Ranolazine Implantable Cardioverter-Defibrillator Trial (RAID)

Late Sodium Current Blockade in High-Risk ICD Patients

The purpose of the study is to see how effective a drug called ranolazine is in reducing the risk of ventricular arrhythmia and death in people with implantable cardioverter-defibrillators (ICDs). This drug will be used with standard medications that is routinely prescribed in enrolled patients.

Study Overview

• Status: Completed
• Conditions: Heart Failure; Ischemic Cardiomyopathy; Nonischemic Cardiomyopathy
• Intervention / Treatment: Drug: Ranolazine

Detailed Description

There are limited treatment options for patients at high risk of ventricular arrhythmic events. Beta-blockers alone do not provide enough protection, sotalol has limited effectiveness, and amiodarone although effective in some groups of patients is used infrequently due to its side effects and limitations of a long-term use. Ischemia and cardiomyopathies are associated with a sodium overload of myocardial cells. Late sodium current plays a pivotal role in this process. Sodium overload leads to calcium overload of myocardial cells with consequent increased vulnerability of myocardium to ventricular tachyarrhythmias as well as increased impairment of diastolic relaxation of myocardium thereby augmenting the risk of ischemia and myocardial damage.

Ranolazine is a novel drug with anti-ischemic and antiarrhythmic properties that uniquely blocks late sodium current, decreases intracellular calcium overload, and improves diastolic relaxation of the ventricles. The antiischemic and antiarrhythmic properties of ranolazine might decrease the likelihood of arrhythmic events and improve the clinical course of patients with ventricular arrhythmias.

We designed a randomized double-blind placebo-controlled clinical trial enrolling 1,440 high-risk ICD patients who will be treated with ranolazine or placebo in addition to optimal medical therapy to test the hypothesis that late sodium current blockade contributes to significant reduction in the risk of arrhythmic events or death in high-risk ICD/cardiac resynchronization therapy-D patients.

