and Executive Committee (as necessary).  
Events that are determined to be serious, unexpected, and related to the study treatments will be 
reported to the site investigators, CIRB, and to the VA Cooperative Studies Program Central 
Office. 
SAE Forms will be sent to the Perry Point CSPCC as directed.  The CSPCRPCC will also have 
access to the information on the SAE Forms. 
2.
SAE Follow-up Reporting
If additional information is required the CSPCC or CSPCRPCC will fax or email a request to the 
site personnel reporting the SAE. The site should handle requests for SAE follow-up information 
in the same prompt manner that original SAE reports are handled. Serious adverse events should 
be followed to resolution, stabilization, or the participant’s last active study contact , whichever 
occurs first.  If an SAE is still ongoing by the time the SAE Form is submitted to the Perry Point 
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CSPCC, complete an SAE Follow-up Form every 30 days until the SAE is resolved or stabilized. 
SAE Follow-up Forms will be sent to the Perry Point CSPCC as directed.  The CSPCRPCC will 
also have access to the information on the follow-up SAE Forms.
It is the responsibility of the site investigator / coordinator at each participating site to know and 
comply with the SAE reporting requirements of the VA CIRB.  
The CSPCRPCC is responsible, in conjunction with the CSPCC, for coding study safety data 
into the MedDRA (Medical Dictionary for Regulatory Affairs) Dictionary and creating event 
tabulations.  The study biostatistician will present a summary of those events to the data 
monitoring committee (DMC) on a schedule set by the DMC. The DMC will recommend to the 
CSRD Director whether the study should continue or be stopped for safety reasons. Summary 
reports from the DMC will be provided to each site for their records. 
Unexpected SAEs will be reported to the Study Chairs’ Office.  The Study Chairs and the 
CSPCC Directors will report SAEs that are determined to be both related to the investigative 
treatment and unexpected to the CSRD Director and site investigators after review.
E.
Risks to participant

Risks related to transfusions:  Known risks related to blood transfusions include, but 
are not limited to, infection or irritation where the needle is placed, temporary 
reaction such as fever, chills, or skin rashes. Other rare but more serious 
complications may occur such as allergic reactions. Symptoms of allergic reactions 
include anxiety, chest and/or back pain, trouble breathing, fever, chills, flushing, and 
clammy skin, a quick pulse, and/or nausea (feeling sick to the stomach). Other rare 
but more serious complications include: heart failure due to fluid overload, acute 
pulmonary edema (fluid leaking into the lungs), shock, or death. Transfusions of 
blood involves a small risk of transmission of diseases such as Hepatitis B (1 in 
137,000), Hepatitis C (1 in 1,000,000), and HIV/AIDS (1 in 1,900,000). There is also 
a small risk of bacterial infection when blood products are transfused. 
The risk associated with receiving too much blood is heart failure due to fluid 
overload and an iron overload. Getting too many blood transfusions can cause too 
much iron to build up in the blood. People who have a blood disorder like 
thalassemia, which requires multiple transfusions, are at risk for iron overload. Iron 
overload can damage the liver, heart, and other parts of the body.
Receiving too little blood may reduce the body’s ability to deliver oxygen to organs 
and other vital systems. Without oxygen, critical functions of the body will be 
interrupted and/or damaged.  
Acute immune hemolytic reaction is very serious, but also very rare. It occurs if the 
blood type received during a transfusion does not match or work with the recipient’s 
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blood type. The body attacks the new red blood cells, which then produce substances 
that harm the kidneys. Symptoms of acute immune hemolytic reaction include chills, 
fever, nausea, pain in the chest or back, and dark urine.
Delayed hemolytic reaction is a much slower version of acute immune hemolytic 
reaction. The body destroys red blood cells so slowly that the problem can go 
unnoticed until the red blood cell level is very low. Both acute and delayed hemolytic 
reactions are more common in patients who have had previous transfusions. 
Graft-versus-host disease (GVHD) is a condition in which white blood cells in the 
new blood attack  tissues. GVHD usually is fatal. People how have weakened 
immune systems are the most likely to get GVHD. Symptoms start within a month of 
the blood transfusion. They include fever, rash, and diarrhea. To protect against 
GVHD, people who have weakened immune systems receive blood that has been 
treated so the white blood cells can’t cause GVHD.            

Risks related to venipunctures needed for the blood draw procedure: temporary 
discomfort, slight pain, weakness, dizziness, or bruising. Rarely, a blood clot may 
form in the vein that was used for the blood draw. The blood clot may cause serious 
discomfort that may require a short period of anti-inflammatory medications or to 
fully resolve. The blood clot may also lead to infection.

Risks related to EKGs: skin irritation due to the pads that are placed on the skin and 
some risk of pain when the pads are removed from the skin

Risks related to the loss of confidentiality: minimal risk for the loss of confidentiality.
In addition to the risks identified above, there may be unknown risks associated with 
these procedures 
 
F.
Benefits for study
Veterans will be notified that there are no benefits from taking part in this research study.  All 
participants will receive $25 per outpatient clinic visit or phone call visit as compensation for 
travel and meal related expenses. 
XII.
QUALITY CONTROL PROCEDURES
A.
Standardization/Validation of Measurements
Prior to the start of the study recruitment, all of the site investigators and research coordinators 
will be provided with in-depth trainings on different aspects of the conduct of the study during a 
“kick-off” meeting to ensure proper understanding of the technical aspects of the protocol, to 
ensure uniformity in the completion and submission of the case report forms and to ensure 
uniformity in implementing and performing the study procedures.
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Site investigators and research coordinators will also receive informed consent and study 
procedures training by the CSPCC staff during the kick-off meeting.  CSPCC staff will provide 
training on study procedures including the use of the study SharePoint portal, data collection on 
the iDataFax platform, randomization and assessment schedules.  
B.
Participant Management
This research study will be conducted in full accordance with ethical principles of human 
research, including the provisions of the World Medical Association Declaration of Helsinki.
All participants will be screened for study eligibility using the same inclusion/exclusion criteria 
as defined in this protocol.  Those participants who qualify will be engaged in the study consent 
process by the clinical care team in collaboration with the research coordinator and led by the 
surgeon investigator.  For those who agree to participate, local sites will adhere to their 
institution’s established best clinical practices in the care of the participants with exception to 
allowing for randomization postoperatively once the participant’s Hb falls below 10 gm/dl.  
Participants will be followed throughout their hospital stay for research data collection including 
any serious adverse events (e.g. major adverse cardiac events).  Usual post-operative care will 
follow institutional standards
 Participants will be encouraged to seek medical attention as instructed upon discharge from the 
hospital.  Throughout the duration of the study participation, the participant will be encouraged 
to maintain a point of contact with the local site investigator and the study coordinator for 
research related activities and questions. The study team at each site will maintain a dedicated 
point of contact for all participants seeking information during their study participation. The 
study coordinator at each site will communicate any necessary medical information to the 
surgeon investigator and the clinical care team.  
C.
Protocol Violations
Any protocol violation will be reported immediately to the Chairman’s office and the Perry Point 
CSPCC.  Each of these groups then reserves the right to forward notification, as required by local 
policy and regulation.  Protocol violations will be forwarded to the VA central IRB based upon 
guidelines provided.  Approved  instances for transfusion strategy halting include: transfusion of 
a participant regardless of group (restrictive or liberal) assignment in case of rapid bleeding; 
stopping transfusion due to adverse reactions to blood transfusion; and halting transfusion 
protocol, at the attending surgeon’s discretion, if the participant develops a post-randomization 
MI.  Any other deviation from the protocol will be considered a protocol violation.
D.
Plans to be implemented if recruitment goals are not met
If recruitment has fallen short of anticipated goals, the following will be considered to improve 
participant recruitment:

