Reduced Anticoagulation Targets in Extracorporeal life support

Rationale:
ECLS 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 ECLS during the 30 months of the study.

Intervention:
Randomization between a target of 2-2.5 times baseline aPTT (usual care, about 60-75 sec.), 1.5-2.0 times (45-60 sec.) or 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, or acute pump failure; 3) mortality at 6 months.
Secondary outcome parameters are: 1) blood transfusions; 2) quality of life (HR-QoL) at 6 months; 3) exchange of the membrane oxygenator (ECMO); 4) vessel thrombosis after ECLS removal detected by echography; 5) pulmonary embolism; 6) costs; 7) the individual components of the composite outcome; 8) all thromboembolic complications combined; and 9) all hemorrhagic complications combined.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:
We estimate that with an aPTT target of 45-60 sec. or with use of LMWH the primary endpoint will be met in 60% of patients compared to 70% with usual care. To show non-inferiority 91 patients per group are needed. To compensate for a lower effect and drop-outs 330 patients will be enrolled. Results will be analyzed by intention to treat.
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 questionnaire to measure health-related quality of life. A risk may be that reduced anticoagulation target or anticoagulation with LMWH is inferior to standard practice. A benefit may be that reduced anticoagulation target or anticoagulation with LMWH is superior to standard practice.

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.

Enrollment will start January 2020

Randomization between a target of 2-2.5x baseline aPTT (usual care, about 60-75 sec.), 1.5-2.0x (45-60 sec.) and therapeutic LMWH guided by weight and renal function.