title: The HARMONY Trial: Combined Ranolazine and Dronedarone in the Management of Paroxysmal Atrial Fibrillation: Mechanistic and Therapeutic Synergism.
abstract: BACKGROUND
  Atrial fibrillation (AF) requires arrhythmogenic changes in atrial ion channels/receptors and usually altered atrial structure. AF is commonly treated with antiarrhythmic drugs; the most effective block many ion channels/receptors. Modest efficacy, intolerance, and safety concerns limit current antiarrhythmic drugs. We hypothesized that combining agents with multiple anti-AF mechanisms at reduced individual drug doses might produce synergistic efficacy plus better tolerance/safety.
  
  
  RESULTS
  HARMONY tested midrange ranolazine (750 mg BID) combined with 2 reduced dronedarone doses (150 mg BID and 225 mg BID; chosen to reduce dronedarone's negative inotropic effect-see text below) over 12 weeks in 134 patients with paroxysmal AF and implanted pacemakers where AF burden (AFB) could be continuously assessed. Patients were randomized double-blind to placebo, ranolazine alone (750 mg BID), dronedarone alone (225 mg BID), or one of the combinations. Neither placebo nor either drugs alone significantly reduced AFB. Conversely, ranolazine 750 mg BID/dronedarone 225 mg BID reduced AFB by 59% versus placebo (P=0.008), whereas ranolazine 750 mg BID/dronedarone 150 mg BID reduced AFB by 43% (P=0.072). Both combinations were well tolerated.
  
  
  CONCLUSIONS
  HARMONY showed synergistic AFB reduction by moderate dose ranolazine plus reduced dose dronedarone, with good tolerance/safety, in the population enrolled.
  
