Strategies for Anticoagulation During Venovenous ECMO: The SAFE-ECMO Pilot Trial
Phase: NA
Conditions: Acute Hypoxemic Respiratory Failure, Anticoagulant-induced Bleeding, Thromboembolism
Sponsor: Vanderbilt University Medical Center

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Strategies For Anticoagulation During Venovenous ECMO: The SAFE-
ECMO Pilot Trial  
 
 
 
 
Title 
Strategies For Anticoagulation During Venovenous ECMO: The 
SAFE-ECMO Pilot Trial  
Acronym 
 
Version   
 
Version 1.1 
 
Date 
 
 
December 21, 2022 
 
Protocol Co-Chairs 
Sarah Bloom, MSN 
Whitney D. Gannon, MSN 
Wren Sherrill, MSN 
John W. Stokes, MD 
 
Coordinating Center 
Vanderbilt University Medical Center  
DCC Chair: Jonathan D. Casey, MD 
CCC Chair: Todd W. Rice, MD, MSc 
 
Network 
Pragmatic Critical Care Research Group (PCCRG)   
Steering Committee Chair: Matthew W. Semler, MD, MSc 
 
Sponsor 
Vanderbilt Institute for Clinical and Translational Research grant 
support (UL1 TR000445 from NCATS/NIH) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents 
 
1 
Background 
7 
2 
Rationale, Aims, and Hypotheses 
8 
2.1 
Study Aims 
8 
3 
Study Description 
8 
4 
Study Population, Inclusion and Exclusion Criteria 
8 
4.1 
Study Population 
8 
4.2 
Inclusion Criteria 
8 
4.3 
Exclusion Criteria 
9 
5 
Determination of Eligibility, Consent, Enrollment, and Randomization 
9 
5.1 
Study Sites 
9 
5.2 
Determination of Eligibility 
9 
5.3 
Process of Obtaining Informed Consent 
9 
5.4 
Enrollment 
10 
5.5 
Randomization and Blinding 
10 
6  
Study Procedures 
10 
6.1 
Study Interventions 
10 
6.1.1 
Low Intensity Anticoagulation Group 
11 
6.1.2 
Moderate Intensity Anticoagulation Group 
11 
6.2 
Post-Decannulation Surveillance and Anticoagulation Management 
12 
7  
Data Collection and Outcome Measures 
13 
7.1 
Data Collection 
13 
7.2 
Outcome Measures 
15 
7.2.1 
Primary Efficacy Outcome 
15 
7.2.2 
Primary Safety Outcome 
15 
7.2.3 
Feasibility Outcomes 
15 
7.2.4 
Secondary Outcomes 
16 
8 
Data Quality Monitoring and Storage 
16 
8.1 
Data Quality Monitoring 
16 
8.2 
Data Storage 
16 
9 
Risk Assessment 
17 

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9.1 
Potential Risk to Participants 
17 
9.1.1 
Potential Risks of Receiving Low Intensity Anticoagulation for Patients Receiving V-V 
ECMO 
 
17 
9.1.2 
Potential Risks of Receiving Moderate Intensity Anticoagulation for Patients 
Receiving V-V ECMO 
18 
9.2 
Minimization of Risk 
18 
9.3 
Potential Benefit 
19 
9.4 
Risk in Relation to Anticipated Benefit 
19 
10 
Human Subjects Protections 
19 
10.1 
Selection of Subjects 
19 
10.2 
Justification of Including Vulnerable Subjects 
19 
10.3 
Informed Consent 
20 
10.4 
Continuing Consent 
20 
10.5 
Withdrawal of Consent 
20 
10.6 
Identification of Legally Authorized Representatives 
20 
10.7 
Justification of Surrogate Consent 
21 
10.8 
Confidentiality 
21 
11 
Adverse Events 
22 
11.1 
Adverse Event Definitions 
22 
11.2 
Safety Monitoring 
22 
11.3 
Serious Adverse Events 
23 
12 
Statistical Considerations 
24 
12.1 
General Considerations 
24 
12.2 
Analysis Populations 
24 
12.3 
Statistical Analysis 
25 
13 
Privacy and Confidentiality 
25 
14 
Follow-up and Record Retention 
25 
 
 
 
 
 
 
 
 

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Clinical Trial Protocol 
 
Trial Summary 
 
Title: Strategies For Anticoagulation During Venovenous ECMO: The SAFE-ECMO Pilot 
Trial 
 
Background: Since the inception of extracorporeal membrane oxygenation (ECMO), moderate 
intensity titrated dose anticoagulation has been used to prevent thromboembolism and 
thrombotic mechanical complications. As technology has improved, however, the incidence of 
thromboembolic events has decreased, leading to re-evaluation of the risks of anticoagulation, 
particularly during venovenous (V-V) ECMO. Recent data suggest that bleeding complications 
during V-V ECMO may be more strongly associated with mortality than thromboembolic 
complications, and case series have suggested that V-V ECMO can be safely performed 
without moderate or high intensity anticoagulation. At present, there is significant variability 
between institutions in the approach to anticoagulation during V-V ECMO. A definitive 
randomized controlled trial is needed to compare the effects of a low intensity fixed dose 
anticoagulation (low intensity) versus moderate intensity titrated dose anticoagulation (moderate 
intensity) on clinical outcomes during V-V ECMO. Before such a trial can be conducted, 
however, additional data are needed to inform the feasibility of the future trial.  
 
Primary aim: To demonstrate feasibility of a future large, multi-center randomized controlled 
trial comparing low intensity to moderate intensity anticoagulation among adults receiving V-V 
ECMO by demonstrating the ability to recruit and randomize participants, adhere to assigned 
anticoagulation strategy, and demonstrate adequate separation between groups in therapy 
delivered and intensity of anticoagulation achieved with the assigned anticoagulation strategies. 
 
Secondary aim: To define and estimate the frequency of the primary efficacy, primary safety, 
and secondary outcomes of a future large, multi-center randomized controlled trial comparing 
low intensity vs moderate intensity anticoagulation among adults receiving V-V ECMO. 
 
Inclusion criteria: 
1. Patient receiving V-V ECMO  
2. Patient is located in a participating unit of an adult hospital 
 
Exclusion criteria: 
1. Patient is pregnant 
2. Patient is a prisoner 
3. Patient is < 18 years old 
4. Patient underwent ECMO cannulation greater than 24 hours prior to screening 
5. Presence of an indication for systemic anticoagulation: 
a. Ongoing receipt of systemic anticoagulation 
b. Planned administration of anticoagulation for an indication other than ECMO 
c. Presence of or plan to insert an arterial ECMO cannula 
6. Presence of a contraindication to anticoagulation: 
a. Active bleeding determined by treating clinicians to make anticoagulation unsafe 
b. Major surgery or trauma less than 72 hours prior to randomization 
c. Known history of a bleeding diathesis 
d. Ongoing severe thrombocytopenia (platelet count < 30,000) 
e. History of heparin induced thrombocytopenia (HIT) 
f. Heparin allergy 

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7. The treating clinician determines that the patient’s risks of thromboembolism or bleeding 
necessitate a specific approach to anticoagulation management during V-V ECMO  
 
Consent: Patients or their surrogates will provide written informed consent to study personnel.  
 
Randomization: After enrollment, patients will be randomized in a 1:1 ratio to initiation of either 
low intensity anticoagulation or moderate intensity anticoagulation. The randomization will be 
performed electronically through REDCap using permuted randomized blocks of two, four, and 
six. 
 
