An Example of the Clinical Selectivity of Regadenoson for the A2a Adenosine Receptor

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Gregory S Thomas serves as a consultant for Astellas and Lantheus and is a former consultant for Cardiovascular Therapeutics (now Gilead Sciences). Luiz Berlardinelli is an employee of Gilead Sciences.
American Heart Hospital Journal 2009;7(2):118–21

The US Food and Drug Administration (FDA) approved the first selective A2a adenosine receptor agent for myocardial stress perfusion imaging, regadenoson, on April 10, 2008. The chief goal of this second-generation pharmacological stress agent is to selectively and transiently stimulate the A2a receptors to elicit the coronary vasodilation required for pharmacological single-photon-emission computed tomography (SPECT) imaging while avoiding the stimulation of the three other known adenosine receptor subtypes (i.e. A1, A2b, and A3) and the subsequent undesirable and serious side effects caused by their activation.

Case Report

A 73-year-old, 250lb male with a history of hypertension, dyslipidemia, and diabetes who developed paroxysmal atrial fibrillation was referred for a two-day adenosine sestamibi myocardial perfusion study. He was enrolled in the Adenoscan® Versus Regadenoson Comparative Evaluation for Myocardial Perfusion Imaging (ADVANCE MPI) phase III study of regadenoson.1 As per protocol, he underwent a six-minute adenosine infusion of 140μg/kg/minute while in a supine position. Resting 12-lead electrocardiogram (ECG) was normal, with a normal sinus rhythm of 74bpm and a P–R interval of 0.20 seconds (see Figure 1). Fifty seconds into the infusion, second-degree AV block occurred, followed 18 seconds later by third-degree atrioventricular (AV) block with five consecutive P-waves without corresponding QRS complexes (see Figure 2). This was followed by sinus rhythm for 30 seconds and another episode of third-degree AV block of eight consecutive P-waves without QRS complexes lasting 6.8 seconds (see Figure 3). During this period, the patient was intermittently pre-syncopal. For the remainder of the infusion, the patient was in sinus rhythm at a rate between 30 and 85bpm. By completion of the infusion he had developed 2mm of ST depression in leads V4–6. Perfusion imaging (see Figure 4) revealed a mild reversible distal anteroseptal defect, although interpretation was challenging due to the patient’s weight. Gated SPECT imaging demonstrated normal left ventricular (LV) function 30 minutes post-exercise with an estimated left ventricular ejection fraction (LVEF) of 56%. Two days later the patient returned for randomization as part of the design of the ADVANCE MPI phase III study.1 Following randomization, the patient underwent a second vasodilator stress SPECT MPI study receiving either adenosine or regadenoson in a blinded fashion. Resting ECG demonstrated non-specific changes with sinus rhythm at a rate of 75bpm, P–R interval of 0.20 seconds, and minimal ST depression in leads I and II.

Heart rate increased by 14bpm and the patient did not experience AV block, any other arrhythmia, or significant ECG changes during this stress MPI study. The four-minute post-drug ECG is shown in Figure 5. Perfusion imaging was unchanged from the initial adenosine study. Medical management was recommended. On conclusion of the ADVANCE MPI study, unblinding demonstrated that the patient had received regadenoson during this second stress study.


While coronary vasodilation is the goal of pharmacological stress testing, stimulation of the A1 receptor can result in AV block and bradycardia.2 Regadenoson is a low-affinity agonist (1μM) for the A2a adenosine receptor that, when stimulated, results in coronary vasodilation comparable to intravenous infusion of adenosine. As coronary arteries have a relatively large number of A2a receptors with substantial reserve capacity,3 only a relatively small percentage of receptors require stimulation to cause maximal coronary vasodilation. The A1 receptors have a low receptor reserve so a high percentage of receptors require stimulation to induce a maximal A1 receptor response. Regadenoson selectively binds to the A2a receptor with a Ki of 1.1–1.73μM with a lower affinity for the A1 receptor, Ki >16.46μM.3 Given the difference in receptor reserve, the clinical selectivity for the A2a receptor relative to the A1 receptor is thus magnified.

In the 1,209 patients who received regadenoson in the phase III ADVANCE MPI trials prior to FDA approval, only one patient developed second-degree AV block.1,4 This patient developed Wenckebach block, ‘dropping’ a single beat three minutes post-regadenoson injection. Whereas high-grade AV block occurred in our patient during adenosine infusion, regadenoson administration was not complicated by AV block. The current case study and the phase III study results are consistent with a high clinical selectivity of regadenoson for the A2a relative to the A1 receptor. Further studies, particularly among patients at high inherent risk for AV block with pharmacological stress, such as patients with sick sinus syndrome or history of AV block, would prove helpful to explore the boundaries of the selectivity of regadenoson for the A2a adenosine receptor subtype.

  1. Cerqueira MD, Nguyen P, Staehr P, 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 regadenoson versus adenosine in myocardial perfusion imaging, J Am Coll Cardiol Img, 2008;1:307–16.
  2. Belardinelli L, Shryock JC, Snowdy S, et al., The A2a adenosine receptor mediates coronary vasodilation, J Pharmacol Exp Ther, 1998;284:1066–73.
  3. Gao Z, Li X, Baker SP, et al., Novel short-acting A2a adenosine receptor agonists for coronary vasodilation: inverse relationship between affinity and duration of action of A2a agonists, J Pharmacol Exp Ther, 2001;298(1):209–18.
  4. Lexiscan prescribing information handbook, Lexiscan (regadenoson) prescribing package insert, Deerfield, IL: Astellas Pharma; January 2009.