Reduced Anticoagulation Targets in ECLS (RATE) (RATE)

October 14, 2021 updated by: Walter M. van den Bergh, University Medical Center Groningen
The objective of the RATE-trial is to study if reduced anticoagulation targets during ECLS diminish bleeding complications without an increase in thromboembolic complications or a negative impact on outcome.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Rationale: ECMO treatment has a mortality of 38%, for a large part treatment related due to complications. The most feared complication is ischemic stroke for which heparin is administered with an aPTT target 2.0-2.5 times baseline (approximately 60-75 sec).

However, there is no relation between aPTT and the occurrence of stroke (1.2%), but there is a relation with the much more frequent occurrence of bleeding complications (55%) and blood transfusion. Both are strongly related to outcome.

Objective: Our objective is to study if reduced anticoagulation targets diminish bleeding complications without an increase in thromboembolic complications or a negative impact on outcome.

Study design: Three-arm non-inferiority RCT.

Study population: All adult Dutch patients treated with ECMO during the 30 months of the study.

Intervention: Randomization between heparin administration with a target of 2-2.5 times baseline aPTT (usual care, about 60-75 sec.), 1.5-2.0 times baseline aPTT (45-60 sec.) or low molecular weight heparin (LMWH) guided by weight and renal function.

Main study parameters/endpoints: The primary outcome parameter is a combined endpoint consisting of: 1) major bleeding including hemorrhagic stroke according to the ELSO definitions; 2) severe thromboembolic complication defined as ischemic stroke, limb ischemia (not related with distal perfusion catheter), or acute pump failure with emergency exchange; 3) mortality at 6 months.

Secondary outcome parameters are: 1) blood transfusions; 2) health related quality of life (HR-QoL) at 6 months; 3) exchange of the membrane oxygenator; 4) vessel thrombosis after ECMO removal detected by echography; 5) pulmonary embolism; 6) costs; 7) the individual components of the composite outcome; and 8) all thromboembolic complications combined.

Expected outcomes: We expect that with a target of 1.5-2.0x baseline aPTT or with LMWH the primary composite endpoint will be reached in 60% of patients compared to 70% in usual care. To show non-inferiority with a significance level (alpha) of 5%, power of 80% and a non-inferiority limit (delta) of 7.5% the corresponding sample size is 91 patients per group. In other words, if there is a true difference in favor of the experimental treatment of 10%, then 91 patients per group are required to be 80% sure that the upper limit of a one-sided 95% confidence interval (or equivalently a 90% two-sided confidence interval) will exclude a difference in favor of the standard group of more than 7.5%. To compensate for a lower effect and drop-outs 330 patients will be enrolled. Apart from anticoagulation targets, treatment will be as usual so study participation will not lead to a burden for the patient, e.g. no extra blood sampling, tests or visits. After 6 months the patients will be contacted for a short questionnaire to measure health-related quality of life.

Study Type

Interventional

Enrollment (Anticipated)

330

Phase

  • Phase 3

Contacts and Locations

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

Study Contact

Study Contact Backup

Study Locations

  • Netherlands
      • Groningen, Netherlands, 9700RB
    • Gelderland
    • Limburg
      • Maastricht, Limburg, Netherlands, 6229HX
        • Recruiting
        • Maastricht Universitair Medisch Centrum+
        • Contact:
    • Noord-Holland
      • Amsterdam, Noord-Holland, Netherlands, 1091AC
      • Amsterdam, Noord-Holland, Netherlands, 1100DD
    • Overijssel
      • Zwolle, Overijssel, Netherlands, 8025AB
    • Utrecht
    • Zuid-Holland
      • Leiden, Zuid-Holland, Netherlands, 2300RC
        • Recruiting
        • Leids Universitair Medisch Centrum
        • Contact:
      • Rotterdam, Zuid-Holland, Netherlands, 3000CA

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

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • ECMO treatment during the study period in one of the participating centers
  • Age above 18 years
  • Written informed consent

Exclusion Criteria:

  • Patients in whom the ECMO is only used to bridge a procedure
  • Vital indication for robust anticoagulation (e.g. mechanic valve, pulmonary embolism)
  • History of heparin induced thrombocytopenia

