Strategies for Anticoagulation During Venovenous ECMO

NCT04997265 | Completed Results

• 1 other identifier: 202210
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Acute Hypoxemic Respiratory Failure; Anticoagulant-induced Bleeding; Thromboembolism

Keywords

ARDS; Hypoxemic respiratory failure; Extracorporeal Membrane Oxygenation

Outcome Measures

Primary Outcomes (2)

• Number of Participants With Major Bleeding Events

  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

  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 Outcomes (12)

• Number of Participants With Cannula-associated Deep Vein Thrombosis

  24-72 hours after decannulation

• Number of Circuit or Circuit Component Exchanges

  From randomization to the date of death or decannulation, whichever came first, through study completion, up to 134 days

• New Heparin Induced Thrombocytopenia Diagnosis

  From randomization to the date of death or decannulation, whichever came first, through study completion, up to 134 days

• Lowest 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

  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

Other Outcomes (2)

• Number of and Specific Reasons for "Missed" Enrollments

  From ECMO cannulation to 24 hours after ECMO cannulation.

• Duration of the Intervention Period (Days)

  From randomization to the first of decannulation or death, up to 134 days.

Study Arms (2)

Low Intensity Anticoagulation

EXPERIMENTAL

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

Moderate Intensity Anticoagulation

ACTIVE COMPARATOR

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

Interventions

Low intensity anticoagulation OTHER

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.

Low Intensity Anticoagulation

Moderate Intensity Anticoagulation OTHER

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.

Moderate Intensity Anticoagulation

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient receiving V-V ECMO
• Patient is located in a participating unit of the Vanderbilt University Medical Center (VUMC) adult hospital.

You may not qualify if:

• Patient is pregnant
• Patient is a prisoner
• Patient is \< 18 years old
• Patient underwent ECMO cannulation greater than 24 hours prior to screening
• Presence of an indication for systemic anticoagulation:
• Ongoing receipt of systemic anticoagulation
• Planned administration of anticoagulation for an indication other than ECMO
• Presence of or plan to insert an arterial ECMO cannula
• Presence of a contraindication to anticoagulation:
• Active bleeding determined by treating clinicians to make anticoagulation unsafe
• Major surgery or trauma less than 72 hours prior to randomization
• Known history of a bleeding diathesis
• Ongoing severe thrombocytopenia (platelet count \< 30,000)
• History of heparin-induced thrombocytopenia (HIT)
• Heparin allergy

Sponsors & Collaborators

• Vanderbilt University Medical Center: lead

Study Sites (1)

Vanderbilt University Medical Center

Nashville, Tennessee, 37209, United States

Location

Related Publications (22)

• Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005 Apr;3(4):692-4. doi: 10.1111/j.1538-7836.2005.01204.x.

  PMID: 15842354 BACKGROUND

• Aubron C, DePuydt J, Belon F, Bailey M, Schmidt M, Sheldrake J, Murphy D, Scheinkestel C, Cooper DJ, Capellier G, Pellegrino V, Pilcher D, McQuilten Z. Predictive factors of bleeding events in adults undergoing extracorporeal membrane oxygenation. Ann Intensive Care. 2016 Dec;6(1):97. doi: 10.1186/s13613-016-0196-7. Epub 2016 Oct 6.

  PMID: 27714705 BACKGROUND

• Aubron C, Cheng AC, Pilcher D, Leong T, Magrin G, Cooper DJ, Scheinkestel C, Pellegrino V. Factors associated with outcomes of patients on extracorporeal membrane oxygenation support: a 5-year cohort study. Crit Care. 2013 Apr 18;17(2):R73. doi: 10.1186/cc12681.

  PMID: 23594433 BACKGROUND

• Zangrillo A, Landoni G, Biondi-Zoccai G, Greco M, Greco T, Frati G, Patroniti N, Antonelli M, Pesenti A, Pappalardo F. A meta-analysis of complications and mortality of extracorporeal membrane oxygenation. Crit Care Resusc. 2013 Sep;15(3):172-8.

