Effect of aminophylline administration on the diag

Authors: Hussein Abu Daya Fadi G Hage

Publish Date: 2016/06/03

Volume: 24, Issue: 5, Pages: 1579-1582

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Abstract

A Time dependence of 400 and 500 µg of IV regadenoson bolus on average peak coronary flow velocity APV ratio B Effects of 400 µg of IV regadenoson bolus on APV ratio and heart rate before and after administration of 100 mg of IV aminophylline modified from Lieu et al12 and Zoghbi et al24In this issue of the Journal Fughhi et al10 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 doubleblinded placebocontrolled randomized clinical trials the ASSUAGE and ASSUAGECKD trials911 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 semiquantitative summed difference score SDS The secondary end point was the presence of myocardial ischemia as defined by SDS ≥2 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 followup period of 29 ± 14 monthsThe 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 ≥4 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 ≥4 of prior MI and demonstrated similar prevalence of myocardial ischemia and abnormal perfusion between the two groups There was no difference in the eventfree 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 ≥2 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 regadenosoninduced adverse effects without a detectable effect on the diagnostic performance of MPIFollowing IV bolus administration of regadenoson the maximal venous plasma concentration of the drug is usually reached after 13 minutes and myocardial blood flow MBF velocity increases by 25 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 al12 the peak MBF velocity 31 ± 05 fold associated with 400 µg IV bolus of regadenoson was reached within 0523 minutes with a mean of 33 seconds range of 2040 seconds to reach ≥85 of maximal flow In addition the increase in peak flow velocity by 25fold was maintained for a mean of 23 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 regadenosoninduced coronary hyperemia Figure 1B raising concerns that early administration of an adenosine receptor antagonist after a regadenoson bolus may attenuate MPI abnormalities12In a canine model of ischemia that evaluated myocardial uptake and clearance of 99mTctetrofosmin relative to microsphere flow Sinusas et al13 demonstrated that 99mTctetrofosmin cleared rapidly from the blood and was retained by the myocardium whereby its uptake and clearance by ischemic and nonischemic myocardium plateaus almost 100 seconds after its injection Similarly Takahashi et al14 showed in bloodperfused rat hearts that the net tissue extraction of 99mTctetrofosmin plateaus within 100 seconds14 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 al10 is based administered aminophylline at 90 seconds after tracer administrationIt is important to interpret the results of the study by Fughhi et al10 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 previously15Caffeine another adenosine receptor antagonist also has the potential to oppose the effects of regadenoson16 A recent study investigated the use of IV and oral caffeine as a potential alternative to aminophylline for the reversal of regadenosoninduced adverse effects17 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 ie ≤2 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 contraindication23The study by Fughhi et al10 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 guidelines23 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

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