Heart Rate Response to Regadenoson and Sudden Cardiac Death

The purpose of this study is to determine whether a blunted heart rate response to regadenoson is an independent predictor of sudden cardiac death.

Study Overview

• Status: Completed
• Conditions: Sudden Cardiac Death; Left Ventricular Systolic Dysfunction
• Intervention / Treatment: Drug: regadenoson

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 90
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • UAB

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Regadenoson; 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. Medications (including beta-blockers) will be withheld on the morning of the test. The heart rate and blood pressure will be measured at baseline and every minute after regadenoson bolus for at least 5 minutes and until the heart rate and blood pressure are clearly returning towards baseline. --------------------------------------------------------------------------------

Drug: regadenoson; 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. Medications (including beta-blockers) will be withheld on the morning of the test. The heart rate and blood pressure will be measured at baseline and every minute after regadenoson bolus for at least 5 minutes and until the heart rate and blood pressure are clearly returning towards baseline.; Other Names: Lexiscan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sudden Cardiac Death	Sudden cardiac death will be defined as death within 1 hour of symptom onset, or an unobserved death in which the patient was seen and known to be doing well within 24 hours of death. Survivors of aborted sudden cardiac death, resuscitated cardiac arrest, and those receiving appropriate ICD therapy will also be considered to have experienced sudden cardiac death and will be included in the primary end point.	Until end of follow-up, median follow-up 40 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause Death	death from any cause	Until end of follow-up, median follow-up 40 months
First Appropriate ICD Therapy	antitachycardia pacing therapy or shock for tachyarrhythmia determined by evaluation of the clinical information and by device diagnostics to be either ventricular fibrillation or ventricular tachycardia	Until end of follow-up, median follow-up 40 months
Inappropriate ICD Therapy	unnecessary antitachycardia pacing or shock delivered by the ICD for a rhythm that is not a true ventricular fibrillation or ventricular tachycardia	Until end of follow-up, median follow-up 40 months
All-cause Death or First Appropriate ICD Therapy	death or antitachycardia pacing therapy or shock for tachyarrhythmia determined by evaluation of the clinical information and by device diagnostics to be either ventricular fibrillation or ventricular tachycardia	Until end of follow-up, median follow-up 40 months
Sudden Cardiac Death or Appropriate ICD Therapy	Sudden cardiac death or antitachycardia pacing therapy or shock for tachyarrhythmia determined by evaluation of the clinical information and by device diagnostics to be either ventricular fibrillation or ventricular tachycardia	Until end of follow-up, median follow-up 40 months

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Collaborators: Astellas Scientific & Medical Affairs, Inc.
• Investigators: Principal Investigator: Fadi G Hage, MD, University of Alabama at Birmingham

Publications and helpful links

General Publications

• Hage FG, Heo J, Franks B, Belardinelli L, Blackburn B, Wang W, Iskandrian AE. Differences in heart rate response to adenosine and regadenoson in patients with and without diabetes mellitus. Am Heart J. 2009 Apr;157(4):771-6. doi: 10.1016/j.ahj.2009.01.011. Epub 2009 Mar 6.
• Hage FG, Perry G, Heo J, Iskandrian AE. Blunting of the heart rate response to adenosine and regadenoson in relation to hyperglycemia and the metabolic syndrome. Am J Cardiol. 2010 Mar 15;105(6):839-43. doi: 10.1016/j.amjcard.2009.11.042.
• Hage FG, Dean P, Bhatia V, Iqbal F, Heo J, Iskandrian AE. The prognostic value of the heart rate response to adenosine in relation to diabetes mellitus and chronic kidney disease. Am Heart J. 2011 Aug;162(2):356-62. doi: 10.1016/j.ahj.2011.05.014. Epub 2011 Jul 18.
• Hage FG, Dean P, Iqbal F, Heo J, Iskandrian AE. A blunted heart rate response to regadenoson is an independent prognostic indicator in patients undergoing myocardial perfusion imaging. J Nucl Cardiol. 2011 Dec;18(6):1086-94. doi: 10.1007/s12350-011-9429-1. Epub 2011 Jul 22.
• Iqbal FM, Al Jaroudi W, Sanam K, Sweeney A, Heo J, Iskandrian AE, Hage FG. Reclassification of cardiovascular risk in patients with normal myocardial perfusion imaging using heart rate response to vasodilator stress. Am J Cardiol. 2013 Jan 15;111(2):190-5. doi: 10.1016/j.amjcard.2012.09.013. Epub 2012 Oct 27.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2013
• Primary Completion (Actual): April 1, 2020
• Study Completion (Actual): July 1, 2022

Study Registration Dates

• First Submitted: March 13, 2013
• First Submitted That Met QC Criteria: April 26, 2013
• First Posted (Estimate): April 29, 2013

Study Record Updates

• Last Update Posted (Actual): October 18, 2022
• Last Update Submitted That Met QC Criteria: October 12, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: sudden cardiac death; regadenoson; Implantable cardiac defibrillator; heart rate response
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Death, Sudden; Heart Arrest; Death; Death, Sudden, Cardiac; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Purinergic Agents; Purinergic P1 Receptor Agonists; Purinergic Agonists; Adenosine A2 Receptor Agonists; Regadenoson
• Other Study ID Numbers: REGA 12D05