Clinical trial NCT01842035
Conditions: Left Ventricular Systolic Dysfunction Sudden Cardiac Death
Keywords: Implantable cardiac defibrillator regadenoson sudden cardiac death heart rate response
Sponsor: University of Alabama at Birmingham
Start date: 2013-02-01; Completion date: 2022-07-01
Enrollment: 90 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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.

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.

Arms: arm 1: 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.

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Interventions: intervention 1: regadenoson
Intervention descriptions: intervention 1: 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.

Protocol documents:
Prot_SAP_000.pdf: 
Heart Rate Response to Regadenoson and Sudden Cardiac Death 
 
 
Study Protocol & Statistical Analysis Plan 
 
 
NCT01842035 
 
 
January 14, 2021 
 
 
Fadi G Hage, MD Principal Investigator 
University of Alabama at Birmingham 
Birmingham, AL 35294 
 


Heart rate response to regadenoson and sudden cardiac death 
 
Objectives: 
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 
implanted cardiac defibrillator (ICD) on top of traditionally used indicators. 
 
Hypotheses: 
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. 
 
Background: 
In patients with left ventricular systolic dysfunction and in those with a history of sudden cardiac 
death, an ICD reduces mortality.1-3 However, not all patients with an ICD receive appropriate 
therapy from it (In a large study, only one third of patients received appropriate therapy from an 
ICD over the first 3 years of follow-up)4, and inappropriate ICD shocks are common and are 
associated with worse quality of life and increased mortality.5 Furthermore, ICDs are expensive 
(the procedure costs ~$35,000) and place a toll on the health care system. Establishing a better 
predictor of risk of sudden cardiac death and of response to ICD is desirable. 
Adenosine and regadenoson are routinely used as pharmacological stress agents to induce 
coronary hyperemia for myocardial perfusion imaging (MPI) in lieu of exercise. The increase in 
heart rate seen during adenosine infusion has previously been attributed to its vasodilatory effect 
on the systemic circulation and has thus generated little interest. Recently, it was recognized that 
this rise in heart rate is related to a direct stimulation of the sympathetic nervous system by 
adenosine therefore allowing for a novel simple method for the evaluation of autonomic function.6 
Using data from the ADenoscan Versus RegAdenosoN Comparative Evaluation for Myocardial 
Perfusion Imaging (ADVANCE MPI 1 and 2) Trials, we demonstrated that patients with diabetes 
mellitus have a blunted heart rate response to adenosine presumably due to cardiac autonomic 
dysfunction.7 Furthermore, the heart rate response associated with multiple risk factors of sudden 
cardiac death.7, 8 Since cardiac autonomic dysfunction has been linked to increased 


cardiovascular risk,9 we postulated that the heart rate response may carry useful prognostic 
information. Recently we showed that a blunted heart rate response to adenosine is associated 
with increased mortality in the overall population and that it assisted in the risk stratification of 
patients at high risk (such as those with diabetes mellitus or chronic kidney disease) when added 
to traditional MPI findings.10 In a Cox regression model, a blunted heart rate response was the 
strongest predictor of mortality and provided additional prognostic data to MPI after controlling for 
age, gender, race, history of myocardial infarction, diabetes mellitus, chronic kidney disease and 
beta-blocker use. We also demonstrated that a decreasing heart rate response to regadenoson 
is associated with stepwise increase in mortality.11 In a Cox proportional model for mortality that 
adjusted for age, gender, diabetes mellitus, renal disease and MPI findings, heart rate response 
to regadenoson in the lowest quartile was independently associated with 5-fold increase in 
mortality compared to the highest quartile. Patients with a normal heart rate response had a 
relatively low annualized total mortality despite the presence of risk factors. 
We propose that patients with a blunted heart rate response to regadenoson have an altered 
autonomic nervous system (cardiac autonomic neuropathy) that places them at higher risk of 
sudden cardiac death. Using this novel and easily measured parameter, we will be able to select 
patients who are high risk and will benefit from an ICD and, at the same time, identify patients 
who are at low risk of experiencing sudden cardiac death despite satisfying current criteria for 
having an ICD (mainly a low left ventricular ejection fraction). In this proposal, we will be able to 
verify this using a highly selected population that is being continuously monitored for the 
occurrence of ventricular arrhythmias through their implanted devices. 
 
Study Design: Prospective Observational 
 
Population: 
A total of 150 patients (18-80 years) with an indication for ICD implantation for primary 
prevention of sudden cardiac death as defined in the current American College of 
Cardiology/American Heart Association/Heart Rhythm Society Practice Guidelines.12 
Specifically we will recruit: 
1. Patients with left ventricular ejection fraction (LVEF) 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. 
2. Patients with nonischemic dilated cardiomyopathy who have an LVEF less 
than or equal to 35% and who are in NYHA functional Class II or III. 
3. Patients with LV dysfunction due to prior myocardial infarction who are at least 
40 days post--myocardial infarction, have an LVEF less than 30%, and are in 
NYHA functional Class I. 
 
Protocol 


1. 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. The peak heart rate will be defined as the maximum achieved heart rate after 
regadenoson injection. The peak blood pressure will be defined as the blood pressure 
when the systolic component is at a minimum during the test. The heart rate and blood 
pressure response will be calculated for each patient as the maximum percent change 
from baseline.7, 8 A heart rate response in the lowest tertile will be defined as blunted. A 
heart rate response in the highest tertile will be defined as normal.  Secondary analyses 
will be performed with the heart rate response as a continuous variable and using the 
following cut-offs, <20% (blunted), ≥40% (normal).10, 11   
2. An ICD will be placed for clinical indications using standard techniques. 
 