• Study Type: Interventional
• Enrollment (Actual): 1012
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Quebec, Canada, G1V 4G5
    • IUCPQ
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • University of Calgary
    • Edmonton, Alberta, Canada, T5H 3V9
      • Royal Alexandra Hospital
  • Ontario
    • Kingston, Ontario, Canada, K7L 2V7
      • Queen's University
  • Quebec
    • Montreal, Quebec, Canada, H1T 1C8
      • Montreal Heart Institute
    • Montreal, Quebec, Canada, H3G1A4
      • McGill University Health Centre
    • Sherbrooke, Quebec, Canada, J1H5N4
      • CHUS (Sherbrooke University)
• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Arkansas Cardiology
  • California
    • East Palo Alto, California, United States, 94303
      • Sequoia Hospital
    • Los Angeles, California, United States, 90017
      • Good Samaritan Hospital
    • Pasadena, California, United States, 91105
      • Huntington Memorial Hospital
    • Sacramento, California, United States, 95819
      • Regional Cardiology Associates
    • Stockton, California, United States, 95210
      • Delta Heart and Medical Clinic
  • Colorado
    • Colorado Springs, Colorado, United States, 80909
      • University of Colorado Health - MHS
  • Connecticut
    • Bridgeport, Connecticut, United States, 06610
      • Bridgeport Hospital
    • Hartford, Connecticut, United States, 06102
      • Hartford Hospital
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Washington Electrophysiology/Cardiovascular Research Institute
  • Florida
    • Brandon, Florida, United States, 33511
      • Bay Area Cardiology Associates, P.A.
    • Gainesville, Florida, United States, 32610
      • University of Florida/Cardiovascular Medicine
    • Jacksonville, Florida, United States, 32209
      • University of Florida Health Science Center at Jacksonville
    • Lakeland, Florida, United States, 33805
      • Watson Clincia Center for Research Inc.
    • Orlando, Florida, United States, 32803
      • Florida Hospital
    • Tallahassee, Florida, United States, 32308
      • Tallahassee Research Institute, Inc.
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Georgia Health Sciences University
    • Macon, Georgia, United States, 31201
      • Georgia Arrhythmia Consultants
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Hospital
  • Indiana
    • Fort Wayne, Indiana, United States, 46845
      • Peakview Research Center
    • Hobart, Indiana, United States, 46342
      • LaPorte Hospital
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Kentucky
    • Lexington, Kentucky, United States, 40503
      • Central Baptist Hospital
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Louisiana State University Health Sciences Center- New Orleans
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center
    • Clinton, Maryland, United States, 20735
      • MedStar Southern Maryland Hospital Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts-New England Medical Center
    • Burlington, Massachusetts, United States, 01805
      • Lahey Clinic
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts-Worchester
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
    • Royal Oak, Michigan, United States, 48073
      • William Beaumont Hospital - Royal Oak
    • Ypsilanti, Michigan, United States, 48197
      • Michigan Heart
  • Minnesota
    • Duluth, Minnesota, United States, 55805
      • St. Luke's Hospital Association of Duluth
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Missouri
    • Columbia, Missouri, United States, 65212
      • University of Missouri
    • Kansas City, Missouri, United States, 64114
      • Kansas City Heart Foundation
  • New Jersey
    • Camden, New Jersey, United States, 08043
      • Cooper University Hospital
    • Morristown, New Jersey, United States, 07962
      • Morristown Memorial Hospital- Gagnon Cardiovascular Institute
  • New York
    • Brooklyn, New York, United States, 11219
      • Maimonides Medical Center
    • Brooklyn, New York, United States, 11203
      • SUNY downstate Medical Center
    • Brooklyn, New York, United States, 11215
      • New York Methodist Hospital
    • New York, New York, United States, 10021
      • Weill Cornell Medical College/New York Presbyterian Hospital
    • New York, New York, United States, 10025
      • St. Luke's-Roosevelt Hospital
    • Poughkeepsie, New York, United States, 12601
      • Hudson Valley Heart Center
    • Ridgewood, New York, United States, 07450
      • The Valley Hospital
    • Rochester, New York, United States, 14642
      • University of Rochester
    • Stony Brook, New York, United States, 11794
      • Stony Brook University Medical Center,
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Durham, North Carolina, United States, 27705
      • Durham VA Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati
    • Cincinnati, Ohio, United States, 45219
      • The Lindner Center for Research & Education
    • Cleveland, Ohio, United States, 44109
      • The MetroHealth System - Heart and Vascular Dept.
    • Toledo, Ohio, United States, 43615
      • The Toledo Hospital/Northwest Ohio Cardiology Consultants
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
    • Portland, Oregon, United States, 97239
      • Portland VA Medical Ctr
  • Pennsylvania
    • Abington, Pennsylvania, United States, 19001
      • Abington Medical Specialists
    • Doylestown, Pennsylvania, United States, 18901
      • Doylestown Cardiology Associates - VIAA
    • Doylestown, Pennsylvania, United States, 18901
      • Doylestown Health Cardiology/Central Bucks
    • Lancaster, Pennsylvania, United States, 17602
      • Lancaster Heart & Stroke Foundation
    • Philadelphia, Pennsylvania, United States, 19102
      • Drexel University College of Medicine
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center-Presbyterian
    • Pittsburgh, Pennsylvania, United States, 15240
      • VA Pittsburgh Healthcare Center
    • Wynnewood, Pennsylvania, United States, 19096
      • Lankenau Institute for Medical Research
  • Rhode Island
    • Warwick, Rhode Island, United States, 02886
      • Brigham and Women's Cardiovascular Associates
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • The Stern Cardiovascular Center
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Austin, Texas, United States, 78705
      • Texas Cardiac Arrhythmia Research Foundation
    • Dallas, Texas, United States, 75230
      • Cardiopulmonary Research Science and Technology Inst.
    • Houston, Texas, United States, 77090
      • Medicus Alliance CRO, Inc
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Health System
    • Chesapeake, Virginia, United States, 23320
      • Cardiovascular Associates Ltd.
    • Portsmouth, Virginia, United States, 20889
      • Walter Reed NMMC
    • Richmond, Virginia, United States, 23219
      • Virginia Commonwealth University
  • Washington
    • Spokane, Washington, United States, 99204
      • Kootenai Heart Clinics, LLC
    • Tacoma, Washington, United States, 98405
      • Cardiac Study Center
  • West Virginia
    • Charleston, West Virginia, United States, 25304
      • CAMC Institute
  • Wisconsin
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic
    • Milwaukee, Wisconsin, United States, 53215
      • Aurora St. Luke's Medical Center
    • Racine, Wisconsin, United States, 53402
      • Wheaton Franciscan All Saints

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1,440 high-risk patients with ischemic/nonischemic cardiomyopathy who receive their ICDs as standard of care for primary or secondary prevention of mortality following approved indications for ICD therapy. High-risk patients will be defined as:

Secondary Prevention Patients Subjects with ischemic or nonischemic cardiomyopathy, qualified for or with existing ICD (or CRT-D) after documented VT/VF or cardiac arrest (secondary prevention of mortality). Secondary prevention subjects with existing implants are eligible regardless of when the implant was received (subjects could be recruited from outpatient clinics or from inpatient activity including during re-implant or other procedures).

Primary Prevention Patients

1. Patients with primary prevention indications for ischemic or non-ischemic cardiomyopathy with EF≤35%, with existing devices (ICD/CRT-D), regardless of when the device was implanted, who have experienced at least ONE episode of VT/VF appropriately treated with ICD therapy (ATP or shock) or had untreated NSVT lasting at least 10 beats with heart rate of at least 170 bpm, documented by electrogram of their implanted device.

