Reduced Anticoagulation Targets in ECLS (RATE)

Study Overview
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Brief Summary
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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
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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.

Official Title
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Reduced Anticoagulation Targets in ECLS (RATE)

Conditions
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Heart Failure, Respiratory Failure, Extracorporeal Membrane Oxygenation, Bleeding, Thrombosis

Intervention / Treatment
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* Drug: Heparin
* Drug: LMWH


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomization between anticoagulation targets during ECLS of: 1). 2-2.5 times baseline aPTT (usual care, about 60-75 sec.), 2). 1.5-2.0 times baseline aPTT (45-60 sec.) or 3). LMWH guided by weight and renal function.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Target of 2-2.5 times baseline aPTT (usual care, about 60-75)<br>Administration of heparin during ECLS with an aPTT target of 2-2.5 times baseline. | Drug: Heparin<br>* Administration of heparin with a target of 2-2.5 or 1.5-2.0 times baseline aPTT during ECLS.<br>* Other names: Unfractionated heparin;|
| Active Comparator: Target of 1.5-2.0 times baseline aPTT (45-60 sec.)<br>Administration of heparin during ECLS with an aPTT target of 1.5-2.0 times baseline. | Drug: Heparin<br>* Administration of heparin with a target of 2-2.5 or 1.5-2.0 times baseline aPTT during ECLS.<br>* Other names: Unfractionated heparin;|
| Active Comparator: LMWH guided by weight and renal function.<br>Administration of LMWH guided by weight and renal function during ECLS. | Drug: LMWH<br>* Administration of LMWH guided by weight and renal function during ECLS.<br>* Other names: Tinzaparine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemorrhagic complications | 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 | Severe thromboembolic complication defined as ischemic stroke, limb ischemia, or acute pump failure | Through ECLS completion, an average of 14 days | 
| Mortality | Mortality at 6 months | 6 months after ECLS | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ECMO, Extracorporeal membrane oxygenation, Extracorporeal life support, ECLS, Anticoagulation, Complications