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(Circulation. 2004;109:457-464.)
© 2004 American Heart Association, Inc.

Clinical Investigation and Reports

Randomized, Controlled Dose-Ranging Study of the Selective Adenosine A_2A Receptor Agonist Binodenoson for Pharmacological Stress as an Adjunct to Myocardial Perfusion Imaging

James E. Udelson, MD; Gary V. Heller, MD, PhD; Frans J.Th. Wackers, MD; Andrew Chai, MD; David Hinchman, MD; Patrick S. Coleman, MD; Vasken Dilsizian, MD; Marcello DiCarli, MD; Rory Hachamovitch, MD; James R. Johnson, PhD; Richard J. Barrett, PhD; Raymond J. Gibbons, MD

From the Division of Cardiology, Tufts-New England Medical Center, Boston, Mass (J.E.U.); Henry Low Heart Center, Hartford Hospital, Hartford, Conn, and the University of Connecticut School of Medicine, Farmington (G.V.H.); Cardiovascular Division, Yale University School of Medicine, New Haven, Conn (F.J.T.W.); Idaho Cardiology Associates, Boise, Idaho (A.C., D.H.); Northern California Medical Associates, Santa Rosa, Calif (P.S.C.); Division of Nuclear Medicine, University of Maryland School of Medicine, Baltimore, Md (V.D.); Division of Cardiology, University of Southern California Medical School, Los Angeles, Calif (R.H.); Division of Nuclear Medicine, Brigham and Women’s Hospital, Boston, Mass (M.D.); King Pharmaceuticals Research and Development, Cary, NC (J.R.J., R.J.B.); and Cardiovascular Division, Mayo Clinic, Rochester, Minn (R.J.G.).

Correspondence to James E. Udelson, MD, Division of Cardiology, Box 70, Tufts-New England Medical Center, 750 Washington St, Boston, MA 02111. E-mail judelson{at}tufts-nemc.org

Received September 18, 2003; de novo received October 29, 2003; revision received December 3, 2003; accepted December 5, 2003.

	Abstract

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Background— Dipyridamole and adenosine cause frequent side effects as a result of nonspecific adenosine receptor stimulation. Selective agonism of the adenosine A_2A receptor should result in a similar degree of coronary vasodilation (and thus similar perfusion images) with fewer side effects.

Methods and Results— In a multicenter, randomized, single-blind, 2-arm crossover trial, 240 patients underwent 2 single photon emission computed tomographic (SPECT) imaging studies in random order, first after pharmacological stress with adenosine and a second study with the selective adenosine A_2A receptor agonist binodenoson, using 1 of 4 dosing regimens. Safety, tolerability, and SPECT image concordance between the 2 agents were examined. Exact categorical agreement in the extent and severity of reversible perfusion defects ranged from 79% to 87%, with kappa values from 0.69 to 0.85, indicating very good to excellent agreement between binodenoson and adenosine. The risk of any safety event/side effect was significantly lower with any dose of binodenoson than with adenosine (P0.01) because of a dose-related reduction in subjective side effects, as objective events were infrequent. There was a reduction in the severity of chest pain, dyspnea, and flushing in all binodenoson doses compared with adenosine (P<0.01), and the magnitude of severity reduction was dose-related.

Conclusions— The selective adenosine A_2A receptor agonist binodenoson results in an extent and severity of reversible perfusion defects on SPECT imaging similar to nonselective adenosine receptor stimulation, accompanied by a dose-related reduction in the incidence and severity of side effects.