2. Patients with ischemic or non-ischemic cardiomyopathy with EF≤35%, who have been implanted within the last 2 years (initial ICD/CRT-D implants, including upgrades from pacemakers) who have NOT experienced VT/VF treated with ICD therapy (ATP or shock), AND who have one of the following additional criteria: BUN≥26 mg/dl or QRS>120ms or Atrial Fibrillation or NSVT documented by ECG/Holter or >500 Ventricular Premature Beats (VPBs)documented in a 24-hour Holter.

   • Stable optimal pharmacologic therapy for the cardiac condition
   • Age: equal to 21 years without upper limit

Exclusion Criteria:

• Patient receiving first device with coronary artery bypass graft surgery within the last 3 calendar months prior to date consent obtained
• Patients receiving first device with percutaneous coronary intervention within the last 1 calendar month prior to date consent obtained
• Patient receiving first device with enzyme-positive myocardial infarction with the past 3 calendar months prior to date consent obtained
• Patient receiving first device with angiographic evidence of coronary disease who are candidates for coronary revascularization and are likely to undergo coronary artery bypass graft surgery or percutaneous coronary intervention in the foreseeable future
• Patient in NYHA Class IV
• Patients receiving prophylactic ablation of ventricular substrate
• Patients with preexisting QTc prolongation >550ms
• Patients on strong CYP3A inhibitors (including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir and saquinavir and moderate CYP3A inhibitors, including, diltiazem, verapamil, aprepitant, erythromycin, fluconazole and grapefruit juice or grapefruit-containing products.
• Patients on CYP3A inducers such as rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine and St.John's wort
• Patients with inherited arrhythmia disorders such as Brugada's, ARVD, LQTS or hypertrophic cardiomyopathy
• Patient who is pregnant or plans to become pregnant during the course of the trial (patients at child bearing age who use prescribed pharmaceutical contraceptives could be enrolled)
• Patient with irreversible brain damage from preexisting cerebral disease
• Patient with presence of any disease, other than the patient's cardiac disease, associated with a reduced likelihood of survival for the duration of the trial, e.g., cancer, uremia, liver failure, etc.
• Patient with chronic renal disease with creatinine >2.5 mg/dl or creatinine clearance <30 ml/min
• Patient participating in any other clinical trial
• Patient unwilling or unable to cooperate with the protocol
• Patient who lives at such a distance from the clinic that travel for follow-up visits would be unusually difficult
• Patient who does not anticipate being a resident of the area for the scheduled duration of the trial
• Patients who are decisionally impaired adults, those of questionable capacity, and those who cannot consent for themselves will not be recruited for this study.
• Patient unwilling to sign the consent for participation

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ranolazine; At enrollment, patients will be randomized to ranolazine or placebo. In the active drug arm each patient will be started on a 500 mg twice a day dose for one week with subsequent increase to 1000 mg twice a day at end of first week. For patients on anti-arrhythmic therapy at the time of randomization, their ECG will be checked at end of first week on 500 mg dose and again at end of second week on 1000 mg dose. For patients with CrCl <60ml/min prior to randomization, their CrCl will be checked again at 2 weeks and study drug discontinued if <30ml/min. For patients with CrCl <60ml/min at 2 weeks, their CrCl will be checked again at 4 weeks and study drug discontinued if <30ml/min.	Drug: Ranolazine; At enrollment, patients will be randomized to ranolazine or placebo. In the active drug arm each patient will be started on a 500 mg twice a day dose for one week with subsequent increase to 1000 mg twice a day at beginning of second week.; Other Names: Ranexa
Placebo Comparator: Placebo; At enrollment, patients will be randomized to ranolazine or placebo. In the active drug arm each patient will be started on a 500 mg twice a day dose for one week with subsequent increase to 1000 mg twice a day at end of first week. For patients on anti-arrhythmic therapy at the time of randomization, their ECG will be checked at end of first week on 500 mg dose and again at end of second week on 1000 mg dose. For patients with CrCl <60ml/min prior to randomization, their CrCl will be checked again at 2 weeks and study drug discontinued if <30ml/min. For patients with CrCl <60ml/min at 2 weeks, their CrCl will be checked again at 4 weeks and study drug discontinued if <30ml/min.	Drug: Ranolazine; At enrollment, patients will be randomized to ranolazine or placebo. In the active drug arm each patient will be started on a 500 mg twice a day dose for one week with subsequent increase to 1000 mg twice a day at beginning of second week.; Other Names: Ranexa

