ELITE is a prospective, multi-center, open-label, randomized controlled trial, with a 2×2 partial factorial design to evaluate early CRRT support and beta-blockade on 30-day mortality in a broad range of ECMO patients admitted to hospitals in China from July 2018. In arm A, patients are randomized to early CRRT within 24 hours of initiation of ECMO or to control, regardless of whether there is a conventional indication, or to the control where patients only receive CRRT according to a conventional indication. In arm B, patients are randomized to intravenous esmolol group or usual care. The trial design and protocol adhere to the Recommendations
for Interventional Trials (SPIRIT) criteria20. (table 1) and checklist (see Additional file)
Broad inclusion criteria are used for both arms, whereby adult patients who have received ECMO for any reason within 24 hours and 7 days, for arms A and arm B, respectively, are eligible (Tables 2 and 3). Patients are excluded from arms A and B if they had a definite indication or contraindication to either CRRT or beta-blockers, respectively. As ECMO is often initiated by a specialist team to rescue and transfer patients to larger hospitals in China, a timeframe of 24 hours after ECMO implantation was used for early CRRT in arm A, while a relatively stable hemodynamic status (dopamine/dobutamine <5 μg/kg/min, with no administration of adrenaline or norepinephrine) and within 7 days after initiation of ECMO was required for eligibility into arm B.
All eligible patients are centrally randomized in a 1:1 ratio to either early CRRT or conventional indication CRRT, and/or beta-blocker group or usual care (control) groups, via a computer-generated randomization schedule, stratified by age (<65 vs. ≥65 years) and implantation of ECMO for extracorporeal cardiopulmonary resuscitation (yes vs no). Investigators use a cellphone application to confirm eligibility and obtain the randomized treatment allocation.
Patients assigned to early CRRT should have it applied concurrently with ECMO treatment and continued for ≥12 hours. Those assigned to standard therapy should receive CRRT according to 2012 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for AKI stage 3 and have at least one of the following criteria met: severe hyperkalemia (> 6.5 mmol/L); metabolic acidosis (pH < 7.2); pulmonary edema unresponsive to diuretic therapy; requiring oxygen flow rate of > 5L/min to maintain an oxygen saturation (SpO2) of >95%, or requiring a forced inspired oxygen concentration (FiO2) of >50% on ventilation; blood urea nitrogen level >112 mg/dL; or oliguria (urine output < 200 mL per 12 hours) for > 72 hours. CRRT can be initiated or discontinued according to the attending clinician’s decision in managing the patient.
In arm B, patients assigned to the intervention group are to receive a continuous infusion of esmolol on top of conventional management, commencing at 25 mg/hour and increasing by 25 mg/hour every 20 minutes until the heart rate reduced to 75±5 bpm or an upper dose limit of 2000 mg/hour is reached. Esmolol infusion should be continued to maintain the heart rate threshold or according to the clinician’s discretion until discharge from the intensive care unit (ICU) (or death, if sooner). Oral beta-blockers should be introduced before esmolol is withdrawn. Esmolol can be transiently stopped or completely withdrawn should a patient develops third-degree atrial-ventricular block , bradycardia (< 60 bpm), extreme left ventricular systolic dysfunction, aortic valve dysfunction, or severe cardiogenic pulmonary edema. Patients in the control group will not receive any type of beta-blockers, unless the clinician considers there is a strong indication. Concomitant diseases will be treated following current guidelines.
The primary outcome for both arms is all-cause mortality at 30 days. Secondary outcomes are all-cause mortality at 365 days; use of long-term RRT; success in weaning from ECMO, defined as survival after 24 hours from weaning; health-related quality of life according to scores on the EuroQoLEQ-5D-5L questionnaire at 365 days; length of stay at ICU and hospital; unplanned hospital readmission; separately on cardiac and non-cardiac death; any serious adverse event (SAE) in ICU ( Table 4 outlines SAE definitions).
Data are collected on patient demography, medical history, concomitant therapy, duration of CRRT, and dose and duration of esmolol. Vital and health status are assessed at the time of weaning from ECMO, discharged from ICU and hospital, unplanned hospital readmission, EQ-5D scores, and SAEs, during follow-up via telephone, face-to-face, or remote medical consultation over 365 days. To improve monitoring adherence, the clinician will take time to explain about need of follow-up surveillance and encourage the participants to undergo routine examinations. Data are entered into a secure password protected electronic data capture system and checked for quality by research staff. All queries are listed for content and raised and resolved dates. All study records required by the coordinating center at the Heart Health Research Center (HHRC) and applicable regulatory bodies are maintained for 15 years.
For each arm, a total of 496 patients (248 per group) are required based on the following assumption: a 70% 30-day mortality in the control group; a 20% relative risk reduction for each intervention (early CRRT and beta-blocker); no loss of follow-up or crossover; no interaction between interventions; and 5% type I error and 20% type II error.
All analyses will be conducted according to the intention-to-treat principle. Baseline characteristics between groups will be reported as frequencies and percentages for categorical variables, and as means and standard deviations (SD) or medians and interquartile ranges (IQR) for continuous variables. The primary outcome will be compared between groups in a log-rank test. Other efficacy and safety endpoints will be reported with t test or Wilcoxon test, and chi-square test for continuous and categorial variables, respectively, as appropriate. All tests are two-sided, and the nominal level of α will be 5%.
In subgroup analysis by age and ECPR will be defined by the presence or absence of a pre-randomization variable and the primary outcome as in the main analysis. The main analysis for each subgroup will be an unadjusted test of interaction in a logistic model to determine whether the effect of treatment differs significantly across categories. The missing values will not be imputed unless substantial and reported with the number of observations used in the analysis.
The Data monitoring committee (DMC) consists of a critical care physician, nephrologist, and cardiovascular expert, all experienced in clinical research. Principal Investigator will report the process of the trial, quality of data collected, adverse events, and protocol deviation and violation to the DMC. The DMC will meet every 6 months during conduction of the trial. No interim analysis for efficiency is planned as the assumptions in sample size calculation is less likely to be changed.
There have been 92 patients enrolled form 10 hospitals into study A and the enrollment is still ongoing(see Appendix for the hospital list). However, Study B was stopped in August 2019 in the absence of any patients being enrolled. Although we aimed to test the hypothesis that beta-blockers would protect the myocardium in ECMO patients, we found this too challenging to undertake as of these patients have low BP, which is a contraindication to such treatment and raised concerns of harms among investigators. Moreover, the short time window for enrollment was another barrier to recruitment, and by the time a patient is stable and without vasopressors, it is near the time to wean them off ECMO. Consequently, we decided to close recruitment into arm B.