Reduced Anticoagulation Targets in ECLS (RATE)

Phase 3

Completed

• Conditions: Heart Failure; Extracorporeal Membrane Oxygenation; Respiratory Failure; Bleeding; Thrombosis
• Interventions: Drug: LMWH; Drug: Heparin

• Registration Number: NCT04536272
• Lead Sponsor: University Medical Center Groningen

Brief Summary

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.

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 Timeline

• Study First Submitted: 2020-08-24
• Study First Submitted QC: 2020-08-28
• Study First Posted: 2020-09-02
• Study Start: 2020-10-01
• Primary Completion: 2025-03-07
• Study Completion: 2025-03-07
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-01
• Last Update Posted: 2025-05-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 330

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
LMWH guided by weight and renal function.	LMWH	Administration of LMWH guided by weight and renal function during ECLS.
Target of 2-2.5 times baseline aPTT (usual care, about 60-75)	Heparin	Administration of heparin during ECLS with an aPTT target of 2-2.5 times baseline.
Target of 1.5-2.0 times baseline aPTT (45-60 sec.)	Heparin	Administration of heparin during ECLS with an aPTT target of 1.5-2.0 times baseline.

Primary Outcome Measures

Name	Time	Method
Hemorrhagic complications	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.
Severe thromboembolic complications	Through ECLS completion, an average of 14 days	Severe thromboembolic complication defined as ischemic stroke, limb ischemia, or acute pump failure
Mortality	6 months after ECLS	Mortality at 6 months

Secondary Outcome Measures

Name	Time	Method
All thromboembolic complications combined	Through ECLS completion, an average of 14 days	The occurrence of all thromboembolic complications combined during ECLS
Number of blood transfusions	Through ECLS completion, an average of 14 days	Number of blood transfusions during ECLS
Quality of life at 6 months	6 months after ECLS	Quality of life (HR-QoL) measured 6 months after decannulation from ECMO
Exchange of the membrane oxygenator	Through ECLS completion, an average of 14 days	Number of echanges of the membrane oxygenator during ECLS
Vessel thrombosis after ECLS removal	After ECLS completion, an average of 14 days	Vessel thrombosis after ECLS removal detected by echography
Cost- effectiveness	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.
Pulmonary embolism	Through ECLS completion, an average of 14 days	The occurrence of Pulmonary embolism during ECLS

Trial Locations

Locations (8)

Radboud UMC; 🇳🇱 Nijmegen, Gelderland, Netherlands

Maastricht Universitair Medisch Centrum+; 🇳🇱 Maastricht, Limburg, Netherlands

OLVG, location East; 🇳🇱 Amsterdam, Noord-Holland, Netherlands

Amsterdam UMC, location AMC; 🇳🇱 Amsterdam, Noord-Holland, Netherlands

Isala Clinics; 🇳🇱 Zwolle, Overijssel, Netherlands

Leids Universitair Medisch Centrum; 🇳🇱 Leiden, Zuid-Holland, Netherlands

Erasmus MC; 🇳🇱 Rotterdam, Zuid-Holland, Netherlands

University Medical Center Groningen; 🇳🇱 Groningen, Netherlands