Cardiologist-Administered Midazolam vs. Anaesthesiologist-Assisted Propofol Sedation For Transoesophageal Echocardiography-Guided Cardioversion of Atrial Fibrillation (CARDIOZOLAM-1)

Cardiologist-Administered Midazolam vs. Anaesthesiologist-Assisted Propofol Sedation For Transoesophageal Echocardiography-Guided Cardioversion of Atrial Fibrillation (CARDIOZOLAM-1)

Irregular heart rhythms, known as atrial fibrillation or atrial flutter, are common conditions that can increase the risk of stroke and heart failure. A standard treatment to restore a normal rhythm is a controlled electric shock, known as cardioversion. However, if the irregular rhythm has lasted more than 24 hours, if the duration is uncertain, and if the patient has not been on blood-thinning medication for at least three weeks, doctors must first check for blood clots in the heart. This is done using a special ultrasound scan of the heart through the food pipe.

Both the scan and the electric shock treatment require sedation to make the patient relaxed or asleep. The scan uses mild sedation from a cardiologist, while the shock needs a stronger sedative given by an anaesthesiologist. But needing this extra doctor can cause delays, so patients often wait longer for treatment and to go home.

This study will test whether a cardiologist can safely handle both steps using a sedative called midazolam. This study will include 220 adults at multiple hospitals in Denmark and compare this new approach to standard care. Researchers will track how quickly patients go home, how well the treatment works, any serious side effects, what patients think about the experience, and how much money can be saved.

If proven safe and effective, this new method could reduce treatment delays, shorten hospital stays, and lower healthcare costs-ultimately improving care for patients and making the healthcare system more efficient.

Study Overview

• Status: Not yet recruiting
• Conditions: Atrial Flutter; Atrial Fibrillation (AF)
• Intervention / Treatment: Other: One-step cardiologist-only midazolam sedation; Other: Two-step anaesthesiologist-assisted propofol sedation

Detailed Description

Background: Atrial fibrillation or flutter (AF/AFL) are the most common sustained arrhythmias, with significant public health and economic implications. Direct current cardioversion (DCC) is a standard treatment to restore sinus rhythm. Transoesophageal echocardiography (TOE) is indicated before DCC to exclude cardiac thrombi, if AF/AFL duration is uncertain or >24 hours and anticoagulation is insufficient. Current standard care for TOE-guided DCC involves a two-step sedation process: cardiologist-administered benzodiazepine sedation for TOE, followed by anaesthesiologist-assisted propofol sedation for DCC. In patients requiring subacute TOE-guided DCC (e.g., due to severe symptomatology), this anaesthesiology-dependent two-step model poses logistical challenges, leading to treatment delays, prolonged hospitalisations, increased costs, and reduced patient satisfaction. Alternative sedatives for DCC not requiring anaesthesiology assistance, such as benzodiazepines, may help address these issues. Some centres in Denmark and abroad have introduced a one-step cardiologist-only approach using continuous midazolam sedation for TOE-guided DCC, with uptake driven by assumed safety and cost-effectiveness.

While cardiologist-only sedation with midazolam has proven safe and effective for DCC in acute and elective settings, no trial has evaluated the outcomes of cardiologist-only midazolam sedation for subacute TOE-guided DCC. Correspondingly, expert opinion varies, with some expressing safety concerns about procedural sedation without anaesthesiology support. Thus, one-step cardiologist-only midazolam sedation for TOE-guided DCC, despite its increasing use in clinical practice, is being implemented without robust randomised evidence, creating genuine clinical equipoise and thereby providing the ethical basis for a randomised trial to address this critical gap in knowledge.

Aims and hypotheses: To conduct a randomised clinical trial (CARDIOZOLAM-1) to generate patient-centred and system-relevant evidence on sedation strategies for subacute TOE-guided DCC of AF/AFL. We hypothesise that one-step cardiologist-only midazolam sedation (intervention), compared with two-step anaesthesiologist-assisted propofol sedation (standard care), (1) reduces length of hospitalisation, (2) provides comparable efficacy and safety, (3) improves patient satisfaction, and (4) is associated with lower per-patient costs.

