Anticoagulation-free VV ECMO for Acute Respiratory Failure

Extracorporeal Membrane Oxygenation Complication Clinical Trial

— A-FREE ECMO  

Official title:

Anticoagulation-free VV ECMO for Acute Respiratory Failure: A Pilot Safety and Feasibility Randomized Clinical Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04273607
• Other study ID #: 19-5692.0
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: September 1, 2022
• Est. completion date: June 30, 2024

Study information

• Verified date: August 2022
• Source: University Health Network, Toronto
• Contact: Damian Ratano, MD
• Phone: +1 416-340-3601
• Email: damian.ratano[@]chuv.ch
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Currently international experts recommend therapeutic anticoagulation for veno-venous extracorporeal membrane oxygenation (VV-ECMO). Reports and case series suggest that the absence of therapeutic anticoagulation is safe for VV-ECMO. No randomized control trials have assessed this. The aim of this pilot study is to assess safety and feasibility of an "anticoagulation-free strategy" for veno-venous ECMO (VV-ECMO) in Acute respiratory distress syndrome (ARDS).

Description:

Although anticoagulation targets and monitoring strategies vary around the world, the current practice is still to anticoagulate patients on ECMO, mostly with UFH. However, the use of heparin coated circuits has changed their thrombogenicity. Preliminary data suggest that a low-dose unfractionated heparin (UFH) strategy is non-inferior to a therapeutic dose UFH. Indeed, in daily practice, when a patient on ECMO has severe bleeding complications, UFH is often stopped until the hemorrhagic issue is under control, sometimes for days. This has led some to hypothesize that anticoagulation might not be necessary for VV-ECMO, and a few case series report little to no increase in adverse events as a result. There are currently no randomized controlled trials comparing anticoagulation to no anticoagulation for patients supported with ECMO. Anticoagulation is, for physiological reasons, less necessary during VV-ECMO than VA-ECMO and this is the reason why our pilot study will focus on VV-ECMO only. Whereas the whole ECMO device is identical for both configurations, the risk of systemic embolization (e.g., stroke) and its severe complications is much higher in VA-ECMO where blood is reinjected directly into the systemic arterial system. Moreover, in the presence of severely decreased left ventricular function requiring VA-ECMO, the risk of left ventricular thrombus is very high and requires anticoagulation. During VV-ECMO, the risk of systemic embolization is low because the whole circuit is on the right side of the heart and relatively preserved biventricular function is needed to perform VV-ECMO The hypothesis is that VV-ECMO is safe and feasible without therapeutic anticoagulation for adults with ARDS. The objectives of this study is to assess, through a pilot study, the safety and feasibility of an "anticoagulation free strategy" for veno-venous ECMO (VV-ECMO) in acute respiratory failure

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. completion date: June 30, 2024
• Est. primary completion date: December 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Adult patient with ARDS on VV-ECMO

Exclusion Criteria:

• Contraindication to anticoagulation with UFH (known heparin-induced thrombocytopenia, active hemorrhage, any surgery precluding the use of anticoagulation),
• Indication for therapeutic anticoagulation (pulmonary embolism or deep vein thrombosis, chronic anticoagulation therapy before ECMO insertion)
• Low-flow (<2 liters/min) VV-ECMO (ECCO2R)

Related Conditions & MeSH terms

• Extracorporeal Membrane Oxygenation Complication
• Respiratory Insufficiency

Intervention

Drug:
• Subcutaneous Heparin
The intervention group will receive prophylactic heparin instead of standard of care therapeutic intravenous heparin

Locations

Country	Name	City	State
Canada	Toronto General Hospital	Toronto	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
Damian Ratano	PSI Foundation, Toronto, Ontario

Country where clinical trial is conducted

Canada, 

References & Publications (9)

Dornia C, Philipp A, Bauer S, Stroszczynski C, Schreyer AG, Müller T, Koehl GE, Lehle K. D-dimers Are a Predictor of Clot Volume Inside Membrane Oxygenators During Extracorporeal Membrane Oxygenation. Artif Organs. 2015 Sep;39(9):782-7. doi: 10.1111/aor.12460. Epub 2015 Apr 7. — View Citation

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. — View Citation

Lehle K, Philipp A, Gleich O, Holzamer A, Müller T, Bein T, Schmid C. Efficiency in extracorporeal membrane oxygenation-cellular deposits on polymethylpentene membranes increase resistance to blood flow and reduce gas exchange capacity. ASAIO J. 2008 Nov-Dec;54(6):612-7. doi: 10.1097/MAT.0b013e318186a807. — View Citation

