Effect of aminophylline administration on the diagnostic yield of vasodilator myocardial perfusion imaging
Effect of aminophylline administration on the diagnostic yield of vasodilator myocardial perfusion imaging
Hussein Abu Daya 0 3
Fadi G. Hage 0
FASNC 0 1 2
0 Reprint requests: Fadi Hage , MD, FACC, FASH, FASNC , University of Alabama at Birmingham, Lyons Harrison Research Building 306, 1900 University BLVD, Birmingham, AL 35294; J Nucl Cardiol 1071-3581/$34.00 Copyright 2016 American Society of Nuclear Cardiology
1 Division of Cardiovascular Disease, University of Alabama at Birmingham , Birmingham, AL
2 Section of Cardiology, Birmingham Veterans Affairs Medical Center , Birmingham, AL
3 Department of Medicine, University of Pittsburgh , Pittsburgh, PA
The last few decades have witnessed a steady
increase in the proportion of myocardial perfusion
imaging (MPI) tests that utilize pharmacologic stress
instead of exercise.1 Currently regadenoson, a pyrazole
derivative of adenosine selective for the A2A receptor, is
the most commonly used vasodilator agent accounting
for more than 80% of all pharmacological stress tests
performed in the USA.2 The widespread utilization of
regadenoson is supported by multiple factors including
its similar diagnostic and prognostic performance to
adenosine when used for MPI, the simpler and more
rapid infusion protocol, and the better safety profile in
specific patient groups.3-6 Although better tolerated by
patients, regadenoson shares with adenosine similar
adverse effects such as flushing, headaches, and
gastrointestinal symptoms.3,7 Aminophylline, a
nonselective adenosine receptor antagonist, has been
available on the market for decades and used to reverse the
adverse effects of dipyridamole and adenosine and more
recently been shown to be safe and effective for use with
In this issue of the Journal, Fughhi et al.10 address
the concern that use of aminophylline to ameliorate the
adverse effects of regadenoson may reverse its effects on
coronary vasodilation and subsequent myocardial
hyperemia reducing the sensitivity of MPI for detecting
perfusion abnormalities. The data for the current study
were pooled from two double-blinded,
placebo-controlled randomized clinical trials, the ASSUAGE and
ASSUAGE-CKD trials,9,11 which demonstrated the
effectiveness of aminophylline in attenuating the
adverse effects associated with regadenoson in patients
undergoing MPI. In both trials, patients were
randomized to receive 75 mg of intravenous aminophylline or
placebo administered at 90 seconds after radioisotope
injection (*2 minutes following regadenoson). The
primary end point of the current report was the degree of
reversibility of the perfusion defect on imaging as
measured by the semi-quantitative summed difference
score (SDS). The secondary end point was the presence
of myocardial ischemia as defined by SDS C2. The
authors also examined the effect of aminophylline use
on the prognostic value of myocardial ischemia
detection by MPI for cardiac events including cardiac death,
myocardial infarction (MI), and coronary
revascularization over a follow-up period of 29 ± 14 months.
The myocardial ischemic burden (primary outcome)
and the presence of myocardial ischemia (secondary
outcome) on MPI were similar between the two groups.
However, there was a trend towards a higher proportion
of abnormal perfusion (summed stress score, SSS C4,
34% vs 27%, P = .08) in the placebo group that the
authors attributed to the significantly higher rate of prior
MI (20% vs 13%, P = .03) in this group. To account for
this imbalance, the authors performed a sensitivity
analysis in patients without clinical or MPI evidence
(summed rest score, SRS C4) of prior MI, and
demonstrated similar prevalence of myocardial ischemia and
abnormal perfusion between the two groups. There was
no difference in the event-free survival between the
study groups after adjusting for SDS, SRS, prior MI, and
left ventricular ejection fraction, and no interaction
between aminophylline use and SDS or myocardial
ischemia (SDS C2) as a determinant of cardiac events in
the overall cohort and after excluding patients with prior
MI. Reassuringly, there was no difference in events
between the two groups in the cohort of patients with
normal perfusion on imaging. The authors concluded
that aminophylline administration *2 minutes after
regadenoson injection ameliorated regadenoson-induced
adverse effects without a detectable effect on the
diagnostic performance of MPI.