  
  BACKGROUND
  ClinicalTrials.gov; Unique identifier: NCT01522651.
authors.affiliation: From the Division of Cardiology, Department of Medicine, Columbia University, New York, NY (J.A.R.); Department of Cardiovascular Sciences, St Georges University of London, London, United Kingdom (A.J.C.); Cardiovascular Clinical Research, Gilead Sciences, Inc, Foster City, CA (L.B., D.Z., E.K.-P., A.O.); Division of Cardiology, Department of Medicine, University of Rochester Medical Center, NY (W.Z., S.R.); Lankenau Institute for Medical Research, Wynnewood, PA (P.K.); and Division of Cardiovascular Diseases, Department of Medicine, Thomas Jefferson University, Philadelphia, PA (P.K.). jar2@cumc.columbia.edu.
authors.forename: James A
authors.initials: JA
authors.lastname: Reiffel
authors.affiliation: From the Division of Cardiology, Department of Medicine, Columbia University, New York, NY (J.A.R.); Department of Cardiovascular Sciences, St Georges University of London, London, United Kingdom (A.J.C.); Cardiovascular Clinical Research, Gilead Sciences, Inc, Foster City, CA (L.B., D.Z., E.K.-P., A.O.); Division of Cardiology, Department of Medicine, University of Rochester Medical Center, NY (W.Z., S.R.); Lankenau Institute for Medical Research, Wynnewood, PA (P.K.); and Division of Cardiovascular Diseases, Department of Medicine, Thomas Jefferson University, Philadelphia, PA (P.K.).
authors.forename: A John
authors.initials: AJ
authors.lastname: Camm
authors.affiliation: From the Division of Cardiology, Department of Medicine, Columbia University, New York, NY (J.A.R.); Department of Cardiovascular Sciences, St Georges University of London, London, United Kingdom (A.J.C.); Cardiovascular Clinical Research, Gilead Sciences, Inc, Foster City, CA (L.B., D.Z., E.K.-P., A.O.); Division of Cardiology, Department of Medicine, University of Rochester Medical Center, NY (W.Z., S.R.); Lankenau Institute for Medical Research, Wynnewood, PA (P.K.); and Division of Cardiovascular Diseases, Department of Medicine, Thomas Jefferson University, Philadelphia, PA (P.K.).
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.affiliation: From the Division of Cardiology, Department of Medicine, Columbia University, New York, NY (J.A.R.); Department of Cardiovascular Sciences, St Georges University of London, London, United Kingdom (A.J.C.); Cardiovascular Clinical Research, Gilead Sciences, Inc, Foster City, CA (L.B., D.Z., E.K.-P., A.O.); Division of Cardiology, Department of Medicine, University of Rochester Medical Center, NY (W.Z., S.R.); Lankenau Institute for Medical Research, Wynnewood, PA (P.K.); and Division of Cardiovascular Diseases, Department of Medicine, Thomas Jefferson University, Philadelphia, PA (P.K.).
authors.forename: Dewan
authors.initials: D
authors.lastname: Zeng
authors.affiliation: From the Division of Cardiology, Department of Medicine, Columbia University, New York, NY (J.A.R.); Department of Cardiovascular Sciences, St Georges University of London, London, United Kingdom (A.J.C.); Cardiovascular Clinical Research, Gilead Sciences, Inc, Foster City, CA (L.B., D.Z., E.K.-P., A.O.); Division of Cardiology, Department of Medicine, University of Rochester Medical Center, NY (W.Z., S.R.); Lankenau Institute for Medical Research, Wynnewood, PA (P.K.); and Division of Cardiovascular Diseases, Department of Medicine, Thomas Jefferson University, Philadelphia, PA (P.K.).
authors.forename: Ewa
authors.initials: E
authors.lastname: Karwatowska-Prokopczuk
authors.affiliation: From the Division of Cardiology, Department of Medicine, Columbia University, New York, NY (J.A.R.); Department of Cardiovascular Sciences, St Georges University of London, London, United Kingdom (A.J.C.); Cardiovascular Clinical Research, Gilead Sciences, Inc, Foster City, CA (L.B., D.Z., E.K.-P., A.O.); Division of Cardiology, Department of Medicine, University of Rochester Medical Center, NY (W.Z., S.R.); Lankenau Institute for Medical Research, Wynnewood, PA (P.K.); and Division of Cardiovascular Diseases, Department of Medicine, Thomas Jefferson University, Philadelphia, PA (P.K.).
authors.forename: Ann
authors.initials: A
authors.lastname: Olmsted
authors.affiliation: From the Division of Cardiology, Department of Medicine, Columbia University, New York, NY (J.A.R.); Department of Cardiovascular Sciences, St Georges University of London, London, United Kingdom (A.J.C.); Cardiovascular Clinical Research, Gilead Sciences, Inc, Foster City, CA (L.B., D.Z., E.K.-P., A.O.); Division of Cardiology, Department of Medicine, University of Rochester Medical Center, NY (W.Z., S.R.); Lankenau Institute for Medical Research, Wynnewood, PA (P.K.); and Division of Cardiovascular Diseases, Department of Medicine, Thomas Jefferson University, Philadelphia, PA (P.K.).
authors.forename: Wojciech
authors.initials: W
authors.lastname: Zareba
authors.affiliation: From the Division of Cardiology, Department of Medicine, Columbia University, New York, NY (J.A.R.); Department of Cardiovascular Sciences, St Georges University of London, London, United Kingdom (A.J.C.); Cardiovascular Clinical Research, Gilead Sciences, Inc, Foster City, CA (L.B., D.Z., E.K.-P., A.O.); Division of Cardiology, Department of Medicine, University of Rochester Medical Center, NY (W.Z., S.R.); Lankenau Institute for Medical Research, Wynnewood, PA (P.K.); and Division of Cardiovascular Diseases, Department of Medicine, Thomas Jefferson University, Philadelphia, PA (P.K.).
authors.forename: Spencer
authors.initials: S
authors.lastname: Rosero
authors.affiliation: From the Division of Cardiology, Department of Medicine, Columbia University, New York, NY (J.A.R.); Department of Cardiovascular Sciences, St Georges University of London, London, United Kingdom (A.J.C.); Cardiovascular Clinical Research, Gilead Sciences, Inc, Foster City, CA (L.B., D.Z., E.K.-P., A.O.); Division of Cardiology, Department of Medicine, University of Rochester Medical Center, NY (W.Z., S.R.); Lankenau Institute for Medical Research, Wynnewood, PA (P.K.); and Division of Cardiovascular Diseases, Department of Medicine, Thomas Jefferson University, Philadelphia, PA (P.K.).
authors.forename: Peter
authors.initials: P
authors.lastname: Kowey
mesh_terms: D000368:Aged; D000638:Amiodarone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000188:drug therapy*; D004311:Double-Blind Method; D000077764:Dronedarone; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D010138:Pacemaker, Artificial; D000069458:Ranolazine / Q000008:administration & dosage / Q000627:therapeutic use*; D026941:Sodium Channel Blockers / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000889:Anti-Arrhythmia Agents; D026941:Sodium Channel Blockers; D000069458:Ranolazine; D000077764:Dronedarone; D000638:Amiodarone
keywords: antiarrhythmic drug; atrial fibrillation; clinical trial; dronedarone; drug therapy; ranolazine