Systematic review

Ranolazine for the prevention or treatment of atrial fibrillation: a systematic review Nikolaos Dagres, Efstathios K. Iliodromitis, John P. Lekakis, Panagiotis Simitsis, Dimitrios Karatzas, Loukianos S. Rallidis, Eftihia Simeonidou and Maria Anastasiou-Nana The use of currently available antiarrhythmic drugs for atrial fibrillation is limited by their moderate efficacy and the considerable proarrhythmic risk. Ranolazine, an antianginal agent, has been reported to possess antiarrhythmic properties, resulting in a reduction of supraventricular and ventricular arrhythmias. We performed a systematic review of the clinical studies reporting the outcome of patients treated with ranolazine for the prevention or treatment of atrial fibrillation in various clinical settings. We searched PubMed and abstracts of major conferences for clinical studies using ranolazine, either alone or in combination with other antiarrhythmic agents for the prevention or treatment of atrial fibrillation. Ten relevant records were identified. These included both randomized trials and retrospective cohort studies concerning the use of ranolazine in different clinical settings; prevention of atrial fibrillation in patients with acute coronary syndrome, prevention as well as conversion of postoperative atrial fibrillation after coronary artery bypass grafting, conversion of recent-onset atrial fibrillation, sinus rhythm maintenance in drug-resistant recurrent atrial fibrillation and facilitation of electrical cardioversion in cardioversion-resistant patients. A beneficial, mostly modest effect of ranolazine was

Introduction Atrial fibrillation is the most common human arrhythmia with significant morbidity and mortality. The use of currently available antiarrhythmic drugs is limited by their moderate efficacy and the considerable risk of proarrhythmia.1–3 Ranolazine is an antianginal agent intended to be used in patients with coronary artery disease. Interestingly, several investigators have observed an antiarrhythmic effect of this drug resulting in a reduction of both supraventricular and ventricular arrhythmias.4–13 In order to gain a thorough insight into the clinical usefulness of ranolazine for the prevention and treatment of atrial fibrillation, we performed a systematic review of the clinical studies reporting the outcome of patients treated with ranolazine for the prevention or treatment of atrial fibrillation in various clinical settings.

Methods The study was performed according to the preferred reporting items for systematic reviews and meta-analyses 1558-2027 ß 2014 Italian Federation of Cardiology

homogeneously reported in all clinical settings. There were no substantial proarrhythmic effects. No meta-analysis could be performed because for most of the clinical scenarios, there was only one study investigating the effect of ranolazine. Except for one large randomized trial, all the other studies were either relatively small randomized studies or retrospective cohort analyses, which in several cases lacked a control group. This systematic review indicates a modest beneficial effect of ranolazine administered for the prevention or treatment of atrial fibrillation across several clinical settings without substantial proarrhythmic risk. J Cardiovasc Med 2014, 15:254–259 Keywords: atrial fibrillation, ranolazine, systematic review Second Cardiology Department, Attikon University Hospital, University of Athens, Athens, Greece Correspondence to Nikolaos Dagres, MD, Second University Cardiology Department, Attikon University Hospital, Rimini 1, Haidari, 12462 Athens, Greece Tel: +30 2105832193; fax: +30 2105832351; e-mail: [email protected] Received 26 May 2013 Revised 30 June 2013 Accepted 1 August 2013

(PRISMA) statement for systematic reviews and meta-analyses.14 Search strategy and selection criteria

We performed a literature search in PubMed for clinical studies using ranolazine either alone or in combination with other antiarrhythmic agents for the prevention or treatment of patients with atrial fibrillation. The search term in PubMed was ‘Ranolazine AND atrial fibrillation’. There was no limitation regarding the clinical setting of atrial fibrillation (e.g. conversion of postoperative atrial fibrillation, prevention of recurrence after cardioversion, rhythm control in recurrent paroxysmal atrial fibrillation, etc.). The search was performed on 4 April 2013. We additionally reviewed the reference lists of retrieved articles and searched the abstracts of the annual Scientific Sessions of the American Heart Association, the American College of Cardiology and of the annual congresses of the European Society of Cardiology. The search for abstracts of major conferences was performed as follows: DOI:10.2459/JCM.0b013e328365b554

Copyright © Italian Federation of Cardiology. Unauthorized reproduction of this article is prohibited.