Eligibility criteria will be reassessed to determine if there are any alterations in 
inclusion/exclusion criteria that could be made to increase recruitment. A conference 
call/meeting of the Executive Committee with local site investigators will occur to 
discuss any change in eligibility criteria.
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
We will expand the study population to include patient undergoing high-yield, 
common orthopedic operations, such as hip and knee replacement. 

Additional sites will be considered, if needed.
E.
Site Performance Monitoring
1.
Monitoring Medical Center Performance
Strict adherence to the protocol will be expected of every participating center and 
monitored by the DMC and the Executive Committee. Documentation of protocol 
noncompliance will be required, and medical centers with repeated protocol 
noncompliance may be subject to termination. 
If a participating investigator feels that adherence to the protocol will in any way be 
detrimental to a particular participant's health and well-being, the interest of the 
participant must take precedence. Those instances may arise during the course of usual 
patient care, but the participating investigator will need to provide justification for the 
actions and the circumstances that led to noncompliance. 
By agreeing to participate in the study, the medical center delegates responsibility for 
global monitoring of the ongoing study to the Cooperative Studies Program and 
personnel listed above. However, the Research and Development (R&D) Committee and 
the IRB of record may require the participating investigator to submit annual and final 
progress reports concerning the status of the study at the medical center for local 
monitoring purposes.
2.
Guidelines for Special Attention, Probation or Early Termination of a  
Participating Site 
During the course of a study, it may be necessary to critically review participating 
medical centers on recruitment and protocol compliance measures. Such actions will be a 
collaborative effort between study leadership and an individual site. 
Early termination is usually based on recommendations from the Executive Committee 
and/or the Data Monitoring Committee. Often, it reflects inadequate participant intake or 
serious non-adherence to the protocol or with Good Clinical Practices (GCP) Guidelines. 
This action will always in the best interests of the study and study participants and does 
not necessarily imply poor performance on the part of the SI or the medical center. 
Termination will be conducted per CSP policies. All site termination decisions will have 
the prior approval of the CSPCC Director and the Director, CSP.
3.
Premature Termination of the Study
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The director, CSP, can terminate a cooperative study before completion. The DMC 
makes recommendations as to whether the study should continue or be terminated. The 
decision to terminate a study prematurely is a complex one involving many factors. The 
DMC may consider the following circumstances as grounds for early termination:
a.
If participant accrual falls far below that which is predicted (e.g., 75% of 
expected accrual), it will be necessary to reassess the study design and the 
potential value of its continuation.
b.
If participant accrual far exceeds the predicted, this study could be 
completed at an earlier date.
c.
If serious adverse events or deaths are noted to be excessive in either 
treatment group. 
d.
If interim analyses indicate a trend in the data which is unlikely to change 
prior to study completion.
e.
If, during interim analyses on the primary end point, the significance level 
crosses the efficacy boundary established by the DMC.
4. Recruitment Issues
The study chair and the study biostatistician will monitor the intake rate and operational 
aspects of the study. Participating medical centers that do not maintain adequate 
participant intake may be terminated from the study. The Executive Committee may also 
recommend the discontinuation of recruitment at a center with the concurrence of the 
CSPCC Director and Director, CSP. 
The leadership team along with potential input from the Executive Committee and/or 
DMC will determine the feasibility and necessity of excluding participating medical 
centers. Other options that may be considered include: probation with a detailed action 
plan, inclusion of new medical centers, minor modifications to the inclusion/exclusion 
criteria, or extending the recruitment period. 
If a participating medical center is placed on probation, the study chair will confer with 
the site personnel and may visit the site, if necessary, to help improve the rate of 
recruitment. If there is no improvement in accrual during the probation period, the site 
may be subject to reduced funding or possible discontinuation as a study site. To plan for 
the possible termination of one or more sites and the addition of any new sites, back-up 
sites with CIRB approval may be identified prior to study initiation to minimize the delay 
in adding a new site. Actions to discontinue a site will occur with the concurrence of the 
CSPCC Director and CSP Director and/or the Executive Committee. If a site is 
terminated from the trial, resources will be reallocated to other medical centers or used to 
start up a back-up site.
5. Non-adherence to the protocol and/or Good Clinical Practice (GCP) Guidelines
Strict adherence to the protocol and GCP guidelines will be expected of every 
participating medical center and monitored by the DMC, the Executive Committee, and 
the Study Group. Documentation of protocol deviations  will be required.  Medical 
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centers with repeated major protocol non-compliance or repeated failures to follow GCP 
Guidelines will be recommended for termination to the DMC, the CSPCC Director, and 
the Director, CSP. If a participating investigator feels that adherence to the protocol may 
result in an apparent immediate hazard to the participant, the interest of the participant 
must take precedence.
Protocol violations must be immediately reported to the CSPCC on the appropriate case 
report form and may require reporting to the Central IRB of record to ensure immediate 
hazard to the participant did not occur.  
XIII.
DATA MANAGEMENT
A.
Data Collection and Data Entry
Data management will be performed by the VA CSPCC Perry Point, MD using DataFax data 
management software.  The CSPCC will have overall responsibility for the data at the end of the 
study.
All data will be collected at the study sites on source documents, which will be entered at the site 
into paper CRFs.  The blank CRFs will be supplied by the CSPCC.  CRFs are to be completed on 
an ongoing basis during the study.  The medical chart and the source documents are the source of 
verification of data.  CRFs should be completed according to the instructions in the study 
operations manual.  The Site Investigator is responsible for maintaining accurate, complete and 
up-to-date records for each participant. The Site Investigator is also responsible for maintaining 
any source documentation related to the study.
  
