Strategies for Anticoagulation During Venovenous ECMO (SAFE-ECMO)

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: Recruiting
• Conditions: Thromboembolism; Acute Hypoxemic Respiratory Failure; Anticoagulant-induced Bleeding
• Intervention / Treatment: Other: Low intensity anticoagulation; Other: Moderate Intensity Anticoagulation

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 (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Whitney D Gannon, MSN, MS; Phone Number: 6109095789; Email: whitney.gannon@vumc.org
• Study Contact Backup: Name: Jonathan D Casey, MD, MSc; Phone Number: 502-645-0153; Email: jonathan.d.casey@vumc.org

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37209
      • Recruiting
      • Vanderbilt University Medical Center
      • Contact: Whitney Gannon, MS; Phone Number: 610-909-5789; Email: whitney.gannon@vumc.org

Participation Criteria

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

How is the study designed?

Design Details

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

Number of Arms

2

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
Frequency of major bleeding events	Major bleeding event, according to the International Society on Thrombosis and Hemostasis, defined as: Fatal bleeding; Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome; 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 until the date of death or the date 24 hours after decannulation, whichever came first, through study completion, an average of 2 years.
Frequency of thromboembolic events	Thromboembolic event defined as: Deep venous thrombosis (DVT); Acute pulmonary embolism (PE); Intra-cardiac thrombosis; Ischemic stroke; Acute circuit thrombosis requiring urgent circuit exchange; Acute arterial thromboembolism	From randomization to until the date of death or the date 24 hours after decannulation, whichever came first, through study completion, an average of 2 years.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of cannula-associated deep vein thrombosis	Cannula-associated deep vein thrombosis, as measured by four-extremity venous ultrasounds obtained 24-72 hours following decannulation among patients who were decannulation	24-48 hours after decannulation
Bleeding events per ECMO day	Number of major bleeding events per day of V-V ECMO	From from randomization to 24 hours after decannulation
Thromboembolic events per ECMO day	Number of thromboembolic events per day of V-V ECMO	From from randomization to 24 hours after decannulation
Bleeding events from randomization to the first of death or discharge	Number of bleeding events from date of randomization until the date of death or hospital discharge, whichever came first, up to 100 months	From date of randomization until the date of death or hospital discharge, whichever came first, through study completion, an average of 2 years.
Thromboembolic events from randomization to the first of death or discharge	Number of thromboembolic events from randomization until the date of death or hospital discharge, whichever came first, up to 100 months	From randomization until the date of death or hospital discharge, whichever came first, through study completion, an average of 2 years.
Frequency of circuit or circuit component exchanges	Circuit or circuit component exchange during ECMO support	From randomization to the date of death or decannulation, whichever came first, through study completion, an average of 2 years.
ECMO circuit durability	The number of calendar days from randomization to death or decannulation divided by the Number of ECMO circuits used	From randomization to the date of death or decannulation, whichever came first, through study completion, an average of 2 years.
Red blood cell transfusion volume per ECMO day	Total volume of packed red blood cells transfused from randomization to death or decannulation divided by the number of calendar days during this period	From randomization to the date of death or decannulation, whichever came first, through study completion, an average of 2 years.
New Heparin Induced Thrombocytopenia diagnosis	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, an average of 2 years.
Lowest platelet count	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, an average of 2 years.
Highest total and indirect bilirubin values	Highest clinically obtained total and indirect bilirubin values	From randomization to the the date of death or the date 24 hours after decannulation, whichever came first, through study completion, an average of 2 years.
Highest lactate dehydrogenase value	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, an average of 2 years.
Death attributable to a major bleeding event	In-hospital mortality attributable to a major bleeding event	From randomization to the date of death or discharge, whichever came first, through study completion, an average of 2 years.
Death attributable to a thromboembolic event	In-hospital mortality attributable to a thromboembolic event	From randomization to the date of death or discharge, whichever came first, through study completion, an average of 2 years.
Ventilator-free 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, an average of 2 years.
ICU-free days	Number of days alive and not in the ICU between randomization and day 28.	From randomization to the date of death or discharge, whichever came first, through study completion, an average of 2 years.
Hospital-free days	Number of days alive and not in the hospital between randomization and day 28.	From randomization to the date of death or discharge, whichever came first, through study completion, an average of 2 years.
In-hospital mortality	Death prior to hospital discharge	From randomization to the date of death or discharge, whichever came first, through study completion, an average of 2 years.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients screened per month	Number of patients screened for study enrollment per month	Through study completion, an average of 2 years.
Number of and specific reasons for "missed" enrollments	Reasons for "missed" enrollments (e.g. unavailability of research staff, refusal of clinical team to allow randomization, patient refusal of informed consent)	Through study completion, an average of 2 years.
Number of patients enrolled per month	Number of patients enrolled in the study per month	Through study completion, an average of 2 years.
Proportion of patients adhering to randomized assignment	Adherence to the assigned anticoagulation strategy will be adequate if more than 80% of patients have fewer than 10% of monitored values as major protocol violations.	Through study completion, an average of 2 years.
Number of patients eligible for the study	Number of patients who are eligible for the study per month	Through study completion, an average of 2 years.
Number of and the specific exclusion criteria met	The specific exclusion criteria met (for any patient ineligible for enrollment)	Through study completion, an average of 2 years.
Hours receiving low intensity or moderate intensity anticoagulation	Hours receiving low intensity or moderate intensity anticoagulation per day	Through study completion, an average of 2 years.
Time from ECMO cannulation to randomization (hours)	Time from ECMO cannulation to randomization in hours	Through study completion, an average of 2 years.
Duration of the intervention period (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)	Through study completion, an average of 2 years.

Collaborators and Investigators

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

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• ELSO. ELSO Anticoagulation Guidelines. 2014.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 12, 2022
• Primary Completion (Estimated): May 12, 2024
• Study Completion (Estimated): May 12, 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): September 21, 2023
• Last Update Submitted That Met QC Criteria: September 15, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: ARDS; Extracorporeal Membrane Oxygenation; Hypoxemic respiratory failure
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Respiration Disorders; Embolism and Thrombosis; Respiratory Insufficiency; Thromboembolism
• 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