Key Words: scintigraphy • adenosine • imaging • nuclear medicine

	Introduction

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Seminal studies by Gould et al^1–3 described the mechanisms and physiological consequences of pharmacological stress for inducing coronary hyperemia and the effect of a coronary stenosis in animal models. Dipyridamole and adenosine both induce coronary arteriolar vasodilation associated with a hyperemic coronary flow due to stimulation of adenosine A_2A receptors on arteriolar vascular smooth muscle cells, causing vasorelaxation.^4,5 Adenosine also nonselectively activates adenosine A₁, A_2B, and A₃ receptors, contributing to many of the common and untoward side effects associated with pharmacological stress testing. Less frequent serious effects such as high-degree atrioventricular (AV) block and bronchospasm may also result from stimulation of the A₁ and A_2B adenosine receptors, respectively.^6–9

More selective agonism of the adenosine A_2A receptor subtype should theoretically result in a similar degree of coronary vasodilation with fewer and/or less severe side effects than nonselective adenosine receptor stimulation. Binodenoson {2 [{cyclohexylmethylene}hydrazino]adenosine), also known as MRE0470 and WRC0470} is a highly selective agonist at the adenosine A_2A receptor with much weaker affinity for the adenosine A₁, A_2B, and A₃ receptor subtypes.^10–12 Binodenoson has been studied predominantly in the catheterization laboratory setting, producing dose-related increases in coronary blood flow velocity, with mean maximal coronary vasodilatory responses equivalent to those produced by intracoronary adenosine.^13,14 Maximal hyperemic responses were maintained for several minutes—a period long enough for the myocardium to extract sufficient ²⁰¹thallium or ^99mTc-based tracers to produce high-quality single photon emission computed tomographic (SPECT) images.

The hypothesis of this study was that administration of this agent would result in myocardial perfusion images similar to those of nonselective adenosine receptor stimulation, accompanied by fewer and/or less severe symptoms and adverse events. We also examined a range of doses of binodenoson that appeared efficacious in coronary flow studies to select the optimal dose for future studies.

	Methods

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Study Design
This study was designed as a multicenter, randomized, single-blind, 2-arm crossover trial. After signing informed consent, eligible patients underwent an adenosine SPECT myocardial perfusion imaging (MPI) study and a binodenoson SPECT study in random order and were also randomized to 1 of the 4 binodenoson dosing regimens. The following 4 binodenoson dosing regimens were evaluated: 0.5 µg/kg bolus over 30 seconds, 1 µg/kg bolus over 30 seconds, 1.5 µg/kg bolus over 30 seconds, and 0.5 µg/kg · min^-1 infusion for 3 minutes (1.5 µg/kg total dose). The second MPI procedure was performed within 2 to 7 days of the first MPI procedure, under similar conditions. By design, results of the clinically ordered adenosine study were not to be reported until both imaging studies were completed. The study was approved by appropriate Human Investigation Review Boards for all participating centers.

Study Population
To optimize the occurrence of reversible perfusion defects that were of primary interest for the concordance analysis, only symptomatic patients with known coronary artery disease (CAD; ie, history of myocardial infarction, revascularization, or documented CAD by prior angiography) or a high pretest likelihood of CAD (as determined by the American College of Cardiology/American Heart Association Guidelines for Exercise Stress Testing¹⁵) were enrolled. Criteria for ineligibility included the following: history of acute myocardial infarction or revascularization within 30 days, history of asthma or bronchospasm, presence of baseline second- or third-degree AV block in the absence of permanent pacemaker, or left ventricular ejection fraction 0.35.

MPI Studies
Both of the MPI procedures for each patient were conducted under identical conditions, including the following: background medication, radiopharmaceuticals (including isotope doses and times of injection after study medication), image acquisition protocols, image acquisitions at consistent times after isotope injection, use of the same camera and all technical/camera details, imaging at approximately the same time of day, fasting for the same amount of time before each MPI procedure, and discontinuation of caffeine and methylxanthines for 24 hours. Antianginal medications were withheld before each MPI procedure according to each imaging laboratory’s usual practices.

Images were acquired after injection with ²⁰¹thallium and/or ^99mTc-sestamibi at doses recommended per protocol. SPECT image acquisition parameters and quality control procedures were recommended according to the guidelines of the American Society of Nuclear Cardiology.¹⁶

Drug administration for pharmacological stress was performed in a single-blind manner, with the patient unaware of treatment assignment. Adenosine was used according to the FDA-approved dose of 140 µg/kg · min^-1 for 6 minutes, with isotope injection at the third minute of infusion. Patients were dosed with binodenoson according to their body weight using dosing nomograms. The 3 binodenoson bolus doses were injected over 30 seconds into a peripheral vein, and isotope was injected for stress imaging at 3.5 minutes after starting the bolus injection. The 1.5 µg/kg infusion was administered over 3 minutes via an infusion pump, and isotope was injected at the end of the 3-minute infusion. Selection of these doses was based on results of catheterization laboratory trials,^13,14 suggesting that the optimal binodenoson dose was between 0.5 and 1.5 µg/kg.