Completed CRFs will be submitted by site personnel on a regular basis to the iDataFax system at 
the CSPCC.  iDataFax provides the options for site personnel to enter data elements into local 
study computer linked to CSPCC database as well as to fax the CRF to the CSPCC, and allows 
the clinical centers to retain the original CRF and source documents while providing an image to 
the CSPCC.  Data entered into the database or faxed within the image are then checked for 
accuracy/completeness and entered into the study’s database using iDataFax software.  Data 
received at the CSPCC will be reviewed, verified and edited before being entered into the main 
study database.  If incomplete or inaccurate data are found, a data clarification request will be 
forwarded to the clinical site for a response.  Sites will resolve data inconsistencies and errors 
before resending the corrected CRFs to the CSPCC.  All corrections and changes to the data will 
be reviewed before being entered into the main study database.  The participating sites will 
receive reports at least monthly regarding the quality and quantity of data submitted to the 
CSPCC.
Site investigators agree to routine data audits by the staff of the VA CSP monitoring unit, as well 
as by the CSPCC staff.  The VA CSP monitors will routinely visit each site to assure that data 
submitted on the appropriate forms are in agreement with source documents at the sites.  They 
will also verify that participant informed consent for study participation has been obtained and 
documented in the participant’s progress notes, all essential documents required by GCP 
regulations are on file, and sites are conducting the study according to the research protocol.  
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Any inconsistencies will be resolved, and any changes to the data forms will be made using 
established the CSPCC procedures.
When the study is completed and all data have been entered into the database and the database 
has been checked for quality and is locked, the CSPCC statisticians will perform statistical 
analyses of the data in accordance with the Statistical Analysis Plan (SAP).  Periodically, during 
the study, the CSPCC will prepare various summary reports of the data so that progress of the 
study can be monitored.  These reports will be prepared for the Data Monitoring Committee 
(DMC) and other committees, as appropriate.
B.
Archiving Study Data
Study documentation includes all paper CRFs, data clarification forms, source documents, 
monitoring logs and appointment schedules, investigator correspondence and regulatory 
documents (e.g., signed protocol and amendments, IRB correspondence and approved consent 
form and signed informed consent forms, Statement of Investigator form, etc.). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the study.  Thus, source 
documents include, but are not limited to clinical reports, participant completed assessments, 
progress notes, hospital charts or pharmacy records and any other reports or records of any 
procedure performed in accordance with the protocol.
Whenever possible, the original recording of an observation should be retained as the source 
document; however, a photocopy is acceptable provided that it is a clear, legible, and exact 
duplication of the original document.
Research records for all study participants are to be maintained by the investigator in accordance 
with the VA record control schedule until notified by the CSPCC.  These records are to be 
maintained in compliance with IRB, State and Federal requirements, whichever is longest. It is 
the investigator’s responsibility to retain copies of the completed CRFs until notified in writing 
by the CSPCC that they can be destroyed.  In all instances, the site must get permission from the 
CSPCC prior to disposition of any study documentation and materials. 
XIV.
DATA SECURITY PLANS
The clinical data management system to be used in this study will be fully compliant with US 
Federal regulations regarding electronic web-based data capture systems established by the Food 
and Drug Administration under 21 CFR 11.  Data entered directly into the database provides the 
official clinical record for data collection.  Source documentation is handled in the same manner 
as a paper-based system.  All paper-based records will be kept in locked file cabinets.  
The servers housing the study databases will be located at a secure VA facility and housed 
behind the VA firewall on VA owned and maintained servers. The information housed within the 
data management system will have the same level of security as all forms of VA protected and/or 
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highly sensitive information. The system will be monitored to ensure that all applicable VA 
regulations and directives are strictly followed. 
Access to the study data is restricted by the CSPCC to properly-credentialed research staff who 
have completed required VA security trainings.  An individual site’s study staff may only see the 
data for participants from their site. Only CSP-approved individuals (such as: staff at the study 
site, CSPCC, and CSP Clinical Research Pharmacy Coordinating Center (CSPCRPCC)) will 
have access to the personal health information (PHI) of study participants. In addition to the VA 
CSP, the Study Chair’s Office will have access to identifiable information so that they can call 
the study participant one year after their surgery. Identifiable information shared with the Chair’s 
Office will include: SSNs, phone numbers, and names. The Study Chair’s Office is located at the 
VA New York Harbor Health Care System in Brooklyn, NY.
Research data will only be stored on secure VA servers within the VA firewall.  The data will be 
coded with a unique study identifier for each participant and stored using that study identifier. 
Identifiable information will be collected for participant tracking and safety purposes, and to 
collect health care usage and cost data. Coded clinical data will be stored separately from the 
participant’s personal identifying information (i.e., participant’s name, contact information, and 
real SSN). Access to the cross-walk file linking the participant’s identifiers and their study data 
will be restricted to the clinical site and to the study staff at the CSPCC.
Microsoft SharePoint will be used to store study documents and as an alternative solution to 
transmit data from study sites to the CSPCC.  Security protocols for SharePoint will be in place:

Access and Permissions: Site Specific permissions, document library access will be 
limited to the appropriate personnel.

