Successful Reversal of Bradycardia and Dyspnea With Aminophylline After Ticagrelor Load

Introduction

Ticagrelor, a P2Y₁₂ receptor antagonist, is an antiplatelet agent approved for the treatment of patients with acute coronary syndromes (ACSs). ¹ Ticagrelor use increased following the Platelet Inhibition and Patient Outcomes (PLATO) trial, which demonstrated significant reduction in rates of myocardial infarction, stent thrombosis, cardiovascular death, and all-cause mortality when compared to clopidogrel in patients with ACS. ² Further elucidation of the pharmacodynamic properties of ticagrelor ensued, and increased adenosine plasma concentrations were identified as a result of inhibition of adenosine reuptake by ticagrelor. ^{3 –5} Increased adenosine exposure has been theorized to explain the unique adverse effects of dyspnea and bradyarrhythmia reported with ticagrelor therapy. ^{1 –5} Potential treatment options for ticagrelor-associated dyspnea and bradyarrhythmia may include adenosine antagonism. This case describes successful reversal of ticagrelor-induced dyspnea and bradyarrhythmia using aminophylline, an adenosine receptor antagonist, following percutaneous coronary intervention in a patient with significant respiratory disease.

Case

A 69-year-old white male presented for elective coronary angiography. Pertinent medical history included multivessel coronary artery disease, heart failure with preserved ejection fraction of 54% on echocardiogram, non–small cell lung cancer with resultant radiation pneumonitis requiring 3 L/min of oxygen via nasal cannula, obstructive sleep apnea, hypertension, hypercholesteremia, diabetes mellitus, and obesity. Diagnostic coronary angiography revealed a lesion in the left anterior descending artery deemed nonsignificant by fractional flow reserve following 180 µg of intracoronary adenosine administration. Additionally, a proximal 80% lesion was identified in the first obtuse marginal artery, for which a PROMUS 2.5 × 16 mm drug-eluting stent (Boston Scientific, Natick, Massachusetts) was placed. Ticagrelor 180 mg and aspirin 325 mg were given orally within 15 minutes of stent deployment. All vitals remained stable during the intervention and immediately following, and the patient reported no new symptoms immediately following the intervention.

Approximately 4 hours following ticagrelor administration, the patient experienced new-onset shortness of breath. Oxygen therapy was increased to 5 L/min via nasal cannula from 3 L/min required at baseline, bronchodilator treatment was provided, and ultimately a nonrebreather mask was applied. Additionally, 3 episodes of sinus pause were identified on cardiac telemetry, with the longest pause lasting 10 seconds. The patient reported dyspnea, feeling “doomed,” and as though he “blacked out.” Subsequent electrocardiogram and cardiac enzyme evaluations indicated no evidence of new myocardial injury. To reverse the adenosine-mediated adverse effects of ticagrelor, 100 mg of aminophylline was administered via intravenous push over 3 to 5 minutes. Neither atropine nor epinephrine was required. Following aminophylline administration, the patient reported improvement in shortness of breath and was weaned to his home oxygen requirements of 3 L/min. No further sinus pauses occurred following aminophylline. Ultimately, ticagrelor was discontinued, and the patient was loaded with clopidogrel 600 mg followed by 75 mg daily. The patient remained in normal sinus rhythm and was discharged 2 days later without any further complications.

Discussion

The proposed mechanism behind ticagrelor-induced bradyarrhythmia and dyspnea is the inhibition of adenosine reuptake into red blood cells, providing increased adenosine concentrations in both in vitro and in vivo studies. ^{3,6 –8} Although bradyarrhythmia and dyspnea have not been definitively reported to occur simultaneously despite sharing a proposed mechanism, both symptoms have been reported separately. ^{9 –11} The proposed mechanism behind adenosine-induced dyspnea is stimulation of vagal C fibers within the lungs as opposed to bronchospasm. ^{12 –14} The incidence of ticagrelor-associated dyspnea reportedly occurs in 10% to 40% of patients, with an absolute increase ranging from 4% to 29% relative to clopidogrel. Onset commonly occurs within the first week of therapy, with mild-to-moderate symptoms and infrequent drug discontinuation. ² More recently, however, an evaluation of ticagrelor therapy following ACS identified discontinuation rates in 17% of patients within the first month, of which 56% were due to dyspnea. ¹⁵ Symptom resolution reportedly occurs after ticagrelor discontinuation, and no underlying pathologic cardiac or pulmonary abnormalities have been identified. ^{16 –18}