  PMID: 23944202 BACKGROUND

• Combes A, Leprince P, Luyt CE, Bonnet N, Trouillet JL, Leger P, Pavie A, Chastre J. Outcomes and long-term quality-of-life of patients supported by extracorporeal membrane oxygenation for refractory cardiogenic shock. Crit Care Med. 2008 May;36(5):1404-11. doi: 10.1097/CCM.0b013e31816f7cf7.

  PMID: 18434909 BACKGROUND

• Munshi L, Walkey A, Goligher E, Pham T, Uleryk EM, Fan E. Venovenous extracorporeal membrane oxygenation for acute respiratory distress syndrome: a systematic review and meta-analysis. Lancet Respir Med. 2019 Feb;7(2):163-172. doi: 10.1016/S2213-2600(18)30452-1. Epub 2019 Jan 11.

  PMID: 30642776 BACKGROUND

• Murphy DA, Hockings LE, Andrews RK, Aubron C, Gardiner EE, Pellegrino VA, Davis AK. Extracorporeal membrane oxygenation-hemostatic complications. Transfus Med Rev. 2015 Apr;29(2):90-101. doi: 10.1016/j.tmrv.2014.12.001. Epub 2014 Dec 18.

  PMID: 25595476 BACKGROUND

• Chlebowski MM, Baltagi S, Carlson M, Levy JH, Spinella PC. Clinical controversies in anticoagulation monitoring and antithrombin supplementation for ECMO. Crit Care. 2020 Jan 20;24(1):19. doi: 10.1186/s13054-020-2726-9.

  PMID: 31959232 BACKGROUND

• Saini A, Spinella PC. Management of anticoagulation and hemostasis for pediatric extracorporeal membrane oxygenation. Clin Lab Med. 2014 Sep;34(3):655-73. doi: 10.1016/j.cll.2014.06.014. Epub 2014 Jul 24.

  PMID: 25168949 BACKGROUND

• Doyle AJ, Hunt BJ. Current Understanding of How Extracorporeal Membrane Oxygenators Activate Haemostasis and Other Blood Components. Front Med (Lausanne). 2018 Dec 12;5:352. doi: 10.3389/fmed.2018.00352. eCollection 2018.

  PMID: 30619862 BACKGROUND

• Tauber H, Ott H, Streif W, Weigel G, Loacker L, Fritz J, Heinz A, Velik-Salchner C. Extracorporeal membrane oxygenation induces short-term loss of high-molecular-weight von Willebrand factor multimers. Anesth Analg. 2015 Apr;120(4):730-6. doi: 10.1213/ANE.0000000000000554.

  PMID: 25565317 BACKGROUND

• Kasirajan V, Smedira NG, McCarthy JF, Casselman F, Boparai N, McCarthy PM. Risk factors for intracranial hemorrhage in adults on extracorporeal membrane oxygenation. Eur J Cardiothorac Surg. 1999 Apr;15(4):508-14. doi: 10.1016/s1010-7940(99)00061-5.

  PMID: 10371130 BACKGROUND

• Menaker J, Tabatabai A, Rector R, Dolly K, Kufera J, Lee E, Kon Z, Sanchez P, Pham S, Herr DL, Mazzeffi M, Rabinowitz RP, O'Connor JV, Stein DM, Scalea TM. Incidence of Cannula-Associated Deep Vein Thrombosis After Veno-Venous Extracorporeal Membrane Oxygenation. ASAIO J. 2017 Sep/Oct;63(5):588-591. doi: 10.1097/MAT.0000000000000539.

  PMID: 28857905 BACKGROUND

• Cooper E, Burns J, Retter A, Salt G, Camporota L, Meadows CI, Langrish CC, Wyncoll D, Glover G, Ioannou N, Daly K, Barrett NA. Prevalence of Venous Thrombosis Following Venovenous Extracorporeal Membrane Oxygenation in Patients With Severe Respiratory Failure. Crit Care Med. 2015 Dec;43(12):e581-4. doi: 10.1097/CCM.0000000000001277.