Semi-Annual Audit of Permissions:  the SharePoint Administrator maintains an access 
log.  All access is granted by the SharePoint administrator/site owner and granted based 
on approved requests. 
In case of improper use or disclosure of study data, the facility’s ISO and Privacy Officer, and 
the individual’s direct supervisor will be notified immediately per VA Directive and Handbook 
6500.  Records will be destroyed in accordance with the VHA Records Control Schedule and 
VHA Handbook 1200.05.
The system will utilize technologies to protect data during transmission. All of these 
technologies will meet or exceed current VA standards for data transfer. The data management 
system will use secure socket layer technology and FIPS 140-2 compliant encryption algorithms 
to ensure data are not vulnerable during transport. All data will be stored within the VA firewall 
and password protected at all times. Hard copy data will be sent via a traceable mail system (e.g. 
UPS), courier, or secure fax. 
Quality control checks and clinical monitoring will enable the CSPCC to examine the database 
and the clinical sites to ensure data have not been improperly used or accessed. Audit trails and 
access logs compliant with 21 CFR part 11 will be checked routinely, and clinical monitors will 
provide continuing education on GCP and check clinical site operations for violations of data 
security policies and best practices. 
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XV.
GOOD CLINICAL PRACTICES
A.
Good Clinical Practices (GCP)
This trial will be conducted in compliance with Good Clinical Practices (GCP) regulations.  The 
intent of these regulations is to safeguard participants’ welfare and assure the validity of data 
resulting from the clinical research.  The VA CSP will assist Local Site Investigators (LSIs) in 
complying with GCP requirements through its Site Monitoring, Auditing and Resource Team 
(SMART) based in Albuquerque, NM.  SMART serves as the Quality Assurance arm of CSP for 
GCP compliance.  SMART will provide training, manuals and materials to assist study personnel 
in organizing study files and will be available throughout the trial to advise and assist LSIs 
regarding GCP issues.  
Monitoring of sites participating in the trial will be executed according to VA CSP guidelines.  
SMART will conduct initiation visits at each site soon after the first participant is enrolled. 
Additional monitoring visits may be conducted as deemed necessary by study leadership or 
SMART. 
 Independent routine audits will be conducted at one or more sites per year as determined by 
SMART.  For-cause audits will be conducted as requested by study leadership or CSP Central 
Office.  These audits may be scheduled or unannounced. 
The purpose of these site visits is to encourage and assess compliance with Good Clinical 
Practice requirements.  Monitors/Auditors will examine participant study files including source 
documents in both the clinic files and the participants’ official VA medical records and will also 
review regulatory/essential documents such as correspondence with the VA’s Central IRB and 
Sponsor (CSP).  Areas of particular concern will be participant informed consent issues, protocol 
adherence, safety monitoring, VA’s Central IRB reviews and approvals, regulatory documents, 
participant records, drug accountability and investigator supervision and involvement in the trial. 
Reports will be prepared following the visit and sent to the LSI. In addition, the CSPCC in 
collaboration with SMART will monitor study sites remotely through weekly reports, data 
queries and SC/LSI conference calls.
B.
GCP Training
All primary Site Investigators and primary Study Coordinators will be required to complete CSP 
SMART GCP training and will also maintain ORD required training by taking the on-line CITI 
training (https://www.tms.va.gov) or ORD equivalent every  three years for the duration of the 
study.  All other study personnel must take the on-line CITI training or ORD equivalent prior to 
assuming their role on the study and then every two years thereafter for the duration of the 
study.  If additional sites are added or there is turnover in personnel, any new primary SI or 
primary SC are to satisfy the same requirements as delineated above for the primary SI or 
primary SC. Written verification of GCP/HSP training of study site personnel will be submitted 
to the CSPCC prior to the start of participant recruitment at each site.    
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C.
Summary of Monitoring and Auditing Plans
a.
Monitoring Visits 
(1)  Initiation visits at each site soon after sites randomize their first few 
participants
(2) Additional monitoring visits may be conducted as deemed necessary by study 
leadership or SMART.
b. Audits
(1) Routine audits – independent site visits to one or more sites per year as 
determined by SMART. 
(2) For-Cause audits –independent audit of a site as requested by study leadership 
or CSP Central Office.  
(3) Audits may be scheduled or unannounced.
XVI.
  BIOSTATISTICAL CONSIDERATIONS
A.
Expected Treatment Effects
In order to estimate 90 day composite endpoint rate (defined in Section V) after surgical 
interventions in the VA population, we conducted an analysis of Vascular and General Surgery 
operations identical to those targeted in the proposed trial as described in pages 5-7. Data of 
171,357 VA patients who underwent these vascular or general procedures and had available 
nadir Hb level from the Corporate Data Warehouse (CDW) database was used for this analysis. 
We anticipate in the proposed trial the nadir Hb in the restrictive transfusion group to range 
between 6-9 gm/dl (transfusion trigger Hb < 7 gm/dl). Our database review revealed that 29.8% 
out of 25,343 patients who were at high cardiac risk and had nadir postoperative Hb at this range 
developed the composite endpoint of death, MI, acute renal failure, or coronary revascularization 
within 90 days from the index operation. The breakdown of event rates for the individual 
components of the composite endpoint is shown in Table 2 . Based on the analysis, a baseline 
event rate of 30% for the composite endpoint is expected in the restrictive group.
B.
Sample Size Calculation and Power Analysis
The sample size estimation and power analysis are based on the hypothesis testing of the primary 
composite endpoint, which is the most important measure proposed in the study. According to 
the analysis of event rates outlined in the previous section, we assume that 30% rate for the 
primary endpoint can be anticipated in the restrictive transfusion group. We also assume a 25% 
reduction or 22.5% event rate in the liberal group. The sample size for the study is estimated 
based on a superiority trial design.  To detect the expected 7.5 percentage point difference or 
25% reduction, a sample size of 1444 will be required at 90% power, 5% type-I error rate and 
with a two-sided test (TABLE 3). Assuming 5% dropout rate, then 1520 participants (or 
760/group) will be needed to achieve the desired testing power.  
TABLE 3 Sample Size Estimation and Power Analysis 
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C.
Duration of Study and Number of Participating Sites
To calculate the expected study duration and resources, we assume that the recruitment rate will 
be half of what we anticipate. Under this assumption, various scenarios were examined in order 
to identify an optimal combination between the number of sites, the study duration (which 
includes recruitment period and follow-up period) and the estimated budget. By conducting the 
study with 15 sites and 3 participants/month/site rate of recruitment, the recruitment period was 
found to be approximately four years. This will be followed by three months of active follow-up 
and 9 months of passive follow up for the last subject randomized into the study. Thus, the study 
duration including start-up, will be five years.
D.
Feasibility Phase
In order to confirm the hypothesized control proportion for the primary outcome, to determine 
the feasibility of recruiting average 3 participants per site per month, and to assess other 
operational aspects of the study, a feasibility phase has been built into this study. The planned 
duration of the feasibility phase of the study is one year and will include 3 NODES sites 
(Houston, Minneapolis, and Dallas VA Medical Centers) and five additional sites with existing 
research infrastructure and high expected recruitment rates (Cleveland, Buffalo, Tampa, 
Gainsville, and Little Rock VA Medical Centers). 
During the feasibility phase, several site start-up activities and operational aspects of the study 
will be examined. These activities will include the hiring of site personnel (including 
classification of position descriptions, position announcements and recruitment), the methods by 
which site staff are trained on data collection and management activities, the practicality of 
consent, randomization and attrition (drop-out) rates. The lessons learned during this phase will 
be implemented during activation of the remaining 7 participating sites.
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Recruitment rates at the eight active sites will be closely monitored during this phase.  The initial 
eight sites are each expected to enroll 36 participants in the first year of the study, for a total of 
288 participants at the end of the first year. The actual recruitment experience of the eight sites in 
the first year will be used to revise the projected recruitment rate for the remainder of the study 
and may lead to a lengthening or shortening of the total recruitment period, as appropriate. 
Measures to address unexpectedly low recruitment rates during this feasibility phase have been 
described on page 14. At the completion of the feasibility phase, the study will be moved to a 
continuation phase where the remaining 7 sites will be activated and the remaining participants 
(1232 participants) will be recruited and followed up. 
E.
 Data Analysis Plan
The primary analysis will be performed to test the null hypothesis of no difference in composite 
outcome of all-cause mortality, MI, coronary revascularization, acute renal failure, or post-
randomization stroke between participants randomly assigned to a 10 gm/dl Hb transfusion 
strategy compared to participants assigned to 7 gm/dl transfusion strategy.  If the null hypothesis 
is not rejected, a 95% confidence interval will be constructed about the difference observed to 
inform the medical community as to how large the difference is likely to be in either direction.  
All statistical tests will be two-sided and the primary outcome will be tested at 5% level of 
significance. SAS 9.4 or higher will be used to conduct all the statistical analyses. A variety of 
analytic methods will be used for the primary endpoint, secondary endpoints, tertiary endpoints 
and other analyses (TABLE 4).  
1.
Analysis Populations
Intent-to-Treat (ITT) – This population is defined as the population of participants who will be 
randomized to either of the transfusion strategy groups – Liberal or Restrictive. The participants 
will be categorized (in terms of their transfusion strategy assignment) based on their initial 
randomized group and will be included in analyses irrespective of their status – completer or 
drop out of the study before completion. The testing power for the primary endpoint is estimated 
as 90% in this population.
Modified Intent-to-Treat (mITT) – This population is defined as a subset of the ITT population 
that excludes randomized participants in a justified way, i.e, participants who are found to be 
ineligible (violating major inclusion/exclusion criteria), such as non-Veterans, previous 
participants of this trial.
No-Recent-Transfusion – This population is defined as a subset of the ITT population 
excluding the participants who will receive transfusion(s) within 30 days prior to or during the 
index operation, or after the index operation but before randomization. 
Completers – This population includes all ITT participants who will complete all assessments in 
the hospital stay, as well as 30 day and 90 day follow-up. 
Per Protocol – This population includes all ITT participants who will adhere to transfusion 
protocol in their assigned intervention groups. 
Safety – This population includes all participants who will be randomized to either of the 
transfusion strategy groups – Liberal or Restrictive.
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The primary analysis of the study will be performed on the primary endpoint on the ITT 
population. The secondary analyses will be performed on the secondary and tertiary endpoints on 
the ITT population, as well as the analyses performed on all the primary, secondary, and tertiary 
endpoints on the mITT, No-Recent-Tansfusion, Completers, and Per Protocol populations. SAE 
will be analyzed based on the Safety population. 
2.
Primary endpoint analysis
The primary study endpoint will be composite outcome of all-cause mortality,  MI, coronary 
revascularization, acute renal failure, or post-randomization stroke within 90 days from 
randomization.  This outcome will be compared according to assigned transfusion strategy 
(analysis by intent to treat), using Pearson 2 test. The test for differences between transfusion 
strategies in the primary outcome will be conducted at an overall α-level of 0.05.  Additional 
analysis will be conducted using logistic models to adjust for other clinical factors, such as age, 
RCRI, nadir Hb, and interaction terms. Logistic regression will be used for the primary endpoint 
(y = 1 if a composite outcome, otherwise y = 0) analysis with transfusion strategy group as the 
testing factor ( x ). The following covariates will be included in the model: age (z1), RCRI (z2), 
nadir Hb(z3), site (z4), and the interactions of testing factor with age (w1),  RCRI (w2) and nadir 
Hb (w3). Given the composite outcome probability p=Pr(y=1|x , z1,z2, z3, z4,w1,w2,w3) , the 
basic model is defined as follows:
Logit( p)=ln(
p
1−p)=β0+β1 x+ β2 z1+β3 z2+ β4 z3+β5 z4+β6w1+β7 w2+β8 w3
Odds ratio and 95% confidence interval (CI) will be presented using SAS PROC GENMOD. If 
the coefficient for treatment effect is significant, then the null hypothesis will be rejected. 
Logistic models will be tested for goodness of fit.  We will assess goodness-of-fit using the 
statistic -2 log likelihood, which has a chi-square distribution under the null hypothesis that all 
the explanatory variables in the model are zero. We will also consider the Akaike Information 
Criterion statistic and the Schwartz Criterion statistic, both of which adjust the -2 log likelihood 
for the number of items in the model. Models that show lack of fit will be reconsidered for the 
inclusion of additional variables or use of alternate models with assumptions that are better met 
by the study data.  One alternate model if model fit is poor for logistic regression is a log-linear 
model.
3.
Secondary endpoint analyses
Secondary endpoints included in the analysis are composite endpoints of infectious 
complications (wound infections, pneumonia, and sepsis) and cardiac complications (arrhythmia, 
CHF, exacerbation, and cardiac arrest), composite events of all-cause mortality, MI, coronary 
revascularization, acute renal failure, or post-randomization stroke at 30 days, all-cause mortality 
at one year, and length of hospital stay. For the binary endpoints, the effect of transfusion 
strategy on these endpoints will be analyzed initially with a Pearson chi-square test and 
additional analysis will be performed by taking account of age, RCRI, nadir Hb, site ,and the 
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interaction terms using logistic regressions as described in the primary endpoint analysis.  For 
the length of hospital stay, medians (interquartile ranges) will be presented and Wilcoxon test, a 
nonparametric method, will be used to compare the medians of the length of hospital stay 
between the two intervention groups. In addition, quantile regression will be used to test the 
effect of the intervention on the time until discharge from hospital adjusted for age, RCRI, nadir 
Hb and the interaction terms as described in the primary analysis.  The test for differences 
between transfusion strategies in each secondary outcome will be conducted at an α-level of 
0.01.  
4.
Tertiary endpoint analyses
Tertiary endpoints included in the analysis are individual components of the primary composite 
outcome of all-cause mortality, MI, coronary revascularization, acute renal failure, or post-
randomization stroke at 90 days. All are considered as binary variables in the study, and the 
effect of transfusion strategy on these endpoints will be analyzed initially with a Pearson chi-
square test. The test for differences between transfusion strategies in each tertiary outcome will 
be conducted at an α-level of 0.01. Additional analyses will be carried out by taking account of 
age, RCRI, nadir Hb and the interaction terms using logistic regressions as stated in the 
secondary endpoint analyses. 
5.
Other analyses
Baseline characteristics
Subject demographics and pre-surgical baseline characteristics will be summarized for each 
intervention group and for all participants (ITT and mITT). The subject demographics such as 
age, race, gender, ethnicity etc. and baseline test results such as Hb, albumin, troponin, 
creatinine, EKG, SBP/DBP, BMI, RCRI etc. will be analyzed. For continuous variables, the 
sample size, mean, median, SD, minimum, and maximum values will be calculated and tested 
either by Student t or Wilcoxon test depending on data distributions. For categorical variables, 
the number and percentage of participants by the intervention group will be tabulated and tested 
using Pearson chi-square test.
Disposition status
Subject disposition will be summarized for the ITT and mITT populations. The number and 
percentage of participants who completed or discontinued prematurely from the study by 
intervention group will be tabulated and tested using Pearson chi-square test. The number and 
percentage of participants who discontinued for each reason will be presented for each 
intervention group. The number and percentage of participants who completed or discontinued 
prematurely in each intervention group will also be displayed graphically. 
Adherence
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Participants who change transfusion strategy after randomization or have protocol violations will 
be identified as non-adherence to the intervention (ITT and mITT). The number and percentage 
of non-adherence participants will be summarized by intervention group and tested using 
Pearson chi-square test.
  
