Ticagrelor- induced bradycardia

By Hasan Shubbarov, AICU : Telemetry Technician  

Brilinta (Ticagrelor), a direct-acting and reversible P2Y₁₂-adenosine diphosphate receptor antagonist, is recommended as a first-line antithrombotic agent in patients with acute coronary syndromes. The superiority of ticagrelor over other P2Y₁₂ antagonists is thought to be mediated in part by pleiotropic properties associated with an increased concentration of adenosine, including cardioprotection, anticoagulant effects, and anti-inflammatory properties. However, these pleiotropic properties can also be responsible for major adverse effects, including electrophysiological consequences. Herein, we describe cyclical sinus bradycardia and atrioventricular (AV) block related to ticagrelor.

Ticagrelor can induce significant bradyarrhythmias. Electrophysiologists should, therefore, be aware of this reversible cause of sinus node dysfunction and AV block in order to manage patients appropriately and avoid unnecessary pacemakers. As this case illustrates, it is possible that the combination of ticagrelor-induced Cheyne-Stokes respiration and bradyarrhythmias can provoke a more severe phenotype consisting of cyclical severe sinus bradycardia with concomitant AV block.

In the setting of an acute coronary syndrome, the differential diagnosis considered included ischemia of the conduction system and ischemia-provoked autonomic dysfunction. However, the time course, with onset of the bradyarrhythmia following ticagrelor loading and rapid recovery upon cessation of therapy, favored the diagnosis of an adverse pharmacologic effect. Bradycardia related to ticagrelor was first described in a phase IIb dose-ranging study, where a post hoc analysis of cardiac arrhythmias revealed an unexpected increased incidence of predominantly asymptomatic ventricular pauses. These findings were corroborated by the prospective PLATO (Platelet Inhibition and Patient Outcomes) trail.

The effect of ticagrelor on sinoatrial and AV nodes is believed to be mediated by an increased tissue concentration of adenosine. Animal experiments and in vitro models demonstrated that ticagrelor interferes with adenosine metabolism, resulting in increased adenosine concentrations via inhibition of adenosine uptake by erythrocytes. This is most likely due to inhibition of sodium-independent equilibrative nucleoside transporters. Consistently, in the clinical realm, ticagrelor has been associated with increased coronary blood flow velocity in patients with acute coronary syndromes, providing a plausible mechanistic explanation for its off-target cardioprotective effects. The adenosine-related hypothesis can also explain the predominance of ticagrelor-associated nocturnal pauses due to an increased local adenosine concentration that enhances vagal-mediated nocturnal bradycardia.

Few reports of clinically significant ticagrelor-related bradycardia requiring drug discontinuation have been published.  Cheyne-Stokes respiration frequently occurs in patients with congestive heart failure and has been associated with exaggerated respiratory heart rate variations. Emerging reports suggest that ticagrelor may itself induce central sleep apnea and Cheyne-Stokes respiration. The pathophysiological explanation remains unclear. Proposed mechanisms include antagonism of microglial P2Y12 receptors and effects on pulmonary C fibers, either as a result of increased adenosine tissue levels or because of putative P2Y12 receptors on pulmonary C fibers.

Conclusion. Extreme caution and close monitoring for development of heart block are needed after initiation of ticagrelor, especially in patients with preexisting conduction defect or on AV nodal blocking agent. Beta blockers may not be the only reason for such cases of symptomatic bradycardia or high grade AV block. Ticagrelor should be considered as the possible offending agent. Other P2Y12 platelet receptor inhibitors such as clopidogrel or prasugrel are suitable alternatives if the patient is at risk for development of a potentially life threatening heart block.