Reduced Anticoagulation Targets in ECLS (RATE)

University Medical Center Groningen (UMCG)

Status and phase: Completed; Phase 3

Conditions: Respiratory Failure; Thrombosis; Heart Failure; Extracorporeal Membrane Oxygenation; Bleeding

Treatments: Drug: LMWH; Drug: Heparin

Study type: Interventional

Funder types: Other; NETWORK

Identifiers

NCT04536272

848018014 (Other Grant/Funding Number)

7969 (Registry Identifier)

201900659

2019-004125-24 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 330 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Other

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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330 participants in 3 patient groups

Target of 2-2.5 times baseline aPTT (usual care, about 60-75)

Active Comparator group

Description:

Administration of heparin during ECLS with an aPTT target of 2-2.5 times baseline.

Treatment:

Drug: Heparin

Target of 1.5-2.0 times baseline aPTT (45-60 sec.)

Active Comparator group

Description:

Administration of heparin during ECLS with an aPTT target of 1.5-2.0 times baseline.

Treatment:

Drug: Heparin

LMWH guided by weight and renal function.

Active Comparator group

Description:

Administration of LMWH guided by weight and renal function during ECLS.

Treatment:

Drug: LMWH