Age of blood in relation to 90 day composite endpoint, wound infection, and pneumonia
Analyses will be conducted of the associations between characteristics of transfused blood and 
three outcome measures (90 day composite endpoint, wound infection, and pneumonia).  Current 
data collection plans call for blood expiration dates and the age of each unit of blood transfused 
will be calculated.   Logistic regression models will be fitted to test for association between these 
outcomes and age of blood transfused (entered in different models as oldest unit transfused or as 
mean age of all units transfused). The analyses will be adjusted for age, RCRI, nadir Hb, site, 
and the transfusion intervention. The test for differences of these outcomes will be conducted at 
an α-level of 0.01. The analyses will be done on the ITT, mITT, No-Recent-Tansfusion, 
Completers, and Per Protocol populations. 
Time-to-event analysis for primary and major secondary endpoints
Survival analysis techniques will be used to analyze the time-to-event data for the primary and 
major secondary endpoints. Kaplan-Meier analysis will be used to estimate the survival (not 
experiencing event) over time in the two intervention groups and a log-rank statistic will be used 
to test the equality of the survival function estimates in the two groups.  Cox’s Proportional 
Hazards models will be used to test the effect of the intervention on the time until endpoint 
events adjusted for age, RCRI, nadir Hb, site, and the interaction terms as described in the 
primary and secondary endpoint analyses. The analyses will be done on the ITT, mITT, No-
Recent-Tansfusion, Completers, and Per Protocol populations. 
 
