Heart Rate Response to Regadenoson and Sudden Cardiac Death

• Sponsor: University of Alabama at Birmingham (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01842035
• Collaborator: Astellas Scientific & Medical Affairs, Inc. (Industry)
• Enrollment: 90
• Location: 1
• Arm: 1
• Anticipated Duration (Months): 111.9
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Left Ventricular Systolic Dysfunction; Sudden Cardiac Death	Drug: regadenoson	N/A

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 Design

• Study Type: Interventional
• Actual Enrollment: 90 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: Heart Rate Response to Regadenoson and Sudden Cardiac Death
• Actual Study Start Date: Feb 1, 2013
• Actual Primary Completion Date: Apr 1, 2020
• Anticipated Study Completion Date: Jun 1, 2022

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Sudden Cardiac Death [Until end of follow-up, median follow-up 40 months]

   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.

Secondary Outcome Measures

1. All-cause Death [Until end of follow-up, median follow-up 40 months]

   death from any cause

2. First Appropriate ICD Therapy [Until end of follow-up, median follow-up 40 months]

   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

3. Inappropriate ICD Therapy [Until end of follow-up, median follow-up 40 months]

   unnecessary antitachycardia pacing or shock delivered by the ICD for a rhythm that is not a true ventricular fibrillation or ventricular tachycardia

4. All-cause Death or First Appropriate ICD Therapy [Until end of follow-up, median follow-up 40 months]

   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

5. Sudden Cardiac Death or Appropriate ICD Therapy [Until end of follow-up, median follow-up 40 months]

   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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UAB	Birmingham	Alabama	United States	35294

Sponsors and Collaborators

• University of Alabama at Birmingham
• Astellas Scientific & Medical Affairs, Inc.

Investigators

• Principal Investigator: Fadi G Hage, MD, University of Alabama at Birmingham

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 14, 2021

More Information

Publications

• 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.
• 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.
• 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.

• Responsible Party: Fadi Hage, MD, MD, University of Alabama at Birmingham
• ClinicalTrials.gov Identifier: NCT01842035
• Other Study ID Numbers: REGA 12D05
• First Posted: Apr 29, 2013
• Last Update Posted: Apr 4, 2022
• Last Verified: Mar 1, 2022

• Keywords provided by Fadi Hage, MD, MD, University of Alabama at Birmingham: Implantable cardiac defibrillator; regadenoson; sudden cardiac death; heart rate response
• Additional relevant MeSH terms: Death, Sudden, Cardiac; Death; Regadenoson

Study Results

Participant Flow

Arm/Group Title	Regadenoson
Arm/Group Description	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. -------------------------------------------------------------------------------- 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.
Period Title: Overall Study
STARTED	90
COMPLETED	90
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Regadenoson
Arm/Group Description	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. -------------------------------------------------------------------------------- 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.
Overall Participants	90
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60 (14)
Sex: Female, Male (Count of Participants)
Female	36 40%
Male	54 60%
Race/Ethnicity, Customized (Count of Participants)
Black	36 40%
White	54 60%
Region of Enrollment (participants) [Number]
United States	90 100%

Outcome Measures

1. Primary Outcome

Title	Sudden Cardiac Death
Description	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.
Time Frame	Until end of follow-up, median follow-up 40 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Heart Rate Response Greater Than Median	Heart Rate Response Less Than Median
Arm/Group Description	Heart rate response >= 24%	Heart rate response < 24%
Measure Participants	44	46
Count of Participants [Participants]	2 2.2%	6 NaN

2. Secondary Outcome

Title	All-cause Death
Description	death from any cause
Time Frame	Until end of follow-up, median follow-up 40 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Heart Rate Response Greater Than Median	Heart Rate Response Less Than Median
Arm/Group Description	Heart rate response >= 24%	Heart rate response < 24%
Measure Participants	44	46
Count of Participants [Participants]	8 8.9%	8 NaN

3. Secondary Outcome

Title	First Appropriate ICD Therapy
Description	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
Time Frame	Until end of follow-up, median follow-up 40 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Heart Rate Response Greater Than Median	Heart Rate Response Less Than Median
Arm/Group Description	Heart rate response >= 24%	Heart rate response < 24%
Measure Participants	44	46
Count of Participants [Participants]	6 6.7%	12 NaN

4. Secondary Outcome

Title	Inappropriate ICD Therapy
Description	unnecessary antitachycardia pacing or shock delivered by the ICD for a rhythm that is not a true ventricular fibrillation or ventricular tachycardia
Time Frame	Until end of follow-up, median follow-up 40 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Heart Rate Response Greater Than Median	Heart Rate Response Less Than Median
Arm/Group Description	Heart rate response >= 24%	Heart rate response < 24%
Measure Participants	44	46
Count of Participants [Participants]	3 3.3%	2 NaN

5. Secondary Outcome

Title	All-cause Death or First Appropriate ICD Therapy
Description	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
Time Frame	Until end of follow-up, median follow-up 40 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Heart Rate Response Greater Than Median	Heart Rate Response Less Than Median
Arm/Group Description	Heart rate response >= 24%	Heart rate response < 24%
Measure Participants	44	46
Count of Participants [Participants]	13 14.4%	16 NaN

6. Secondary Outcome

Title	Sudden Cardiac Death or Appropriate ICD Therapy
Description	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
Time Frame	Until end of follow-up, median follow-up 40 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Heart Rate Response Greater Than Median	Heart Rate Response Less Than Median
Arm/Group Description	Heart rate response >= 24%	Heart rate response < 24%
Measure Participants	44	46
Count of Participants [Participants]	8 8.9%	15 NaN

Adverse Events

Time Frame	Adverse Events were monitored for 1 day and deaths were monitored until end of follow-up, median of 40 months
Adverse Event Reporting Description	Adverse events were monitored for 1 day while outcomes were monitored until end of follow-up.
Arm/Group Title	Regadenoson
Arm/Group Description	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. -------------------------------------------------------------------------------- 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.
All Cause Mortality
	Regadenoson
	Affected / at Risk (%)	# Events
Total	16/90 (17.8%)
Serious Adverse Events
	Regadenoson
	Affected / at Risk (%)	# Events
Total	0/90 (0%)
Other (Not Including Serious) Adverse Events
	Regadenoson
	Affected / at Risk (%)	# Events
Total	24/90 (26.7%)
Cardiac disorders
chest pain	1/90 (1.1%)
Ventricular tachycardia	0/90 (0%)	0
Gastrointestinal disorders
Gastrointestinal symptoms	9/90 (10%)	9
Respiratory, thoracic and mediastinal disorders
bronchospasm	0/90 (0%)	0
shortness of breath	14/90 (15.6%)	14
Skin and subcutaneous tissue disorders
flushing	11/90 (12.2%)	11
Vascular disorders
symptomatic hypotension	0/90 (0%)	0

Limitations/Caveats

The lower than planned sample size decreased the power of the study. To partially compensate, we allowed for longer than planned follow-up.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.