Strategies for Anticoagulation During Venovenous ECMO (SAFE-ECMO)

June 16, 2025 updated by: Whitney Gannon, Vanderbilt University Medical Center

Strategies for Anticoagulation During Venovenous ECMO: The SAFE-ECMO Pilot Trial

Moderate intensity titrated dose anticoagulation has been used in patients receiving extracorporeal membrane oxygenation (ECMO) 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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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. 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. 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. The sheer stress on blood components during ECMO also lead to destruction of high-molecular-weight von Willebrand multimers, interrupting primary hemostasis.

Both bleeding and thromboembolism are common complications during ECMO. Bleeding events have been associated with poor clinical outcomes, likely mediated by an increased incidence of intracranial hemorrhage during ECMO. 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.

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. 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. 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.

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, and anticoagulation practices are highly variable across institutions. 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.

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.

Primary aim of the study: 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 of the study: 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.

Study Type

Interventional

Enrollment (Actual)

26

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Tennessee
      • Nashville, Tennessee, United States, 37209
        • Vanderbilt University Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Patient receiving V-V ECMO
  2. Patient is located in a participating unit of the Vanderbilt University Medical Center (VUMC) 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:

    1. Ongoing receipt of systemic anticoagulation
    2. Planned administration of anticoagulation for an indication other than ECMO
    3. Presence of or plan to insert an arterial ECMO cannula

  6. Presence of a contraindication to anticoagulation:

    1. Active bleeding determined by treating clinicians to make anticoagulation unsafe
    2. Major surgery or trauma less than 72 hours prior to randomization
    3. Known history of a bleeding diathesis
    4. Ongoing severe thrombocytopenia (platelet count < 30,000)
    5. History of heparin-induced thrombocytopenia (HIT)
    6. Heparin allergy
  7. Positive SARS-CoV-2 test within prior 21 days or high clinical suspicion for COVID-19
  8. The treating clinician determines that the patient's risks of thromboembolism or bleeding necessitate a specific approach to anticoagulation management during V-V ECMO

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 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.
Other: Low intensity anticoagulation
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.
Active Comparator: 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.
Other: Moderate Intensity Anticoagulation

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 and is similar to protocols widely adopted for patients receiving V-V ECMO at other centers.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants With Major Bleeding Events
Time Frame: From randomization to the date of death or the date 24 hours after decannulation, whichever came first, through study completion, up to 134 days.

Major bleeding event, according to the International Society on Thrombosis and Hemostasis, defined as:

  1. Fatal bleeding
  2. Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome
  3. 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
From randomization to the date of death or the date 24 hours after decannulation, whichever came first, through study completion, up to 134 days.
Number of Participants With Thromboembolic Events
Time Frame: From randomization to the date of death or the date 24 hours after decannulation, whichever came first, through study completion, up to 134 days.

Thromboembolic event defined as:

  1. Deep venous thrombosis (DVT)
  2. Acute pulmonary embolism (PE)
  3. Intra-cardiac thrombosis
  4. Ischemic stroke
  5. Acute circuit thrombosis requiring urgent circuit exchange
  6. Acute arterial thromboembolism
From randomization to the date of death or the date 24 hours after decannulation, whichever came first, through study completion, up to 134 days.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants With Cannula-associated Deep Vein Thrombosis
Time Frame: 24-72 hours after decannulation
Cannula-associated deep vein thrombosis, as measured by four-extremity venous ultrasounds obtained 24-72 hours following decannulation among patients who were decannulation
24-72 hours after decannulation
Number of Circuit or Circuit Component Exchanges
Time Frame: From randomization to the date of death or decannulation, whichever came first, through study completion, up to 134 days
Circuit or circuit component exchange during ECMO support
From randomization to the date of death or decannulation, whichever came first, through study completion, up to 134 days
New Heparin Induced Thrombocytopenia Diagnosis
Time Frame: From randomization to the date of death or decannulation, whichever came first, through study completion, up to 134 days
New diagnosis of Heparin Induced Thrombocytopenia as measured by clinically obtained serotonin release assay
From randomization to the date of death or decannulation, whichever came first, through study completion, up to 134 days
Lowest Platelet Count
Time Frame: From randomization to the the date of death or the date 24 hours after decannulation, whichever came first, through study completion, up to 134 days
Lowest clinically obtained platelet count
From randomization to the the date of death or the date 24 hours after decannulation, whichever came first, through study completion, up to 134 days
Highest Total Bilirubin Values
Time Frame: From randomization to the the date of death or the date 24 hours after decannulation, whichever came first, through study completion, up to 134 days
Highest clinically obtained total bilirubin values
From randomization to the the date of death or the date 24 hours after decannulation, whichever came first, through study completion, up to 134 days
Highest Lactate Dehydrogenase Value
Time Frame: From randomization to the the date of death or the date 24 hours after decannulation, whichever came first, through study completion, up to 134 days
Highest clinically obtained lactate dehydrogenase value
From randomization to the the date of death or the date 24 hours after decannulation, whichever came first, through study completion, up to 134 days
Death Attributable to a Major Bleeding Event
Time Frame: From randomization to the date of death or discharge, whichever came first, through study completion, up to 134 days
In-hospital mortality attributable to a major bleeding event
From randomization to the date of death or discharge, whichever came first, through study completion, up to 134 days
Death Attributable to a Thromboembolic Event
Time Frame: From randomization to the date of death or discharge, whichever came first, through study completion, up to 134 days
In-hospital mortality attributable to a thromboembolic event
From randomization to the date of death or discharge, whichever came first, through study completion, up to 134 days
Ventilator-free Days
Time Frame: From randomization to the date of death or discharge, whichever came first, through study completion, up to 134 days
Number of days alive and free from mechanical ventilation between randomization and day 28.
From randomization to the date of death or discharge, whichever came first, through study completion, up to 134 days
ICU Length of Stay
Time Frame: From randomization to the date of death or discharge, whichever came first, through study completion, up to 134 days
Number of days in the ICU following randomization.
From randomization to the date of death or discharge, whichever came first, through study completion, up to 134 days
Hospital Length of Stay
Time Frame: From randomization to the date of death or discharge, whichever came first, through study completion, up to 134 days
Number of days in the hospital following randomization
From randomization to the date of death or discharge, whichever came first, through study completion, up to 134 days
In-hospital Mortality
Time Frame: From randomization to the date of death or discharge, whichever came first, through study completion, up to 134 days
Death prior to hospital discharge
From randomization to the date of death or discharge, whichever came first, through study completion, up to 134 days

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of and Specific Reasons for "Missed" Enrollments
Time Frame: From ECMO cannulation to 24 hours after ECMO cannulation.
Reasons for "missed" enrollments (e.g. unavailability of research staff, refusal of clinical team to allow randomization, patient refusal of informed consent)
From ECMO cannulation to 24 hours after ECMO cannulation.
Duration of the Intervention Period (Days)
Time Frame: From randomization to the first of decannulation or death, up to 134 days.
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 (days)
From randomization to the first of decannulation or death, up to 134 days.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Vanderbilt University Medical Center

Investigators

  • Study Director: Jonathan D Casey, MD, MSc, Vanderbilt University Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 12, 2022

Primary Completion (Actual)

January 10, 2024

Study Completion (Actual)

January 10, 2024

Study Registration Dates

First Submitted

July 23, 2021

First Submitted That Met QC Criteria

August 2, 2021

First Posted (Actual)

August 9, 2021

Study Record Updates

Last Update Posted (Actual)

June 18, 2025

Last Update Submitted That Met QC Criteria

June 16, 2025

Last Verified

June 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 202210

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Request will be reviewed by the study team and approval will be contingent upon the execution of a data use agreement.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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