Follow-up: 2-years from the time of ICD implantation. 
 
Duration of study: 4 years 
 
Endpoints:  
1. Primary Endpoint: Sudden cardiac death 
2. Secondary Endpoints 
a. All-cause death 
b. First appropriate ICD therapy 
c. All-cause death or first appropriate ICD therapy 
d. Inappropriate ICD therapy 
 
Patients will be followed up at 6 months intervals with ICD interrogation. ICD therapy (shocks or 
anti-tachycardia pacing) will be determined as appropriate or inappropriate by an experienced 
clinical electrophysiologist (H.D.) after review of the intra-cardiac electrograms. If patient fails to 
show up at their scheduled appointment, patients or their designated relatives will be contacted 
to verify their status. In case of death, relatives will verify circumstances of death. 
SCD will be strictly 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 SCD, resuscitated cardiac arrest, and those receiving appropriate ICD therapy will also 
be considered to have experienced SCD and will be included in the primary end point.13, 14 
 


Sample Size: 
In a recent study from our group, patients with ICD implanted for primary prevention at our center 
experienced an event rate of death or first appropriate ICD therapy ~ 20% over first 2 years.15 In 
our recent study on the heart rate response to regadenoson, patients in the lowest heart response 
tertile experienced a 4-fold increased risk of death compared to those in the highest tertile.11 We 
believe that is a conservative estimate of risk for this study since the heart rate response should 
be a better predictor of sudden cardiac death than overall mortality. A sample size of 126 patients 
will provide a 90% power to detect a 4-fold increase in risk of the primary outcome for patients in 
the lowest compared to the highest tertile of the heart rate response to regadenoson (40% vs. 
10% over 2 years) at a preset P value of 0.05. We plan for a sample size of 150 to account for 
any dropouts and or loss of follow-up. 
 
Statistical Plan: 
All statistical analyses will be carried out using SPSS version 17 for Windows (SPSS Inc., 
Chicago, Illinois). We will collect data on patient demographics (age, gender, race, education), 
patient characteristics (height, weight), co-morbidities (history of myocardial infarction, diabetes 
mellitys, hypertension, dyslipidemia, atrial fibrillation, stroke), prior cardiovascular procedures 
(percutaneous coronary intervention or coronary artery bypass grafting), habits (tobacco use), 
symptoms (NYHA classification), medication intake (aspirin, beta-blocker, calcium channel 
blocker, angiotensin converting enzyme inhibitor (ACE-I), angiotensin receptor blocker (ARB), 
aldosterone antagonist, loop diuretic, statin, insulin), electrocardiographic characteristics (left 
bundle branch block, right bundle branch block, QRS, QT, PR) and laboratory results (serum 
creatinine, electrolytes, brain natriuretic peptide). 
The population will be divided into 3 groups with 50 patients in each group based on tertiles of 
the heart rate response on regadenoson. Continuous variables will be presented as mean ± SD 
and discrete variables as frequencies and percentages. The chi-square test or an analysis of 
variance (ANOVA) will be used for the comparison of categorical variables. Continuous variables 
will be compared using the unpaired student t test or the Mann-Whitney U test, as appropriate. In 
order to determine the predictors of the HRR to regadenoson, a linear regression model will be 
constructed with the HRR as the dependent variable and all the characteristics that are associated 
with the HRR (p<0.2) as dependent variables. An estimation of the effect of each of the variables 
on the HRR will be determined based on the coefficient of the variable in the regression equation. 
Follow-up time will be calculated from the time of evaluation to sudden cardiac death or to end of 
follow-up censored at 2 years from time of evaluation. Event-free survival curves will be 
constructed using the product-limit method (Kaplan-Meier) and differences among survival curves 
will be estimated by the log-rank test. Cox proportional hazard analysis will be used to estimate 
unadjusted and age, gender and LVEF adjusted (multivariate) risks for sudden cardiac death. We 
will introduce interaction terms to test for interaction between HRR and the different variables in 
the model. Estimated risks will be reported as hazard ratios (HR) with correspondent 95% 
confidence intervals (CI). All tests will be 2-tailed, and a p value of <0.05 will be considered 
statistically significant. 


 
Amendments 
During the conduction of the trial, the following amendment were introducted: 
1. The original protocol enrolled patients with a clinical indication for an implanted cardiac 
defibrillator (ICD) for primary prevention of sudden cardiac death. We amended the 
protocol to enroll patients who are undergoing an ICD implantation or a generator 
exchange for clinical indications.  
2. The original protocol enrolled patients prior to implantation of a clinically indicated ICD. 
We amended the protocol to include patients with an implanted ICD for primary prevention 
of sudden cardiac death who are undergoing a clinically indicated regadenoson MPI. We 
have extensive data from our laboratory showing that the heart rate response to 
regadenoson at the time of clinically indicated MPI has important prognostic implications.7, 
11, 16-19   
3. Shorten the duration of follow-up and sample size. The original protocol allows for 2 years 
of follow-up from the time of ICD implantation.  We modified this to follow-up from time of 
regadenoson MPI to end of study.  
 
 


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