Study Sample Size
Statistical comparisons were to be based on a 1-sided test of significance for differences in concordance, at a 10% level of significance, and a power of 80%, for all pairwise treatment comparisons. Assumptions regarding concordance and safety and tolerability yielded a sample size of 52 patients per binodenoson dosing regimen. An additional 15% (8 patients) were to be enrolled in each binodenoson dosing regimen to account for dropouts and study withdrawals, for a total sample size of 240 patients. The intention-to-treat population included all patients who received any study medication and was used to establish the comparative side effect profile. The SPECT image concordance population included all patients who completed both adenosine and binodenoson SPECT studies and was used to evaluate SPECT image concordance.

Safety and Symptomatic Side Effect Analysis
The prespecified major safety analysis compared of binodenoson and adenosine for the objective safety endpoints of second- or third-degree AV block, tachycardia (heart rate >125 bpm), bronchospasm (with confirmation of wheezing), or significant hypotension (systolic blood pressure <70 mm Hg).

A composite patient tolerability assessment analyzed the 3 most common symptoms seen with adenosine, chest pain, shortness of breath, and/or flushing. Patients who reported 1 of these side effects within 60 minutes of receiving either study agent were asked to rate the intensity using a validated visual analog scale of 1 to 10 (VAS).¹⁷ The total score for each patient thus could range from 0 for patients who did not experience any of the symptoms to 30 for patients who experienced all 3 symptoms at maximum intensity.

Where appropriate, tests of statistical significance between each of the 4 binodenoson dosing regimens and adenosine in the same patients and between the 4 binodenoson dosing regimens were completed. Pairwise statistical comparisons between binodenoson dosing regimens were performed. The frequency distribution of VAS scores was summarized for each binodenoson dose and adenosine, and analyzed using the Fisher exact test. The mean composite patient tolerability VAS scores for each binodenoson dose compared with adenosine were evaluated with ANOVA techniques.

Image Analysis
All SPECT images that were acquired during binodenoson stress and adenosine stress were read by 2 expert nuclear cardiologists at a core nuclear imaging laboratory. The 2 blinded readers analyzed all of the images, were independent of the study (ie, were not involved in data acquisition as study site investigators), and were unaware of the protocol objectives or specifics of the study design. Both sets of stress and rest images from an individual patient were displayed side by side in random order. Each reviewer independently interpreted the images blinded to the stress agent (and dose, for the binodenoson studies) and to the patient’s identity and clinical data. SPECT images were assessed using a 17-segment model and a semiquantitative visual score on a 5-point scale.¹⁶ Summed stress (SSS) and summed rest scores (SRS) were calculated, as was a summed difference score (SDS), to represent the extent and severity of reversible perfusion defects (SDS=SSS-SRS). If the 2 independent readers differed in total SDS score by 2, the scores were averaged to give a final SDS score that was used in the analysis. If there was a discrepancy >2 between the SDS assigned by the 2 primary readers, a third expert nuclear cardiologist read the images. Remaining discrepancies were resolved by consensus. Concordance was based on differences between SDS from each binodenoson and adenosine image, using agreement for prespecified categories of SDS. SDS scores were prospectively defined and grouped as nonischemic (SDS 0 to 1), mildly ischemic (SDS 2 to 4), moderately ischemic (SDS 5 to 8), and severely ischemic (SDS >8) for analysis. In addition, kappa statistics,¹⁸ with corresponding asymptotic standard errors and 95% confidence intervals, were computed. Probability values <0.05 were considered significant.

