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Comparison of Effectiveness of Ranolazine Plus Metoprolol Combination vs. FlecainidE pluS Metoprolol Combination in ATrial Fibrillation Recurrences FOllowing PhaRmacological or Electrical CardioverSion of AtRial Fibrillation (PRESERVE-SR)

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ClinicalTrials.gov Identifier: NCT03162120
Recruitment Status : Withdrawn (new study type, it will be re-organiZed as an Investigator Initiated Study (IIS))
First Posted : May 22, 2017
Last Update Posted : May 13, 2019
Sponsor:
Information provided by (Responsible Party):
Elpen Pharmaceutical Co. Inc.

Brief Summary:
Atrial fibrillation (AF) is the most common arrhythmia in clinical practice with a prevalence reaching 5% in patients older than 65 years and an incidence that increases progressively with age.1 According to the most recent guidelines, class Ic anti-arrhythmic drugs are considered the first line treatment in patients without significant structural heart disease. Flecainide is effective in preventing AF recurrences in 31-61% of cases according to different studies.2-5 A recent study showed that the combination of Flecainide and Metoprolol improves effective rhythm control in patients with persistent symptomatic AF compared to Flecainide or Metoprolol alone.6 In contrast, the combination of Flecainide and Metoprolol conferred no significant benefit over Flecainide alone in patients with paroxysmal AF. This suggests different underlying mechanisms for paroxysmal and persistent AF. Pulmonary veins are likely the main focus triggering paroxysmal AF while in persistent AF the role of pulmonary veins is less important.

Condition or disease Intervention/treatment Phase
Atrial Fibrillation Recurrence Drug: Ranolazine plus Metoprolol Combination Drug: FlecainidE pluS Metoprolol Combination Phase 2 Phase 3

Detailed Description:

Ranolazine (RN) is a novel antianginal agent with increasingly appreciated antiarrhythmic properties that can suppress ventricular and supraventricular arrhythmias including AF. The antiarrhythmic actions of RN are mainly attributed to its ability to block INa, INaL, and the rapidly activating delayed rectifier potassium current (IKr).7 In experimental studies, RN proved very effective in suppressing late phase 3 early afterdepolarization and delayed afterdepolarization mediated triggered activity in pulmonary vein sleeves.8 RN was shown very effective in suppressing persistent, vagally mediated AF in animal models.9 Clinical evidence of an AF-suppressing effect of RN comes mainly from small caliber studies. Murdock et al, reported a high conversion rate (72%) after administration of 2,000 mg of RN (in a "pill-in-the-pocket" fashion) in patients with short lasting (<48 hours) new onset paroxysmal AF.10 Our group demonstrated both the superior efficacy and the accelerated action of the combined therapy of Amiodarone with RN compared to Amiodarone alone in patients with paroxysmal AF. Notably, the efficacy benefit of this combination was more pronounced in patients with dilated left atria which is also more likely to occur in cases of persistent AF.11, 12 In a prospective, randomized, double-blind, placebo-control phase II study, different doses of RN were tested in the prevention of AF recurrence after successful electrical cardioversion. Despite the fact that the study did not reach its primary end-point since none of the individual doses of RN significantly delayed the time to first AF recurrence as compared with placebo, an antiarrhythmic efficacy for the two higher doses of RN (500 and 750mg bd) was strongly suggested. The same study confirmed the safety of RN with no evidence for proarrhythmia.13 Notably, beta-blockers were used in less than 50% of patients studied in this study.

