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)

May 10, 2019 updated by: Elpen Pharmaceutical Co. Inc.

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

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.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Phase

  • Phase 2
  • Phase 3

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 90 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / 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 Names:
  • 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 Names:
  • FM group

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
48 hours

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Elpen Pharmaceutical Co. Inc.

Investigators

  • Study Chair: Vasilios Vasilikos, MD, 3rd University Cardiology Clinic of Ippokrateion Hospital, Thessaloniki, Greece

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

September 1, 2018

Primary Completion (Anticipated)

December 1, 2018

Study Completion (Anticipated)

December 1, 2018

Study Registration Dates

First Submitted

May 17, 2017

First Submitted That Met QC Criteria

May 19, 2017

First Posted (Actual)

May 22, 2017

Study Record Updates

Last Update Posted (Actual)

May 13, 2019

Last Update Submitted That Met QC Criteria

May 10, 2019

Last Verified

December 1, 2018

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IIS-EL-VASS-2017

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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