Study interventions: 
• 
Low intensity anticoagulation: For patients assigned to the low intensity 
anticoagulation strategy, clinical teams will be instructed to initiate low intensity 
anticoagulation at doses and frequencies commonly used for deep vein thrombosis 
(DVT) prophylaxis. The choice of anticoagulant, dose, and frequency of administration 
will be deferred to treating clinicians. 
• 
Moderate intensity anticoagulation: For patients assigned to the moderate intensity 
anticoagulation group, clinical teams will be instructed to initiate a continuous infusion of 
moderate intensity anticoagulation targeting either a partial thromboplastin time (PTT) of 
40-60 seconds or an Anti-Xa level of 0.2 to 0.3 IU/mL. The choice of anticoagulant and 
approach to dosing will be deferred to treating clinicians. 
 
Duration of Study Interventions: 
• 
The protocol will control the anticoagulation strategy from randomization until the first of: 
diagnosis of a major bleeding event, diagnosis of a thromboembolic event, placement of 
an arterial ECMO cannula, decannulation from ECMO, or death. Treating clinicians may 
change anticoagulation strategy at any point if determined to be necessary for optimal 
patient care. 
 
Primary efficacy outcome: 
• 
Major bleeding, according to the International Society on Thrombosis and Hemostasis 
definition1, from randomization to 24 hours after decannulation defined as: 
a. Fatal bleeding 
b. Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with 
compartment syndrome 
c. Clinically overt bleeding associated with either a drop in hemoglobin level by at 
least 2.0 grams/dL or leading to transfusion of two or more units of packed red 
blood cells 
 
Primary safety outcome:  
• 
Thromboembolic event from randomization to 24 hours after decannulation, defined as: 
a. Deep venous thrombosis (DVT)  
b. Acute pulmonary embolism (PE) 
c. Intra-cardiac thrombosis  
d. Ischemic stroke  
e. Acute circuit thrombosis requiring urgent circuit exchange 
f. Acute arterial thromboembolism 
 
 

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Feasibility outcomes: 
• 
Number of patients screened per month 
• 
Number of patients who are eligible per month 
• 
The specific exclusion criteria met (for any patient ineligible for enrollment)  
• 
Reasons for “missed” enrollments (e.g. unavailability of research staff, refusal of clinical 
team to allow randomization, patient refusal of informed consent) 
• 
Number of patients enrolled per month 
• 
Adherence to the assigned anticoagulation strategy  
• 
Separation between groups in anticoagulation treatment received 
• 
Time from ECMO cannulation to randomization 
• 
Duration of the intervention period, defined as the time from randomization to the first of: 
diagnosis of a major bleeding event, diagnosis of a thromboembolic event, placement of 
an arterial ECMO cannula, decannulation from ECMO, or death 
 
Secondary outcomes: 
• 
Cannula-associated DVT, as measured by four-extremity venous ultrasounds obtained 
24-72 hours following decannulation 
• 
Bleeding events per ECMO day 
• 
Thromboembolic events per ECMO day 
• 
Bleeding events from randomization to the first of death or discharge 
• 
Thromboembolic events from randomization to the first of death or discharge 
• 
Circuit or circuit component exchange required during ECMO support 
• 
ECMO circuit durability, calculated as the number of calendar days from randomization 
to death or decannulation divided by the number of ECMO circuits used  
• 
RBC transfusion volume per ECMO day, calculated as the total volume of packed red 
blood cells transfused from randomization to death or decannulation divided by the 
number of calendar days during this period 
• 
New diagnosis of HIT from randomization to the death or decannulation from ECMO, as 
measured by clinically obtained serotonin release assay 
• 
Lowest documented platelet count from randomization to 24 hours after decannulation 
• 
Highest Total and indirect bilirubin values from randomization to 24 hours after 
decannulation 
• 
Highest LDH value values from randomization to 24 hours after decannulation  
• 
Death attributable to a major bleeding event 
• 
Death attributable to a thromboembolic event 
• 
Ventilator-free days 
• 
ECMO-free days 
• 
ICU-free days 
• 
Hospital-free days 
• 
In-hospital mortality  
 
 
 
 
 
 
 

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1 
Background 
 
 
Since the inception of Extracorporeal Membrane Oxygenation (ECMO), moderate intensity 
titrated dose anticoagulation has been used to prevent clinically harmful thromboembolism and 
thrombotic mechanical complications. The impact of thromboembolic events on clinical 
outcomes during venovenous (V-V) extracorporeal membrane oxygenation (ECMO), however, 
is unclear, and complications related to bleeding are common and associated with increased 
morbidity and mortality.2-7 These findings have led many experts to suggest that anticoagulation 
strategies during V-V ECMO should be re-evaluated. 
 
Critical illness, in general, is associated with both coagulopathy and impaired hemostasis.8  
These problems are compounded during ECMO by the artificial interface between blood and the 
non-biologic surface of the circuit components, which leads to activation of the coagulation 
system, consumptive thrombocytopenia, fibrinolysis, and thrombin generation.8-10 The sheer 
stress on blood components during ECMO also lead to destruction of high-molecular-weight von 
Willebrand multimers, interrupting primary hemostasis.11  
 
Both bleeding and thromboembolism are common complications during ECMO.2-7 Bleeding 
events have been associated with poor clinical outcomes, likely mediated by an increased 
incidence of intracranial hemorrhage during ECMO.2,12 During intra-operative cardiopulmonary 
bypass and venoarterial (V-A) ECMO, ischemic strokes are a common and potentially deadly 
complication.  During V-V ECMO, however, the majority of thromboembolic events are cannula-
associated DVT and circuit thromboses requiring exchange, which are of unclear clinical 
significance.13-15 
 
Various anticoagulation strategies have been proposed to balance the risks of bleeding and 
thromboembolism during V-V ECMO, including high intensity anticoagulation, moderate 
intensity anticoagulation, and low intensity anticoagulation (the equivalent of DVT prophylaxis).  
Observational studies have suggested that, compared to moderate intensity anticoagulation, low 
intensity anticoagulation reduces transfusion requirements without affecting the incidence of 
thrombosis, hemorrhage, or death.16-18 In one case series of 60 patients who were treated with 
only low-intensity subcutaneous heparin during V-V ECMO, rates of transfusions were lower 
than historical controls without any effect on the rate of thrombotic events.16 Similarly, a recent 
systematic review suggested that the rates of thromboembolism and circuit thrombosis among 
patients managed with a moderate intensity anticoagulation strategy during V-V ECMO were 
comparable to the rates reported among patients managed with a less intense anticoagulation 
strategy.19 
 
To date, there are no randomized controlled trials comparing low intensity to moderate intensity 
anticoagulation during V-V ECMO.  Guidelines from the Extracorporeal Life Support 
Organization (ELSO), the pre-eminent group for ECMO education and research, provide little 
guidance for the selection of anticoagulation strategy,20 and anticoagulation practices are highly 
variable across institutions.8,21 A large, multicenter, randomized trial is needed to determine the 
ideal strategy to anticoagulation during V-V ECMO.  Before such a trial can be conducted, 
however, additional data are needed on the feasibility of randomizing patients to a specific 
anticoagulation strategy and study measurements. 
 
 
 
 

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2 
Rationale, Aims, and Hypotheses 
 
To facilitate a large, multicenter randomized controlled trial comparing low intensity 
anticoagulation to moderate intensity anticoagulation during V-V ECMO, a pilot trial is needed to 
establish feasibility and the performance of the primary outcome measures. 
 
