Ranolazine Implantable Cardioverter-Defibrillator Trial
- Conditions
- Ischemic CardiomyopathyNonischemic CardiomyopathyHeart Failure
- Interventions
- Registration Number
- NCT01215253
- Lead Sponsor
- University of Rochester
- Brief Summary
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.
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 1012
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
-
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.
-
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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Ranolazine 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. Placebo 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.
- Primary Outcome Measures
Name Time Method Number of Patients With Ventricular Tachycardia (VT) or Ventricular Fibrillation (VF) or Death 2 years of follow-up on average 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.
- Secondary Outcome Measures
Name Time Method Number of Patients With VT or VF Requiring ICD Shock or Death 2 years of follow-up on average Implantable cardioverter-defibrillator (ICD) shock for VT or VF or death, whichever occurs first.
Number of Recurrent Episodes of VT or VF Requiring Antitachycardia Pacing (ATP) or ICD Shock Therapies 2 years of follow-up on average Total number of recurrent ICD therapies requiring antitachycardia pacing (ATP) or shock will be analyzed, not just first event
Number of Patients With First Inappropriate ICD Shock 2 years of follow-up on average Number of patients with first inappropriate ICD shock for other reasons than VT or VF
Number of Patients With Hospitalization for Cardiac Causes or Death, Whichever Occurred First. 2 years of follow-up on average Number of patients with a composite endpoint of cardiovascular hospitalization or death, whichever occurred first.
Number of Patients With Heart Failure Hospitalization or Death, Whichever Occurred First 2 years of follow-up on average Number of patients with a composite endpoint of heart failure hospitalization or death, whichever occurred first.
Death 2 years of follow-up on average Death as a safety endpoint of the trial
Mean Meters Walked in 6 Minutes 1 year of follow-up Exercise capacity measured by the 6-minute walk test
Quality of Life Measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) 1 year follow-up 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.
Number of Recurrent Inappropriate ICD Shocks 2 years of follow-up on average Number of recurrent inappropriate ICD shocks in all patients combined.
Trial Locations
- Locations (90)
University of Arizona
🇺🇸Tucson, Arizona, United States
Hartford Hospital
🇺🇸Hartford, Connecticut, United States
University of Mississippi Medical Center
🇺🇸Jackson, Mississippi, United States
Cooper University Hospital
🇺🇸Camden, New Jersey, United States
Texas Cardiac Arrhythmia Research Foundation
🇺🇸Austin, Texas, United States
Bridgeport Hospital
🇺🇸Bridgeport, Connecticut, United States
Johns Hopkins University
🇺🇸Baltimore, Maryland, United States
Lahey Clinic
🇺🇸Burlington, Massachusetts, United States
Drexel University College of Medicine
🇺🇸Philadelphia, Pennsylvania, United States
Cardiopulmonary Research Science and Technology Inst.
🇺🇸Dallas, Texas, United States
CAMC Institute
🇺🇸Charleston, West Virginia, United States
University of Minnesota
🇺🇸Minneapolis, Minnesota, United States
Good Samaritan Hospital
🇺🇸Los Angeles, California, United States
Huntington Memorial Hospital
🇺🇸Pasadena, California, United States
Arkansas Cardiology
🇺🇸Little Rock, Arkansas, United States
Delta Heart and Medical Clinic
🇺🇸Stockton, California, United States
Georgia Arrhythmia Consultants
🇺🇸Macon, Georgia, United States
University of Iowa
🇺🇸Iowa City, Iowa, United States
University of Maryland Medical Center
🇺🇸Baltimore, Maryland, United States
Henry Ford Hospital
🇺🇸Detroit, Michigan, United States
Michigan Heart
🇺🇸Ypsilanti, Michigan, United States
William Beaumont Hospital - Royal Oak
🇺🇸Royal Oak, Michigan, United States
St. Luke's Hospital Association of Duluth
🇺🇸Duluth, Minnesota, United States
Morristown Memorial Hospital- Gagnon Cardiovascular Institute
🇺🇸Morristown, New Jersey, United States
SUNY Downstate Medical Center
🇺🇸Brooklyn, New York, United States
Weill Cornell Medical College/New York Presbyterian Hospital
🇺🇸New York, New York, United States
Durham VA Medical Center
🇺🇸Durham, North Carolina, United States
The Valley Hospital
🇺🇸Ridgewood, New York, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
The Toledo Hospital/Northwest Ohio Cardiology Consultants
🇺🇸Toledo, Ohio, United States
The MetroHealth System - Heart and Vascular Dept.