TABLE 4: Statistical Analysis Schema
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F.
Criteria for Study Termination
There will be three interim analysis of the primary oucome measure performed in the 
studywhen 25%, 50%, 75% of the planned participants completed their participation in the 
study . If analysis of the primary outcome rates at the time of interim analysis indicates that the 
null hypothesis can be rejected the study will be recommended for termination for safety reasons. 
G.
Handling of Missing Data
Every effort will be made to minimize the occurrence of missing data, particularly for the 
primary and main secondary outcome measures. For the primary outcome, every effort will be 
made to contact the participants over the phone until participant termination.  In the event of a 
potential drop out, every effort will be made to capture the primary outcome data from the VA 
databases. For participants who drop out during the study, multiple imputation (MI) method may 
be used for certain endpoint analyses. Multiple imputations will be based on Rubin’s procedure 
using SAS PROC MI and PROC MIANALYZE.  Sensitivity analysis will be performed to 
compare the results from the imputed data and the complete data without imputation. 
      
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H.
Reporting of Any Deviations from the Original Statistical Plan
A more detailed statistical analysis plan (SAP) will be generated which will include the 
details of each statistical analysis plan for each outcome measure along with the suggested table 
shells for any reports that will be produced during the study and at the end of the study. Any 
deviations in the statistical plan from the protocol will be specified in the SAP. Any deviations 
from the SAP will be specified in a revised main manuscript which will be prepared and 
published at the end of the study. 
XVII. STUDY ORGANIZATION AND ADMINISTRATION
A.
Requirements for Participating Medical Centers
All participating medical centers must be willing and able to adhere to the study protocol.  
Minimum requirements for participating medical centers will include:
1. Local Site Investigator
 
 .  The local site investigator will be an individual with a clinical 
degree (e.g. psychologist, psychiatrist, nurse) who agrees to support the study 
enthusiastically and devote sufficient time and energy to ensure that recruitment goals are 
achieved and that study participants are followed appropriately.  The Site Investigator 
will have at least a 5/8 VA appointment.
2. Study Coordinator
 
 .  The Site Investigator will recruit a Study Coordinator to assist in all 
aspects of study conduct including recruitment, participant monitoring, and assistance 
with all study procedures.  The Site Investigator will make all efforts to ensure that the 
chosen Study Coordinator is competent and enthusiastic.  Experience in the conduct of 
clinical investigation is highly desirable.  The Study Coordinator is expected to work 
diligently with the Site Investigator to meet the goals of the study.  In addition, the Study 
Coordinator will be expected to work collaboratively with the staff at the Chairman’s 
office and the CSPCC.
3. Administrative Support
 
 .  Each site must provide a letter from the Director and/or the 
Chief of Staff ensuring that its Site Investigator will receive full administrative support 
during the conduct of this study.  
4. Local Approvals and Reporting Requirements
 
 .  Sites will be required to agree to allow 
the VA Central IRB to be the primary IRB for the study and agree to use the VA Central 
IRB’s informed consent template updated only for site specific items in the template 
(e.g., names of the Site Investigator).  Site Investigators will be responsible for 
coordinating the medical center’s interactions with the VA Central IRB.  All sites will 
require Research and Development Committee approval of the study, and some sites may 
still require local IRB approval.  The Site Investigator will be responsible for obtaining 
initial approval for the protocol and the informed consent form from his/her VA medical 
center’s Research and Development Committee and from the Human Studies 
Subcommittee/IRB. Copies of the minutes for the meeting documenting approval by 
these committees or a letter from the Chair of the appropriate Committee stating when the 
Committee met, what their concerns were, and their final recommendation, will be 
submitted to the CSPCC before any participants are enrolled at the local center.  It will be 
the responsibility of the Site Investigator to maintain continuing approval of the protocol 
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at the local site.  Documentation of this continuing approval will be submitted to the 
CSPCC.
5. Global Monitoring and Reporting Responsibilities Delegated
 