Following IV bolus administration of regadenoson,
the maximal venous plasma concentration of the drug is
usually reached after 1-3 minutes and myocardial blood
flow (MBF) velocity increases by [2.5 folds for at least
2 minutes allowing for adequate radionuclide uptake
which is a prerequisite for successful MPI12
(Figure 1A). In the study by Lieu et al.,12 the peak MBF
velocity (3.1 ± 0.5 fold) associated with 400 lg IV
bolus of regadenoson was reached within 0.5-2.3
minutes with a mean of 33 seconds (range of
2040 seconds) to reach C85% of maximal flow. In
addition, the increase in peak flow velocity by [2.5-fold was
maintained for a mean of 2.3 minutes. In the same study,
administration of 100 mg IV aminophylline at 1 minute
after regadenoson did not alter peak MBF increase but it
did significantly abbreviate regadenoson-induced
coronary hyperemia (Figure 1B) raising concerns that
early administration of an adenosine receptor antagonist
after a regadenoson bolus may attenuate MPI
In a canine model of ischemia that evaluated
myocardial uptake and clearance of 99mTc-tetrofosmin
relative to microsphere flow, Sinusas et al.13
demonstrated that 99mTc-tetrofosmin cleared rapidly from the
blood and was retained by the myocardium whereby its
uptake and clearance by ischemic and non-ischemic
myocardium plateaus almost 100 seconds after its
injection. Similarly, Takahashi et al.14 showed in
bloodperfused rat hearts that the net tissue extraction of
99mTc-tetrofosmin plateaus within 100 seconds.14 Thus,
at least theoretically, antagonism of adenosine receptors
at least 100 seconds after regadenoson administration
should not interfere with myocardial uptake of the
tracer. Based on these data, and allowing 10 seconds for
the drug to reach the coronary capillary bed, The
ASSUAGE trials, on which the study by Fughhi et al.10
is based, administered aminophylline at 90 seconds after
It is important to interpret the results of the study by
Fughhi et al.10 with caution since the findings are based
on post hoc analysis of studies that were not designed or
powered to address this issue. As pointed out earlier, the
higher prevalence of abnormal myocardial perfusion in
the placebo group is another reason to pause when
interpreting the findings although the authors have
attributed this to the imbalance in the distribution of
patients with prior MI between the 2 randomized groups.
Ultimately, the optimal study to assess the effect of
aminophylline on the diagnostic performance of
regadenoson MPI would be a crossover clinical trial in which
patients, in addition to the rest scan, undergo two stress
scans and are randomized to receive aminophylline or
placebo after regadenoson administration. The proper
analysis of such a study has been discussed previously.15
Caffeine, another adenosine receptor antagonist, also
has the potential to oppose the effects of regadenoson.16
A recent study investigated the use of IV and oral caffeine
as a potential alternative to aminophylline for the reversal
of regadenoson-induced adverse effects.17 The
significance of prior caffeine consumption on
regadenosoninduced coronary hyperemia and the diagnostic
sensitivity of MPI for detection of perfusion abnormalities
have been recently debated in the Journal.18-22 Our view
is that moderate caffeine consumption (i.e., B2 cups of
coffee more than 1 hour prior to presentation to the stress
laboratory) does not alter coronary flow reserve to such
an extent to significantly impact myocardial perfusion
pattern on MPI. In line with this view, the recently
released American Society of Nuclear Cardiology
imaging guidelines for SPECT nuclear cardiology
procedures: Stress protocols and tracers states that
ingestion of caffeinated foods or beverages within the last
12 hours prior to regadenoson MPI (or other vasodilator
stress agents) should be avoided but downgraded this
from an absolute to a relative contraindication.23
The study by Fughhi et al.10 provides some
reassurance that administration of aminophylline, when
delayed by at least 2 minutes, does not substantially
interfere with the effects of regadenoson on myocardial
perfusion by MPI. Therefore, when significant
complications are encountered as summarized in the recent
guidelines,23 reversal of regadenoson should be
considered without concern for altering findings on imaging.
Whether reversal of regadenoson using IV
aminophylline or caffeine should be undertaken on a routine
basis irrespective of symptom development continues to
be a matter of debate.
Dr Hage reports grant funding from Astellas Pharma
1. Rozanski A , Gransar H , Hayes SW , Min J , Friedman JD , Thomson LE , et al. Temporal trends in the frequency of inducible myocardial ischemia during cardiac stress testing: 1991 to 2009 . J Am Coll Cardiol 2013 ; 61 : 1054 - 65 .
2. American Society of Nuclear Cardiology/MedAxiom Nuclear Survey 2013 . J Nucl Cardiol 2014 ; 21 Suppl 1 : 5 - 88
3. Iskandrian AE , Bateman TM , Belardinelli L , Blackburn B , Cerqueira MD , Hendel RC , et al. Adenosine versus regadenoson comparative evaluation in myocardial perfusion imaging: Results of the ADVANCE phase 3 multicenter international trial . J Nucl Cardiol 2007 ; 14 : 645 - 58 .
4. Hage FG , Ghimire G , Lester D , McKay J , Bleich S , El-Hajj S , et al. The prognostic value of regadenoson myocardial perfusion imaging . J Nucl Cardiol 2015 ; 22 : 1214 - 21 .
