Heart Failure, Ischemic Cardiomyopathy, Nonischemic Cardiomyopathy
Conditions
Keywords
Sudden Death, Ranolazine, Heart failure, Ventricular tachycardia, Ventricular fibrillation, Implantable cardioverter-defibrillator
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.
Interventions
DRUGRanolazine
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.
Sponsors
University of Rochester
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Whose First VT/VF Required Antitachycardia Pacing (ATP) | 2 years of follow-up on average | Number of patients whose first VT or VF required antitachycardia pacing (ATP) |
| Number of Patients Whose First VT/VF Required ICD Shock | 2 years of follow-up on average | number of patients whose first VT or VF required ICD shock |
Countries
Canada, United States
Participant flow
Recruitment details
1012 patients were recruited from 88 centers in the US and 7 centers in Canada
Participants by arm
| Arm | Count |
|---|---|
| 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.
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. | 510 |
| 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 beginning of second week. | 502 |
| Total | 1,012 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 6 | 4 |
| Overall Study | Other | 14 | 12 |
| Overall Study | Physician Decision | 9 | 12 |
| Overall Study | Withdrawal by Subject | 57 | 35 |
Baseline characteristics
| Characteristic | Ranolazine | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 64.3 years STANDARD_DEVIATION 10.3 | 64.3 years STANDARD_DEVIATION 11.1 | 64.2 years STANDARD_DEVIATION 9.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants | 29 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 493 Participants | 983 Participants | 490 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 85 Participants | 170 Participants | 85 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 12 Participants | 14 Participants | 2 Participants |
| Race (NIH/OMB) White | 404 Participants | 814 Participants | 410 Participants |
| Region of Enrollment Canada | 31 Participants | 62 Participants | 31 Participants |
| Region of Enrollment United States | 479 Participants | 950 Participants | 471 Participants |
| Sex: Female, Male Female | 100 Participants | 186 Participants | 86 Participants |
| Sex: Female, Male Male | 410 Participants | 826 Participants | 416 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 70 / 510 | 78 / 502 |
| other Total, other adverse events | 69 / 510 | 17 / 502 |
| serious Total, serious adverse events | 0 / 510 | 0 / 502 |
Outcome results
Primary
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.
Time frame: 2 years of follow-up on average
Population: This outcome measure was an intent-to-treat analysis therefore all randomized subjects were included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ranolazine | Number of Patients With Ventricular Tachycardia (VT) or Ventricular Fibrillation (VF) or Death | 174 Participants |
| Placebo | Number of Patients With Ventricular Tachycardia (VT) or Ventricular Fibrillation (VF) or Death | 198 Participants |
p-value: 0.11795% CI: [0.67, 1.05]Regression, Cox
Secondary
Death
Death as a safety endpoint of the trial
Time frame: 2 years of follow-up on average
Population: This outcome measure was an intent-to-treat analysis therefore all randomized subjects were included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ranolazine | Death | 70 Participants |
| Placebo | Death | 78 Participants |
p-value: 0.87195% CI: [0.69, 1.37]Regression, Cox
Secondary
Mean Meters Walked in 6 Minutes
Exercise capacity measured by the 6-minute walk test
Time frame: 1 year of follow-up
Population: Data was not collected on 86 patients in the placebo arm and 99 patients in the Ranolazine arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranolazine | Mean Meters Walked in 6 Minutes | 314 meters | Standard Deviation 127.5 |
| Placebo | Mean Meters Walked in 6 Minutes | 309 meters | Standard Deviation 123.5 |
p-value: 0.508nonparametric Wilcoxon rank-sum test
Secondary
Number of Patients With First Inappropriate ICD Shock
Number of patients with first inappropriate ICD shock for other reasons than VT or VF
Time frame: 2 years of follow-up on average
Population: This outcome measure was an intent-to-treat analysis therefore all randomized subjects were included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ranolazine | Number of Patients With First Inappropriate ICD Shock | 16 Participants |
| Placebo | Number of Patients With First Inappropriate ICD Shock | 20 Participants |
p-value: 0.39895% CI: [0.38, 1.47]Regression, Cox
Secondary
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.