Material and methods

1. Design: An investigator-initiated, multicentre, randomised, open-label, two-arm parallel-group, superiority trial (CARDIOZOLAM-1). The trial is pragmatic by design: usual treating clinicians deliver sedation according to flexible protocols, and baseline data and outcomes are captured primarily through existing electronic health record systems to ensure minimal staff burden, enhance feasibility and cost-efficiency, reduce bias from the open-label design, and improve generalisability.
2. Population: Eligible patients, as defined under "Eligibility" section, will be enrolled from cardiology departments in the Central Denmark Region.
3. Intervention and comparator: We will use minimised randomisation (by 5-year age group, sex, and arrythmia type) to compare the intervention with standard care, as outlined in "Arms and Interventions" section. As all patients will be sedated for TOE, participants will provide pre-TOE informed consent to post-TOE randomisation. Consenting patients will then be randomised to the intervention or standard care.
4. Outcomes: The primary outcome is time-to-discharge after TOE, defined as mean hours-to-discharge, serving as a proxy for healthcare resource use. Secondary outcomes include time-to-shock delivery (measure of treatment delay), cardioversion rate (efficacy outcome), complication rate (safety outcome), and patient-reported outcomes. Detailed definitions are presented in "Outcome Measures" section. Patient-relevance of these outcomes has been evaluated through a dedicated Patient and Public Involvement activity.
5. Statistical analysis: Assuming a between-person standard deviation in mean time-to-discharge of 2 hours, randomisation of 220 participants would provide ≥90% power (at a 2-sided significance level of 0.05) to detect a difference in mean time-to-discharge of 1 hour (minimum difference deemed clinically meaningful for patients and the healthcare system), even in the case of 10% cross-over between groups. Although we anticipate a larger reduction, a 1-hour improvement may determine whether discharge occurs within routine working hours or is deferred, thereby increasing the likelihood of overnight admission and avoidable bed occupancy at regional and national levels. To estimate treatment effects with 95% confidence intervals (CI), we will use linear regression to compare differences in means and log-binomial models for categorical outcomes to estimate risk ratios. Continuous outcomes with non-normal distribution will be log-transformed prior to analysis. Adjustment will be done for minimisation factors. Sample size-assumptions and statistical model choice have been informed by a feasibility study.

• Study Type: Interventional
• Enrollment (Estimated): 220
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Central Jutland
    • Herning, Central Jutland, Denmark, 7400
      • Gødstrup Hospital
      • Contact: Usama Sikandar, MD, PhD Student; Phone Number: +45 51 43 18 08; Email: usama.sikandar@rm.dk
      • Contact: Morten Schmidt, MD, PhD, DMSc, MSc (Oxon); Email: morsch@rm.dk
    • Randers, Central Jutland, Denmark
      • Randers Regional Hospital
      • Contact: Kasper Glerup Lauridsen, MD, PhD; Phone Number: +45 78 42 17 70; Email: kglerup@clin.au.dk
      • Contact: Bo Løfgren, MD, PhD, FESC, FAHA; Email: bl@clin.au.dk

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Adult patients (≥18 years) with atrial fibrillation or flutter
• Scheduled for transoesophageal echocardiography-guided direct current cardioversion

Exclusion Criteria:

1. Previous enrolment in the trial

2. Expected prolonged hospitalisation (>8 hours) despite sinus rhythm restoration:

   • Ongoing medical needs after cardioversion (e.g., decompensation or infection)
   • Planned procedures after cardioversion (same-day TTE or pacemaker test allowed)
   • Social barriers for same-day discharge

3. Indication for anaesthesiology assistance:

   • Haemodynamic instability (systolic blood pressure <90 mmHg)
   • Known severe pulmonary disease (FVC or FEV1 <50% predicted)
   • Body mass index >40 kg/m2
   • Previous complications or allergic reactions to sedation

4. Contraindications:

   • Pregnant or breastfeeding
   • Intracardiac thrombus
   • Total benzodiazepine dose used for TOE >20 mg