 .  By agreeing to participate 
in the study, centers delegate responsibility for global monitoring of the ongoing study to 
the VA Central IRB, DMC, HRC, CSSEC, CSPCC, and the CSPCRPCC.  In addition, 
the local Research and Development Committee and the local Human Studies 
Subcommittee/IRB will require the Site Investigator to submit annual reports concerning 
the status of the study for local monitoring purposes.
B.
Study Management
CSPCC:  The Perry Point Cooperative Studies Program Coordinating Center (CSPCC), located 
in Perry Point, Maryland, will provide administrative, data processing, and statistical support for 
the study. All data forms will be submitted to the CSPCC for processing. The CSPCC will edit 
the data and create the study database.  The CSPCC staff will provide guidance on completion of 
forms, including SAE reports. All reports during the ongoing phase of the study and the final 
statistical analyses will be the responsibility of the CSPCC.  The CSPCC staff will also monitor 
study progress to ensure that the study is proceeding as scheduled.  This team will be headed by 
the study biostatistician and will include a CSPCC project manager, a statistical programmer, a 
database programmer, two computer assistants, and a quality assurance nurse.
Office of the Chairman:  Chairs will be in routine contact with the participating centers to ensure 
that the study is performed in accordance with the protocol and to encourage the local study team 
to keep recruitment and follow-up activities on schedule.  The Study Chairman will preside over 
all meetings of study participants and will represent the study, along with the study 
biostatistician, at all meetings of outside review committees. The Chairman’s Office will be 
funded with a full-time National Study Coordinator (1.0 FTE). 
National Study Coordinator: The National Study Coordinator is responsible for maintaining 
enthusiasm for the study at all sites, discussing problems of mutual interest related to the study, 
and identifying any procedural/definitional modifications that might be required.  The National 
Study Coordinator will be responsible to oversee all study activities in the Chairman’s Office on 
a day-to-day operational basis. Specifically, the National Study Coordinator will: 
1. Assist the Study Chairpersons in coordinating and administering all aspects of the study;
2. Assist the Study Chairpersons in monitoring the progress of the study;
3. Maintain close contact with the participating investigators/local study research Site 
Coordinators and assist them in any procedural details of the study: 
4. Maintain close contact with the study’s supervisory committees; and 
5. Work collaboratively with the Perry Point CSP Coordinating Center team to organize and 
plan periodic meetings of participating investigators for the purposes of reporting 
progress of the study. 
The CSP Clinical Research Pharmacy Coordinating Center (CSPCRPCC): is responsible for 
monitoring and reporting the safety of trial participants through the review, assessment, and 
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communication of serious adverse events and serious adverse events reported by study 
personnel. The CSPCRPCC’s responsibilities occur through ongoing communication with the 
Study Chairman, Executive Committee, Perry Point CSPCC, and CSP Central Office. The 
reporting activities include the filing of regulatory documents involving adverse events to meet 
applicable federal regulations and CSP policies. In conjunction with the Perry Point CSPCC, the 
CSPCRPCC prepares reports safety data for various committees including the Data Monitoring 
Committee, the IRB, Executive Committee, and the study group. If any new harzards occurs, the 
CSPCRPCC will prepare and send an approved document to notify all site investigators within 
after the conference call of the identification of the new safety information.
Endpoint Committee: The Endpoint Committee is a group of experts comprised of a cardiologist, 
a surgeon, a nephrologist, and an internal medicine/cardiology physician. The committee is 
responsible for the endpoint outcome measure adjudication. 
Study Sites:  The Site Investigator at each of the participating medical centers will be responsible 
for all aspects of the study at his/her site.  This includes participant recruitment and follow-up, 
obtaining initial and yearly local R&D Committee and IRB approvals, ensuring adequate 
coverage for the study in his/her absence or the absence of other study participating staff, and 
ensuring the integrity of the study protocol and data from his/her site.  A Study Coordinator will 
be funded for each site and the Site Investigator will be responsible for hiring and supervising 
this person.  In no case should any local Study Coordinator be assigned duties not related to this 
study.  The primary goal for this position is successful recruitment, explaining informed consent, 
gathering data, and coordination of follow-up assessments.  Funding for this position may be 
terminated or reduced if insufficient participants are recruited and/or data collection and follow-
up are deemed to be unsatisfactory.  Each Study Coordinator will work with the National Study 
Coordinator (located at the Study Chairman’s office) to develop and to implement a recruitment 
plan.  The Study Coordinator at the sites will participate in periodic conference calls with the 
other Study Coordinators and study staff.  
C.
Monitoring of the Study 
1.
Monitoring bodies
The groups charged with monitoring the various aspects of the study will be the Executive 
Committee, the Data Monitoring Committee (DMC), the VA’s Central IRB, and the Perry Point 
Human Rights Committee.  These committees will meet at regular intervals according to the 
current Cooperative Studies Program guidelines: prior to the beginning of participant intake and 
at least every twelve months thereafter.  In addition, the CSP Site Monitoring, Auditing and 
Resource Team (SMART), located at the CSP Clinical Research Pharmacy Coordinating Center 
(CSPCRPCC), will monitor the trial for GCP compliance. 
The  Executive Committee is chaired by the Principal Proponent and consists of the study 
Biostatisticians,  study  Project  Manager,  study  Research  Pharmacist,  selected  participating 
investigators, and expert consultants. The Executive Committee is concerned with overall study 
management and is the decision-making body for the operational aspects of the study. The 
Executive Committee monitors the performance of participating medical centers and quality of 
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data collected, plans the publications, and oversees the publication and presentation of all data 
from the study. The Executive Committee must grant permission before any study data may be 
used for presentation or publication. This committee meets by conference call typically on a 
monthly basis to review the study progress and meets every 12 months to review blinded study 
data, decide upon changes in the study, determine the fate of sites whose performance is 
substandard, initiate any sub-protocols, and discuss publication of the study results. 
The Data Monitoring Committee (DMC) will review the progress of the study and will monitor 
participant intake, outcomes, adverse events, and other issues related to participant safety.  The 
DMC makes recommendations to the Director of the Clinical Science Research and 
Development (CSRD) Service about whether the study should continue or be stopped. The DMC 
will include experts in clinical trials, biostatistics, and ethics.  These experts will not be 
participants in the trial and will not have participated in the planning of the protocol. The DMC 
will consider safety or other circumstances as grounds for early termination, including either 
compelling internal or external evidence of treatment differences or the unfeasibility of 
addressing the study hypothesis (e.g., poor participant intake, poor adherence to the protocol).   
At each of its meetings during the study period, the DMC will review the randomization rates 
and assess the difference between the actual and the projected rates, as well as the impact of 
these assessments on overall trial size.  If the study recruitment is inadequate, the reasons for 
exclusion may be scrutinized and actions may be suggested.  An assessment of whether the trial 
should be continued will be made followed by recommendations, as appropriate. All serious 
adverse events will be reported on a regular basis to the DMC for their review.  Unexpected 
serious adverse events will be reported to the DMC as soon as they become known based upon 
the consensus of the Study Chair, the Study Biostatistician, the Director, Perry Point CSPCC, 
and the Study Pharmacist.  The Study Biostatistician will provide the appropriate data to the 
DMC at specified intervals for this purpose.  Conditional power estimates will be provided to the 
DMC to assist them in making their decisions and recommendations. 
As  an  independent  oversight  committee,  DMC  will  be  monitoring  study  progress  at 
predetermined time points over the entire duration of the study. The committee will receive 
analyses of the study recruitment status, demographics of recruited participants, adverse effects, 
and study protocol adherence on a routine basis. In general, this committee will meet at six to 
nine months after the start of subject recruitment and yearly thereafter. The committee will 
receive reports about three weeks prior to their annual meetings and at six-month intervals in 
between the annual meetings. In order for the DMC to make its recommendation for continuation 
of the study, it will be necessary for them to see the analyses for the primary outcome measure 
annually.  Periodic monitoring of interim results can significantly affect the probability of 
making  an incorrect  decision.   A  number  of  formal  techniques  have  been  developed  for 
interpreting interim results and the DMC will review these options at their first meeting and prior 
to the start of data collection.  For this study, a Haybittle-Peto interim analysis is proposed. The 
detailed  analysis  is  described  in  the  biostatistical  research  and  data  processing 
procedure/statistical analysis plan.
The VA’s Central IRB will be the study’s primary IRB and the IRB of record for the study.  It 
will be responsible for the initial and continuing IRB reviews of the study.  The VA Central IRB 
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must review and approve amendments (changes to inclusion/exclusion criteria, protocols, 
informed consents, etc), deviations, and review reports about adverse events and problems, 
complaints, terminations, etc. and that the investigation must provide the VA Central IRB all 
supporting documentation.  The CSPCC will be responsible for providing the VA Central IRB 
with all materials that are required for each review and to respond to the VA Central IRB’s 
queries and requests for additional materials.  The VA Central IRB approves the original 
informed consent template and any requested changes to the informed consent forms.
The Human Rights Committee (HRC) at the Coordinating Center may be asked to convene if 
there is any serious adverse event requiring its attention. 
Site Monitoring Auditing & Resource Team (SMART) will conduct an initial site visit at each 
site soon after study start-up. Additional monitoring visits may be conducted as deemed 
necessary by study leadership or SMART. Monitoring of sites participating in the trial will be 
executed according to Cooperative Studies Program (CSP) guidelines.  Independent routine 
audits will be conducted at one or more sites per year as determined by SMART.  For-cause 
audits will be conducted as requested by study leadership or the VA CSP Central Office.  These 
audits may be scheduled or unannounced. 
The Study Group, which consists of all participating investigators and study coordinators, will 
meet annually to discuss the progress of the study and any problems encountered during the 
conduct of the trial.  
D.
Monitoring data quality and protocol adherence
By utilizing Risk Based Monitoring (RBM), CSPCC will remotely monitor the study team.  Each 
participating site’s performances and data quality, completeness of follow-up and adherence to 
the protocol will continuously be measured. Regularly scheduled conference calls (at least 
monthly) with the sites, CSPCC and Chairman’s office will be held to address data collection, 
protocol procedures and other issues. Strict adherence to the protocol will be expected of every 
participating center and will be monitored by the DMC, the Executive Committee, and the 
CSPCC.  Documentation of protocol breaches will be required and any medical center with 
repeated protocol violations will be recommended to the Executive Committee for termination.  
If a participating site investigator feels that adherence to the protocol will in any way be 
detrimental to a particular participants’s health or well-being, the interest of the participant must 
take precedence. In addition, CSPCC, the Executive Committee and the DMC will monitor 
protocol adherence centrally. The Executive Committee will consider recommending a for-cause 
GCP audit be conducted by SMART for any site with repeated protocol violations and will 
consider terminating the site from the trial. 
Data quality and the completeness of data retrieval will be closely monitored on an ongoing basis 
by the Coordinating Center. The study biostatisticians will present interim monitoring reports to 
the Executive Committee and the DMC that will include the following types of information: 