  PMID: 26308437 BACKGROUND

• Esper SA, Welsby IJ, Subramaniam K, John Wallisch W, Levy JH, Waters JH, Triulzi DJ, Hayanga JWA, Schears GJ. Adult extracorporeal membrane oxygenation: an international survey of transfusion and anticoagulation techniques. Vox Sang. 2017 Jul;112(5):443-452. doi: 10.1111/vox.12514. Epub 2017 May 3.

  PMID: 28466601 BACKGROUND

• Krueger K, Schmutz A, Zieger B, Kalbhenn J. Venovenous Extracorporeal Membrane Oxygenation With Prophylactic Subcutaneous Anticoagulation Only: An Observational Study in More Than 60 Patients. Artif Organs. 2017 Feb;41(2):186-192. doi: 10.1111/aor.12737. Epub 2016 Jun 3.

  PMID: 27256966 BACKGROUND

• Carter KT, Kutcher ME, Shake JG, Panos AL, Cochran RP, Creswell LL, Copeland H. Heparin-Sparing Anticoagulation Strategies Are Viable Options for Patients on Veno-Venous ECMO. J Surg Res. 2019 Nov;243:399-409. doi: 10.1016/j.jss.2019.05.050. Epub 2019 Jul 2.

  PMID: 31277018 BACKGROUND

• Wood KL, Ayers B, Gosev I, Kumar N, Melvin AL, Barrus B, Prasad S. Venoarterial-Extracorporeal Membrane Oxygenation Without Routine Systemic Anticoagulation Decreases Adverse Events. Ann Thorac Surg. 2020 May;109(5):1458-1466. doi: 10.1016/j.athoracsur.2019.08.040. Epub 2019 Sep 26.

  PMID: 31563493 BACKGROUND

• Olson SR, Murphree CR, Zonies D, Meyer AD, Mccarty OJT, Deloughery TG, Shatzel JJ. Thrombosis and Bleeding in Extracorporeal Membrane Oxygenation (ECMO) Without Anticoagulation: A Systematic Review. ASAIO J. 2021 Mar 1;67(3):290-296. doi: 10.1097/MAT.0000000000001230.

  PMID: 33627603 BACKGROUND

• ELSO. ELSO Anticoagulation Guidelines. 2014.

  BACKGROUND

• Bembea MM, Annich G, Rycus P, Oldenburg G, Berkowitz I, Pronovost P. Variability in anticoagulation management of patients on extracorporeal membrane oxygenation: an international survey. Pediatr Crit Care Med. 2013 Feb;14(2):e77-84. doi: 10.1097/PCC.0b013e31827127e4.

  PMID: 23287906 BACKGROUND

• Gannon WD, Pratt EH, Vogelsong MA, Adkisson WH, Bacchetta M, Bloom SL, Ford DJ, Guenthart BA, Landsperger JS, Qian ET, Rackley CR, Rice TW, Fielding-Singh V, Stokes JW, Stollings JL, Semler MW, Casey JD; Pragmatic Critical Care Research Group. Low-Intensity vs Moderate-Intensity Anticoagulation for Venovenous Extracorporeal Membrane Oxygenation: The Strategies for Anticoagulation During Venovenous Extracorporeal Membrane Oxygenation Pilot Trial. Chest. 2025 Sep;168(3):639-649. doi: 10.1016/j.chest.2025.02.032. Epub 2025 Mar 11.

  PMID: 40081660 DERIVED

MeSH Terms

Conditions

Respiratory Insufficiency; Thromboembolism

Condition Hierarchy (Ancestors)

Respiration Disorders; Respiratory Tract Diseases; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases

Results Point of Contact

• Title: Whitney Gannon
• Organization: Vanderbilt University Medical Center

whitney.gannon@vumc.org

6109095789

Study Officials

• Jonathan D Casey, MD, MSc

  Vanderbilt University Medical Center

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Acute Care Nurse Practitioner

Model Details: Single center, open-label, parallel-group, randomized pilot trial

Study Record Dates

• First Submitted: July 23, 2021
• First Posted: August 9, 2021
• Study Start: May 12, 2022
• Primary Completion: January 10, 2024
• Study Completion: January 10, 2024
• Last Updated: June 18, 2025
• Results First Posted: June 18, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF

Locations

US (1)