Original Article
Asystole following regadenoson infusion in stable outpatients

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Abstract

Regadenoson is a selective A2A receptor agonist approved for use as a pharmacologic stress agent for myocardial perfusion imaging after several multicenter trials demonstrated its equivalence in diagnostic accuracy for the detection of coronary artery disease and a decreased incidence of serious side effects as compared to adenosine. Recently, the FDA released a safety announcement advising of the rare but serious risk of heart attack and death associated with regadenoson and adenosine in cardiac stress testing, particularly in patients with unstable angina or cardiovascular instability. We report two cases of asystole with hemodynamic collapse in stable outpatients soon after receiving a standard regadenoson injection. The prevalence of potentially life threatening bradycardia, including asystole, associated with the use of regadenoson may be greater than previously expected. These cases highlight the need for cardiac stress labs to anticipate the potential for serious side effects with all patients during the administration of coronary vasodilators.

Introduction

Regadenoson is a selective A2A receptor agonist approved for use as a pharmacologic stress agent for myocardial perfusion imaging (MPI) in 2008 after several multicenter trials demonstrated its equivalence to adenosine in diagnostic accuracy for the detection of coronary artery disease (CAD).1,2 Based on the molecule’s designed selectivity to the A2A receptor compared to the A1, A2B, and A3 receptors, fewer undesirable side effects such as flushing, dyspnea, hypotension, and bronchospasm were expected. Results of the Advance MPI Trial reported the incidence of serious side effects was significantly lower in the regadenoson vs the adenosine group.3 Based on a tenfold reduction in affinity for the A1 receptor, the incidence of symptomatic bradycardia was also expected to be minimal. Phase 3 trials did not report episodes of high grade atrioventricular (AV) block. However, post-marketing surveillance has identified a case of complete heart block and a case of asystole.3,4 Recently, the FDA released a safety announcement advising of the rare but serious risk of heart attack and death associated with regadenoson and adenosine in cardiac stress testing, particularly in patients with unstable angina or cardiovascular instability.5, 6, 7 We report two cases of life threatening asystole with hemodynamic collapse in stable outpatients soon after receiving a standard regadenoson injection.

A 65-year-old female with a history of heart failure with preserved ejection fraction, hypertension, dyslipidemia, bilateral knee osteoarthritis, and diabetes mellitus was seen in follow-up for CAD 3 years after drug eluting stent placement in the left anterior descending, right, and posterior descending coronary arteries. Prior stress tests had all been exercise echocardiograms, the most recent of which was over 3 years ago, prior to her PCI. Due to easy fatigability, pharmacologic MPI was requested to evaluate for ischemia. The patient’s medications at the time of evaluation were carvedilol, lisinopril, aspirin, rosuvastatin, fenofibrate, furosemide, fish oil, liraglutide, subcutaneous insulin, ferrous sulfate, and levothyroxine. Her baseline electrocardiogram (ECG) showed normal sinus rhythm with nonspecific ST-T wave abnormalities and nondiagnostic q waves in the inferior leads (Figure 1A). Carvedilol was held the day of the exam.

Utilizing a standard protocol, 0.4 mg of regadenoson was injected over 15 seconds while the patient was walking at a 1 mph on a 0% incline treadmill. Within seconds, she felt lightheaded, her heart rate (HR) decreased from 87 to 60 bpm, and her blood pressure (BP) from 144/98 to 103/40 mm Hg. Thirty seconds after regadenoson infusion, downsloping ST depression were noted in leads II, III, and aVF (Figure 1B). Forty-five seconds after infusion, she developed severe sinus bradycardia with first degree atrioventricular delay and subsequent asystole (Figure 1C). Cardiopulmonary resuscitation was performed for 2 minutes. Circulation was restored prior to the administration of aminophylline or other medications. She was pale and diaphoretic yet alert, oriented and without focal neurologic deficit. Intermittent nonsustained ventricular tachycardia was noted. Over 8 minutes after infusion, she continued to demonstrate nonspecific ST depression (Figure 1D). She was emergently transported for inpatient monitoring.

