reduced anticoagulation targets in ecls (rate)

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

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.

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

Keywords: extracorporeal membrane oxygenation extracorporeal life support ecmo ecls anticoagulation complications