2.1 
Study Aims 
 
● Primary aim: To demonstrate feasibility of a future large, multi-center randomized 
controlled trial comparing low intensity to moderate intensity anticoagulation among 
adults receiving V-V ECMO by demonstrating the ability to recruit and randomize 
participants, adhere to assigned anticoagulation strategy, and demonstrate adequate 
separation between groups in therapy delivered and intensity of anticoagulation 
achieved with the assigned anticoagulation strategies. 
 
● Secondary aim: To define and measure the primary efficacy, primary safety, and 
secondary outcomes of a future large, multi-center randomized controlled trial 
comparing low intensity vs moderate intensity anticoagulation among adults 
receiving V-V ECMO. 
 
 
3 
Study Description 
 
 
To address these aims, we propose a single center, open-label, parallel-group, randomized pilot 
trial comparing low intensity anticoagulation to moderate intensity anticoagulation among 
patients receiving V-V ECMO. All patients who receive V-V ECMO in a participating ICU of an 
adult hospital and meet all inclusion and no exclusion criteria will be eligible for participation. 
Eligible participants or surrogate decision makers will be approached for consent. Following 
documentation of written informed consent, patients will be enrolled and randomly assigned to 
low intensity or moderate intensity anticoagulation. The study will control anticoagulation from 
randomization until the first of: diagnosis of a major bleeding event, diagnosis of a 
thromboembolic event, placement of an arterial ECMO cannula, decannulation from ECMO, or 
death. All other decisions regarding critical care support, interventional therapies, and medical 
treatment will remain at the discretion of the treating physician and consulting clinical teams.  
 
 
4 
Study Population, Inclusion and Exclusion Criteria 
 
 
4.1 
Study Population 
 
All adult patients receiving V-V ECMO will be screened for eligibility. Patients meeting all 
inclusion and no exclusion criteria will be approached for consent. To be eligible for enrollment, 
the patient must meet all inclusion criteria and no exclusion criteria at the time of screening and 
randomization. Screening and randomization must be accomplished within 24 hours of ECMO 
cannulation.  
 
 
 
4.2 
Inclusion Criteria 

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1. Patient receiving V-V ECMO  
2. Patient is located in a participating unit of an adult hospital 
 
4.3 
Exclusion Criteria 
1. Patient is pregnant 
2. Patient is a prisoner 
3. Patient is < 18 years old 
4. Patient underwent ECMO cannulation greater than 24 hours prior to screening 
5. Presence of an indication for systemic anticoagulation: 
a. Ongoing receipt of systemic anticoagulation 
b. Planned administration of anticoagulation for an indication other than ECMO 
c. Presence of or plan to insert an arterial ECMO cannula 
6. Presence of a contraindication to anticoagulation: 
a. Active bleeding determined by treating clinicians to make anticoagulation unsafe 
b. Major surgery or trauma less than 72 hours prior to randomization 
c. Known history of a bleeding diathesis 
d. Ongoing severe thrombocytopenia (platelet count < 30,000) 
e. History of heparin induced thrombocytopenia (HIT) 
f. Heparin allergy 
7. The treating clinician determines that the patient’s risks of thromboembolism or bleeding 
necessitate a specific approach to anticoagulation management during V-V ECMO 
 
 
5 
Determination of Eligibility, Consent, Enrollment, and Randomization 
 
 
5.1 
Study Sites 
 
1. Participating intensive care units at the VUMC adult hospital. 
2. Participating intensive care units at Stanford Medical Center 
3. Participating intensive care units at Duke University Medical Center 
 
5.2 
Determination of Eligibility  
 
All patients meeting inclusion criteria will be screened for eligibility and assigned a deidentified 
study identification number. If a patient appears to meet all inclusion criteria and no exclusion 
criteria, the site investigator or delegate will approach the treating clinician to ask permission to 
approach the patient or Legally Authorized Representative (LAR) to confirm eligibility, discuss 
potential study recruitment, and proceed with informed consent.   
 
For all excluded patients, including refusal by the treating clinician or patient/surrogate, a small 
number of de-identified variables will be collected including month and year the patient met 
screening criteria, patient location, and reason(s) patient was excluded.   
 
5.3 
Process of Obtaining Informed Consent 
 
Written informed consent will be obtained from the patient or from a surrogate decision maker if 
the patient lacks decision-making capacity. Consent will be obtained by a key study personnel 
who has undergone good clinical practice (GCP) training and is authorized to obtain written 
informed consent.   

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Given that patients are critically ill and frequently receiving invasive mechanical ventilation at the 
time of cannulation for V-V ECMO, it is expected that consent will be provided from a surrogate 
decision maker in the majority of cases. Further, decisions regarding anticoagulation must be 
made shortly after cannulation. ECMO cannulation is an emergent procedure so surrogate 
decision makers may not be available in-person at the time of screening and consent.  
Therefore, in addition to the traditional approach of in-person, written informed consent, we will 
use an electronic/e-consent approach to allow remote consent of surrogate decision makers. 
 
This approach complies with relevant regulations and sub-regulator guidance at 45 CFR 46.117, 
45 CFR 164.512, 21 CFR 11 Subpart C (11.100–11.300), https://www.hhs.gov/ohrp/regulations-
and-policy/guidance/use-electronic-informed-consent-questions-and-answers/index.html, 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/informed-consent. 
 
The information for the informed consent discussion will be provided in a formal document (or 
electronic equivalent) that has been approved by the IRB and in a language comprehensible to 
the potential participant, using an interpreter if necessary. The information presented in the 
consent form and by the research staff will detail the nature of the trial and what is expected of 
participants, including any potential risks or benefits of taking part. It will be clearly stated that 
the participant is free to withdraw from the trial at any time for any reason without prejudice to 
future care, and with no obligation to give the reason for withdrawal.  
 
5.4 
Enrollment 
 
Patients who meet inclusion criteria but no exclusion criteria and provide written informed 
consent will be enrolled immediately after written informed consent has been obtained and 
eligibility has been confirmed with the treating physician. Patients who initially meet all inclusion 
criteria and no exclusion criteria at the time of screening but develop a change in clinical status 
that prohibits receipt of either study treatment prior to randomization (i.e. development of one or 
more exclusion criteria or death) will be excluded from study participation and prospectively 
recorded. 
 
5.5 
Randomization and Blinding 
 
Immediately following enrollment patients will be randomized in a 1:1 ratio to either a low 
intensity or moderate intensity anticoagulation strategy. The randomization will be performed 
through REDCap using random permuted blocks of two, four, and six, stratified by site. The 
study group assignment will remain concealed to study personnel and treatment teams until 
after the decision has been made to enroll the patient in the study and written informed consent 
has been obtained. Following randomization, the treatment team and ECMO consultant team 
will be notified of a patient’s assigned anticoagulation strategy. Given the nature of the 
intervention blinding is not feasible. 
 
 
6  
Study Procedures 
 
 
6.1 
Study Interventions 
 
Determination of eligibility, written informed consent, study enrollment, and randomization must 
be completed within 24 hours of ECMO cannulation in order for a patient to be included in the 

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study. Prior to randomization, the anticoagulation management strategy will be left to the 
discretion of the treatment team.   
 
Following randomization, the study controls maintenance anticoagulation strategy until the first 
of: diagnosis of a major bleeding event, diagnosis of a thrombotic event, placement of an arterial 
ECMO cannula, decannulation from ECMO, or death.   
 
The study does not control anticoagulation for procedural indications (e.g. during ECMO 
cannulation or cardiac catheterization), and it does not control the use of anti-platelet agents 
(e.g. aspirin or clopidogrel). 
 