Lubnow M, Philipp A, Dornia C, Schroll S, Bein T, Creutzenberg M, Diez C, Schmid C, Pfeifer M, Riegger G, Müller T, Lehle K. D-dimers as an early marker for oxygenator exchange in extracorporeal membrane oxygenation. J Crit Care. 2014 Jun;29(3):473.e1-5. doi: 10.1016/j.jcrc.2013.12.008. Epub 2013 Dec 30. — View Citation

Lubnow M, Philipp A, Foltan M, Bull Enger T, Lunz D, Bein T, Haneya A, Schmid C, Riegger G, Müller T, Lehle K. Technical complications during veno-venous extracorporeal membrane oxygenation and their relevance predicting a system-exchange--retrospective analysis of 265 cases. PLoS One. 2014 Dec 2;9(12):e112316. doi: 10.1371/journal.pone.0112316. eCollection 2014. — View Citation

Panigada M, E Iapichino G, Brioni M, Panarello G, Protti A, Grasselli G, Occhipinti G, Novembrino C, Consonni D, Arcadipane A, Gattinoni L, Pesenti A. Thromboelastography-based anticoagulation management during extracorporeal membrane oxygenation: a safety and feasibility pilot study. Ann Intensive Care. 2018 Jan 16;8(1):7. doi: 10.1186/s13613-017-0352-8. — View Citation

Sidebotham D, Allen SJ, McGeorge A, Ibbott N, Willcox T. Venovenous extracorporeal membrane oxygenation in adults: practical aspects of circuits, cannulae, and procedures. J Cardiothorac Vasc Anesth. 2012 Oct;26(5):893-909. doi: 10.1053/j.jvca.2012.02.001. Epub 2012 Apr 13. Review. — View Citation

Wen PH, Chan WH, Chen YC, Chen YL, Chan CP, Lin PY. Non-heparinized ECMO serves a rescue method in a multitrauma patient combining pulmonary contusion and nonoperative internal bleeding: a case report and literature review. World J Emerg Surg. 2015 Mar 12;10:15. doi: 10.1186/s13017-015-0006-9. eCollection 2015. — View Citation

Whittlesey GC, Drucker DE, Salley SO, Smith HG, Kundu SK, Palder SB, Klein MD. ECMO without heparin: laboratory and clinical experience. J Pediatr Surg. 1991 Mar;26(3):320-4; discussion 324-5. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Increase in d-dimer levels	D-dimers level (>5000ng/ml or >50% increase in 24 h); Need for transfusion of blood and blood-derived products related or not to a bleeding event; Coagulation parameters during the ECMO period; Amount of clot and fibrin visualized in the pre- and post-membrane side of the oxygenator daily (visual assessment) and after ECMO removal (assessed by a photographic quantification method).	through ECMO completion, an average of 14 days
Other	Transfusion of blood and blood-derived products related or not to a bleeding event	Amount of blood products transfused to patients in each groups during the course of ECMO	through ECMO completion, an average of 14 days
Other	Coagulation parameters on ECMO	Evaluation of fibrinogen (g/l), activated partial thromboplastin time (aPTT, seconds), prothrombin time (PT, seconds), thromboelastogram (if available), activated clotting time (ACT, seconds; if available)	through ECMO completion, an average of 14 days
Other	Amount of clot and fibrin visualized in the pre- and post-membrane side	Pragmatic quantification of clot visualized on both sides of the oxygenator by direct evaluation and by a photographic quantification method	through ECMO completion, an average of 14 days
Primary	ECMO associated thrombotic complications	Composite outcome of: ECMO membrane oxygenator function assessed by trans-membrane pressure drop (> 10mmHg/l/min) and a membrane PaO2/FiO2 ratio (< 200mmHg); Need to change ECMO circuit due to clotting or dysfunction; Platelets drop >50% in 24 hours and <50 /mm3; Development of a clinically significant thromboembolic event; Clinical deep vein thrombosis, clinically suspected and confirmed by ultrasound; Acute ischemic stroke, clinically suspected and confirmed by head-CT	through ECMO completion, an average of 14 days
Secondary	Hemorrhagic complications	Hemorrhagic complications assessed and adapted as per Bleeding Academic Research Consortium (BARC); Type 0: No bleeding; Type 1: Bleeding requiring transfusion of packed red blood cells (PRBC) or reduction of UFH; Type 2: Bleeding requiring transfusion of PRBC and reduction of UFH; Type 3: Life-threatening bleeding requiring, transfusion of PRBC, surgical intervention or discontinuation of ECMO; Type 4: Any fatal bleeding	through ECMO completion, an average of 14 days