	Results

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Study Patient Population
Two hundred forty patients were randomized into 1 of the 4 binodenoson groups, of whom 231 received any study medication. Nine patients did not receive any amount of either agent, most often because of consent withdrawal. Of 231 patients receiving study medication, 203 patients formed the SPECT image concordance population, having completed both imaging procedures under identical conditions. The remaining 28 patients were excluded for protocol violations, most often caffeine consumption before either of the imaging sessions, differences in background medications, or incomplete image data.

The demographic and clinical characteristics of the study population are depicted in Table 1. There were no significant differences in any of the baseline characteristics. Imaging protocols used for the patients in the study included same-day rest-stress ^99mTc-sestamibi in 150 patients (74%), dual-isotope rest thallium201/stress ^99mTc-sestamibi in 38 patients (19%), 2-day ^99mTc-sestamibi in 6 patients (3%), and ²⁰¹Tl stress-reinjection in 9 patients (4%).

View this table: [in this window] [in a new window]   TABLE 1. Baseline Characteristics of the Study Population

SPECT Image Concordance
Percent exact agreement in SDS category as well as kappa statistics are shown in Table 2, with correlations depicted in Figure 1. Exact categorical agreement ranged from 79% to 87%, with kappa values from 0.69 to 0.85, indicating very good to excellent agreement in categorizing the extent and severity of reversible perfusion defects between binodenoson and adenosine (Tables 2 and 3 ). On examining individual data points representing SDS (Figure 1), all doses showed good general correlation, with the 1.5 µg/kg bolus dose displaying the closest correlation (Table 2 and Figure 2). The slopes of the regression lines for the 1.5 µg/kg bolus dose and the infusion dose were not significantly different than the line of identity (Figure 1).

View this table: [in this window] [in a new window]   TABLE 2. Concordance of Binodenoson SPECT Reversible Defects with Adenosine SPECT Reversible Defects

View larger version (26K): [in this window] [in a new window]   Figure 1. Correlations of SDSs, representing the extent and severity of reversible perfusion defects, between adenosine (x axes) and the 4 dosing regimens of binodenoson (y axes). SDS scores from all binodenoson doses showed good general correlation with scores obtained during adenosine, with the 1.5 µg/kg bolus dose displaying the closest correlation (Table 2). All patient data are represented; patients with similar data are represented by a single point.

View this table: [in this window] [in a new window]   TABLE 3. Summary of Agreement in SPECT Image Abnormality Categories for Binodenoson and Adenosine

View larger version (72K): [in this window] [in a new window]   Figure 2. Two examples of the concordance of SPECT image results between adenosine (Adeno) and binodenoson at the 1.5 µg/kg bolus dose (Bino 1.5 bolus). The short-axis (top left) and horizontal long-axis (bottom left) SPECT images in patient A demonstrate septal and apical reversible defects similar in extent and severity after pharmacological stress with the 2 agents and a fixed inferior defect. In patient B, short-axis (top right) and vertical long-axis (bottom right) adenosine and binodenoson SPECT images show a concordantly severe reversible anterior defect.

Safety Assessments
The occurrence of second- or third-degree AV block, hypotension, tachycardia >125 bpm, or bronchospasm is depicted in Table 4. These events were uncommon. Seven (3%) of the 226 patients experienced second-degree (n=6) or third-degree (n=1) AV block during adenosine, which was not observed with any of the binodenoson doses (P=0.0075 by Fisher exact test). Significantly fewer patients reported any of the prespecified subjective side effects (chest pain, dyspnea, and flushing) after bolus binodenoson doses than during adenosine infusion (Table 4). There were also fewer side effects seen during the binodenoson 3-minute infusion compared with adenosine, but the difference was not significant. There was a dose-related reduction in the relative risk of experiencing any of the prespecified objective safety events or symptomatic side effects with binodenoson compared with adenosine (Table 4).