🇺🇸Cleveland, Ohio, United States
Oregon Health & Science University
🇺🇸Portland, Oregon, United States
Lancaster Heart & Stroke Foundation
🇺🇸Lancaster, Pennsylvania, United States
The Stern Cardiovascular Center
🇺🇸Germantown, Tennessee, United States
Lankenau Institute for Medical Research
🇺🇸Wynnewood, Pennsylvania, United States
Abington Medical Specialists
🇺🇸Abington, Pennsylvania, United States
University of Virginia Health System
🇺🇸Charlottesville, Virginia, United States
Kootenai Heart Clinics, LLC
🇺🇸Spokane, Washington, United States
Walter Reed NMMC
🇺🇸Portsmouth, Virginia, United States
Cardiac Study Center
🇺🇸Tacoma, Washington, United States
Cardiovascular Associates Ltd.
🇺🇸Chesapeake, Virginia, United States
McGill University Health Centre
🇨🇦Montreal, Quebec, Canada
Montreal Heart Institute
🇨🇦Montreal, Quebec, Canada
CHUS (Sherbrooke University)
🇨🇦Sherbrooke, Quebec, Canada
New York Methodist Hospital
🇺🇸Brooklyn, New York, United States
St. Luke's-Roosevelt Hospital
🇺🇸New York, New York, United States
Hudson Valley Heart Center
🇺🇸Poughkeepsie, New York, United States
Sequoia Hospital
🇺🇸East Palo Alto, California, United States
University of Florida Health Science Center at Jacksonville
🇺🇸Jacksonville, Florida, United States
University of Colorado Health - MHS
🇺🇸Colorado Springs, Colorado, United States
Bay Area Cardiology Associates, P.A.
🇺🇸Brandon, Florida, United States
University of Florida/Cardiovascular Medicine
🇺🇸Gainesville, Florida, United States
MedStar Southern Maryland Hospital Center
🇺🇸Clinton, Maryland, United States
Washington Electrophysiology/Cardiovascular Research Institute
🇺🇸Washington, District of Columbia, United States
University of Chicago Hospital
🇺🇸Chicago, Illinois, United States
Peakview Research Center
🇺🇸Fort Wayne, Indiana, United States
Georgia Health Sciences University
🇺🇸Augusta, Georgia, United States
Tufts-New England Medical Center
🇺🇸Boston, Massachusetts, United States
Central Baptist Hospital
🇺🇸Lexington, Kentucky, United States
Louisiana State University Health Sciences Center- New Orleans
🇺🇸New Orleans, Louisiana, United States
University of Massachusetts-Worchester
🇺🇸Worcester, Massachusetts, United States
Doylestown Health Cardiology/Central Bucks
🇺🇸Doylestown, Pennsylvania, United States
VA Pittsburgh Healthcare Center
🇺🇸Pittsburgh, Pennsylvania, United States
Doylestown Cardiology Associates - VIAA
🇺🇸Doylestown, Pennsylvania, United States
University of Rochester
🇺🇸Rochester, New York, United States
Portland VA Medical Ctr
🇺🇸Portland, Oregon, United States
University of Missouri
🇺🇸Columbia, Missouri, United States
Kansas City Heart Foundation
🇺🇸Kansas City, Missouri, United States
The Lindner Center for Research & Education
🇺🇸Cincinnati, Ohio, United States
University of Cincinnati
🇺🇸Cincinnati, Ohio, United States
Stony Brook University Medical Center,
🇺🇸Stony Brook, New York, United States
Brigham and Women's Cardiovascular Associates
🇺🇸Warwick, Rhode Island, United States
University of Pittsburgh Medical Center-Presbyterian
🇺🇸Pittsburgh, Pennsylvania, United States
Vanderbilt University Medical Center
🇺🇸Nashville, Tennessee, United States
Medicus Alliance CRO, Inc
🇺🇸Houston, Texas, United States
University of Calgary
🇨🇦Calgary, Alberta, Canada
Virginia Commonwealth University
🇺🇸Richmond, Virginia, United States
Marshfield Clinic
🇺🇸Marshfield, Wisconsin, United States
Royal Alexandra Hospital
🇨🇦Edmonton, Alberta, Canada
Wheaton Franciscan All Saints
🇺🇸Racine, Wisconsin, United States
Queen's University
🇨🇦Kingston, Ontario, Canada
IUCPQ
🇨🇦Quebec, Canada
Florida Hospital
🇺🇸Orlando, Florida, United States
Watson Clincia Center for Research Inc.
🇺🇸Lakeland, Florida, United States
Tallahassee Research Institute, Inc.
🇺🇸Tallahassee, Florida, United States
LaPorte Hospital
🇺🇸Hobart, Indiana, United States
Maimonides Medical Center
🇺🇸Brooklyn, New York, United States
Regional Cardiology Associates
🇺🇸Sacramento, California, United States
Aurora St. Luke's Medical Center
🇺🇸Milwaukee, Wisconsin, United States
Thomas Jefferson University
🇺🇸Philadelphia, Pennsylvania, United States