Regadenoson-induced bradycardia and hypotension: Possible mechanism and antidote

Abstract

Regadenoson was first approved by the US Food and Drug Administration in 2008 and the USA has the largest experience of its use. The European Medicines Agency gave approval in 2010 and we were the first site outside the Americas to use regadenoson in routine clinical practice. We were therefore surprised to encounter a number of adverse events consisting of bradycardia and hypotension occurring shortly after administration because such episodes had not previously been published. The recent report in this journal of two instances of asystole related to regadenoson indicates that the phenomenon is not unique to our practice. 1Following the report of our first year's experience, 2 occasional vaso-vagal reactions have continued, albeit at a very low frequency. Regadenoson remains our default form of pharmacological stress for myocardial perfusion scintigraphy, but we have become cautious in using it in patients who may not be able to tolerate prolonged hypotension, such as those with severe ischemic left ventricular dysfunction, severe left ventricular outflow obstruction, known cerebrovascular disease and the elderly.We have not been able to identify any predisposing features for bradycardia and hypotension but we have an unproven hypothesis that submaximal exercise and distraction with conversation reduces the risk. A few severe episodes have been preceded by nausea and retching and this may provide a pointer to the mechanism. Although speculative, the association with nausea points to vagal stimulation initiated by A2 receptors in the area postraema, a medullary structure in the floor of the fourth ventricle related to vomiting and autonomic control. Another observation that supports this hypothesis is that we have not been successful in reversing them with aminophylline. One patient with a prolonged sinus bradycardia of 20/minutes and unrecordable blood pressure did not respond to a total of 250 mg aminophylline IV over 2 minutes but did respond within 30 seconds to 0.6 mg atropine IV.Those who use regadenoson should therefore consider the risk of vagal stimulation in each patient and choose an appropriate form of stress. They might also consider atropine in patients with regadenoson-induced bradycardia and/or hypotension that does not respond to simple measures such as head-down posture and/or gentle leg exercise.

Adverse effects associated with regadenoson myocardial perfusion imaging

“…4 Despite this initial observation, there have since been isolated case reports and small case series describing the occurrence of de novo advanced heart block and asystole following regadenoson and requiring immediate management and stabilization. [29][30][31][32][33][34][35] As of June 2017, a total of 56 cases of third-degree heart block and 26 cases of sinus arrest associated with regadenoson stress testing were reported via FAERS. 15 In a recent meta-analysis, the incidence of overall and high-grade AV block-defined as secondand third-degree AV block-related to the administration of regadenoson at the dose given during MPI was low (less than 0.5%) and observed much less frequently with regadenoson compared to adenosine (incidence of de novo overall AV block with adenosine was 8.58%; 95% CI 5.55% to 12.21% vs. regadenoson which was 0.30%; 95% CI 0.04% to 0.82%, P \ 0.001, OR 30.6; 95% CI 11.0 to 85.3; incidence of high-grade AV block for adenosine was 5.21%; 95% CI 2.81%-8.30% vs regadenoson which was 0.05%; 95% CI \ 0.001%-0.19%, P \ 0.001, OR 77.2; 95% CI 20.3 to 293.0) (Figure 1).…”

Regadenoson in Myocardial Perfusion Study - First Institutional Experiences in Bosnia and Herzegovina

“…Post-regadenoson hypotension was attributed to age and insufficient contractility of myocardium. We considered other possible mechanisms such as vagal stimulation proposed by Underwood et al (13) but in our patient hypotension was isolated sign followed by reflex tachycardia without nausea.…”

Serious complications associated with regadenoson administration for myocardial perfusion imaging: A commentary

“…[2][3][4][5][6] One of us summarized the available data on the safety of regadenoson with respect to MI and asystole from clinical trials and post-marketing surveillance and detailed the limitations posed by these sources on our understanding of risk associated with regadenoson use. 7 Underwood et al, 8 in a letter to the editor, describe their experience with regadenoson in Europe. During the first year of using regadenoson for MPI at their center (1,581 consecutive patients, 90% of all patients stressed) they encountered no deaths, MIs, or hospital admissions following MPI but eight patients had adverse events; one experienced bronchospasm and seven had symptomatic hypotension with inappropriate bradycardia.…”

“…5 While one case occurred prior to regadenoson administration and was likely related to intravenous cannulation, two cases progressed to sinus arrest and asystole and required cardiopulmonary resuscitation. After the first year of using regadenoson, Underwood et al 8 report that they continued to experience such events (which they label as vasovagal) at very low frequency. Although they have not been able to identify patients that are at higher risk, they speculate that these events are driven by vagal stimulation and propose that atropine may be more effective at reversing these hemodynamic effects than aminophylline.…”