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.
