Ranolazine Implantable Cardioverter-Defibrillator Trial

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.

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