6.1.1 Low Intensity Anticoagulation Group 
 
Participants assigned to the low intensity anticoagulation strategy will receive anticoagulation at 
doses used for DVT prophylaxis in critically ill patients.  The choice of agent (e.g. heparin or 
enoxaparin) and specific dosing will be at the discretion of the treating clinicians and will be 
prospectively recorded. 
 
This strategy of anticoagulation is intended to expose the patient to less systemic 
anticoagulation and was chosen to balance the risks of bleeding and thromboembolism during 
V-V ECMO.  While most available guidelines recommend moderate intensity anticoagulation 
during V-V ECMO for patients without contraindications, it has been noted that bleeding events 
are common and frequently associated with poor clinical outcomes. Further, patients with 
contraindications to anticoagulation (e.g. recent surgery or trauma) are frequently managed 
without any anticoagulation during V-V ECMO and studies have suggested that the incidence of 
thromboembolism and circuit thrombosis among these patients is similar to that observed 
among patients receiving moderate intensity anticoagulation. 
 
6.1.2 Moderate Intensity Anticoagulation Group 
 
Patients assigned to the moderate intensity anticoagulation strategy will receive anticoagulation 
targeting a PTT goal of 40-60 seconds or anti-Xa level of 0.2 to 0.3 IU/mL.   
 
Choice of anticoagulant and monitoring strategy (PTT or anti-Xa level) will be at the discretion of 
the treating clinicians and will be prospectively recorded. Anticoagulant drips will be titrated 
according to institutional protocols. For patients who survive to decannulation, the infusion will 
be stopped one hour prior to decannulation.   
 
This approach to anticoagulation reflects the current approach for patients receiving V-V ECMO 
at Vanderbilt University Medical Center. While there is significant variation in practice regarding 
anticoagulation management across ECMO centers15,22, this protocol is similar to protocols 
widely adopted for patients receiving V-V ECMO at other centers.20  
 
 
6.1.3 Criteria for Changing Anticoagulation Strategy 
 
The intent of the study is to control maintenance anticoagulation strategy for patients receiving 
V-V ECMO without a clear indication for, or contraindication to anticoagulation because the 
relative risks and benefits of low intensity vs. moderate intensity anticoagulation remain unclear 
in these patients. 
 

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If a study participant experiences a major bleeding event, a thromboembolic event (e.g. DVT, 
PE, stroke, or acute circuit thrombosis), or an arterial ECMO cannula is inserted (which 
increases the risk of a clinically meaningful thromboembolic event) the study will cease to 
control anticoagulation strategy and all further decisions regarding anticoagulation will be at the 
discretion of the clinical team.  
 
There are other conditions that occur commonly in the course of critical illness that may prompt 
the clinical team to change anticoagulation strategy. If the patient develops any of the following 
conditions, the protocol will allow the clinical team to change anticoagulation strategy if felt to be 
in the best interest of the patient, but the protocol will not mandate termination of the assigned 
anticoagulation strategy: 
• 
Atrial fibrillation 
• 
Acute coronary syndrome 
• 
Thrombocytopenia 
• 
Hemolysis 
• 
Suspected bleeding 
• 
Suspected thromboembolism 
• 
Clinically apparent bleeding not meeting the definition for major bleeding 
• 
Planned procedure 
• 
Lack of parenteral access 
• 
Coagulopathy (elevated INR) 
• 
Suspected or confirmed heparin-induced thrombocytopenia 
• 
Recurrent oxygenator failure 
• 
Anticoagulation given to support continuous renal replacement therapy 
o There are no data to suggest that anticoagulation is superior to a Citrate infusion 
or no intervention to improve patency of the continuous renal replacement 
therapy circuit. If the treatment team chooses to intervene to improve continuous 
renal replacement therapy patency, they will be encouraged to preferentially 
select a Citrate infusion. Ultimately, the decision will be at the discretion of the 
treatment team and if anticoagulation is selected to support continuous renal 
replacement therapy, this will be recorded.  
• 
Visible clot within the ECMO circuit 
• 
Elevated transmembrane pressure or other circuit parameter concerns 
• 
Low ECMO blood flow 
 
At any point during the study, the clinical team will have the ability to change the anticoagulation 
strategy and use whatever strategy is needed for patient safety.  
 
6.2 
Post-Decannulation Surveillance and Anticoagulation Management 
 
Following decannulation, anticoagulation management will be left to the discretion of the treating 
physician. At 24 to 72 hours post-decannulation, all participants will undergo routine, four-
extremity venous ultrasonography for cannula-associated DVT surveillance, in concordance 
with the current practice for cannula-associated DVT surveillance at Vanderbilt University 
Medical Center. The exact timing of surveillance and the treatment of any identified DVT will be 
left to the discretion of the treating physician based on the perceived risks of bleeding relative to 
benefits of anticoagulation treatment. The presence of any DVT identified by routine 
surveillance following decannulation will be prospectively recorded.  
 
 

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7  
Data Collection and Outcome Measures 
 
 
7.1 
Data Collection 
 
Data will be collected non-invasively as a part of usual care. No additional data will be obtained 
beyond that which is obtained by bedside observation and from the electronic medical record. 
The intervention is defined as the time from randomization until the first of: diagnosis of a major 
bleeding event, diagnosis of a thrombotic event, placement of an arterial ECMO cannula, 
decannulation from ECMO, or death.    
 
The following variables will be recorded: 
 
Baseline Variable Collection: 
• 
Date and time of hospital admission 
• 
Date and time of ICU admission 
• 
Date and time of intubation (if applicable) 
• 
Age 
• 
Assigned gender at birth 
• 
Height 
• 
Weight 
• 
Body mass index 
• 
Self-reported race 
• 
SAPS II score  
• 
Physiologic parameters at randomization (e.g. heart rate, blood pressure, respiratory 
rate), receipt of vasopressors (agent, dose) 
• 
Measures of mental status and delirium at randomization [e.g. Richmond Agitation-
Sedation Score (RASS), Confusion Assessment Method for the ICU (CAM-ICU), 
Glasgow Coma Scale (GCS)] 
• 
Indication for ECMO 
• 
Respiratory support immediately prior to ECMO cannulation (e.g. nasal cannula, high 
flow nasal cannula, non-invasive ventilation, or invasive ventilation) 
• 
Fraction of inspired oxygen immediately prior to ECMO cannulation 
• 
Positive end-expiratory pressure immediately prior to ECMO cannulation 
• 
History of chronic lung disease 
• 
History of lung transplantation 
• 
History of thromboembolism 
• 
History of stroke 
• 
History of major bleeding event 
• 
Chronic receipt of anticoagulation 
• 
Receipt of anticoagulation at the time of randomization (e.g. aspirin, clopidogrel, 
warfarin, direct-acting oral anticoagulants) in the 7 days prior to randomization 
• 
Active medical problems at randomization (e.g. sepsis, septic shock, acute renal failure 
requiring renal replacement therapy) 
• 
Most recent complete blood count, creatinine, PTT, Anti-Xa, and INR values prior to 
randomization 

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• 
Most recent arterial blood prior to ECMO cannulation 
• 
Date and time of ECMO cannulation 
• 
ECMO configuration at randomization 
• 
Number and location of ECMO cannula sites at randomization 
• 
Manufacturer and model of ECMO circuit at randomization 
• 
Manufacturer and model of oxygenator at randomization 
• 
ECMO settings at randomization (blood flow, revolutions per minute, sweep gas flow, 
fraction of delivered oxygen) 
 
