Comparative Efficacy of 100-, 200-, & 400-mg Amiodarone in Patients With Paroxysmal AF Depending on Plasma Concentration (AMIODETECT)

Randomized Study of Integrated Assessment of Amiodarone Effects Based on Clinical Evaluation and Plasma Concentration Control in Patients With Paroxysmal Atrial Fibrillation in Parallel Groups

Amiodarone is a highly effective drug for the treatment and prevention of arrhythmias. In the 1970s and 1980s, numerous experimental and clinical studies comprehensively examined the mechanisms of amiodarone's antiarrhythmic action, as well as its effectiveness in various types of arrhythmias. This explains why drug therapy is so widespread today. According to the CAMIAT study, which included 1,202 patients with ventricular extrasystole who had suffered a myocardial infarction, amiodarone administration reduced the risk of arrhythmic death by 48.5%, and by 35% in the EMIAT study. In the GESICA study, amiodarone therapy was documented to reduce overall mortality by 45%, the incidence of sudden cardiac death by 54%, and mortality from progressive heart failure by 40%. In Russia, amiodarone is prescribed as a first-line drug for AF in 41% of cases with organic myocardial disease, in 52% as a second-line drug, and in 12.5% in the absence of organic heart damage. Moreover, the effectiveness of maintaining sinus rhythm in atrial fibrillation varies from 30 to 95.2%, which is a significant range when predicting the effectiveness of treatment. Attempts to assess amiodarone concentrations during therapy and to analyze the correlation with the achieved effects have been made repeatedly. While assessing amiodarone concentrations is generally considered inappropriate, based on the results of numerous studies, the use of monitoring is justified in certain clinical situations where the desired clinical effect or adverse events are absent. A detailed analysis of systemic reviews revealed significant shortcomings in the formation of such judgments. The groups were heterogeneous, small in number, and included, among other things, individual clinical situations and different routes of drug administration. A literature review did not reveal any data on the analysis of the concentration of amiodarone and desethylamiodarone as an anti-relapse therapy for atrial fibrillation when used consistently in doses acceptable by clinical guidelines with the possibility of titration under laboratory monitoring.

Study Overview

• Status: Enrolling by invitation
• Conditions: Treatment Decisions; Paroxysmal AF; Therapeutic Drug Monitoring (TDM)
• Intervention / Treatment: Drug: Pharmacotherapy with amiodarone 200 mg per day; Drug: Treatment with Amiodarone at a dose 100 mg per day; Drug: Treatment with Amiodarone at a dose 400 mg per day

Detailed Description

Attempts to personalize amiodarone therapy and to identify a correlation between its concentration and the efficacy and safety of therapy have been made repeatedly.

A serious problem in arrhythmology is the fact that amiodarone is a drug with a narrow therapeutic window, which is associated with objective problems in its dosage: even minor changes in its pharmacokinetics, leading to changes in the concentration of the active substance in the blood, can lead to both a decrease in efficacy and an increase in toxicity. In a review of bioequivalence studies conducted between 1996 and 2007, the FDA found that the average difference in pharmacodynamics between generic and brand-name drugs was about 4%; in nearly 98% of the studies reviewed, generic drug properties differed from those of the original drug by less than 10%. Approval of a generic version of a brand-name drug by the U.S. Food and Drug Administration requires demonstration of "chemical equivalence" (similar amounts and availability of the active ingredient in the brand-name and generic drugs) and "bioequivalence" (usually determined by absorption parameters) that range from 80% to 125% of the results obtained with the proprietary agent under the same testing conditions. This spread is acceptable for groups with a wider therapeutic window. Because measurement of amiodarone and its metabolites in serum is not standard clinical practice, the effects of switching between the original and generic drug and back, or between generic amiodarone products, may take several weeks to become apparent, which, in the context of routine patient monitoring, remains without due attention. A large systematic review in 2017 presented a list of studies providing the achieved concentrations of amiodarone and desethylamiodarone in patients with various heart rhythm disorders (Hrudikova E.V. et al., 2017). In a study by R.G. Tieleman et al. (1997), restoration of sinus rhythm was associated with an increase in the concentration of desethylamiodarone in the patient's plasma. However, amiodarone concentrations <1.2 mg/L and desethylamiodarone concentrations <0.9 mg/L were ineffective in cardioversion. A group of other researchers found that in patients treated with amiodarone for resistant ventricular or supraventricular arrhythmia, rhythm disorders recurred in 47% of patients with serum amiodarone concentrations less than 1.0 mg/L, whereas at higher concentrations, recurrences were observed in only 14% [C.I. [Haffajee et al., 1983]. In the treatment of atrial tachycardia and ventricular tachycardia, the mean serum amiodarone concentration did not differ between responders and non-responders, with relapses also observed at amiodarone concentrations less than 1.0 mg/l [H.H. Rotmensch et al., 1983]. These studies suggest that maintaining plasma concentrations of at least 1.0 mg/L appears optimal for preventing recurrences. However, in a study by S.J. Connolly et al. (1988), 67% of patients with frequent ventricular extrasystoles responded to amiodarone concentrations below 1.0 mg/L.

