Heart Rate Response to Regadenoson and Sudden Cardiac Death

In patients with heart failure and in those with a history of sudden cardiac death, an
Implantable Cardiac Defibrillator (ICD) reduces death rates. However, not all patients with
an ICD receive appropriate therapy from it. Inappropriate ICD shocks are common and are
associated with worse quality of life and increased death rate. We hope to establish a better
predictor of risk of sudden cardiac death and of response to ICD. We are conducting a
prospective observational study of 150 patients (18-80 years) with an indication for ICD
implantation for primary prevention of sudden cardiac death. Prior to the implantation of a
clinically indicated ICD, the heart rate response to regadenoson will be assessed.
Regadenoson will be administered intravenously as a fixed intravenous bolus dose of 400 μg
followed by a 5 mL saline flush.

The main objectives of this proposal are to investigate whether:

1. A blunted heart rate response to regadenoson is an independent predictor of sudden
cardiac death.

2. A blunted heart rate response to regadenoson can be used as a predictor of response to
ICD on top of traditionally used indicators.

We Hypothesize that:

1. Patients with a blunted heart rate response to regadenoson are at higher risk of sudden
cardiac death (death or appropriate cardiac defibrillation). This risk is maintained
after controlling for age, gender, left ventricular ejection fraction, heart failure
symptoms and medication use.

2. Patients with a normal heart rate response to regadenoson have a low rate of events
(death or appropriate cardiac defibrillation) despite meeting current indications for
having an ICD.

Inclusion criteria:

- Age 19-80 years

- Female subjects must be (a) at least one year post-menopause or surgically sterile or
(b) be non-pregnant and (c) non-lactating.

- Subject must be able and willing to provide written informed consent

- Subject must be referred for a clinically indicated ICD and fall into one of the
following groups:

- subjects with left ventricular ejection fraction less than 35% due to prior
myocardial infarction who are at least 40 days post-myocardial infarction and are
in NYHA functional Class II or III.

- subjects with non-ischemic dilated cardiomyopathy who have a left ventricular
ejection fraction less than or equal to 35% and who are in NYHA functional Class
II or III.

- Subjects with left ventricular dysfunction due to prior myocardial infarction who
are at least 40 days post-myocardial infarction, have a left ventricular ejection
fraction less than 30%, and are in NYHA functional Class I.

Exclusion Criteria:

- Female subject who is pregnant or lactating

- Subject with active severe asthma or chronic obstructive pulmonary disease which, in
the Investigator's opinion, places the subject at risk for severe bronchoconstriction

- Treatment with dipyridamole, theophylline, aminophylline or pentoxifylline within 24
hours of receiving regadenoson

- Treatment with any investigational drug within 30 days or 5 half lives - whichever is
longer prior to study entry

- Subject with any prior allergic response to aminophylline or other contraindication to
receiving intravenous regadenoson

- Subjects with second or third degree atrioventricular block or dependent on pacemaker

- Subject with uncontrolled severe hypertension (systolic > 200 mmHg or diastolic >120
mmHg) or pretreatment hypotension (systolic BP <90 mmHg)

- Subject with hemodynamically significant aortic stenosis or outflow tract obstruction

- Subject with decompensated heart failure (NYHA functional class IV)

- Subject with acute myocardial infarction, new onset of ischemia, percutaneous coronary
intervention, or coronary artery bypass grafting within 30 days of receiving
regadenoson

- Subject is on dialysis for end stage renal disease or has an estimated glomerular
filtration rate < 15 mL/min

- Subjects with cardiac transplantation