Assessments between Randomization and Hospital Discharge 
• 
Date and time of all major bleeding events from randomization to hospital discharge 
• 
Date and time of all thromboembolic events from randomization to hospital discharge 
• 
Anticoagulation strategy at 7 AM each day from randomization to the first of: diagnosis of 
a major bleeding event, diagnosis of a thrombotic event, placement of an arterial ECMO 
cannula, decannulation from ECMO, or death; indication for receiving anticoagulation 
strategy other than intervention strategy 
• 
Randomized assignment to low intensity or moderate intensity anticoagulation strategy 
• 
Number of hours during the intervention period receiving moderate intensity 
anticoagulation  
• 
Number of hours during the intervention period receiving low intensity anticoagulation 
• 
Date, time, and value of all PTTs and all Anti-XA laboratory results from randomization 
to 24 hours following decannulation 
• 
Date, time, and type of all major bleeding events from randomization to hospital 
discharge 
• 
Date, time, and type of all thromboembolic events from randomization hospital discharge 
• 
ECMO blood flow rate, daily during the intervention period 
• 
ECMO fraction of delivered oxygen, daily during the intervention period 
• 
Transmembrane pressures, daily during the intervention period 
• 
Receipt of continuous renal replacement therapy, daily during the intervention period 
• 
Receipt of anticoagulation for continuous renal replacement therapy patency (drug, 
dose, route of administration), assessed daily during the intervention period 
• 
Volume of packed red blood cells transfused from randomization to 24 hours following 
decannulation 
• 
Volume of platelets transfused from randomization to 24 hours following decannulation 
• 
Volume of fresh frozen plasma transfused from randomization to 24 hours following 
decannulation 
• 
Volume of cryoprecipitate transfused from randomization to 24 hours following 
decannulation 
• 
Lowest documented ECMO blood flow rate during the intervention period 
• 
Date and time of each circuit exchange 
• 
Date and time of each circuit component exchange 
• 
Indication for circuit and circuit component exchanges 
• 
Post-decannulation DVT 
• 
Lowest hemoglobin from randomization to 24 after decannulation 
• 
Lowest documented platelet count from randomization to 24 hours after decannulation 
• 
Highest total and indirect bilirubin values from randomization to 24 hours after 
decannulation 
• 
Highest LDH value values from randomization to 24 hours after decannulation  

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• 
Renal failure requiring renal replacement therapy from randomization to 24 hours after 
decannulation 
• 
Heparin-induced thrombocytopenia diagnosed by positive serotonin release assay test 
• 
Date and time of decannulation 
• 
Date and time of extubation 
• 
Date of ICU discharge 
• 
Date of hospital discharge 
• 
Date and time of death 
• 
Date and time of arterial cannula placement 
• 
Bleeding event as the primary cause of death 
• 
Thromboembolic event as the primary cause of death 
 
7.2 
Outcome Measures 
 
7.2.1 Primary Efficacy Outcome 
 
• 
Major bleeding, according to the International Society on Thrombosis and Hemostasis 
definition1, from randomization to 24 hours after decannulation 
a. Fatal bleeding 
b. Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with 
compartment syndrome 
c. Clinically overt bleeding associated with either a drop in hemoglobin level by at 
least 2.0 grams/dL or leading to transfusion of two or more units of packed red 
blood cells 
 
7.2.2 Primary Safety Outcome 
 
• 
Thromboembolic event from randomization to 24 hours after decannulation, defined as: 
a. Deep venous thrombosis (DVT)  
b. Acute pulmonary embolism (PE) 
c. Intra-cardiac thrombosis  
d. Ischemic stroke  
e. Acute circuit thrombosis requiring urgent circuit exchange 
f. Acute arterial thromboembolism 
 
7.2.3 Feasibility Outcomes 
 
• 
Number of patients screened per month 
• 
Number of patients who are eligible per month 
• 
The specific exclusion criteria met (for any patient ineligible for enrollment)  
• 
Reasons for “missed” enrollments (e.g. unavailability of research staff, refusal of clinical 
team to allow randomization, patient refusal of informed consent) 
• 
Number of patients enrolled per month 
• 
Adherence to the assigned anticoagulation strategy  
• 
Separation between groups in anticoagulation treatment received 
• 
Time from ECMO cannulation to randomization 

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• 
Duration of the intervention period, defined as the time from randomization to the first of: 
diagnosis of a major bleeding event, diagnosis of a thromboembolic event, placement of 
an arterial ECMO cannula, decannulation from ECMO, or death 
 
 
 
7.2.4 Secondary Outcomes 
 
• 
Cannula-associated DVT, as measured by four-extremity venous ultrasounds obtained 
24-72 hours following decannulation 
• 
Bleeding events per ECMO day 
• 
Thromboembolic events per ECMO day 
• 
Bleeding events from randomization to the first of death or discharge 
• 
Thromboembolic events from randomization to the first of death or discharge 
• 
Circuit or circuit component exchange required during ECMO support 
• 
ECMO circuit durability, calculated as the number of calendar days from randomization 
to death or decannulation divided by the number of ECMO circuits used  
• 
RBC transfusion volume per ECMO day, calculated as the total volume of packed red 
blood cells transfused from randomization to death or decannulation divided by the 
number of calendar days during this period 
• 
New diagnosis of HIT from randomization to the death or decannulation from ECMO, as 
measured by clinically obtained serotonin release assay 
• 
Lowest documented platelet count from randomization to 24 hours after decannulation 
• 
Highest Total and indirect bilirubin values from randomization to 24 hours after 
decannulation 
• 
Highest LDH value values from randomization to 24 hours after decannulation  
• 
Death attributable to a major bleeding event 
• 
Death attributable to a thromboembolic event 
• 
Ventilator-free days 
• 
ECMO-free days 
• 
ICU-free days 
• 
Hospital-free days 
• 
In-hospital mortality  
 
 
8 
Data Quality Monitoring and Storage 
 
 
8.1 
Data Quality Monitoring 
 
Data quality will be reviewed remotely using front-end range and logic checks at the time of data 
entry and back-end monitoring of data using a secure web platform for building and managing 
online databases (REDCap) to generate data reports. We will perform routine monitoring to 
examine the completeness and accuracy of informed consent documents for study participants, 
documentation of eligibility criteria, and the completeness of study outcome collection. 
 
8.2 
Data Storage  
 

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Data will be entered into a secure online database. All data will be maintained in the secure 
online database (REDCap) until the time of study publication. At the time of publication, a de-
identified version of the database will be generated. 
 
 
 
 
9 
Risk Assessment 
 
 
9.1 
Potential Risk to Participants 
 
Anticoagulation strategy and monitoring tools vary within and across institutions. There are no 
randomized controlled trials evaluating safety or comparing the effect of different strategies on 
clinical outcomes. In this trial, two anticoagulation strategies are proposed: 1. Low intensity 
anticoagulation administered at doses and frequencies commonly used for DVT prophylaxis and 
2. Moderate intensity anticoagulation titrated to a PTT goal of 40-60 seconds or an Anti-Xa level 
of 0.2-0.3 IU/mL. This first strategy of low intensity anticoagulation (a strategy congruent with 
usual DVT prophylaxis) is being studied in this trial with the goal of decreasing life-threatening 
bleeding, a common and potentially catastrophic complication during V-V ECMO. This strategy 
is not the standard of care. The second strategy of moderate intensity reflects usual care at our 
institution for patients receiving V-V ECMO at our institution; however, it has been documented 
that patients with a contraindication to anticoagulation (e.g. recent surgery) can be safely 
managed on V-V ECMO without any anticoagulation. Therefore, regardless of treatment arm, 
patients randomized in this study will receive an anticoagulation strategy that they may have 
received even if they were not included in the study and would, therefore, not experience any 
additional risks beyond usual care.  
 
