Regadenoson myocardial perfusion imaging

Regadenoson
Myocardial Perfusion Imaging
George Angelidis, MD
Department of Nuclear Medicine, Army Share Fund Hospital (417 NIMTS)

Myocardial Perfusion Imaging
Cardiovascular disease is the main cause of death in most European countries, representing half of all
deaths
Approximately 3 million people in the EU are discharged from hospitals with CAD
MPI is a non-invasive procedure that determines the functional consequence of an obstruction
resulting from CAD
SPECT MPI facilitates diagnosis of CAD, assesses the risk of future cardiac events and guides clinical
decisions regarding medical treatment, re-vascularization or urgent intervention
Pharmacological stress SPECT MPI (adenosine, dipyridamole, dobutamine) is an established method
of non-invasive cardiac imaging in patients who cannot exercise adequately
Regadenoson developed specifically to improve upon the existing agents:
1. Simplifying the pharmacological stress dose and administration
2. Improving tolerability
3. Avoiding activation of receptors that cause PR prolongation or are believed to cause a
bronchoconstrictive response in patients with asthma or COPD
Regadenoson was licensed in the United States in 2008
European Union in 2010
Ο Ρόλος της Πυρηνικής Ιατρικής στον Χειρισμό του Καρδιολογικού Ασθενή : Ρεγαδενοσόνη

Regadenoson: A2A Adenosine Receptor Agonist
Low affinity for the A2A adenosine receptors (Ki ≈1.3μM)
Coronary vasodilation => increased coronary blood flow
At least 10-fold lower affinity for the A1 adenosine receptors
Weaker (if any) affinity for the A2B and A3 adenosine receptors
Relatively higher density of
highly responsive A2A adenosine
receptors in the coronary arteries
(receptor reserve)
Activation of only a fraction of
receptors is needed to achieve
maximal coronary vasodilation

Regadenoson: Indications & Usage
Pharmacologic stress agent indicated for radionuclide myocardial perfusion imaging in patients unable
to undergo adequate exercise stress
Recommended Dose: 0.4 mg (5 mL, 0.08 mg/mL) administered as an IV injection within 10 sec
Peripheral vein
5 mL saline flush immediately after regadenoson administration
Radiotracer administration 10-20 sec after saline flush
Regadenoson Administration

Regadenoson Myocardial Perfusion Imaging
Myocardial uptake of the radiotracer is proportional to
coronary blood flow
Regadenoson increases blood flow in normal coronary
arteries with little or no increase in stenotic arteries, and
causes relatively less uptake of the radiotracer in vascular
territories supplied by stenotic arteries
Myocardial radiopharmaceutical uptake after regadenoson
administration is therefore greater in areas perfused by
normal relative to stenosed arteries

Regadenoson: Pharmacodynamics
Rapid increase in CBF which is sustained for a short duration
In clinical studies, the majority of patients had an increase in HR and a decrease in BP within 45 min
after regadenoson administration
The majority of patients experience a rapid increase in HR, the greatest mean change from baseline
(21 bpm) occurs approximately 1 minute after administration
HR returns to baseline within 10 minutes
SBP and DSB changes were variable, with the greatest mean change in SBP of −3 mmHg and in DBP
of −4 mmHg, approximately 1 minute after administration
An increase in blood pressure has been observed in some patients
Patients should remain sitting or lying down and be monitored at frequent intervals after the injection
until the ECG parameters, HR and BP have returned to pre-dose level
Hemodynamic effects after inadequate exercise stress
The changes were not associated with any clinically significant adverse reactions
A2B and A3 adenosine receptors may be implicated in the pathophysiology of bronchoconstriction in
susceptible individuals (i.e. asthma)
However, in in vitro studies, regadenoson has not been shown to hove appreciable binding affinity for
the A2B and A3 adenosine receptors

Lieu HD, et al. Rapiscan, a selective A2A adenosine receptor agonist causes dose-dependent
increases in coronary blood flow velocity in humans. J Nucl Cardiol (2007)

Iskandrian AE, et al. Adenosine versus Rapiscan comparative evaluation in myocardial perfusion
imaging: results of the ADVANCE phase 3 multicenter international trial. J Nucl Cardiol (2007)

Regadenoson: Pharmacokinetics
Absorption
Multi-exponential regadenoson plasma concentration – time profile, 3-compartmental model:
Initial phase: maximal plasma concentration is achieved within 1-4 min after injection and
parallels the onset of the pharmacodynamic response (half-life about 2-4 min)
Intermediate phase: loss of pharmacodynamic effect (half-life on average of 30 min)
Terminal phase: decline in plasma concentration (half-life about 2 hours)
Distribution: regadenoson is moderately bound to human plasma proteins (25-30%).
Biotransformation: regadenoson metabolismis is unknown in humans
Excretion
57% of the regadenoson dose is excreted unchanged in the urine, range 19-77%
Average plasma renal clearance: ≈450 mL/min (in excess of the glomerular filtration rate)
Tubular secretion plays a role in regadenoson elimination
Regadenoson clearance decreases in parallel with a reduction in creatinine clearance, and increases
with increased body weight
Age, gender, and race were found to have minimal effects on regadenoson pharmacokinetics