Ranolazine and atrial fibrillation Dagres et al. 255

(1) Annual Scientific Sessions of the American Heart Association: We searched on the website http:// circ.ahajournals.org/search.dtl for abstracts containing the word ‘ranolazine’ in the title and the phrase ‘atrial fibrillation’ in the title or the abstract body. The search retrieved eight meeting abstracts. (2) Annual Scientific Sessions of the American College of Cardiology: We searched on the website http:// www.cardiosource.org/meetings/previous-meetingsold.aspx for the years 2007–2012 and on the website http://www.abstractsonline.com/pp8/index.html#!/ 3042/ for the year 2013 for abstracts containing the title word ‘ranolazine’. The search retrieved 26 results. (3) Annual congresses of the European Society of Cardiology: We searched on the website http://spo. escardio.org/abstract-book/search.aspx for abstracts from the years 2005–2012 containing the word ‘ranolazine’ in the title. The search retrieved 23 results. For the purposes of this review, the following data were collected from the analyzed studies: study design, patient demographics, clinical atrial fibrillation setting, and definition and occurrence of clinical endpoint. If considered necessary, additional data were requested from the study authors. The quality of the studies was graded on a 0–10 visual analog scale based mainly on adherence to the consolidated standards of reporting trials (CONSORT) statement15 for randomized studies and to the strengthening the reporting of observational studies in epidemiology (STROBE) statement16 for observational studies. Our intention was to first perform the systematic review and then a meta-analysis of the studies reporting the effect of ranolazine in the same clinical setting, provided that there were two or more such studies in any of the various clinical settings. Funding

There was no external funding for this work. The authors are solely responsible for the design and conduct of the study, the study analyses and the manuscript.

Acute Coronary Syndrome (MERLIN)-Thrombolysis in Myocardial Infarction (TIMI) 36 trial.4,17 This trial randomized patients hospitalized with a non-STelevation acute coronary syndrome to treatment with ranolazine or placebo in addition to standard medical therapy. In the ranolazine group, ranolazine treatment was initiated intravenously and followed by oral ranolazine extended-release 1000 mg twice daily, or a reduced dose in patients with new renal insufficiency or for those experiencing specific adverse events.17 Patients were monitored with continuous ECG or Holter recording for the first 7-days after randomization. A suitable continuous ECG recording that could be evaluated for arrhythmia analysis was present in 6351 patients (3162 on ranolazine and 3189 on placebo). Mean age was 63  11 years, the index event was unstable angina (47%) or non-ST elevation myocardial infarction (51%), and the great majority of the patients (>86%) had a left ventricular ejection fraction greater than 40%. New-onset atrial fibrillation was observed in fewer patients in the ranolazine group [55 (1.7%) vs. 75 (2.4%) in the placebo group, P ¼ 0.08].4 There was no evidence of an increased proarrhythmic risk under ranolazine. On the contrary, there were fewer patients with an episode of ventricular tachycardia lasting at least 8 beats in the ranolazine group. Subsequently, the investigators of that trial also reported in a conference abstract data on the effect of ranolazine on the overall burden of atrial fibrillation in the continuous ECG recordings, as well as on the incidence of clinical atrial fibrillation-related events during 1 year following randomization.5 The atrial fibrillation burden in continuous ECG monitoring was classified as predominately chronic (>98% of recording time), paroxysmal (>0.01–98%), or clinically insignificant (

Ranolazine for the prevention or treatment of atrial fibrillation: a systematic review.

The use of currently available antiarrhythmic drugs for atrial fibrillation is limited by their moderate efficacy and the considerable proarrhythmic r...
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