A substudy of patients in the PLATO trial underwent Holter monitoring for 6 days following initiation of treatment. Ventricular pauses lasting ≥3 seconds occurred in 5.8% of patients in the ticagrelor group versus 3.6% in the clopidogrel group (P = .006). ¹⁶ The incidents were infrequent, transient, predominantly asymptomatic, and did not affect the mortality benefit of ticagrelor therapy. Importantly, patients at risk for bradyarrhythmia were excluded from the PLATO trial, limiting application to these patients in practice. A recent case report describes a patient who experienced syncope associated with a ventricular pause lasting 11 seconds just 4 hours after a ticagrelor loading dose. ¹⁹ Despite discontinuation of ticagrelor and additive treatment with atropine and dopamine, complete atrioventricular block persisted and emergency pacing was required for 2 days. The patient was successfully transitioned from ticagrelor to clopidogrel and discharged without a pacemaker.

To reverse the effects of adenosine during cardiac stress testing, theophylline and aminophylline have been successfully utilized for their antagonism of adenosine receptors. ^10,20,21 In patients undergoing single photon emission computed tomography imaging for coronary artery disease, theophylline decreased the efficacy of dipyridamole, an antiplatelet agent with more potent inhibition of adenosine reuptake relative to ticagrelor. ^22,23 Furthermore, theophylline improved symptoms of dyspnea in patients treated with ticagrelor undergoing a coronary vasodilation study with adenosine. ⁶ Successful symptom resolution by an adenosine antagonist supports the mechanism of adenosine-mediated dyspnea. The aminophylline dose and route used to manage this patient’s symptoms were consistent with previously reported use for adenosine reversal. ¹⁰

This patient’s onset of symptoms occurred 4 hours following the first dose of ticagrelor, consistent with previous reports. ^2,19 Using the Naranjo assessment to predict adverse drug reactions, ticagrelor resulted as a probable cause of this patient’s bradyarrhythmia and dyspnea, scoring 7 points of 10 for positive prior reports of association, temporal relationship, improvement with drug discontinuation, no alternative causes, and event confirmed by objective evidence. ²⁴ Although concern exists for prolonged exogenous adenosine exposure in patients receiving ticagrelor therapy and undergoing cardiac stress testing, it is less likely that exogenous adenosine contributed to this patient’s symptoms. Adenosine half-life is <10 seconds, and the drug would have cleared completely prior to ticagrelor administration. ²⁵ Underlying respiratory disease may have contributed to dyspnea in this patient but cannot explain ventricular pauses. Given this patient’s symptoms may be explained by the ability of ticagrelor to inhibit adenosine reuptake into red blood cells, aminophylline was administered to reverse the effects of adenosine. The onset of dyspnea and bradycardia for this patient correlated with ticagrelor administration. Furthermore, the prompt resolution after aminophylline strengthens the case of adenosine-induced symptoms.

Conclusion

This case is the first report of resolution of ticagrelor-induced bradyarrhythmia and dyspnea after administration of an adenosine antagonist. A previous case reported unsuccessful management with atropine and dopamine that ultimately required emergency pacing. ¹⁹ Given the severity of symptoms displayed in this case, clinicians should be aware of these potential adverse effects, and new patients should be counseled to report any symptoms immediately. Furthermore, providers should be cognizant of the potential additive exposure of adenosine when patients are receiving ticagrelor and undergo a reperfusion study, as this may worsen symptom severity. The use of adenosine antagonists such as aminophylline for reversal fits the known mechanism of ticagrelor-induced bradyarrhythmia and dyspnea. This case provides support for the use of aminophylline as a potential reversal agent, given the successful resolution of symptoms and outcomes for this patient.