Patient Preparation
Methylxanthines are non-specific adenosine receptor antagonists
Patient should be instructed to avoid consumption of any products containing methylxanthines
(including caffeinated coffee, tea, or other caffeinated beverages), caffeine-containing drug products,
aminophylline, and theophylline for at least 12 h
Ingestion of caffeine was found to decrease the ability to detect reversible ischemic defects
Dipydamole may influence ragadenoson effects
When possible, dipyridamole should be withheld for at least 48 h prior to MPI
In clinical trials, regadenoson has been administered to patients taking other cardio-active medication
without reported adverse reactions or apparent effects on efficacy
β-blockers, calcium channel blockers, ACE inhibitors, nitrates, cardiac glycosides, angiotensin
receptor blockers
Effects on other drugs
Regadenoson does not inhibit the metabolism of substrates for CYP1A2, CYP2C8, CYP2C9,
CYP2C19, CYP2D6, CYP3A4 (unlikely to alter the pharmacokinetics of drugs metabolized by these
cytochrome P450 enzymes)
Regadenoson does not significantly inhibit the transporters OAT1, OAT3, OCT1, OATP1B1,
OATP1B3, MATE1, MATE2-K, BCRP, P-gp, BSEP, ENT 1 or ENT2 at 1 μM
Regadenoson may have a modest inhibitory effect on the active renal transporter, OCT2, and has
been found to be likely substrate for BCRP, ENT1 or ENT2 mediated transport

Regadenoson: Contraindications
1. 2nd or 3rd degree AV block, or sinus node dysfunction
(unless these patients have a functioning artificial pacemaker)
2. Unstable angina that has not been stabilized with medical therapy
3. Severe hypotension
4. Decompensated states of heart failure
5. Hypersensitivity to the active substance or to any of the excipients

Regadenoson Clinical Efficacy & Safety
The efficacy and safety of regadenoson were determined relative to adenosine in two randomized,
double- blind studies (ADVANCE MPI 1 and ADVANCE MPI 2)
Patients with known or suspected CAD, referred for a clinically-indicated pharmacologic stress MPI
Each patient received an initial stress scan using adenosine (6-minute infusion using a dose of 0.14
mg/kg/min, without exercise) with a radionuclide gated SPECT
After the initial scan, patients were randomized to either regadenoson or adenosine, and received a
second stress scan with the same radionuclide imaging protocol as that used for the initial scan
The ADVANCE MPI 1 and ADVANCE MPI 2 studies, individually and combined, demonstrated that
regadenoson is similar to adenosine in assessing the extent of reversible perfusion abnormalities
Cerqueira MD, et al, on behalf of the ADVANCE MPI Trial Investigators. Effects of age, gender,
obesity and diabetes on the efficacy and safety of the selective A2A agonist Rapiscan versus
adenosine: integrated ADVANCE MPI trial results. J Am Coll Cardiol (2008)
Iskandrian AE, et al. Adenosine versus Rapiscan comparative evaluation in myocardial perfusion
imaging: results of the ADVANCE phase 3 multicenter international trial. J Nucl Cardiol (2007)

Regadenoson: Adverse Effects
Most common adverse reactions reported during
clinical development (1,651 patients/subjects):
1. Dyspnea (29%)
2. Headache (27%)
3. Flushing (23%)
4. Chest pain (19%)
5. Gastrointestinal discomfort (15%)
6. Dizziness (11%)
No symptoms
41%
1 symptom
31%
>1 symptoms
28%
Regadenoson-related symptoms
Grade 1
53%
Grade 2
45%
Grade 3
2%
Regadenoson-related symptoms
133 patients (82 males, mean age 69.6 y.o)
18 patients suffered from COPD
80 patients had abnormal MPI studies
Symptoms were reported in 79 patients
Most common symptoms were:
1. Dyspnea (38/133)
2. Discomfort (20/133)
3. Dizziness (17/133).

