Reduced Anticoagulation Targets in ECLS (RATE)

Heart Failure Clinical Trial

— RATE  

Official title:

Reduced Anticoagulation Targets in ECLS (RATE)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04536272
• Other study ID #: 201900659
• Secondary ID: 8480180147969201
• Status: Recruiting
• Phase: Phase 3
• Start date: October 1, 2020
• Est. completion date: March 1, 2024

Study information

• Verified date: October 2021
• Source: University Medical Center Groningen
• Contact: O. van Minnen
• Phone: +31503616161
• Email: o.van.minnen[@]umcg.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 330
• Est. completion date: March 1, 2024
• Est. primary completion date: March 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Bleeding
• Extracorporeal Membrane Oxygenation
• Heart Failure
• Respiratory Failure
• Respiratory Insufficiency
• Thrombosis

Intervention

Drug:
• Heparin
Administration of heparin with a target of 2-2.5 or 1.5-2.0 times baseline aPTT during ECLS.
• LMWH
Administration of LMWH guided by weight and renal function during ECLS.

Locations

Country	Name	City	State
Netherlands	Amsterdam UMC, location AMC	Amsterdam	Noord-Holland
Netherlands	OLVG, location East	Amsterdam	Noord-Holland
Netherlands	University Medical Center Groningen	Groningen
Netherlands	Leids Universitair Medisch Centrum	Leiden	Zuid-Holland
Netherlands	Maastricht Universitair Medisch Centrum+	Maastricht	Limburg
Netherlands	St. Antonius Ziekenhuis	Nieuwegein	Utrecht
Netherlands	Radboud UMC	Nijmegen	Gelderland
Netherlands	Erasmus MC	Rotterdam	Zuid-Holland
Netherlands	Isala Clinics	Zwolle	Overijssel

Sponsors (9)

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

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Severe thromboembolic complications	Severe thromboembolic complication defined as ischemic stroke, limb ischemia, or acute pump failure	Through ECLS completion, an average of 14 days
Primary	Mortality	Mortality at 6 months	6 months after ECLS
Secondary	Number of blood transfusions	Number of blood transfusions during ECLS	Through ECLS completion, an average of 14 days
Secondary	Quality of life at 6 months	Quality of life (HR-QoL) measured 6 months after decannulation from ECMO	6 months after ECLS
Secondary	Exchange of the membrane oxygenator	Number of echanges of the membrane oxygenator during ECLS	Through ECLS completion, an average of 14 days
Secondary	Vessel thrombosis after ECLS removal	Vessel thrombosis after ECLS removal detected by echography	After ECLS completion, an average of 14 days
Secondary	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
Secondary	Pulmonary embolism	The occurrence of Pulmonary embolism during ECLS	Through ECLS completion, an average of 14 days
Secondary	All thromboembolic complications combined	The occurrence of all thromboembolic complications combined during ECLS	Through ECLS completion, an average of 14 days