Participant intake

Randomization errors

Breaches of protocol

Adherence and compliance with original treatment assignment
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
Missed study visits

Completeness of follow-up

Data quality: data query and error rates

Audit and site visit results.
If a site is identified as an outlier in terms of data quality, a site conference call or site visit will 
be initiated to assess the reasons why problems are occurring and how they can be corrected. If 
the problems continue, the site may be placed on probation or terminated from the study.
E.
Monitoring of safety, efficacy and futility
Trial safety will be monitored by CSPCC and the CSPCRPCC, and the Study Chair’s Office 
throughout the study. Safety reports will be submitted to the DMC approximately every 6 months 
after recruitment begins, or more frequently, if requested by the DMC. For reports to the DMC 
closed session, serious adverse events will be summarized by treatment groups, and relatedness to the 
assigned interventions.
The DMC will review the accumulating data and be responsible for determining whether or not 
to recommend that the trial be stopped for efficacy, futility or safety. Data summaries will be 
prepared for the DMC for these purposes. Frequent summaries of serious adverse events will be 
prepared for the DMC for the monitoring of safety, i.e., at least semi-annually. To aid the DMC 
in their deliberations, other relevant information inside (e.g., secondary analyses) and outside 
(e.g., other studies) will be made available. Complete details of the interim monitoring plans for 
the study are given in Section XI:  Biostatistical Considerations.
XVIII.PUBLICATIONS
A.
Publication of Research Results
It is the policy of the Cooperative Studies Program not to reveal outcome data to participating 
investigators until the data collection phase of the study is complete.  This policy is meant to 
prevent possible biases that might affect data collection.  Members of the DMC and the CSPCC 
Human Rights Committee will be reviewing outcome results to ensure that the study will be 
terminated early if a treatment is identified as prohibitively dangerous or if a definitive answer is 
reached prior to the scheduled study termination date.  
All presentations and publications resulting from this study will follow CSP policy as specified 
by the CSP guidelines.  The presentation or publication of any or all data collected by 
participating investigators on participants entered into a Department of Veterans Affairs 
Cooperative Study is under the direct control of the study’s Executive Committee.  No individual 
participating investigator has the right to use this study’s data to perform analyses or 
interpretations, or to make public presentations or seek publication of any or all of the data 
without the specific approval of the Executive Committee. 
The Executive Committee has the authority to establish any number of publication committees, 
which usually will comprise subgroups of participating investigators and some members of the 
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Executive Committee, for the purpose of producing manuscripts for presentation and publication. 
Any presentation or publication related to this study should be circulated to participating 
investigators for review, comments and suggestions at least four weeks prior to submission of the 
manuscript to the presenting or publishing body. 
All publications must give proper recognition to the funding source and should list all study 
personnel(not necessarily as authors of the manuscript).  If an investigator’s major salary support 
and/or commitment is from the VA, it is obligatory that the investigator lists the VA as his/her 
primary institutional affiliation.  Submission of manuscripts or abstracts must follow the usual 
VA policy; ideally, a subtitle states, “A Department of Veterans Affairs Cooperative Study.”  
The CSP also requires that every manuscript be reviewed and approved by the CSPCC Director 
prior to submission as a final quality control step.  Mechanisms for appeal by a dissatisfied 
investigator will follow procedures defined by the VA Office of Research and Development.
Participation in Department of Veterans Affairs Cooperative Studies is voluntary.  Any 
investigator who cannot accept these operation guidelines regarding publication policy should 
not volunteer to participate in the study.
B.
Planned Publications
Upon completion of the study, manuscripts will be prepared that focuses on the following 
objectives:  

Primary publication:  Upon completion of the study, a manuscript will be prepared that 
focuses on the primary outcome, i.e. liberal vs. restrictive composite rates of 90 day all-
cause mortality, MI, acute renal failure, coronary revascularization or stroke. 

Other publications:  TBD
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XIX.
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