Importantly, the analyses of available publications included all references regarding amiodarone and desethylamiodarone concentrations and treatment effects. Thus, the reviews included all cases of both intravenous and oral administration, acute and chronic therapy, and supraventricular and sustained ventricular tachyarrhythmias. Reports on the relationship between plasma and tissue concentrations of amiodarone and desethylamiodarone were contradictory, due in part to heterogeneity in the sample, routes of drug administration, observation periods, types of rhythm disturbances, and target population. Many observations were conducted on small patient samples or included isolated clinical cases. While there is a lack of definitive data on the relationship between plasma concentrations and efficacy, it is known that concentrations below 0.5-1 mg/L are often ineffective, and concentrations above 2.5 mg/L are inadvisable. In this case, plasma concentration measurements can be used to identify patients whose levels are unusually low and who may benefit from increasing the dose, or unusually high and who may benefit from decreasing the dose in hopes of minimizing side effects [Approved FDA Drugs prescribing information: cordarone October 2018.]. Despite the proven high activity of the metabolite, estimates of the therapeutic effective concentration range in reports are based primarily on the concentration of amiodarone itself. This underestimation of the significance of desethylamiodarone concentration leads to false conclusions. A 2023 review analyzed reports over the past 10 years using the keywords "amiodarone," "therapeutic drug monitoring," or "serum/plasma/blood" [Adam El Mongy Jørgensen et al, 2023]. Of the 19 publications included in the analysis, only 1 concerned the analysis of the concentration of amiodarone and desethylamiodarone in patients after catheter treatment as anti-relapse therapy with a stable dose of 200 mg with an increase in case of arrhythmia recurrence [E. Hrudikova, 2017]. Moreover, out of 68 patients, the effectiveness of maintaining rhythm was 83% of cases, only 11 patients had recurrences of arrhythmia. When analyzing the concentration of amiodarone and desethylamiodarone using high-performance liquid chromatography with ultraviolet detection, differences were shown, which was due to an increase in the dose in the group of recurrent arrhythmias. In any case, the relationship between concentration changes and dose changes became clear. The authors did not note any cases of rhythm restoration with increasing doses and concentrations of amiodarone and desethylamiodarone; however, this assessment focused on the ability of amiodarone to induce cardioversion, not to maintain sinus rhythm.

In our literature review, we did not find any studies evaluating the efficacy and safety of amiodarone in maintaining sinus rhythm in paroxysmal atrial fibrillation without the use of catheter-based treatment methods or in cases of arrhythmia recurrence after its implementation when analyzing the concentration of amiodarone and desethylamiodarone in blood plasma and titration of the drug dose In Russia, there is currently no accepted clinical practice method for monitoring the concentration of amiodarone and desethylamiodarone in the blood of patients with cardiac arrhythmias requiring long-term maintenance use, in particular as antiarrhythmic therapy for AF. Clinical practice is based on the use of amiodarone as a reserve drug in patients without organic myocardial damage or in the presence of organic myocardial damage (in this case, it is one of two possible or the only possible antiarrhythmic drug for therapy). The maintenance dose is 200 mg for long-term daily use to maintain sinus rhythm in patients with atrial fibrillation. It is important that in cases of lack of effect and recurrence of arrhythmia, the tactics of possible titration of the dose to increase the effectiveness in comparison with the achieved concentration of amiodarone and desethylamiodarone in the blood plasma (within the limits of the therapeutic maintenance dose permitted by the recommendations) are not accepted in routine clinical practice, which leads to unjustified discontinuation of the drug while maintaining the safety profile or continued observation of the patient while maintaining the previous dose in the absence of alternative tactics.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 4

