Clinical trial NCT04536272: Reduced Anticoagulation Targets in ECLS (RATE)
Official title: Reduced Anticoagulation Targets in ECLS (RATE)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Heart Failure
Respiratory Failure
Extracorporeal Membrane Oxygenation
Bleeding
Thrombosis
Keywords: Extracorporeal membrane oxygenation
Extracorporeal life support
ECMO
ECLS
Anticoagulation
Complications
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
Collaborators: name: ZonMw: The Netherlands Organisation for Health Research and Development
name: Erasmus Medical Center
name: Leiden University Medical Center
name: St. Antonius Hospital
name: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: Isala
name: OLVG
name: Radboud University Medical Center
First posted: 2020-09-02
Enrollment: 330
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: OTHER

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.

Eligibility criteria: 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

Primary outcomes:
measure: Hemorrhagic complications
timeFrame: Through ECLS completion, an average of 14 days
measure: Severe thromboembolic complications
timeFrame: Through ECLS completion, an average of 14 days
measure: Mortality
timeFrame: 6 months after ECLS
Secondary outcomes:
measure: Number of blood transfusions
timeFrame: Through ECLS completion, an average of 14 days
measure: Quality of life at 6 months
timeFrame: 6 months after ECLS
measure: Exchange of the membrane oxygenator
timeFrame: Through ECLS completion, an average of 14 days
measure: Vessel thrombosis after ECLS removal
timeFrame: After ECLS completion, an average of 14 days
measure: Cost- effectiveness
timeFrame: 6 months after ECLS
measure: Pulmonary embolism
timeFrame: Through ECLS completion, an average of 14 days
measure: All thromboembolic complications combined
timeFrame: Through ECLS completion, an average of 14 days
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboud UMC
state: Gelderland
city: Maastricht
country: Netherlands
facility: Maastricht Universitair Medisch Centrum+
state: Limburg
city: Amsterdam
country: Netherlands
facility: OLVG, location East
state: Noord-Holland
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC, location AMC
state: Noord-Holland
city: Zwolle
country: Netherlands
facility: Isala Clinics
state: Overijssel
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum
state: Zuid-Holland
city: Rotterdam
country: Netherlands
facility: Erasmus MC
state: Zuid-Holland
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
Study officials:
affiliation: University Medical Center Groningen
name: W.M. van den Bergh, PhD, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: van Minnen O, Oude Lansink-Hartgring A, van den Boogaard B, van den Brule J, Bulpa P, Bunge JJH, Delnoij TSR, Elzo Kraemer CV, Kuijpers M, Lambermont B, Maas JJ, de Metz J, Michaux I, van de Pol I, van de Poll M, Raasveld SJ, Raes M, Dos Reis Miranda D, Scholten E, Simonet O, Taccone FS, Vallot F, Vlaar APJ, van den Bergh WM. Reduced anticoagulation targets in extracorporeal life support (RATE): study protocol for a randomized controlled trial. Trials. 2022 May 16;23(1):405. doi: 10.1186/s13063-022-06367-w.