View this table: [in this window] [in a new window]   TABLE 4. Incidence of Patients (% of dose group) Reporting any Qualifying Composite Objective Safety Adverse Event (AE) or Composite Subjective Tolerability Adverse Event

Composite VAS scores, used to evaluate the severity of the symptomatic side effects rather than simply their occurrence, are shown in Table 5. There was a significant reduction in the composite VAS score in all binodenoson doses compared with adenosine, with the magnitude of reduction related to dose (r=0.96, P=0.014). Among all binodenoson doses, there were very few reported side effects at the high severity end of the scoring system (ie, >6) compared with adenosine.

View this table: [in this window] [in a new window]   TABLE 5. Patient-Graded Mean (SD) Visual Analog Scores for the Intensity of Subjective Adverse Events

There were no significant differences in the reductions in systolic or diastolic blood pressure between any of the individual binodenoson dosing groups and adenosine administration (Table 6). Maximal changes in heart rate ranged from +18 to +31 bpm. The binodenoson 1.5 µg/kg bolus and the 1.5 µg/kg infusion groups had slightly greater elevations in heart rate than were seen with adenosine in the same patients, a difference of approximately +8 bpm.

View this table: [in this window] [in a new window]   TABLE 6. Comparisons of Maximal Changes in Hemodynamic Parameters with Binodenoson Relative to Adenosine, Mean (SD)

	Discussion

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The results of this study demonstrate that MPI with the selective adenosine A_2A receptor agonist binodenoson results in SPECT images that are concordant with regard to the extent and severity of reversible perfusion defects with those produced by nonselective adenosine receptor agonism. Consistent with more selective agonism at the adenosine A_2A receptor, second- or third-degree AV block was not observed, subjective side effects with binodenoson occurred less commonly than with adenosine and were significantly less severe.

Of 9256 patients who received intravenous (IV) adenosine in multicenter studies, 81% reported at least 1 adverse effect.⁸ More than one third experienced chest pain, dyspnea, and/or flushing, and 5% experienced second- or third-degree AV block. Adverse effects associated with dipyridamole are usually less severe but more often require reversal with IV aminophylline.^9,19 Both adenosine and dipyridamole may produce bronchospasm in patients with asthma and are contraindicated in such patients.

The development of more selective adenosine A_2A receptor agonists has opened the possibility of effective pharmacological stress for MPI with fewer and/or less severe side effects. The current study was designed to examine the range of binodenoson doses found to produce adequate coronary hyperemia, to determine whether effective SPECT imaging could be performed with these doses, and also to examine the comparative incidence and severity of significant side effects compared with adenosine. Previous studies have examined dose responses with adenosine or dipyridamole for maximizing coronary blood flow reserve.^20–22 Because none of the approved radiopharmaceuticals for MPI track myocardial blood flow well at the high flows achievable with pharmacological stress,²³ this study was designed to assess the dosing of binodenoson using the relevant endpoint for which its use is intended, that is, to induce reversible myocardial perfusion abnormalities. As this agent has substantial selectivity for the adenosine A_2A receptor, this study was designed to find the dose with the highest image concordance with adenosine that was associated with the lowest incidence and severity of side effects.

The results demonstrated very good to excellent image concordance of the binodenoson SPECT data compared with adenosine, with the most concordant imaging data occurring with the 1.5 µg/kg bolus dose. The incidence and severity of side effects during binodenoson administration were dose-related, with fewer and less severe side effects seen at all doses compared with those observed during adenosine, consistent with the receptor selectivity. The results also suggest that bolus dosing results in effective MPI data, obviating the need for an infusion pump required during adenosine administration.

Despite the very high selectivity for the adenosine A_2A receptor in preclinical studies, side effects attributable to other adenosine receptor subtypes,²⁴ such as chest pain, were still observed, albeit less often than with adenosine. It is possible that chest pain was due to myocardial ischemia from a coronary steal in patients with underlying CAD, rather than as a side effect related to adenosine A₁ receptor agonism. The fact that adenosine produced high-grade AV block in 7 patients (3%) but binodenoson had no such effect supports the lack of affinity of binodenoson for the A₁ receptor subtype. As the first selective adenosine A_2A agonist to be administered to humans, binodenoson provides an opportunity to define the human pharmacological responses to stimulation of this receptor. It is possible that the selectivity of binodenoson for the A_2A receptor may not be as high in vivo in humans as in animal models and in isolated cells and tissues. Nonetheless, the lower frequency and severity of side effects observed in this study with binodenoson compared with adenosine infusion is consistent with clinically relevant A_2A receptor selectivity.