Contacts and Locations

Study Locations

• Russia
  • Tomsk, Russia, 634012
    • Kievskaya street 111a Cardiology research institute

Participation Criteria

Eligibility Criteria

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

Description

Inclusion criteria:

1. The patient must have a documented electrocardiogram (ECG) or 24-hour ECG monitoring for paroxysmal AF.
2. Patient age >18 years.
3. Signed informed consent for participation in the study.
4. Indications for amiodarone.

Exclusion criteria for the study

1. Contraindications to the administration of amiodarone according to the drug's instructions for use
2. Patients with coronary artery disease with confirmed ischemia based on stress tests and the need for revascularization based on coronary angiography and multispiral computed tomography coronary angiography.
3. Patients with resistant arterial hypertension.
4. Planned catheter treatment of atrial fibrillation during the follow up period or early within 3 months postoperative period for catheter treatment of atrial fibrillation.
5. Thrombosis of the heart cavities.
6. Concomitant therapy with psychotropic drugs, antiarrhythmics of class IA and III, antibiotics, antifungal drugs, antimalarial and antiprotozoal drugs, antitumor, antiemetic drugs and drugs affecting gastrointestinal motility, antihistamines;
7. Patients incapacitated due to psychoneurological conditions;
8. Pregnant women or women of childbearing age planning pregnancy during the study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Treatment with Amoidarone at a dose 200 mg per day; Patients in this group are treated with amiodarone at a dose 200 mg per day for three months	Drug: Pharmacotherapy with amiodarone 200 mg per day; Patients are treated with amiodarone at a dose of 200 mg per day.; Other Names: Amiodarone 200 mg
Active Comparator: Treatment with Amiodarone at a dose 100 mg per day; Patients in this group are treated with amiodarone at a dose 100 mg per day for three months in case of sufficient clinical efficacy of this dose or in case of adverse drug reactions to 200-mg amiodarone administered at higher dose before.	Drug: Treatment with Amiodarone at a dose 100 mg per day; Patients are treated with amiodarone at a dose of 100 mg per day.; Other Names: Amiodarone 100 mg
Active Comparator: Treatment with Amiodarone at a dose 400 mg per day; Patients in this group are treated with amiodarone at a dose 400 mg per day for three months in case of insufficient clinical efficacy and in the absence of adverse drug reactions to 200 mg.	Drug: Treatment with Amiodarone at a dose 400 mg per day; Patients are treated with amiodarone at a dose of 400 mg per day.; Other Names: Amiodarone 400 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of of patients with recurrent atrial fibrillation paroxysms (percentage)	The primary endpoint is an incidence (percentage) of patients with recurrent atrial fibrillation paroxysms during amiodarone therapy after reaching a steady-state saturation concentration of amiodarone and desethylamiodarone. Median saturation time is 16 days. After reaching saturation concentration of amiodarone in plasma, patients are followed up for three months.	106 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heart rate (bpm)	The secondary endpoint is heart rate (beats per minute) in patients with recurrent atrial fibrillation paroxysms during amiodarone therapy after reaching a steady-state saturation concentration of amiodarone and desethylamiodarone. Median saturation time is 16 days. After reaching saturation concentration of amiodarone in plasma, patients are followed up for three months.	106 days
Incidence (percentage) of patients with prolongation of the QT interval up to 500 ms and more	The secondary endpoint is incidence (percentage) of prolongation of the QT interval up to 500 ms and more in patients with recurrent atrial fibrillation paroxysms during amiodarone therapy after reaching a steady-state saturation concentration of amiodarone and desethylamiodarone. Median saturation time is 16 days. After reaching saturation concentration of amiodarone in plasma, patients are followed up for three months.	106 days
Duration of the QT interval (ms)	The secondary endpoint is duration of the QT interval (ms) in patients with recurrent atrial fibrillation paroxysms during amiodarone therapy after reaching a steady-state saturation concentration of amiodarone and desethylamiodarone. Median saturation time is 16 days. After reaching saturation concentration of amiodarone in plasma, patients are followed up for three months.	106 days
Rate of second-degree atrioventricular conduction blocks on the ECG and 24-hour ECG (persantage)	The secondary endpoint is rate of second-degree atrioventricular conduction (persantage) blocks on the ECG and 24-hour ECG in patients with recurrent atrial fibrillation paroxysms during amiodarone therapy after reaching a steady-state saturation concentration of amiodarone and desethylamiodarone. Median saturation time is 16 days. After reaching saturation concentration of amiodarone in plasma, patients are followed up for three months.	106 days
Rate of third-degree atrioventricular conduction blocks on the ECG and 24-hour ECG (persantage)	The secondary endpoint is rate of third-degree atrioventricular conduction (persantage) blocks on the ECG and 24-hour ECG in patients with recurrent atrial fibrillation paroxysms during amiodarone therapy after reaching a steady-state saturation concentration of amiodarone and desethylamiodarone. Median saturation time is 16 days. After reaching saturation concentration of amiodarone in plasma, patients are followed up for three months.	106 days
Plasma concentration of amodarone (µg/mL)	Concentration of amodarone (µg/mL)) in blood plasma is assessed by the method of high-performance liquid chromatography in patients with recurrent atrial fibrillation paroxysms during amiodarone therapy after reaching a steady-state saturation concentration of amiodarone and desethylamiodarone. Median saturation time is 16 days. After reaching saturation concentration of amiodarone in plasma, patients are followed up for three months.	106 days
concentration of desethylamiodarone (µg/mL)	Concentration of desethylamiodarone (µg/mL) in blood plasma is assessed by the method of high-performance liquid chromatography in patients with recurrent atrial fibrillation paroxysms during amiodarone therapy after reaching a steady-state saturation concentration of amiodarone and desethylamiodarone. Median saturation time is 16 days. After reaching saturation concentration of amiodarone in plasma, patients are followed up for three months.	106 days
Rate of ventricular tachycardia on the ECG and 24-hour ECG (persantage)	The secondary endpoint is rate of ventricular tachycardia on the ECG and 24-hour ECG (persantage) in patients with recurrent atrial fibrillation paroxysms during amiodarone therapy after reaching a steady-state saturation concentration of amiodarone and desethylamiodarone. Median saturation time is 16 days. After reaching saturation concentration of amiodarone in plasma, patients are followed up for three months.	106 days