ECG Changes
ST segment changes (18%)
Premature atrial complexes
Premature ventricular complexes
1st degree AV block (PR >220 msec)
2nd degree AV block
AV conduction abnormalities (other than AV blocks)
Ventricular conduction abnormalities
Atrial fibrillation
Atrial flutter
Supraventricular arrhythmia
Ventricular arrhythmia
Wandering atrial pacemaker
Ischemic ECG changes and
arrhythmias were observed in
14/133 patients

Myocardial Ischemia
Fatal & non-fatal MI, ventricular arrhythmias, and cardiac arrest have occurred following regadenoson
administration
Adherence to the recommended duration of regadenoson injection, longer injection time may increase
the duration and magnitude of increase in CBF
Avoid use in patients with acute myocardial ischemia (e.g. cardiovascular instability, unstable angina)
Regadenoson should be used in caution in patients with recent MI
Clinical trials conducted with regadenoson excluded patients with recent (within 3 months)
myocardial infarction
Aminophylline administration to shorten the duration of increased coronary blood flow, if serious
reactions to regadenoson occur
Cardiac resuscitation equipment, trained staff immediately available

Sinoatrial & Atrioventricular Nodal Block
Regadenoson can depress the SA and AV nodes and may cause 1st, 2nd, or 3rd degree AV blocks , or
sinus bradycardia requiring intervention
Andrikopoulou E, et al. Incidence of atrioventricular block with vasodilator stress SPECT: A meta-
analysis. J Nucl Cardiol (2017)
.
AV block is seen in about 4% of patients undergoing vasodilator stress test
Both overall and high-grade AV are more frequent with adenosine compared to regadenoson.

Hypotension
Regadenoson induces arterial vasodilation and hypotension
In clinical trials, decreased SBP (>35 mmHg) and decreased DBP (>25 mmHg) were reported in 7%
and 4% of patients, respectively, within 45 min of regadenoson administration
Syncope, transient ischmeic attacks, or seizures have been observed
Higher risk: autonomic dysfunction, hypovolemia, left main coronary artery stenosis, stenotic valvular
heart disease, pericarditis, pericardial effusions, stenotic carotid artery disease with cerebrovascular
insufficiency

Hypertension
Regadenoson administration may result in clinically significant increases in BP, which in some patients
can lead to hypertensive crisis
Within minutes of injection, most increases resolve within 10-15 min
In some cases increases were reported at 45 min following injection
Higher risk: patients with uncontrolled hypertension, low-level exercise
Consideration should be given to delaying regadenoson administration until blood pressure is well
controlled

Bronchoconstriction & Respiratory Arrest
Regadenoson administration may cause dyspnea, bronchoconstriction, or respiratory compromise
Patients with known or suspected bronchoconstrictive disease, COPD, or asthma
The incidence of a FEV1 reduction > 15% from baseline after administration was assessed in three
randomized, controlled clinical studies
1st study: 12% and 6% following regadenoson and placebo dosing
2nd study: 4% following both regadenoson and placebo dosing
3rd study: 1.1% and 2.9% in patients with asthma and 4.2% and 5.4% in patients with COPD
following regadenoson and placebo dosing
Dyspnea was reported more frequently as an adverse reaction following regadenoson dosing , in
comparison to placebo
Relationship between increased disease severity and increased incidence of dyspnoea was apparent
in patients with asthma, but not in patients with COPD
Appropriate bronchodilator therapy and resuscitative measures should be available prior to and
following regadenoson injection

Bronchoconstriction & Respiratory Arrest
Thomas GS, et al Safety of regadenoson, a selective adenosine A2A agonist, in patients with chronic
obstructive pulmonary disease: A randomized, double-blind,placebo-controlled trial (RegCOPD trial). J
Nucl Cardiol (2008)
Leaker BR, et al. Safety of regadenoson, an adenosine A2A receptor agonist for myocardial perfusion
imaging, in mild asthma and moderate asthma patients: A randomized, double-blind, placebo-
controlled trial. J Nucl Cardiol (2008)
Prenner BM, et al. A randomized, double-blind, placebo controlled study assessing the safety and
tolerability of regadenoson in subjects with asthma or chronic obstructive pulmonary disease. J Nucl
Cardiol (2012)

Risk of Seizure or Stroke
Regadenoson may lower the seizure threshold, new-onset or recurrence of convulsive seizures has
reported following administration
Some seizures are prolonged requiring emergent anticonvulsive management
Aminophylline may increase the risk of seizures
Methylxanthine use is not recommended in patients who experience a seizure associated with
regadenoson administration
Caution should be used when administering regadenoson to patients with a history of seizures or
other risk factors for seizures, including the concomitant administration of medicinal products that
lower seizure threshold (e.g. antipsychotics, antidepressants, theophyllines, tramadol, systemic
steroids, quinolones)
Hemorrhagic and ischemic cerebrovascular accidents have been observed
Regadenoson hemodynamic effects, including hypotension and hypertension, may be related to these
adverse reactions