Upon arrival to the hospital, she was hemodynamically stable and her serum electrolytes, creatinine and CK-MB were within normal limits. Troponin T was undetectable. Thyroid stimulating hormone level was within normal limits 3 months prior to admission. Stress imaging was performed and demonstrated a subtle anterior and anteroseptal defect (Figure 2A). Coronary angiography showed modest progression of native coronary artery disease, patent stents, mildly elevated filling pressures, and normal left ventricular systolic function (Figure 2B, C). Subsequent merging of the outpatient and inpatient SPECT scans suggested no significant ischemia. She was managed with an adjusted medical regimen.

In follow-up 1 week later, she was doing well except for some mild sternal discomfort which was attributed to the CPR. Twenty-four-hour Holter monitoring revealed rare supraventricular ectopic beats and one ventricular ectopic beat. Two months after her stress test, was back working full time.

A 73-year-old male with history of hypertension, paroxysmal atrial fibrillation, mild obstructive sleep apnea effectively treated with continuous positive airway pressure ventilation, and osteoarthritis was referred for regadenoson Tc99m sestamibi SPECT to evaluate 2 months of progressive dyspnea on exertion and fatigue. Stress echocardiography 8 years prior had been unremarkable. His baseline medications included aspirin, fish oil, finasteride, folic acid, and vitamins A, C, and B12. He held his atenolol the morning of the test.

The resting ECG showed atrial fibrillation at 72 bpm (Figure 3A). Thirty seconds after injection of 0.4 mg of regadenoson while at rest, he felt warm and lightheaded. The ECG at that time showed atrial fibrillation with a ventricular rate of 69 bpm and was without significant change from baseline. Forty-two seconds after injection, he became unresponsive and continuous ECG monitoring showed asystole (Figure 3B). After several chest compressions, circulation returned with a ventricular rate in the 30-40 bpm range. He was responsive, diaphoretic, and had borderline hypotension. His consciousness waxed and waned for several seconds. Aminophylline 75 mg IV and a normal saline bolus were administered. Two minutes after regadenoson administration, there was one further abrupt asystolic event that spontaneously resolved with restoration of atrial fibrillation with a ventricular response of 30-40 bpm (Figure 3C). No ischemic changes were noted on the ECG. Normal perfusion was demonstrated with Tc99m sestamibi SPECT. He was monitored in the cardiology clinic until complete resolution of his symptoms. He remained hemodynamically stable and neurocognitively intact, and was released with close outpatient follow-up.

One week later, he reported improved exertional capacity on adjusted rate controlling agents for his atrial fibrillation. Four months later, after several weeks of therapeutic oral anticoagulation, he underwent direct current cardioversion to restore sinus rhythm. One month after cardioversion, he reported intermittent mild palpitations and was noted to be back in atrial fibrillation. He elected to continue with a rate control and anticoagulation strategy.

Section snippets

Discussion

The receptor affinity profile for the A2A receptor agonist regadenoson was intended to affect coronary vasodilation by achieving coronary hyperemia while minimizing undesirable side effects associated with activation of other adenosine receptors. Despite no episodes of serious bradycardia during large-scale multicenter clinical trials, multiple cases of high grade AV block have been identified since its approval by the FDA.3,4 Recently, the FDA has released warnings of heart attack and death

New Knowledge Gained

Asystole with hemodynamic collapse was not previously recognized as an adverse effect of regadenoson in stable patients. The risk factors for and mechanism behind these events remain undefined but might involve a heightened vasovagal response in susceptible individuals, possibly in combination with an as yet undefined effect on hypothalamic and cardiac A2A receptors.

Conclusion

Currently, the FDA warning on use of these cardiac nuclear stress-testing agents applies to patients with unstable angina or cardiovascular instability; however, the cases in this report represented outpatient stress tests in stable patients without angina. Until further data is available, we emphasize the importance of having readily available resuscitation equipment during and after administration of vasodilators for MPI. Staff must be trained and knowledgeable about the rare but potentially

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