Collaborators and Investigators

• Sponsor: Tomsk National Research Medical Center of the Russian Academy of Sciences
• Investigators: Study Chair: Roman E Batalov, MD, PhD, Cardiology Research Institute of Tomsk NRMC

Study record dates

Study Major Dates

• Study Start (Actual): January 12, 2026
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): August 1, 2027

Study Registration Dates

• First Submitted: March 17, 2026
• First Submitted That Met QC Criteria: March 17, 2026
• First Posted (Actual): March 23, 2026

Study Record Updates

• Last Update Posted (Actual): March 23, 2026
• Last Update Submitted That Met QC Criteria: March 17, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: atrial fibrillation; amiodarone; High performance liquid chromatography; desethylamiodarone
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Arrhythmias, Cardiac; Pathological Conditions, Signs and Symptoms; Atrial Fibrillation; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Benzofurans; Amiodarone; Therapeutics; Drug Therapy
• Other Study ID Numbers: CRI-281

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Deidentified individual participant data (text, tables, figures, and appendices), underlying the results of the trial, will be shared with researchers to achieve the aims in the approved proposal.
• IPD Sharing Time Frame: Proposals may be submitted up to 36 months following publication of the results of the trial. After 36 months, the data will be available in the Center's data ware house but without investigator support other than deposited metadata.
• IPD Sharing Access Criteria: Information
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

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