Transfusion Trigger After Operations in High Cardiac Risk Patients

Background: Despite the need for clinically appropriate use of blood products in the
postoperative setting, blood transfusion practices are empiric and variable. In the absence
of a physiologic test that can effectively guide transfusion-related decisions after an
operative intervention, hemoglobin-based transfusion triggers have been suggested as clinical
tools. Traditionally, clinicians have transfused patients to maintain hemoglobin (Hb) above a
minimum (typically 10 gm/dl) level, in order to prevent adverse cardiac events and death.
Recent randomized trials, however, have shown that restrictive transfusion policies
(transfusion when Hb falls below 8 gm/dl or even lower) are well tolerated by specific
patient populations. Furthermore, these trials have demonstrated that in some patient subsets
reduced transfusion is associated with reduction in postoperative complications and death.
Thus, guidelines have been developed emphasizing the need for a restrictive transfusion
strategy in most stable hospitalized patients.

Despite the emerging enthusiasm with respect to the safety of restrictive transfusion
strategies, high quality evidence on the value of such an approach in patients at high risk
for postoperative adverse cardiac events remains scarce. This is a serious limitation of the
current literature, as ischemic heart disease (IHD) is highly prevalent and represents the
leading cause of mortality in this country, accounting for the death of one American every
minute. Furthermore, there is evidence from small trials and secondary analyses that in this
subset of patients withholding transfusion when Hb falls below 10 gm/dl increases the risk of
death or myocardial infarction, suggesting that widespread use of restrictive transfusion
policies may actually result in patient harm. This uncertainty on transfusion thresholds in
high cardiac risk patients has created a knowledge gap that requires urgent attention. IHD is
highly prevalent in patients with peripheral arterial disease (PAD), and myocardial
infarction represents the leading cause of postoperative mortality in patients undergoing
PAD-related surgical interventions. Furthermore, a substantial proportion of patients
undergoing Vascular and General Surgery operations have history of prior IHD, making this
patient population an ideal high cardiac risk group in which to analyze the effect of
transfusion strategies. In order to address the knowledge gap of postoperative transfusion
thresholds in patients at high risk for postoperative adverse cardiac events, the
investigators propose the current study under the hypothesis that transfusion strategy will
affect important postoperative outcomes after major surgical interventions in high cardiac
risk patients.

Objectives: The goal of the proposed study is to determine whether a liberal postoperative
transfusion strategy (transfusion trigger at Hb<10gm/dl) in patients at high risk for
postoperative adverse cardiac events will reduce the risk of adverse postoperative outcomes
after major vascular and general surgery operative interventions. The primary end point is
the composite rate of all-cause mortality, acute myocardial infarction (MI), coronary
revascularization, stroke, or acute renal failure within 90 days from the time of
randomization. The secondary end points are rates of postoperative infectious complications
(wound infections, pneumonia, and sepsis), and postoperative cardiac complications (new
cardiac arrhythmias, congestive heart failure exacerbation, and cardiac arrest) at 90 days
post-randomization; the composite rate of all-cause mortality, MI, coronary
revascularization, stroke, or acute renal failure, within 30 days from the time of
randomization; the length of hospital stay; and all-cause mortality up to one year after
randomization.

Design: CSP #599 - TOP study is a randomized, intent-to-treat, two-arm, parallel design,
single blind, multicenter trial. Vascular and General Surgery programs at Veterans Affairs
Medical Centers with expertise in performing the operations of interest will be invited to
participate and participants will be screened for enrollment using established
inclusion/exclusion criteria. Enrolled participants will be randomized to one of the two
arms; liberal (transfusion trigger at Hb < 10gm/dl) or restrictive (transfusion trigger at Hb
< 7gm/dl). Consent for the study will be obtained prior to the index surgical intervention.
Randomization will be performed postoperatively after the patient has a confirmed Hb <
10gm/dl. Assessments will be collected pre/post-operatively and at discharge, or at 30 days
after randomization if the patient is still hospitalized. Follow up forms will be filled out
during a clinic visit after the 30th and 90th post-randomization day. Patients who cannot
present to the clinic will have a phone call for follow up. One year post-randomization
mortality will be ascertained using electronic medical records, phone follow-up, and search
of the national death index.