A potential risk to patients participating in this study involves the collection of protected health 
information (PHI) and the risk of loss of confidentiality. In order to limit the associated risks, the 
minimum amount of PHI necessary for study conduct will be collected. After collection, the data 
will be stored in a secure online database (REDCap) only accessible by the investigators. 
REDCap tools will be used to ensure that the PHI that is collected is only visible to investigators 
at the healthcare system where the patient as enrolled.  To protect participant privacy, REDCap 
tools will be used to ensure that only deidentified data can be exported for use during the 
analyses. 
   
9.1.1 Potential Risks of Receiving Low Intensity Anticoagulation for Patients Receiving 
V-V ECMO 
 
Receiving ECMO carries risks of thromboembolism, hemolysis, consumptive coagulopathies, 
and circuit thrombosis. Moderate intensity anticoagulation may decrease these risks. Potential 
risks of receiving low intensity anticoagulation instead of moderate intensity anticoagulation 
include: 
 
1) Thromboembolism – pulmonary embolism, DVT, ischemic strokes, and cardiac thrombus. 
The risk of thromboembolism applies to all patients receiving venovenous ECMO regardless of 
anticoagulation strategy but may be increased in patients who receive low intensity 
anticoagulation only. 
 

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2) Hemolysis – venovenous ECMO causes shear stress and mechanical trauma to red blood 
cells, which leads to risks of hemolysis. All patients receiving venovenous ECMO are at risk for 
hemolysis. If anticoagulation reduces the risk hemolysis, a less intense anticoagulation strategy 
may increase the risk of hemolysis.  
 
3) Consumptive coagulopathy – the coagulation system is activated by the foreign surfaces of 
the ECMO circuit. This process can lead to damage and consumption of clotting factors and 
platelets, leading to coagulation system dysfunction. Though it has never been demonstrated, a 
less intense anticoagulation strategy, may exacerbate risks of consumptive coagulopathy and 
dysregulation of the coagulation system. Ultimately this could generate higher risks of either 
bleeding, clotting, or both.  
 
2) Circuit thrombosis – fibrin and thrombus can accumulate throughout the components of the 
ECMO circuit (generally the oxygenator) over time due to the non-biologic surfaces of the 
device and turbulent areas of blood flow. The burden of thrombus may either gradually or 
acutely worsen requiring a controlled or emergent circuit component exchange. When a circuit 
component acutely fails to operate, and during any circuit component exchange, the patient may 
be inadequately supported by ECMO temporarily and may experience clinical compromise, 
including hypoxemia, acidemia, hypotension, symptomatic bradycardia, and other cardiac 
arrhythmias. During the majority of circuit exchanges the physiologic derangements are 
transient and without deleterious consequences; nevertheless, in the most severe 
circumstances, these may lead to cardiac arrest. All patients receiving ECMO are at risk for 
requiring a circuit or circuit component exchange, and circuit or circuit component exchange are 
frequently required for patients receiving V-V ECMO regardless of anticoagulation strategy. 
Compared to moderate intensity anticoagulation, a strategy of low intensity anticoagulation 
could increase the risk of circuit thrombosis, but based on available data, this is unknown.  
 
9.1.2 Potential Risks of Receiving Moderate Intensity Anticoagulation for Patients 
Receiving V-V ECMO 
 
One potential risk to participating in this study is receiving the moderate intensity anticoagulation 
strategy rather than the low intensity anticoagulation strategy. Moderate intensity could increase 
the risk of life-threatening bleeding relative to low intensity anticoagulation. Because moderate 
intensity anticoagulation is the standard strategy for patients receiving V-V ECMO at this 
institution, the moderate intensity anticoagulation strategy does not represent any risk beyond 
the risks of receiving V-V ECMO as part of usual care.   
 
9.2 
Minimization of Risk 
 
Federal regulations at 45 CFR 46.111(a)(1) require that risks to participants are minimized by 
using procedures which are consistent with a sound research design. This study protocol 
incorporates numerous design elements to minimize risk to patients that meet this human 
subject protection requirement. Both low intensity and moderate intensity anticoagulation 
(Heparin and Bivalirudin) have been approved by the Food and Drug Administration and have 
been used in clinical practice during ECMO for decades with an established safety profile. 
Experience treating patients receiving venovenous ECMO with both low intensity and moderate 
intensity anticoagulation strategies has been reported in the literature. Data suggest, but do not 
prove, that both strategies are safe. To mitigate risk introduced by either strategy we exclude 
from the study patients with known allergy to heparin, patients with known or suspected active 
bleeding or thromboembolism and patients at higher than usual risk of bleeding or 
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patients with COVID-19, we also exclude patients with a positive SARS-CoV-2 test within 21 
days of screening or for whom the treatment team has a high clinical suspicion for COVID-19. 
Furthermore, the trial specifically excludes all patients for which the treating clinicians believe a 
specific anticoagulation strategy is required, so all enrolled participants will be assessed safe for 
either treatment group by treating clinicians. Finally, at any time during the study, the treatment 
team may change the anticoagulation strategy if and when it is determined to be necessary for 
patient safety. The study protocol includes daily monitoring for protocol adherence and adverse 
events during the period of the study intervention. 
 
9.3 
Potential Benefit 
 
Study participants may or may not receive any direct benefits from their participation in this 
study. Participants who are randomized to the moderate intensity anticoagulation group are 
expected to receive the anticoagulation strategy that they would receive were they to choose 
not to participate in the study; thus, this group is not expected to receive a direct benefit. If 
administration of low intensity anticoagulation improves clinical outcomes among adults 
receiving V-V ECMO, the participants randomized to this group may directly benefit. 
 
9.4 
Risk in Relation to Anticipated Benefit 
 
Federal regulations at 45 CFR 46.111 (a)(2) require that “the risks to subjects are reasonable in 
relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that 
may reasonably be expected to result.” Based on the preceding assessment of risks and 
potential benefits, the risks to participants are reasonable in relation to anticipated benefits. 
Various anticoagulation strategies for patients receiving V-V ECMO have been used in clinical 
practice for decades. Although data do not prove safety or superiority between these strategies 
there are data to suggest either strategy is safe and potentially effective. 
 
 
10 
Human Subjects Protections 
 
 
Each study participant or a LAR must sign and date an informed consent form. Approval of the 
Vanderbilt Institutional Review Board will be required before any participant is entered into the 
study. 
 
10.1 
Selection of Subjects 
 
Federal regulations at 45 CFR 46(a)(3) require the equitable selection of participants. Every 
adult patient for whom V-V ECMO is initiated at Vanderbilt University Medical Center or 
accepted on V-V ECMO from an outside institution will be screened to determine if the patient 
meets inclusion and exclusion criteria. Data that have been collected as part of routine clinical 
care will be reviewed to determine eligibility. If any patient meets criteria for study enrollment, 
then the attending physician responsible for his or her care will be asked for permission to 
approach the patient or his or her LAR for informed consent. Study exclusion criteria neither 
unjustly exclude classes of individuals from participation in the research nor unjustly include 
classes of individuals for participation in the research. Hence, the recruitment of participants 
conforms to the principle of distributive justice. 
 