5. Saab R , Hage FG . Vasodilator stress agents for myocardial perfusion imaging . J Nucl Cardiol 2016 . doi: 10 .1007/s12350-016- 0408-4.
6. Hage FG . Regadenoson for myocardial perfusion imaging: Is it safe ? J Nucl Cardiol 2014 ; 21 : 871 - 6 .
7. Dilsizian V , Gewirtz H , Paivanas N , Kitsiou AN , Hage FG , Crone NE , et al. Serious and potentially life threatening complications of cardiac stress testing: Physiological mechanisms and management strategies . J Nucl Cardiol 2015 ; 22 : 1198 - 213 .
8. Beller GA . Pharmacologic stress imaging . JAMA 1991 ; 265 : 633 - 8 .
9. Doukky R , Morales Demori R , Jain S , Kiriakos R , Mwansa V , Calvin JE . Attenuation of the side effect profile of regadenoson: A randomized double-blinded placebo-controlled study with aminophylline in patients undergoing myocardial perfusion imaging. ''The ASSUAGE trial'' . J Nucl Cardiol 2012 ; 19 : 448 - 57 .
10. Fughhi I , Campagnoli T , Ali A , Doukky R . Impact of a regimented aminophylline administration protocol on the burden of regadenosoninduced ischemia detected by SPECT myocardial perfusion imaging . J Nucl Cardiol 2016 . doi: 10 .1007/s12350-016-0506-3.
11. Doukky R , Rangel MO , Dick R , Wassouf M , Alqaid A , Margeta B . Attenuation of the side effect profile of regadenoson: A randomized double-blind placebo-controlled study with aminophylline in patients undergoing myocardial perfusion imaging and have severe chronic kidney disease-the ASSUAGECKD trial . Int J Cardiovasc Imaging 2013 ; 29 : 1029 - 37 .
12. Lieu HD , Shryock JC , von Mering GO , Gordi T , Blackburn B , Olmsted AW , et al. Regadenoson, a selective A2A adenosine receptor agonist, causes dose-dependent increases in coronary blood flow velocity in humans . J Nucl Cardiol 2007 ; 14 : 514 - 20 .
13. Sinusas AJ , Shi Q , Saltzberg MT , Vitols P , Jain D , Wackers FJ , et al. Technetium-99m-tetrofosmin to assess myocardial blood flow: Experimental validation in an intact canine model of ischemia . J Nucl Med 1994 ; 35 : 664 - 71 .
14. Takahashi N , Dahlberg ST , Gilmore MP , Leppo JA. Effects of acute ischemia and reperfusion on the myocardial kinetics of technetium 99m-labeled tetrofosmin and thallium-201. J Nucl Cardiol 1997 ; 4 : 524 - 31 .
15. Iskandrian AE , Hage FG , Shaw LJ , Mahmarian JJ , Berman DS . Serial myocardial perfusion imaging: Defining a significant change and targeting management decisions . JACC Cardiovasc Imaging 2014 ; 7 : 79 - 96 .
16. Hage FG , Iskandrian AE . The effect of caffeine on adenosine myocardial perfusion imaging: Time to reassess? J Nucl Cardiol 2012 ; 19 : 415 - 9 .
17. Doran JA , Sajjad W , Schneider MD , Gupta R , Mackin ML , Schwartz RG . Aminophylline and caffeine for reversal of adverse symptoms associated with regadenoson SPECT MPI . J Nucl Cardiol 2016 . doi: 10 .1007/s12350-016-0452-0.
18. Saab R , Bajaj NS , Hage FG . Caffeine does not significantly reduce the sensitivity of vasodilator stress myocardial perfusion imaging . J Nucl Cardiol 2016 ; 23 : 442 - 6 .
19. Saab R , Bajaj NS , Hage FG . Caffeine intake and myocardial perfusion imaging . J Nucl Cardiol 2016 ; 23 : 605 .
20. Reyes E. Caffeine reduces the sensitivity of vasodilator MPI for the detection of myocardial ischaemia: Pro . J Nucl Cardiol 2016 ; 23 : 447 - 53 .
21. Christian TF . The judgement of the eye . J Nucl Cardiol 2016 ; 23 : 454 - 6 .
22. Reyes E. Caffeine does not significantly reduce the sensitivity of vasodilator stress MPI: Rebuttal . J Nucl Cardiol 2016 ; 23 : 604 .
23. Henzlova MJ , Duvall WL , Einstein AJ , Travin MI , Verberne HJ . ASNC imaging guidelines for SPECT nuclear cardiology procedures: Stress, protocols, and tracers . J Nucl Cardiol 2016 ; 23 : 606 - 39 .
24. Zoghbi GJ , Iskandrian AE . Selective adenosine agonists and myocardial perfusion imaging . J Nucl Cardiol 2012 ; 19 : 126 - 41 .