Regadenoson Hypersensitivity
1. Anaphylaxis
2. Angioedema
3. Cardiac or respiratory arrest
4. Respiratory distress
5. Decreased oxygen saturation
6. Throat tightness
7. Urticaria and rashes
Resuscitated equipment, trained personnel immediately available
Fewer than 1% of patients

Aminophylline to reverse effects
Aminophylline has been used to terminate persistent pharmacodynamic effects
Methylxanthines are competitive adenosine receptor antagonists
Dose: 50-250 mg over slow IV injection (50-100 mg over 30-60 sec)
Methylxanthine use is not recommended in patients experiencing a seizure due to regadenoson
administration

Renal Impairment
No dose adjustment is needed in patients with renal impairment, including patients with end stage
renal disease and/or dependent on dialysis
With increasing renal impairment, from mild (CLcr 50 to < 80 ml/min) to moderate (CLcr 30 to < 50
ml/min) to severe renal impairment (CLcr < 30 ml/min), the fraction of regadenoson excreted
unchanged in urine and the renal clearance were found to be decreased
However, the maximum observed plasma concentrations as well as volumes of distribution estimates
were similar across subjects with various degrees of renal function and in healthy subjects
Plasma concentration-time profiles were not significantly altered in the early stages after
administration when most pharmacologic effects are observed
Gordi T, et al. Regadenoson pharmacokinetics and tolerability in subjects with impaired renal function.
J Clin Pharmacol (2007)

Hepatic Impairment
No dose adjustment is necessary
The pharmacokinetic parameters of regadenoson have not been specifically evaluated in those with
varying degrees of hepatic impairment
Post-hoc analysis of data from the two Phase 3 clinical trials showed that the pharmacokinetics of
regadenoson were not affected in a small subset of patients with laboratory values suggestive of
impaired hepatic function (2.5-fold transaminase elevation or 1.5-fold elevation of serum bilirubin or
prothrombin time)

Prognostication
The prognostic utility of a regadenoson stress MPI study has been reported in several studies
Iqbal FM, et al. Comparison of the prognostic value of normal regadenoson with normal adenosine
myocardial perfusion imaging with propensity score matching. JACC Cardiovasc Imaging (2012)
Bhatti S, et al. Prognostic value of regadenoson myocardial single-photon emission computed
tomography in patients with different degrees of renal dysfunction. Eur Heart J Cardiovasc Imaging.
(2014)
Hage FG, et al. The prognostic value of regadenoson myocardial perfusion imaging. J Nucl Cardiol.
(2015)
Farzaneh-Far A, et al. Comparison of the prognostic value of regadenoson and adenosine myocardial
perfusion imaging. J Nucl Cardiol (2015)
Thomas GS, et al. The RegEx trial: a randomized, double-blind, placebo- and active-controlled pilot
study combining regadenoson, a selective A2A adenosine agonist, with low-level exercise, in patients
undergoing myocardial perfusion imaging. J Nuclear Cardiol (2009)

Heart Rate Response as prognostic indicator
Although nearly all patients experience an increase in HR, it has been reported that the magnitude of
the heart rate increase is correlated to patient outcome
Proposed mechanism for the prognostic information provided by the HRR is related to the stimulation
of the sympathetic nervous system by A2A activation
Autonomic dysfunction is associated with worse cardiovascular outcomes, and the addition of HRR to
prognostic models is expected to improve risk stratification.
Patients with a good heart rate response (HRR > 43% of baseline heart rate) was associated with
good prognosis, whereas those who experienced a poor HRR (<17% of baseline) was associate with
a poor prognosis
The association of HR and outcomes was independent of the presence or absence of a perfusion
defect, LVEF, β-blocker use, diabetes mellitus, CKD or ESRD
Lack of association of HRR with outcomes in atrial fibrillation may be a reflection of the differential
innervation of the sinus and AV nodes by autonomic fibers
A blunted pre-transplant HRR was predictive of post-RT MACE (asymptomatic ESRD patients being
evaluated for RT)
HRR may be a valuable tool in the risk assessment of RT candidates

Heart Rate Response as prognostic indicator
Hage FG, et al.. A blunted heart rate response to regadenoson is an independent prognostic indicator
in patients undergoing myocardial perfusion imaging. J Nucl Cardiol (2011)
Iqbal FM, et al. Reclassification of cardiovascular risk in patients with normal myocardial perfusion
imaging using heart rate response to vasodilator stress. Am J Cardiol (2013)
AlJaroudi W, et al. The prognostic value of heart rate response during vasodilator stress myocardial
perfusion imaging in patients with end-stage renal disease undergoing renal transplantation. J Nucl
Cardiol (2017)
Uzendu A, et al. The heart rate response to regadenoson in patients with atrial fibrillation. J Nucl
Cardiol (2018)

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