Intravenous regadenoson with aminophylline reversal is safe and equivalent to intravenous adenosine infusion for fractional flow reserve measurements

Abstract

Background

Small studies have shown that adenosine is equivalent to regadenoson when obtaining coronary fractional flow reserve (FFR) measurements. A study that also evaluates time and safety of aminophylline reversal of regadenoson effects has not been presented.

Hypothesis

Reversal of regadenoson with aminophylline is safe and equivalent to adenosine for FFR measurements.

Methods

Forty‐six consecutive patients who underwent clinically indicated FFRs at the time of coronary angiography were enrolled between 4/2012 and 5/2014. Each patient had FFR measured using adenosine 140 mcg/kg/min IV, and following return to baseline, FFR was measured using regadenoson 400 mcg IV, which then was reversed with aminophylline 150 mg IV. Time to baseline hemodynamics was measured. Agreement between the two assessments was compared using linear regression.

Results

FFR results were similar with both agents (R ² = 0.935, P < 0.0001). Also, using the 0.80 cutoff for significantly depressed FFR, there was no divergence regarding studies' significance. After aminophylline reversal of regadenoson, hemodynamics returned to baseline in 111 ± 71 seconds. There were no unexpected side effects or complications.

Conclusions

For FFR measurement, regadenoson and adenosine are equivalent hyperemic agents. Regadenoson with aminophylline reversal may be considered as an alternative to adenosine for FFR measurements.

1. INTRODUCTION

Fractional flow reserve (FFR), a measurement of hyperemic pressure gradient across a stenosis during maximal hyperemia,1 is an established method for assessing the significance of an intermediate coronary stenosis during invasive angiography. Previous studies have shown the utility and safety of FFR assessment, and suggest that FFR‐guided intervention portends favorable outcomes when compared to medical therapy alone or intervention guided solely by visual estimation of coronary stenosis.2, 3 Maximal coronary hyperemia is required for proper FFR measurement, with prior studies utilizing intravenous (IV) adenosine.2, 3 However, adenosine has certain undesirable characteristics, including numerous side effects such as the potential for atrioventricular block, and requires a weight‐based infusion due to its short half‐life. Regadenoson, a selective A_2A adenosine receptor agonist, offers a more favorable side effect profile when compared to adenosine.4 It is given as a single bolus injection, has a longer half‐life, and when compared to adenosine, achieves a similar peak hyperemic response.5 Aminophylline is a nonselective adenosine receptor antagonist that has been used to reverse the adverse effects of regadenoson, adenosine, and dipyridamole.6, 7 There have been a small number of studies that describe the use of regadenoson for the assessment of FFR,8, 9, 10, 11, 12 but none has investigated reversal of regadenoson with aminophylline. The goal of the present study was not only to compare the efficacy of regadenoson to adenosine for the measurement of FFR, but also to assess the impact of aminophylline on the hemodynamics and symptoms following regadenoson bolus.

2. METHODS

2.1. Patient selection

The patient population consisted of 46 consecutive patients presenting for elective coronary angiography who underwent a clinically indicated FFR assessment between April 2012 and May 2014. This study was approved by the Institutional Review Board (IRB) of the Ochsner Clinic. Exclusion criteria included electrical conductance abnormalities (sinus node dysfunction, second‐ or third‐degree AV node block without a permanent pacemaker in place), severe hypotension (systolic blood pressure less than 80 mmHg or diastolic blood pressure less than 40 mmHg), acute myocardial infarction within last 30 days, severe aortic valve stenosis, pregnancy, and aberrant coronary anatomy or calcification that would preclude FFR measurements. Patients were instructed to fast for 4 hours and to abstain from caffeine and theophylline for 24 hours prior to angiography. Written informed consent was provided by all patients. This trial is registered with ClinicalTrials.gov number, NCT01482169.

2.2. Endpoints

The primary endpoints of this prospective, open‐label study were FFR measurements with IV infusion of adenosine (Adenoscan, Astellas Pharma Inc., Deerfield, Illinois), followed by a single IV bolus of regadenoson (Lexiscan, Astellas Pharma Inc.). The secondary endpoint was time to return to baseline following aminophylline reversal of regadenoson.

2.3. FFR measurements

Cardiac catheterization with angiography was performed in patients using a 6‐F coronary guiding catheter via femoral or transradial approach. Heart rate, blood pressure, and heart rhythm were continuously monitored during the procedure. Heparin was administered (maximum of 5000 U) with a goal‐activated clotting time of >250 seconds if FFR was clinically indicated. FFR was measured only if there was uncertainty regarding the hemodynamic significance of the coronary lesion and if the results of FFR measurement would influence management. A 0.014‐in. diameter pressure guidewire (PW Certus, Abbott Laboratories, Lake Bluff, Illinois) was externally calibrated and then advanced through the catheter into the central aorta, as previously described.1 The pressure guidewire was advanced into the coronary artery distal to the lesion of interest and was maintained in this position throughout the remainder of the study. Distal coronary pressure (P _d) and aortic pressure (P _a) were measured simultaneously at baseline and after maximal hyperemia. FFR was measured as the lowest value of P _d/P _a achieved during steady‐state maximum hyperemia.

