Effect of Ranolazine on Arrhythmias and Microvolt T- Wave Alternans (MVTWA) Patients With LV Dysfunction

The device clinic of Aspirus Wausau Hospital follows approximately 2800 patients with
pacemakers and automatic implantable cardioverter defibrillators (AICD). Approximately 300
of these patients have had an AICD inserted for primary or secondary arrhythmia prevention.
From these 300 patients, approximately 20 patients who have an AICD implanted either
prophylactically or for an established malignant arrhythmia will be recruited for this short
study.

This is a study to investigate the effect of ranolazine on arrhythmias detected by their
device to see if it will reduce abnormal beats. It will also study whether ranolazine will
impact microvolt t-wave alternans (MVTWA), a measure of the tendency to have a serious
arrhythmia. Approximately 10 patients with ischemic cardiomyopathy and 10 patients with a
non-ischemic cardiomyopathy will be chosen. All will have an ejection fraction of 40% or
less. Prior to institution of ranolazine, a MVTWA study will be performed (Cambridge Heart
Inc.®). The AICD will be used to generate the increase in the heart rate needed to induce
MVTWA. Each patient will have MVTWA assessed at 80 beats/minute and then again at 110
beats/minute. To eliminate interpretation bias, the auto interpretation feature of the MVTWA
device will be used to determine whether the study is positive (MVTWA present) or negative
(MVTWA absent) or indeterminate. In the coarse of this study, each patient will undergo a
total of 3 MVTWA studies in an identical manner using the AICD to provide the needed changes
in heart rate.

After informed consent is obtained the patient will begin a 10-day "ranolazine run in". Each
randomized participant will be given a 10-day supply of ranolazine to make certain they
tolerate the medication (constipation is by far the most common limiting side effect). Each
participant will be started on 500 mg BID and after 3 days increased to 1000 mg BID.
Participants able to tolerate at least 500 mg BID will then be considered eligible to
participate in the study and randomly assigned to either ranolazine at 1000 mg BID (or 500
mg BID if the 1000 mg dose was not tolerated) or a comparable placebo for the next 4 weeks.

At least 3 days after the run in and prior to randomization, each patient will be brought in
for or the baseline MVTWA and the device clinic will purge the AICD of data and reset the
data counter. The patient will then immediately begin either placebo or ranolazine
according to randomization. After 4 weeks, the MVTWA study will be repeated on either
placebo or ranolazine and the arrhythmia data down loaded from the AICD, recorded and the
arrhythmia counters and device operation counter again reset. Each patient will then cross
over to the other therapy (ranolazine or placebo) for the next 4 weeks and the device
interrogated and the MVTWA study repeated in an identical manner.