Time frame: 2 years of follow-up on average
Population: This outcome measure was an intent-to-treat analysis therefore all randomized subjects were included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ranolazine | Number of Patients With Heart Failure Hospitalization or Death, Whichever Occurred First | 144 Participants |
| Placebo | Number of Patients With Heart Failure Hospitalization or Death, Whichever Occurred First | 140 Participants |
p-value: 0.57795% CI: [0.84, 1.37]Regression, Cox
Secondary
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.
Time frame: 2 years of follow-up on average
Population: This outcome measure was an intent-to-treat analysis therefore all randomized subjects were included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ranolazine | Number of Patients With Hospitalization for Cardiac Causes or Death, Whichever Occurred First. | 237 Participants |
| Placebo | Number of Patients With Hospitalization for Cardiac Causes or Death, Whichever Occurred First. | 222 Participants |
p-value: 0.31695% CI: [0.91, 1.34]Regression, Cox
Secondary
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.
Time frame: 2 years of follow-up on average
Population: This outcome measure was an intent-to-treat analysis therefore all randomized subjects were included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ranolazine | Number of Patients With VT or VF Requiring ICD Shock or Death | 131 Participants |
| Placebo | Number of Patients With VT or VF Requiring ICD Shock or Death | 145 Participants |
p-value: 0.89195% CI: [0.76, 1.26]Regression, Cox
Secondary
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
Time frame: 2 years of follow-up on average
Population: This outcome measure was an intent-to-treat analysis therefore all randomized subjects were included.
| Arm | Measure | Value (COUNT_OF_UNITS) |
|---|---|---|
| Ranolazine | Number of Recurrent Episodes of VT or VF Requiring Antitachycardia Pacing (ATP) or ICD Shock Therapies | 433 VT/VF events |
| Placebo | Number of Recurrent Episodes of VT or VF Requiring Antitachycardia Pacing (ATP) or ICD Shock Therapies | 650 VT/VF events |
p-value: 0.02895% CI: [0.51, 0.96]Anderson-Gill analysis
Secondary
Number of Recurrent Inappropriate ICD Shocks
Number of recurrent inappropriate ICD shocks in all patients combined.
Time frame: 2 years of follow-up on average
Population: This outcome measure was an intent-to-treat analysis therefore all randomized subjects were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ranolazine | Number of Recurrent Inappropriate ICD Shocks | 19 events |
| Placebo | Number of Recurrent Inappropriate ICD Shocks | 26 events |
p-value: 0.41495% CI: [0.36, 1.52]Anderdon-Gill analysis
Secondary
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.
Time frame: 1 year follow-up
Population: Data was not collected in 42 patients in the placebo arm and 61 patients in the Ranolazine arm.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranolazine | Quality of Life Measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) | 73.6 units on a scale | Standard Deviation 24.1 |
| Placebo | Quality of Life Measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) | 72.8 units on a scale | Standard Deviation 24.3 |
p-value: 0.948nonparametric Wilcoxon rank-sum test
Other Pre-specified
Number of Patients Whose First VT/VF Required Antitachycardia Pacing (ATP)
Number of patients whose first VT or VF required antitachycardia pacing (ATP)
Time frame: 2 years of follow-up on average
Population: This outcome measure was an intent-to-treat analysis therefore all randomized subjects were included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ranolazine | Number of Patients Whose First VT/VF Required Antitachycardia Pacing (ATP) | 92 Participants |
| Placebo | Number of Patients Whose First VT/VF Required Antitachycardia Pacing (ATP) | 117 Participants |
p-value: 0.03895% CI: [0.55, 0.98]Regression, Cox
Other Pre-specified
Number of Patients Whose First VT/VF Required ICD Shock
number of patients whose first VT or VF required ICD shock
Time frame: 2 years of follow-up on average
Population: This outcome measure was an intent-to-treat analysis therefore all randomized subjects were included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ranolazine | Number of Patients Whose First VT/VF Required ICD Shock | 79 Participants |
| Placebo | Number of Patients Whose First VT/VF Required ICD Shock | 84 Participants |
p-value: 0.94795% CI: [0.73, 1.41]Regression, Cox