Sample Size and Study Duration: This study will randomize 1520 participants undergoing major
vascular and general operations at 15 VA medical centers with expertise in Vascular and
General surgical procedures. Assuming a recruitment rate of 3 participants per site per
month, total recruitment will take approximately four years to complete. The duration of the
study will be five years with four year recruitment, three months active follow up, and nine
months passive follow up which will be performed by the Chairman's office in order to collect
1-year post-randomization data on all-cause mortality.

Study Population: The study will include a) patients who undergo open (non-endovascular) PAD
- related operations, and b) patients who undergo selected major Vascular and General Surgery
operations and have prior history of PAD or IHD. Vascular Surgery operations examined will
include, but not be limited to, PAD-related: 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,
supra-aortic trunk bypass or endarterectomy, carotid endarterectomy, and major lower
extremity amputations (transfemoral, through the knee, or transtibial); Other vascular
surgeries: 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). General Surgery
operations examined will include open cholecystectomy or other complex biliary reconstruction
(such as open common bile duct exploration for stones, reconstruction as part of oncologic
operations such as palliative pancreatic cancer procedures) , small bowel resection,
pancreatectomy, colon resection, rectal resection, splenectomy, transhiatal esophagectomy,
liver resection, and open ventral hernia repair. Patients will be included in the study if
their postoperative Hb falls below 10gm/dl within 15 days after surgery. Intervention:
Liberal transfusion strategy is the conventional transfusion method for the surgical
procedures the investigators will include in the study, and is defined as transfusion when
the postoperative Hb drops below 10gm/dl, with a goal to maintain Hb above 10 gm/dl.
Restrictive transfusion strategy will be defined as transfusion when the postoperative Hb
drops below 7gm/dl with goal to maintain Hb above 7 gm/dl.

Significance: The proposed CSP# 599 study is uniquely positioned to address the knowledge gap
of postoperative transfusion thresholds in high cardiac risk patients undergoing major
surgical interventions, who are currently transfused based on data from patient populations
with different risk profile. The study will include patients with high IHD burden, a
population that should be the most likely to benefit from a liberal transfusion strategy and
CSP#599 will examine this hypothesis directly. Conversely, if the proposed trial demonstrates
that this high cardiac risk patient population can tolerate restrictive transfusion well,
then the results will be easy to generalize to other patient populations and the question of
transfusion thresholds will be definitively addressed. Thus, the investigators believe that
regardless of outcome this trial will have significant clinical and policy implications, and
will substantially impact the VA and national transfusion-related guidelines.

Inclusion Criteria:

- Males and females older than 18 years of age who have postoperative Hb < 10gm/dl
within 15 days after the index operation

- Patients and undergo an operation in either one of the three following categories:

- 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

- major lower extremity amputations (transfemoral, through the knee, or
transtibial)

- Veterans with past medical history of ischemic stroke or IHD or PAD who undergo
the following general surgery procedures, defined as:

- known prior MI

- ECG 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

- stress test indicating myocardial ischemia

- who undergo the following General Surgery operations:

- Open cholecystectomy or other complex biliary reconstruction

- such as open common bile duct exploration for stones

- reconstruction as part of oncologic operations such as palliative
pancreatic cancer procedures)

- small bowel resection

- pancreatectomy

- colon resection

- rectal resection

- splenectomy

- transhiatal esophagectomy

- liver resection

- gastric resection

- open ventral hernia repair

- Colostomies (reversals and takedowns)

- Veterans with past medical history of ischemic stroke or IHD or PAD who undergo
the following Vascular Surgery operations:

- Open aneurysm repair, including but not limited to:

- carotid

- subclavian

- abdominal aortic

- iliac

- femoral

- 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

- 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.

Exclusion Criteria:

- Veteran unable to consent

- Veteran unwilling to follow protocol (such as Jehovah's witnesses)

- Veteran with known history of hereditary anemias such as Thalassemia or Sickle cell
disease

- Veteran with known history of hereditary bleeding disorders, such as factor VIII or
factor IX deficiency

- Veteran with prior history of adverse reaction to blood administration, such as fever,
rash, or hemolysis

- Veteran does not speak or understand English

- Veteran hemodynamically unstable or in cardiogenic shock

- Veteran participating in another interventional trial whose objective is to evaluate
the effect of transfusion on outcomes

- Pregnancy in female Veterans

- Veteran is a prisoner or in custody of law enforcement

- Prior randomization in the CSP#599