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Ventricular Tachycardia (VT) or Ventricular Fibrillation (VF) or Death	Primary endpoint of the study will be defined as a composite endpoint consisting of Ventricular Tachycardia or Ventricular Fibrillation requiring antitachycardia pacing (ATP) therapy, implantable cardioverter-defibrillator (ICD) shock, or death, whichever occurs first.	2 years of follow-up on average

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With VT or VF Requiring ICD Shock or Death	Implantable cardioverter-defibrillator (ICD) shock for VT or VF or death, whichever occurs first.	2 years of follow-up on average
Number of Recurrent Episodes of VT or VF Requiring Antitachycardia Pacing (ATP) or ICD Shock Therapies	Total number of recurrent ICD therapies requiring antitachycardia pacing (ATP) or shock will be analyzed, not just first event	2 years of follow-up on average
Number of Patients With First Inappropriate ICD Shock	Number of patients with first inappropriate ICD shock for other reasons than VT or VF	2 years of follow-up on average
Number of Patients With Hospitalization for Cardiac Causes or Death, Whichever Occurred First.	Number of patients with a composite endpoint of cardiovascular hospitalization or death, whichever occurred first.	2 years of follow-up on average
Number of Patients With Heart Failure Hospitalization or Death, Whichever Occurred First	Number of patients with a composite endpoint of heart failure hospitalization or death, whichever occurred first.	2 years of follow-up on average
Death	Death as a safety endpoint of the trial	2 years of follow-up on average
Mean Meters Walked in 6 Minutes	Exercise capacity measured by the 6-minute walk test	1 year of follow-up
Quality of Life Measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ)	The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a new, self-administered, 23-item questionnaire that quantifies physical limitations, symptoms, self-efficacy, social interference and quality of life. The scale ranges from 0-100 with lower scores indicating worse outcomes.	1 year follow-up
Number of Recurrent Inappropriate ICD Shocks	Number of recurrent inappropriate ICD shocks in all patients combined.	2 years of follow-up on average

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients Whose First VT/VF Required Antitachycardia Pacing (ATP)	Number of patients whose first VT or VF required antitachycardia pacing (ATP)	2 years of follow-up on average
Number of Patients Whose First VT/VF Required ICD Shock	number of patients whose first VT or VF required ICD shock	2 years of follow-up on average

Collaborators and Investigators

• Sponsor: University of Rochester
• Investigators: Principal Investigator: Wojciech Zareba, MD PhD, University of Rochester

Publications and helpful links

General Publications

• Younis A, Goldenberg I, Farooq S, Yavin H, Daubert J, Raitt M, Mazur A, Huang DT, Mitchell BL, Rashtian MR, Winters S, Vloka M, Aktas M, Bernabei MA, Beck CA, McNitt S, Zareba W. Reduction in Ventricular Tachyarrhythmia Burden in Patients Enrolled in the RAID Trial. JACC Clin Electrophysiol. 2022 Jun;8(6):754-762. doi: 10.1016/j.jacep.2022.02.018. Epub 2022 Apr 27.
• Zareba W, Daubert JP, Beck CA, Huang DT, Alexis JD, Brown MW, Pyykkonen K, McNitt S, Oakes D, Feng C, Aktas MK, Ayala-Parades F, Baranchuk A, Dubuc M, Haigney M, Mazur A, McPherson CA, Mitchell LB, Natale A, Piccini JP, Raitt M, Rashtian MY, Schuger C, Winters S, Worley SJ, Ziv O, Moss AJ; RAID Trial Investigators. Ranolazine in High-Risk Patients With Implanted Cardioverter-Defibrillators: The RAID Trial. J Am Coll Cardiol. 2018 Aug 7;72(6):636-645. doi: 10.1016/j.jacc.2018.04.086.

Study record dates

Study Major Dates

• Study Start: September 1, 2011
• Primary Completion (Actual): February 28, 2017
• Study Completion (Actual): February 28, 2017

Study Registration Dates

• First Submitted: September 30, 2010
• First Submitted That Met QC Criteria: October 4, 2010
• First Posted (Estimate): October 6, 2010

Study Record Updates

• Last Update Posted (Actual): August 27, 2018
• Last Update Submitted That Met QC Criteria: July 27, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: Heart failure; Ventricular fibrillation; Ventricular tachycardia; Ranolazine; Sudden Death; Implantable cardioverter-defibrillator
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Cardiomyopathies; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Sodium Channel Blockers; Ranolazine
• Other Study ID Numbers: U01HL096607 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: The RAID PI and Steering Committee with investigators from enrolling sites have designed a series of secondary substudies that will be disseminated as abstracts and manuscripts. External proposal of analyses of the RAID trial data will be reviewed bye the Steering Committee and analyses will be conducted by the Data Coordinating Center (DCC) of the trial.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• product manufactured in and exported from the U.S.: No