Antithrombin Supplementation in ECMO

Pilot Study of Antithrombin Supplementation During Extracorporeal Membrane Oxigenation

Bleeding is the most feared complication during extracorporeal membrane oxygenation (ECMO) and is associated with high dosing of heparin. There is no consensus on antithrombin (AT) supplementation during ECMO. However, AT is needed by heparin to properly anticoagulate. We hypothesize that maintaining normal antithrombin levels during ECMO is associated with a less heparin dosing and more adequate level of anticoagulation.

Study Overview

• Status: Completed
• Conditions: Extracorporeal Membrane Oxygenation
• Intervention / Treatment: Drug: Antithrombin supplementation; Drug: No antithrombin supplementation

Detailed Description

Extracorporeal membrane oxygenation (ECMO) is a life support for patients with severe acute respiratory failure when conventional treatments failed but it is accompanied by a significant risk of bleeding. Heparin is required during ECMO to avoid circuit thrombosis and its anticoagulant effect is strictly dependent on antithrombin (AT). AT also plays a central role in mediating inflammation. Acquired AT deficiency is common in patients on ECMO, arguably due to long term anticoagulation in addition to sepsis itself. Guidelines suggest to supplement AT in ECMO only when its deficiency coexists with heparin resistance. Few studies evaluated the effect of AT supplementation during ECMO without a consensus on the appropriate level to be maintained. AT supplementation increase anti-Factor Xa (anti-Xa) levels without increasing heparin dosage. This may have a clinical impact because risk of bleeding during ECMO is associated with higher heparin dosage.

We hypothesize that maintaining normal antithrombin activity levels (80%-120%) during ECMO is associated with: I. less heparin dosage, II. a more adequate level of anticoagulation, III. less hemostasis related complications, and IV. a lower level of inflammation.

Adult patients on veno-venous ECMO for respiratory failure will be randomized to maintain AT between 80% and 100% (study group) or no supplementation unless heparin resistance occurs (control group). Sample size of at least 20 patients per group (n=40) is calculated upon the primary outcome measure of reduction of heparin use in the study group compared to the control group. AT and anti-Xa will be measured before ECMO and daily while on ECMO. Anticoagulation will be guaranteed with unfractionated heparin infusion with a target aPTT 1.5-2X normal. Study will end at ECMO removal.

Consistent literature suggests that current ECMO anticoagulation strategies are suboptimal probably due to improper antithrombin supplementation. A normal antithrombin level could guarantee an adequate anticoagulation regimen.

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Italy
  • MI
    • Milano, MI, Italy, 20122
      • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• patients requiring veno-venous ECMO for severe respiratory failure.

Exclusion Criteria:

• patients with pre-existent heparin-induced thrombocytopenia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Antithrombin supplementation; Patients randomized to the study group will receive supplementation of antithrombin concentrate to maintain a functional antithrombin level between 80%-120%.	Drug: Antithrombin supplementation; antithrombin concentrate will be supplemented to maintain a functional antithrombin level between 80%-120%; Other Names: Antithtrombin
ACTIVE_COMPARATOR: No Antithrombin supplementation; Patients randomized to the control group will never receive supplementation of antithrombin unless "heparin resistance" occurs.	Drug: No antithrombin supplementation; supplementation of antithrombin will not be provided unless "heparin resistance" occurs; Other Names: No antithrombin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amount of heparin	Heparin dosage to maintain aPTT ratio between 1.5-2	through study completion, an average of 10 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Bleeding	Bleeding complications	through study completion, an average of 10 days
Adequacy of anticoagulation	Adequacy of anticoagulation, assessed through Anti-Xa levels	through study completion, an average of 10 days
thrombosis	Patient's or circuit thrombosis	through study completion, an average of 10 days
transfusions	Blood products transfusion requirements	through study completion, an average of 10 days

Collaborators and Investigators

• Sponsor: Policlinico Hospital
• Collaborators: The Mediterranean Institute for Transplantation and Advanced Specialized Therapies
• Investigators: Principal Investigator: Mauro Panigada, MD, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano

Publications and helpful links

General Publications

• Panigada M, Spinelli E, De Falco S, Consonni D, Novembrino C, Boscolo Anzoletti M, Panarello G, Occhipinti G, Dos Santos CC, Pesenti A, Arcadipane A, Grasselli G. The relationship between antithrombin administration and inflammation during veno-venous ECMO. Sci Rep. 2022 Aug 22;12(1):14284. doi: 10.1038/s41598-022-17227-7.
• Panigada M, Spinelli E, Cucino A, Cipriani E, De Falco S, Panarello G, Occhipinti G, Arcadipane A, Sales G, Fanelli V, Brazzi L, Novembrino C, Consonni D, Pesenti A, Grasselli G. Antithrombin supplementation during extracorporeal membrane oxygenation: study protocol for a pilot randomized clinical trial. Trials. 2019 Jun 11;20(1):349. doi: 10.1186/s13063-019-3386-4.

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 28, 2017
• Primary Completion (ACTUAL): May 15, 2019
• Study Completion (ACTUAL): May 15, 2019

Study Registration Dates

• First Submitted: July 1, 2017
• First Submitted That Met QC Criteria: July 1, 2017
• First Posted (ACTUAL): July 5, 2017

Study Record Updates

• Last Update Posted (ACTUAL): May 17, 2019
• Last Update Submitted That Met QC Criteria: May 15, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Serine Proteinase Inhibitors; Anticoagulants; Antithrombins; Antithrombin III
• Other Study ID Numbers: GATRA2016; 2016-004534-23 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No