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
ACTIVE_COMPARATOR: Target of 2-2.5 times baseline aPTT (usual care, about 60-75)
Administration of heparin during ECLS with an aPTT target of 2-2.5 times baseline.
Drug: Heparin
Administration of heparin with a target of 2-2.5 or 1.5-2.0 times baseline aPTT during ECLS.
Other Names:
  • Unfractionated heparin
ACTIVE_COMPARATOR: Target of 1.5-2.0 times baseline aPTT (45-60 sec.)
Administration of heparin during ECLS with an aPTT target of 1.5-2.0 times baseline.
Drug: Heparin
Administration of heparin with a target of 2-2.5 or 1.5-2.0 times baseline aPTT during ECLS.
Other Names:
  • Unfractionated heparin
ACTIVE_COMPARATOR: LMWH guided by weight and renal function.
Administration of LMWH guided by weight and renal function during ECLS.
Drug: LMWH
Administration of LMWH guided by weight and renal function during ECLS.
Other Names:
  • Nadroparine
  • Dalteparine
  • Enoxaparine
  • Tinzaparine

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Hemorrhagic complications
Time Frame: Through ECLS completion, an average of 14 days
Severe hemorrhagic complications will be registered according to the Extracorporeal Life Support Organization (ELSO) definitions for major bleeding and is defined as clinically overt bleeding with a decrease in hemoglobin of at least 1,24 mmol/L (2 g/dl)/24 hours, or a transfusion requirement of ≥ 3 EH RBC over that same time period. Bleeding that is retroperitoneal, pulmonary or involves the central nervous system, or bleeding that requires surgical intervention is also considered major bleeding.
Through ECLS completion, an average of 14 days
Severe thromboembolic complications
Time Frame: Through ECLS completion, an average of 14 days
Severe thromboembolic complication defined as ischemic stroke, limb ischemia, or acute pump failure
Through ECLS completion, an average of 14 days
Mortality
Time Frame: 6 months after ECLS
Mortality at 6 months
6 months after ECLS

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of blood transfusions
Time Frame: Through ECLS completion, an average of 14 days
Number of blood transfusions during ECLS
Through ECLS completion, an average of 14 days
Quality of life at 6 months
Time Frame: 6 months after ECLS
Quality of life (HR-QoL) measured 6 months after decannulation from ECMO
6 months after ECLS
Exchange of the membrane oxygenator
Time Frame: Through ECLS completion, an average of 14 days
Number of echanges of the membrane oxygenator during ECLS
Through ECLS completion, an average of 14 days
Vessel thrombosis after ECLS removal
Time Frame: After ECLS completion, an average of 14 days
Vessel thrombosis after ECLS removal detected by echography
After ECLS completion, an average of 14 days
Cost- effectiveness
Time Frame: 6 months after ECLS
Cost- effectiveness will be based on reduced costs of blood transfusions and interventions for bleeding (e.g. surgery, interventional radiology) as well as improved outcome. All medical cost items expected to be affected by the ECMO therapy will be measured and valued according to the Dutch standard guidelines for economic evaluations, e.g. blood transfusion, number of ECMO replacements, surgery, and hospital length of stay.
6 months after ECLS
Pulmonary embolism
Time Frame: Through ECLS completion, an average of 14 days
The occurrence of Pulmonary embolism during ECLS
Through ECLS completion, an average of 14 days
All thromboembolic complications combined
Time Frame: Through ECLS completion, an average of 14 days
The occurrence of all thromboembolic complications combined during ECLS
Through ECLS completion, an average of 14 days

Collaborators and Investigators

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

Sponsor

University Medical Center Groningen

Collaborators

Radboud University Medical Center
Erasmus Medical Center
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
St. Antonius Hospital
Leiden University Medical Center
ZonMw: The Netherlands Organisation for Health Research and Development
OLVG
Isala

Investigators

  • Principal Investigator: W.M. van den Bergh, PhD, MD, University Medical Center Groningen

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)

October 1, 2020

Primary Completion (ANTICIPATED)

March 1, 2023

Study Completion (ANTICIPATED)

March 1, 2024

Study Registration Dates

First Submitted

August 24, 2020

First Submitted That Met QC Criteria

August 28, 2020

First Posted (ACTUAL)

September 2, 2020

Study Record Updates

Last Update Posted (ACTUAL)

October 15, 2021

Last Update Submitted That Met QC Criteria

October 14, 2021

Last Verified

October 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 201900659
  • 848018014 (OTHER_GRANT: ZonMW)
  • 7969 (REGISTRY: Netherlands Trial Register)
  • 2019-004125-24 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.

IPD Sharing Time Frame

Beginning 3 months and ending 5 years following article publication.

IPD Sharing Access Criteria

  • Researchers who provide a methodologically sound proposal which is approved by an independent review panel.
  • To achieve aims in the approved proposal.
  • Proposals should be directed to w.m.van.den.bergh@umcg.nl, requestors will need to sign a data access agreement.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ANALYTIC_CODE

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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