10.2 
Justification of Including Vulnerable Subjects 
 

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The present research aims to investigate the feasibility of a large multicenter trial evaluating the 
safety and efficacy of treating patients receiving V-V ECMO with low intensity anticoagulation. 
Patients receiving V-V ECMO have severe respiratory failure and are at high risk for mortality. 
Due to the nature of this patient population, many of these patients will have impaired decision-
making capabilities. Therefore, this study would be virtually impossible to perform if only those 
participants with retained decision-making capacity were enrolled and would not be 
generalizable to the population of patients receiving venovenous ECMO. Hence, participants 
recruited for this trial are not being unfairly burdened with involvement in this research. 
10.3 
Informed Consent 
 
Federal regulations 45 CFR 46.111(a)(5) require that informed consent will be sought from each 
patient or the patient’s LAR. Study personnel obtaining informed consent are responsible for 
ensuring that the patient or LAR understands the risks and benefits of participating in the study, 
answering any questions the patient or LAR may have throughout the study and sharing any 
new information in a timely manner that may be relevant to the patient’s or LAR’s willingness to 
permit the patient’s continued participation in the trial. The study personnel obtaining informed 
consent will make every effort to minimize coercion. Whenever possible, consent will be 
obtained by a study team member separate from the person who obtained consent for 
cannulation and initiation of ECMO.  All patients or their LARs will be informed of the objectives 
of the study and the potential risks. The informed consent document will be used to explain the 
risks and benefits of study participation to the patient or LAR in simple terms and to confirm that 
the patient or LAR is satisfied with his or her understanding of the risks and benefits of 
participating in the study and desires to participate in the study before the patient is entered into 
the study. The investigator is responsible for ensuring that informed consent is given by each 
patient or LAR. This includes obtaining the appropriate signatures and dates on the informed 
consent document prior to the performance of any protocol procedures including initiation of 
study intervention. If the potential participant is under the care of another physician (not the 
Investigator), the patient’s physician will approach the patient first and obtain permission from 
the patient to be approached by the Investigator regarding the research opportunity. 
 
10.4 
Continuing Consent 
 
Patients for whom consent was initially obtained from a LAR, but who subsequently regain 
decision-making capacity while in hospital will be approached for consent for continuing 
participation, including continuance of data acquisition. The consent form signed by the LAR 
should reflect that such consent should be obtained.  
10.5 
Withdrawal of Consent 
 
Participating patients may withdraw or be withdrawn (by the LAR, treating physician, or 
investigator) from the trial at any time without prejudice. Data recorded up to the point of 
withdrawal will be included in the trial analysis, unless consent to use data has also been 
withdrawn. Withdrawal of consent prior to receipt of the study intervention will constitute a 
screen-failure and will be recorded.  Withdrawal of consent after randomization and initiation of 
the study intervention will lead to discontinuation of study interventions, but site staff will request 
access to medical records for data related to the trial. 
 
10.6 
Identification of Legally Authorized Representatives 
 

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Many of the patients approached for participation in this research protocol will have impaired 
decision-making capacity due to critical illness and will not be able to provide informed consent. 
Accordingly, informed consent will be sought from the patient’s LAR.  
 
Regarding consent from the LAR, the existing federal research regulations (‘the Common Rule’) 
states at 45 CFR 46.116 that “no investigator may involve a human being as a subject in 
research…unless the investigator has obtained the legally effective informed consent of the 
subject or the subject’s legally authorized representative”; and defines at 45 CFR 46 102 (c) a 
LAR as “an individual or judicial or other body authorized under applicable law to consent on 
behalf of a prospective subject to the subject’s participation in the procedures(s) involved in the 
research.” The Office of Human Research Protections (OHRP) defined examples of “applicable 
law” as being state statutes, regulations, case law, or formal opinion of a State Attorney General 
that addresses the issue of surrogate consent to medical procedures. Such “applicable law” 
could then be considered as empowering the LAR to provide consent for participant 
participation in the research. Interpretation of “applicable law” may be state specific and will be 
addressed by the IRB.  
 
According to a previous President’s Bioethics Committee (National Bioethics Advisory 
Committee (NBAC)), an investigator should accept a relative or friend of the potential participant 
who is recognized as an LAR for purposes of clinical decision making under the law of the state 
where the research takes place.46 Finally, OHRP has stated in their determination letters that a 
surrogate could serve as a LAR for research decision making if such an individual is authorized 
under applicable state law to provide consent for the “procedures” involved in the research 
study. 
10.7 
Justification of Surrogate Consent 
 
According to the Belmont Report, respect for persons incorporates at least two ethical 
convictions; first, that individuals should be treated as autonomous agents, and second, that 
persons with diminished autonomy are entitled to protection. One method that serves to protect 
patients is restrictions on the participation of patients in research that presents greater than 
minimal risk. 
 
Commentators and research ethics commissions have held the view that it is permissible to 
include incapable participants in greater than minimal risk research as long as there is the 
potential for beneficial effects and that the research presents a balance of risks and expected 
direct benefits similar to that available in the clinical setting. Several U.S. task forces have 
deemed it permissible to include incapable participants in research. For example, the American 
College of Physicians’ document allows surrogates to consent to research involving incapable 
participants only “if the net additional risks of participation are not substantially greater than the 
risks of standard treatment”. Finally, NBAC stated that an IRB may approve a protocol that 
presents greater than minimal risk but offers the prospect of direct medical benefits to the 
participant, provided that “the potential subject’s LAR gives permission…”. 
 
Consistent with the above ethical sensibilities regarding the participation of decisionally 
incapable participants in research and the previous assessment of risks and benefits in the 
previous section, the present trial presents a balance of risks and potential direct benefits that is 
similar to that available in the clinical setting. 
 
10.8 
Confidentiality 
 

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Federal regulations at 45 CFR 46 111 (a) (7) requires that when appropriate, there are 
adequate provisions to protect the privacy of participants and to maintain the confidentiality of 
data. At no time during the course of this study, its analysis, or its publication will patient 
identities be revealed in any manner.  The minimum necessary data containing patient or 
provider identities will be collected.  All patients will be assigned a unique study ID number for 
tracking.  All data collected for this study will be entered directly into a secure online database.  
All data will be maintained in the secure online database until the time of study publication.  At 
the time of publication, a de-identified version of the database will be generated. 
 
 
11 
Adverse Events 
 
Assuring patient safety is an essential component of this protocol. Both anticoagulation 
strategies have been used for decades in critically ill patients with an established safety profile. 
Treatment with low intensity anticoagulation for patients receiving V-V ECMO, however, raises 
unique safety considerations.  This protocol addresses these considerations through: 
1. Exclusion of patients with active bleeding and patients assessed as at high risk of bleeding 
(for whom the moderate intensity anticoagulation strategy might be unsafe); 
2. Exclusion of patients with active thromboembolism or patients felt to be at high risk of 
thromboembolism (for whom the low intensity anticoagulation strategy might be insufficient); 
3. Proactive education of treating clinicians regarding signs of oxygenator inefficiency and 
failure and ECMO circuit component thrombosis; 
4. On-study monitoring of circuit components for signs of thrombosis and oxygenator 
insufficiency/failure; 
5. Systematic collection of safety outcomes relevant to anticoagulation strategy during V-V 
ECMO; 
6. Structured reporting of adverse events 
11.1 
Adverse Event Definitions 
 
Adverse Event: Any untoward medical occurrence associated with the use of a drug or a study 
procedure, whether or not considered drug related. 
 
Serious Adverse Event: A serious adverse event is any adverse event that results in one of 
the outcomes listed in section 11.3 below.  
 