Although the efficacy of beta-blockers in the maintenance of sinus rhythm is low, the addition of a beta-blocker to an antiarrhythmic agent that exerts its action by inhibiting inward Na+ current like RN and Flecainide may represent an interesting approach in preventing AF relapse. Various laboratory studies have demonstrated that inward Na+ current could be modulated by beta-adrenergic receptors in a variety of cell lines.14, 15 In this context, the beta-blocking activity of Amiodarone or Dronedarone may account for the successful combination with RN in suppressing AF in either experimental or clinical studies.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: A Single Site, Interventional, Comparative Study to Evaluate the Safety and Efficacy of Ranolazine Plus Metoprolol Combination vs. FlecainidE pluS Metoprolol Combination in ATrial Fibrillation Recurrences
Estimated Study Start Date : September 1, 2018
Estimated Primary Completion Date : December 1, 2018
Estimated Study Completion Date : December 1, 2018


Arm Intervention/treatment
Active Comparator: Ranolazine plus Metoprolol Combination
Ranolazine plus Metoprolol Combination in ATrial Fibrillation Recurrences FOllowing PhaRmacological or Electrical CardioverSion of AtRial Fibrillation
Drug: Ranolazine plus Metoprolol Combination
Ranolazine plus Metoprolol Combination in ATrial Fibrillation Recurrences FOllowing PhaRmacological or Electrical CardioverSion of AtRial Fibrillation
Other Name: RM group

Active Comparator: FlecainidE pluS Metoprolol Combination
FlecainidE pluS Metoprolol Combination in in ATrial Fibrillation Recurrences FOllowing PhaRmacological or Electrical CardioverSion of AtRial Fibrillation
Drug: FlecainidE pluS Metoprolol Combination
FlecainidE pluS Metoprolol Combination in ATrial Fibrillation Recurrences FOllowing PhaRmacological or Electrical CardioverSion of AtRial Fibrillation
Other Name: FM group




Primary Outcome Measures :
  1. Number of 1-year-recurrences [ Time Frame: 12 months ]
    efficacy and safety of the combination of RN and Metoprolol vs. the combination of Flecainide and Metoprolol in preventing AF recurrences during a 1-year follow-up period in patients with AF of longer than 24-hour duration who were cardioverted to sinus rhythm either pharmacologically or electrically


Secondary Outcome Measures :
  1. Number of 48-hours-recurrences [ Time Frame: 48 hours ]
    Time to the first documented AF recurrence excluding patients with recurrences in the first 48 hours



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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • patients with AF
  • recently converted to sinus rhythm (>24hrs and < 7 days)
  • admitted in the 3rd University Cardiology Clinic of Ippokrateion Hospital
  • eligible to participate in the study and follow the study procedures
  • signed informed consent

Exclusion Criteria:

  • use of IC antiarrhythmic agents or
  • Sotalol during the last 48 hours,
  • chronic use of oral or intravenous Amiodarone for the last 48 hours,
  • recent acute coronary syndrome,
  • heart failure New York Heart Association class III or IV,
  • severe left ventricular dysfunction with left ventricular ejection fraction <40%,
  • atrioventricular conduction disorders (atrioventricular block,
  • complete left bundle branch block and bi-fascicular block),
  • heart rate < 50 bpm,
  • sick sinus syndrome,
  • thyroid dysfunction and severe pulmonary, renal, or
  • liver disease
  • - not eligible to participate in the study and follow the study procedures
  • no signed informed consent

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03162120


Sponsors and Collaborators
Elpen Pharmaceutical Co. Inc.
Investigators
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Study Chair: Vasilios Vasilikos, MD 3rd University Cardiology Clinic of Ippokrateion Hospital, Thessaloniki, Greece

Publications:
Murdock DK, Reiffel JA, Kaliebe J, Larrain G. The Conversion of Paroxysmal or Initial Onset Atrial Fibrillation with Oral Ranolazine: Implications for a New

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Responsible Party: Elpen Pharmaceutical Co. Inc.
ClinicalTrials.gov Identifier: NCT03162120     History of Changes
Other Study ID Numbers: IIS-EL-VASS-2017
First Posted: May 22, 2017    Key Record Dates
Last Update Posted: May 13, 2019
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Atrial Fibrillation
Recurrence
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Disease Attributes
Metoprolol
Flecainide
Ranolazine
Anti-Arrhythmia Agents
Antihypertensive Agents
Sympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Adrenergic beta-1 Receptor Antagonists
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Sodium Channel Blockers
Membrane Transport Modulators
Voltage-Gated Sodium Channel Blockers