Remimazolam for Postoperative Atrial Fibrillation

Study Overview
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Brief Summary
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Atrial fibrillation (AF) is the most common cardiac severe arrhythmia globally and is associated with an increased risk of mortality and morbidity, with a loss of 6.0 million disability-adjusted life-years worldwide in 2017, conferring 0.24% of total disability-adjusted life-years globally. Due to the absence of knowledge of AF pathogenesis, currently, available therapies do not prevent AF onset or progression in 85% of patients. Despite the identification of novel druggable targets that are involved in the pathogenesis of AF, the translation of these findings to clinical drug studies is limited. Postoperative atrial fibrillation (POAF) is the most common type of secondary AF. The incidence of POAF after coronary artery bypass grafting (CABG) is approximately 30%. About 16% of patients developed POAF in cardiac surgery even with the international guideline recommended perioperative beta-blocker intervention. Remimazolam is a newly approved benzodiazepine sedative indicated for the induction and maintenance of procedural sedation in adults, with significantly reduced sedation and recovery time. It was also found to be with an anti-inflammatory effect and therefore might have an impact on POAF since AF is closely related to the inflammatory response of myocardial tissue and inflammatory factors such as TNF-α. So, the RePAF trial intends to explore whether remimazolam application in induction and maintenance for general anesthesia during cardiac surgery can reduce the incidence of POAF in patients with CABG, and the effect on the postoperative plasma levels of inflammatory factors and stress factors.

Detailed Description
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Postoperative atrial fibrillation (POAF) presented a 30% incidence in cardiac surgery and 16% even under beta-blocker treatment, leading to serious complications. Inflammation is a key mechanism that promotes POAF. Remimazolam is a newly approved benzodiazepine sedative with anti-inflammatory effects. However, the impact of remimazolam on POAF remains unknown. To explore whether or not remimazolam can reduce the POAF in coronary artery bypass grafting (CABG) patients, a first open-phase trial in which 50 patients (randomized 1:1 to Remimazolam and control groups) will be enrolled as a pilot study to obtain parameters for sample size calculation. A double-blind randomized controlled trial will be then conducted to explore remimazolam's effect on POAF and inflammatory factors' blood levels in patients that receive selective CABG. The blood level of inflammatory factors, stress factors (epinephrine, norepinephrine, cortisol, adrenocorticotropic hormone, corticotropin-releasing hormone), myocardial injury markers, and hemodynamic parameters will also be assessed. This 2-phase clinical trial will provide novel evidence for the newly approved sedative drug, remimazolam, and with detailed data for inflammatory and myocardial injury endpoints.

Official Title
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The Effect of Remimazolam on Postoperative New-onset Atrial Fibrillation in Patients Undergoing Coronary Artery Bypass Grafting

Conditions
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Coronary Artery Bypass Grafting, Remimazolam

Intervention / Treatment
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* Drug: Remimazolam
* Drug: midazolam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 50-70 years old; BMI 18-28 kg/m2； Selective CABG surgery will be performed at the Yangzhou Institute Heart and Great Vessels, the Affiliated Hospital of Yangzhou University, Yangzhou, China. Patients agree to participate in this study and sign the informed consent form. Exclusion Criteria: Emergency surgery; with any other type of cardiac surgery; pre-operative supraventricular arrhythmia; with moderate or severe valve disease before surgery; with a history of chemotherapy or radiotherapy; with a history of thoracic or cardiovascular surgery; diuretics usage before the surgery.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A first open-phase trial in which 50 patients (randomized 1:1 to Remimazolam and control groups) will be enrolled as a pilot study to obtain parameters for sample size calculation. A double-blind randomized controlled trial will be conducted to explore remimazolam's effect on POAF and inflammatory factors' blood levels in patients that receive selective CABG.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Remimazolam group<br>General anesthesia was induced with 0.1 mg/kg of remimazolam and maintained with 0.1 mg•kg-1•h-1 remimazolam. | Drug: Remimazolam<br>* Remimazolam is dispensed at 2 mg/ml by the designated researchers who are not involved in enrollment, anesthesia administration, and postoperative follow-up.<br>|
| Active Comparator: Control group<br>General anesthesia was induced with 0.1 mg/kg midazolam. | Drug: midazolam<br>* Midazolam is dispensed at 1 mg/ml by the designated researchers who are not involved in enrollment, anesthesia administration, and postoperative follow-up.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| postoperative Atrial Fibrillation (POAF) | POAF is defined as postoperative new-onset Atrial Fibrillation (AF) lasting more than the 30 s or hemodynamic instability requiring treatment. AF is defined as 1) irregular R-R interval (in the presence of AV conduction), 2) P-wave disappearance, and 3) irregular atrial activity according to the AHA guidelines. | 7 days after the operation. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Inflammatory factors | Blood level of TNF-α | 1) immediately after the operation, 2) 24 hours after the operation. | 
| Stress factors | Blood level of epinephrine, norepinephrine, cortisol, adrenocorticotropic hormone, corticotropin-releasing hormone. | 1) immediately after the operation, 2) 24 hours after the operation. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Remimazolam, CABG, Postoperative atrial fibrillation, Postoperative new-onset atrial fibrillation, Coronary artery disease, CAD, Coronary artery bypass graft, Myocardial infarction, Revascularization, Anesthesia, Ischemic heart disease