Adverse Reaction: An adverse reaction means any adverse event caused by a study 
intervention. An adverse reaction is a subset of all suspected adverse events where there is a 
reason to conclude that the study intervention caused the event.  
 
Suspected Adverse Reaction: Any adverse event for which there is a reasonable possibility 
that the study procedures caused the adverse event. Reasonable possibility means there is 
evidence to suggest a causal relationship between the study procedures and the adverse event. 
A suspected adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction.  
 
Suspected Unexpected Serious Adverse Reaction (SUSAR): An adverse reaction that is 
both unexpected (not consistent with risks outlined in the study protocol or investigator 
brochure), serious, and meets the definition of a suspected adverse reaction. 
 
11.2 
Safety Monitoring 

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Assuring patient safety is an essential component of this protocol. Site investigators have 
primary responsibility for the safety of the individual patients enrolled at their respective 
institutions. Each investigator has primary responsibility for the safety of the individual 
participants under his or her care. The Investigators will evaluate patients for protocol 
adherence and adverse events daily from enrollment through 24 hours after the end of the 
intervention period (the first of diagnosis of a major bleeding event, diagnosis of a thrombotic 
event, placement of an arterial ECMO cannula, decannulation from ECMO, or death). If adverse 
events are identified, site investigators will determine if such adverse events are reportable. 
Thereafter, adverse events are not required to be reported unless the investigator feels the 
adverse event was definitely or possibly related to study intervention or procedures. 
Serious adverse events that are definitely or probably related to study procedures will be 
considered reportable and thus collected in the adverse events case reports forms. 
Investigators will be asked to grade the strength of the relationship of an adverse event to study 
drug or study procedures as follows:  
• 
Definitely Related: The event follows: a) A reasonable, temporal sequence from a study 
procedure; and b) Cannot be explained by the known characteristics of the patient’s 
clinical state or other therapies; and c) Evaluation of the patient’s clinical state indicates 
to the investigator that the experience is definitely related to study procedures.  
• 
Probably Related: The event should be assessed following the same criteria for 
“Definitely Associated”. If in the investigator’s opinion at least one or more of the criteria 
are not present, then “probably” associated should be selected.  
• 
Probably Not Related: The event occurred while the patient was on the study but can 
reasonably be explained by the known characteristics of the patient’s clinical state or 
other therapies.  
• 
Definitely Not Related: The event is definitely produced by the patient’s clinical state or 
by other modes of therapy administered to the patient.  
• 
Uncertain Relationship: The event does not meet any of the criteria previously outlined. 
 
Serious adverse events that are definitely or probably related to study procedures will be 
collected from randomization until death or discharge. 
 
11.3 
Serious Adverse Events 
 
Serious adverse event collection begins after randomization and study procedures have been 
initiated.  If a patient experiences a serious adverse event after consent, but prior to 
randomization or starting study procedures, the event will NOT be collected.  
 
As per the FDA and NIH definitions, a serious adverse event is any adverse event that results in 
one of the following outcomes: 
• 
Death 
• 
A life-threatening experience (that is, immediate risk of dying) 
• 
Prolonged inpatient hospitalization or re-hospitalization 
• 
Persistent or significant disability/incapacity 
Reportable serious adverse events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse events when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
 

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Clinical Outcomes. In this study of critically ill patients at high risk for death and other adverse 
outcomes due to their underlying critical illness, clinical outcomes, including death and organ 
dysfunction, will be systematically collected and analyzed for all patients.  Death and organ 
dysfunction will be reported as outcomes and not as AEs unless the treating clinician or study 
personnel believe the event is related or potentially related to the study OR is more severe or 
prolonged than expected. This approach—considering death and organ dysfunction as 
outcomes rather than AEs and systemically collecting these outcomes for analysis—is common 
in ICU trials.  This approach ensures comprehensive data on death and organ dysfunction for all 
patients, rather than relying on sporadic AE reporting to identify these important events. The 
following is a list of items that will be systematically collected as primary or secondary clinical 
outcomes.  These will not be reported as AEs during this study, unless determined by treating 
clinicians or study personnel to be related or potentially related to the study or more severe or 
prolonged than expected: 
1. Death (all deaths occurring prior to hospital discharge will be reported on the eCRF in 
the vital status at hospital discharge section) 
2. Major or minor bleeding 
3. Thromboembolic event 
4. Cannula-associated DVT 
5. Hemolysis 
6. Thrombocytopenia 
7. Heparin-induced thrombocytopenia 
8. ECMO circuit or circuit component thrombosis 
9. Renal Failure 
10. Duration of ECMO support, ECMO recannulation 
11. Duration of ICU admission, ICU readmission 
12. Duration of hospitalization, hospital readmission 
 
Communication and Reporting of Adverse Events.  In order to ensure proper and timely 
reporting of reportable adverse events, there will be a clear communication plan for all study 
personnel to follow. Site investigators must alert the principal investigator of any serious 
adverse event that is definitely or possibly related to study procedures within 24 hours of 
investigator awareness of the event.  Alerts issued via telephone are to be immediately followed 
with official notification on the adverse event case report form. The principal investigator or a 
delegate will report all unexpected deaths, serious adverse events that are definitely or probably 
related, and SUSARs to the IRB within 7 calendar days of the Investigator's knowledge of the 
event. 
 
12 
Statistical Considerations 
 
12.1 
General Considerations 
We will present summary tabulations by treatment group. For categorical variables, the number 
and percentage of patients within each category (with a category for missing data as needed) of 
the parameter will be presented. For continuous variables, the number of patients, median and 
interquartile range as appropriate, will be presented.  
12.2 
Analysis Populations 

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The intent-to-treat (ITT) population will be the primary outcome analysis population. Patients 
who meet any exclusion criterion will not be a part of the ITT population and will be considered 
screening failures.  Any patient who is randomized will be considered part of the ITT population. 
12.3 
Statistical Analysis 
 
Descriptive statistics including mean, median, standard deviation, and interquartile range will be 
used to analyze continuous variables and frequency and percentage for categorical variables 
and binary outcomes. A pilot trial is not a hypothesis testing study and is unable to provide a 
preliminary test for the hypothesis.23-25 Therefore, variables will be described and presented, 
and no inferential statistical tests will be performed. 
 
12.4 
Sample Size 
 
Given their small size, pilot trials have limited ability to estimate effect sizes that will be 
observed in subsequent large trials trial23,24,26. As this is a descriptive pilot, feasibility trial, no 
formal sample size calculation has been undertaken. We will plan to enroll to the first of 30 total 
patients across all sites or up to November 12, 2023 
 
13 
Privacy and Confidentiality 
 
At no time during the course of this study, its analysis, or its publication will patient identities be 
revealed in any manner.  The minimum necessary data containing patient or provider identities 
will be collected.  All patients will be assigned a unique study ID number for tracking.  Data 
collected from the medical record will be entered into the secure online database REDCap. All 
data will be maintained in the secure online database REDCap until the time of study 
publication.  REDCap tools will be used to ensure that only deidentified data can be exported 
from the online database for analysis.  At the time of publication, all links to identified data will 
be deleted. 
 
 
14 
Follow-up and Record Retention 
 
 
Patients will be followed after enrollment until hospital discharge. Data collected from the 
medical record will be entered into the secure online database REDCap. All data will be 
maintained in the secure online database REDCap until the time of study publication. At the 
time of publication, a de-identified version of the database will be generated and PHI will be 
destroyed. 
 
 
 
 
 

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26 
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