2.4. Pharmacological protocol

The pharmacological protocol is depicted in Figure 1. Following suitable wire position distal to the stenosis, a peripheral IV infusion of adenosine (140 mcg/kg/min) was administered. The infusion was continued for approximately 6 minutes or until steady‐state hyperemia (ie, a persistent FFR nadir) was reached. Following completion of the infusion, the peripheral IV line was flushed with 10 mL of normal saline. After the pressure ratio (P _d/P _a) returned to baseline during a 10 minute washout period,13 a peripheral IV bolus of 400 mcg regadenoson was administered, and FFR measurements were obtained in the same fashion as with adenosine. Regadenoson was then reversed with an IV bolus of 150 mg aminophylline, and the time to return to baseline hemodynamics was recorded.

Figure 1.

Measurement protocol. Measurement protocol for adenosine and regadenoson administration. FFR was measured as the lowest value of distal to proximal pressure (P _d/P _a) achieved during steady‐state maximum hyperemia

2.5. Statistical analysis

Data are presented as mean ± SD. A linear regression analysis with Pearson correlation coefficient and two‐tailed test for significance was performed for FFR data derived from the two hyperemic stimuli. Results were considered statistically significant at P < 0.05. All statistical procedures were performed using SPSS software Version 20.0 (IBM SPSS, Armonk, New York).

3. RESULTS

3.1. Study patients

The baseline characteristics of the 46 patients are presented in Table 1. Mean age was 63 ± 10 years, 80% were male, and there was a high prevalence of atherosclerotic risk factors among patients consented for clinically indicated angiography and FFR. Almost all patients had multiple risk factors for coronary atherosclerosis, including diabetes mellitus in 52%. Of note, 65% reported known CAD, and 15% of patients were current smokers. The breakdown of epicardial vessels undergoing FFR testing was as follows: left anterior descending (54%), left circumflex (24%), right (15%), and left main coronary artery (7%).

Table 1.

Baseline characteristics of study population (N = 46)

Baseline characteristics
Age, years		63 ± 10
Male/female		37/9
Body mass index (kg/m2)		33 ± 7
Clinical characteristics
Hypertension		44 (96%)
Diabetes mellitus		26 (57%)
Dyslipidemia		44 (96%)
Active smoking		7 (15%)
CKD		9 (20%)
Known CAD		30 (65%)
LV ejection fraction (%)		54 ± 13
Angiographic factors
Target vessel	Left main	3 (7%)
	Left anterior descending	25 (54%)
	Left circumflex	11 (24%)
	Right coronary artery	7 (15%)
Percent stenosis	<30%	1 (2%)
	30‐50%	5 (11%)
	50‐70%	17 (37%)
	70‐90%	22 48%)
	>90%	1 (2%)
Time to baseline hemodynamics following aminophylline reversal (seconds)		111 ± 71

Abbreviations: CAD, coronary artery disease; CKD, chronic kidney disease; LV, left ventricular.

3.2. FFR comparison (IV adenosine infusion vs IV regadenoson bolus)

The mean FFR value at peak hyperemia following IV adenosine infusion and regadenoson bolus was 0.832 ± 0.08 and 0.835 ± 0.08, respectively (Table 2). There was a very strong linear correlation between the FFR values of the two hyperemic stimuli (R ² = 0.9346, y = 0.9858x + 0.0151, P < 0.0001) (Figure 2A). The Bland‐Altman plot showed excellent correlation between the two measurement methods with the majority of values (98%) falling between two standard deviations of the mean of the FFR measurements (Figure 2B). Following aminophylline reversal of regadenoson‐induced hyperemia, hemodynamics returned to baseline after 111 ± 71 seconds (Table 1). Using an FFR cutoff ≤0.80, similar numbers of lesions were found to be hemodynamically significant with adenosine and regadenoson, (16 [35%] and 16 [35%], respectively, P = 0.74). Thus, using a ≤ 0.80 cutoff, there were no divergent FFR measurements regarding any lesion's hemodynamic significance. When evaluating the differences in FFR measurements between adenosine and regadenoson, there were no significant overall differences (Figure 2).

Table 2.

Average FFR measurements at baseline and maximal hyperemia

	Baseline	Hyperemia	P value
Drug
FFR of adenosine	0.941 ± 0.05	0.832 ± 0.08	<0.0001
FFR of Regadenoson	0.941 ± 0.05	0.835 ± 0.08	<0.0001

All values shown are mean ± SD.

Figure 2.