The generalizability of the results of this study is constrained by certain limitations. The study was single-blind, such that patients were not aware of whether they were receiving adenosine or binodenoson. As the investigative team was aware of treatment assignment, bias may have entered into the reporting of patient side effects and side effect severity. Efforts were made to minimize such bias by asking patients to score symptom severity using the VAS tool without leading questions. The dose-related differences in side effect profile for binodenoson compared with adenosine suggest a true effect. Definitive evaluation of comparative side effect profile would require double blinding. The study inclusion criteria were designed to optimize the occurrence of reversible defects by limiting inclusion to those with high likelihood of CAD or known CAD with symptoms suggestive of possible ischemia. Future studies will need to incorporate the broader range of patients more typically studied in nuclear cardiology laboratories. The adenosine dosing was that approved by the US FDA in accordance with its labeling. Thus, the data on comparative side effects profiles are not necessarily applicable to other iterations of adenosine dosing, such as shorter infusions or adenosine combined with low-level exercise. Differences between binodenoson and such protocols are likely to be smaller than those observed in this study. Patients with a history of bronchospasm were not included in this study, although the receptor selectivity suggests potential safety of binodenoson in this population. Finally, these data apply to concordance of SPECT radionuclide perfusion images predominantly performed with ^99mTc sestamibi. Full applicability to thallium201 imaging will require more patients studied with that tracer. The data do suggest promise for the use of binodenoson in conjunction with other modalities interrogating myocardial perfusion, such as positron emission tomography or cardiac MRI.

Hence, pharmacological stress with the selective adenosine A_2A receptor agonist binodenoson resulted in an extent and severity of reversible perfusion defects on SPECT imaging similar to that observed with nonselective adenosine receptor stimulation, using predominantly Tc^99m-based imaging. More selective adenosine A_2A receptor agonism was associated with a reduction in the incidence and severity of subjective side effects compared with adenosine administration, and the magnitude of that reduction was related to the dose of binodenoson. The SPECT imaging concordance data and the safety and side effect profile suggest that this agent is an effective pharmacological stress agent for MPI.

	Acknowledgments

 
All authors and/or their institutions received grant support for their participation in this study from King Pharmaceuticals Research and Development, Inc. Drs Udelson and Gibbons are consultants to, and Drs Johnson and Barrett are employees of, King Pharmaceuticals Research and Development, Inc.

This study was funded by King Pharmaceuticals Research and Development, Inc.

The following investigators participated in this study: M. Ahmed, MD; L. Altschul, MD; J. Arrighi, MD; J. Baird, MD; M. Bilsker, MD; E. Botvinick, MD; R. Braastad, MD; C. Brown, MD; D. Calnon, MD; B. Chandler, MD; R. DesPrez, MD; N. Dhruva, MD; J. Foster Jr, MD; R. Gal, MD; A. Gomez, MD; T. Guest, MD; H. Haught, MD; L. Heller, MD; T. Holly, MD; D. Jain, MD; S. Kapadia, MD; M. Klapholz, MD; B. McCallister, MD; R. McGhe, MD; A. Movahed, MD; M. Nathan, MD; S. Port, MD; J. Rosenblatt, MD; G. Shuyler, MD; R. Schwartz, MD; D. Shonkoff, MD; T. Sias, MD; P. Tilkemeier, MD; W. Van Decker, MD; M.N. Walsh, MD; and F. Whittier, MD.

The Imaging Core Laboratory is at Beacon Biosciences, Doylestown, Pa.

Independent Data Monitoring Committee comprised Leslee Shaw, PhD (Chair); Jeffrey Anderson, MD; Patrick O’Gara, MD; Robert O’Rourke, MD; and George Vetrovec, MD.

	Footnotes

 
This article originally appeared Online on January 20, 2004 (Circulation. 2004;109:r15–r22).

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