Abbreviations: FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; TOE, transoesophageal echocardiography; TTE, transthoracic echocardiography.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Health Services Research
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cardiologist-only (intervention)	Other: One-step cardiologist-only midazolam sedation; TOE-guided DCC performed under continuous cardiologist-administered midazolam sedation, without anaesthesiologist involvement. Midazolam is administered intravenously at the discretion of the treating cardiologist. Non-binding dosing guidance is provided to support clinical practice, but dosing may be individualised as clinically indicated.; For the TOE phase, suggested dosing includes an initial IV dose of 1.25-5.0 mg, with repeat doses of 1.25-2.5 mg as needed, and a suggested maximum cumulative dose of 20 mg.; For the DCC phase, suggested dosing includes an initial IV dose of 2.5-7.5 mg, with repeat doses of 2.5 mg as needed. A suggested maximum cumulative dose of 25 mg applies, including doses administered during the TOE phase.
Active Comparator: With anaesthesiology assistance (standard care)	Other: Two-step anaesthesiologist-assisted propofol sedation; TOE performed under cardiologist-administered sedation followed by a wake-up period and subsequent DCC performed under propofol sedation administered by an anaesthesiologist. Sedation for TOE and DCC is administered following established local guidelines.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time-to-discharge	The primary outcome is time-to-discharge after TOE, with the corresponding endpoint operationalised as the mean number of minutes from randomisation (post-TOE) to formal hospital discharge. This outcome is designed to capture the impact on the healthcare system by serving as a proxy for resource use, where shorter time-to-discharge may reduce bed occupancy, staff workload, and overall hospital costs.	Day 1.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time-to-shock delivery	Measure of treatment delay	From time of randomisation until the time of first shock delivery, assessed on day 1
Conversion to sinus rhythm	Measure of procedural effectiveness. Failure to convert is defined as either insufficient sedation to initiate DCC or failure to achieve sinus rhythm after three consecutive shocks	Periprocedural
Complication rate	Defined as a composite of peri-procedural serious adverse reactions requiring clinical intervention: Bradycardia (heart rate <35 beats per minute for >1 minute); Severe hypotension (systolic blood pressure <80 mmHg for >1 minute); Need for invasive ventilation (tracheal intubation); Major adverse events (ventricular tachycardia, cardiac arrest, advanced atrioventricular block, transient ischemic attack, ischemic stroke, or all cause death). Advanced atrioventricular block is defined as Mobitz II, high-grade (≥2:1), or complete atrioventricular block. Non-serious adverse events, such as transient fluctuations in blood pressure or oxygen saturation that do not require advanced management, will not be considered.	From time of sedation initiation until discharge (within 8 hours post-DCC on average)
Patient-reported outcomes	Evaluated using patient-reported outcome measures comprising both quantitative rating scales and open-ended questions, addressing the domains of: pain; discomfort; recall; overall satisfaction	Postprocedural, with the questionnaire being administered after DCC and before discharge (within 8 hours post-DCC on average)

Collaborators and Investigators

• Sponsor: Gødstrup Hospital
• Collaborators: University of Aarhus

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): May 1, 2027

Study Registration Dates

• First Submitted: April 24, 2026
• First Submitted That Met QC Criteria: April 30, 2026
• First Posted (Actual): May 6, 2026

Study Record Updates

• Last Update Posted (Actual): May 6, 2026
• Last Update Submitted That Met QC Criteria: April 30, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Direct current cardioversion; Transoesophageal echocardiography
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Arrhythmias, Cardiac; Pathological Conditions, Signs and Symptoms; Atrial Fibrillation; Atrial Flutter
• Other Study ID Numbers: CARDIOZOLAM-1; 1-10-72-10-26 (Other Identifier: The Central Denmark Region Committees on Health Research Ethics); 1-16-02-95-26 (Other Identifier: The Central Denmark Region's Internal Register of Research Projects)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Pseudonymized data necessary for data analysis, along with the corresponding analytical scripts, may be made available upon request to promote transparency and support independent replication of results.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No