Linear regression analysis of intrapatient FFR. A, Linear regression analysis of fractional flow reserve (FFR) measured with an IV adenosine infusion and IV regadenoson bolus. B, Bland‐Altman plot showing difference between FFR measured with adenosine and FFR measured with regadenoson

3.3. Side effects

There was no adverse side effect reported from either medication. Furthermore, there was no premature termination of the FFR procedure due to unexpected patient symptoms.

4. DISCUSSION

In this study, a single IV bolus of regadenoson was found to be equivalent to weight‐based adenosine infusion with regards to assessing FFR measurements across intermediate coronary stenoses. Time to reversal of regadenoson with aminophylline averaged less than 2 minutes, allowing for safe reversal of the drug should adverse side effects occur.

Aminophylline reversal has been well studied in regadenoson stress myocardial perfusion and cardiovascular magnetic resonance perfusion studies.14, 15 However, the use of aminophylline reversal during regadenoson‐induced hyperemia for FFR measurements has not been studied. To our knowledge, this is the first study that demonstrates the clinical utility of aminophylline reversal following regadenoson administration for FFR testing. Previous single‐center studies have implemented sequential adenosine infusion followed by IV bolus regadenoson in the same patient during clinically indicated FFR testing in order to evaluate the clinical utility of regadenoson.8, 10, 11 Each study demonstrated consistency of final FFR values using both pharmacological agents and concluded that regadenoson was a better tolerated and more rapid option compared to weight‐based adenosine infusion. Furthermore, no significant differences were found between the hemodynamic effects of regadenoson bolus vs adenosine infusion and the mechanism of IV access (peripheral vs central) in FFR testing.10 More recently, a multicenter analysis found potential clinical utility of regadenoson in a more diverse patient population with greater atherosclerotic disease burden, and also supported the use of regadenoson as an alternative to adenosine for FFR coronary measurements.9

Though studies have shown that regadenoson is equivalent to adenosine with regards to FFR testing, there are significant cost differences between these pharmacological agents. Regadenoson with aminophylline is likely to be more expensive when compared to adenosine based on average wholesale pricing16; however, the utility of regadenoson extends beyond cost alone. Although aminophylline is a safe and effective reversal agent for regadenoson, most patients would not require reversal given regadenoson's limited side effect profile. In the same vein, regadenoson can be used in severe COPD and asthmatic patients, two disease states in which adenosine is contraindicated.17 In addition, the quick onset of action of regadenoson and ease of administration would allow for quicker turn around time following procedures. In the appropriate clinical scenario, regadenoson can be used as an alternative agent to adenosine in FFR testing.

FFR plays an important role in the management of patients with CAD, as supported by the FAME I and FAME II trials, which showed the benefit of FFR‐guided angiography compared to angiography alone in patients undergoing percutaneous coronary intervention (PCI).2, 3 Since the publication of these trials, there has been a significant increase in utilization of FFR, with an 18‐fold rise in the number of FFR‐guided PCIs in the United States between 2008 and 2012.18

Given regadenoson's ease of administration, favorable side effect profile and the ability to rapidly reverse hemodynamic effects with aminophylline, its routine use for FFR measurements would allow for the expansion of FFR testing, thus providing guidance regarding possible interventions for moderate coronary artery lesions identified during angiography. Our direct comparison of adenosine and regadenoson shows that these agents produce equivalent FFR measurements, and regadenoson's greater ease of use may eliminate the need for time‐intensive adenosine weight‐based infusions. The application of aminophylline reversal of regadenoson‐induced hyperemia (return to baseline within ~2 minutes) in FFR testing allows for safe administration of regadenoson.

4.1. Limitations

This is a single‐center study with a limited number of patients. All patients received adenosine infusion followed by single IV bolus of regadenoson, and findings could differ if the order of drug administration were randomized. Time measurements were not collected with adenosine given prior well‐studied kinetics of washout period.13 The FFR nadir following regadenoson administration was not measured, as this was not the focus of the study. However, time to reversal with regadenoson was measured once the nadir was reached. We acknowledge that instantaneous wave‐free ratio (iFR), a technology that recent studies have shown may be equivalent to FFR and potentially eliminate the need of either adenosine or regadenoson, was not used in this study.19, 20 As the seminal paper describing iFR was published after our study began enrolling patients, we were unable to analyze the utility of iFR in this setting.21 Furthermore, as the study was limited to one coronary lesion per patient, our data may not be applicable to procedures requiring multiple measurements of FFR.

5. CONCLUSION

The use of regadenoson for FFR measurements provides results consistent with those obtained with adenosine infusion. Aminophylline reversal of regadenoson is fast, well‐tolerated, and safe. Regadenoson with aminophylline reversal may be considered an alternative to adenosine for FFR measurements, and may have positive implications on the ease and utility of FFR testing.

Edward JA, Lee JH, White CJ, Morin DP, Bober R. Intravenous regadenoson with aminophylline reversal is safe and equivalent to intravenous adenosine infusion for fractional flow reserve measurements. Clin Cardiol. 2018;41:1348–1352. 10.1002/clc.23052