Remimazolam for Postoperative Atrial Fibrillation (RePAF)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Coronary Artery Bypass Grafting; Remimazolam
• Intervention / Treatment: Drug: Remimazolam; Drug: midazolam

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Xiaojun He, MD, Ph.D.; Phone Number: +86-13524954567; Email: xhe34baltimore@163.com
• Study Contact Backup: Name: Zhuan Zhang, MD, Ph.D.; Phone Number: +86-15062791355; Email: zhangzhuancg@163.com

Study Locations

• China
  • Jiangsu
    • Yangzhou, Jiangsu, China, 225000
      • Recruiting
      • The Affiliated Hospital of Yangzhou University.
      • Contact: Zhuan Zhang, professor; Phone Number: +8615062791355 +8615062791355; Email: zhangzhuancg@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Myocardial injury markers	Myocardial injury markers (cTnT, cTnI, CK-MB)	7 days after the operation.
Arterial blood pressure (BP)	Hemodynamic parameters	7 days after the operation.
Cardiac index (CI)	Hemodynamic parameters	7 days after the operation.
systemic vascular resistance (SVR)	Hemodynamic parameters	7 days after the operation.
stroke volume variation (SVV)	Hemodynamic parameters	7 days after the operation.

Collaborators and Investigators

• Sponsor: Yangzhou University

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2023
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: May 17, 2023
• First Submitted That Met QC Criteria: June 5, 2023
• First Posted (Actual): June 6, 2023

Study Record Updates

• Last Update Posted (Actual): June 6, 2023
• Last Update Submitted That Met QC Criteria: June 5, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Coronary artery disease; Myocardial infarction; Revascularization; CABG; Anesthesia; Coronary artery bypass graft; CAD; Ischemic heart disease; Postoperative atrial fibrillation; Remimazolam; Postoperative new-onset atrial fibrillation
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam
• Other Study ID Numbers: 2023-YKL01-16

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No