Acute Flecainide Toxicity: A Case Report

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Introduction

Flecainide acetate is an antiarrhythmic agent recommended as one of the first-line therapies for pharmacological conversion as well as maintenance of sinus rhythm in patients with atrial fibrillation and supraventricular tachycardia. Flecainide has the potential to induce proarrhythmic events, even when prescribed as recommended. This is especially true in patients when flecainide is prescribed in higher dosages. Prescribing clinicians should be aware of the clinical manifestations and electrocardiographic changes associated with flecainide-induced drug toxicity. We present a case of a patient with symptomatic atrial fibrillation who experienced acute flecainide toxicity due to the intentional ingestion of 900 mg of flecainide in an attempt to pharmacologically convert his arrhythmia. This case illustrates the importance of prompt symptom and ECG recognition, as well as the specific management of acute flecainide toxicity. It also highlights the clear instruction needed when prescribing “pill-in-the-pocket” drugs such as flecainide in order to prevent consequential adverse events from overdose.

Case Report 

A 76-year-old male with a history of symptomatic paroxysmal atrial fibrillation (PAF) presented to his local emergency room with palpitations, shortness of breath, and near syncope. Initial vital signs included a heart rate of 130 bpm and a blood pressure of 98/63 mmHg. Initial laboratory values included a serum potassium of 4.7 mmol/L, serum magnesium of 2.1 mg/dL, and serum creatinine of 1.97 mg/dL (baseline 0.8 mg/dL). He was found to be in a wide complex tachycardia (QRS duration 180-200 ms) with right bundle branch block morphology and ST segment elevations (Figure 1). Plans were made for urgent transfer to our facility for further management. Initial concern was for acute myocardial injury.

The patient had a history of symptomatic PAF for several months, documented on initial EKG and later confirmed on a 2-week event monitor. There was no evidence of atrial flutter. The patient had a CHA₂DS₂-VASc score of 2 (for age >75), and was not currently on anticoagulation per patient preference. His initial workup included an echocardiogram that demonstrated normal ejection fraction, no significant valvular disease, and mild left atrial dilation, as well as an exercise treadmill stress test without evidence of cardiac ischemia. The patient and his physician decided on a pill-in-the-pocket approach for symptomatic PAF, and he was prescribed flecainide 300 mg and metoprolol 25 mg PO as needed. On the day of presentation, the patient experienced palpitations suggestive of his PAF and as instructed, he took flecainide 300 mg and metoprolol 25 mg at home without acute effect. As he continued to experience symptoms, he took an additional flecainide 300 mg 1 hour later, and another dose of flecainide 300 mg 4 hours later, leading to worsening palpitations and near syncope. 

Based on the history provided by the patient and ECG upon presentation, a diagnosis of acute flecainide toxicity was made and prompt treatment was initiated with intravenous sodium bicarbonate boluses (2 sodium bicarbonate 8.4% 50 mEq ampules) followed by an infusion (sodium chloride 0.45% with sodium bicarbonate 75 mEq) at 75 ml/hr, which resulted in gradual correction of his ECG (Figures 2 and 3) and improvement in symptoms over the next 24 hours. The patient did not exhibit hemodynamic deterioration. He underwent transesophageal echocardiography-guided cardioversion to sinus rhythm (Figure 4) and was discharged home in stable condition. Given his highly symptomatic, drug-refractory atrial fibrillation and atrial flutter, he ultimately underwent combined atrial fibrillation and atrial flutter ablation, and has remained in sinus rhythm and off antiarrhythmic therapy for the past 6 months.

Discussion

Flecainide acetate is a class 1C antiarrhythmic agent indicated for both the pharmacological conversion as well as maintenance of sinus rhythm in patients with atrial fibrillation and supraventricular tachycardia.¹ Flecainide delays phase 0 depolarization of the cardiac action potential by binding to Na_v1.5 cardiac sodium channels, resulting in slowing of conduction in the atrial, His-Purkinje system, and ventricles.² The sodium channel-blocking properties of flecainide are use-dependent, meaning that the effects are more profound at higher heart rates. This allows for flecainide to have more clinical efficacy in treating faster arrhythmias. 

Flecainide has a narrow therapeutic window and can have proarrhythmic potential even at usual doses, particularly in patients with structural heart disease, including coronary artery disease.³ The majority of flecainide is excreted by the kidneys, allowing for flecainide toxicity to occur even in mild renal failure. Flecainide toxicity can result in both sinus node suppression and QRS widening, resulting in significant bradyarrhythmias from both sinus node arrest and atrioventricular block.⁴ Additionally, flecainide toxicity can result in tachyarrhythmias, including conversion of atrial fibrillation to rapidly conducting atrial flutter with and without aberration and ventricular tachycardia, both which often mimic one another on ECG as wide complex tachycardias.⁵ At higher doses, flecainide toxicity can result in hemodynamic collapse, with a mortality rate upward of 10-20%.⁶ Clinical symptoms of flecainide toxicity are both non-cardiac and cardiac. Non-cardiac symptoms include nausea, vomiting, seizures, and coma. Cardiac symptoms relate to both brady- and tachyarrhythmias, including palpitations, syncope, and cardiac arrest. 

Electrocardiographic changes of flecainide toxicity can manifest as a bizarre wide complex supraventricular tachycardia that can easily be mistaken for ventricular tachycardia, resulting in inappropriate therapy. In a systematic review of ECG patterns associated with flecainide toxicity, Valentino et al found 21 articles with 22 ECG tracings published in adult patients with flecainide toxicity.⁷ Their major findings included that patients with QRS duration <200 ms were more likely to have a RBBB pattern and visible P waves, whereas patients with QRS >200 ms were more likely to have a LBBB pattern, absent P waves, and were associated with a need for mechanical circulatory support and an increased risk of death.⁷ ST segment elevation seen with flecainide toxicity can also mimic the Brugada phenotype and can often be mistaken for acute myocardial injury pattern, as was the case in this patient.⁸ 

Acute management of flecainide toxicity, which has mainly been studied through case reports, can be challenging due to nearly 90% oral bioavailability and slow rate of elimination. Moreover, dialysis is often ineffective during flecainide toxicity due to a large volume of distribution. High-dose sodium bicarbonate is the treatment of choice to offset the cardiovascular toxicities associated with flecainide by increasing sodium ion concentration and promoting serum alkalinization.⁹ This combination has been shown to prevent flecainide binding (via sodium ions) and to promote dissociation of flecainide (via alkalinization) from the sodium channel receptor binding sites, thus reversing the flecainide effect on cardiac tissues.^10-11 Additional medical therapy that has been used during flecainide toxicity includes amiodarone for tachyarrhythmias and transcutaneous or transvenous pacing for bradyarrhythmias.¹² Due to the lipophilic properties of flecainide, intravenous fat emulsion has also been shown to be effective to decrease drug levels during acute flecainide toxicity.¹³ In patients with cardiovascular collapse and refractory shock, mechanical circulatory support with veno-arterial ECMO has also been used in the setting of acute flecainide toxicity.^14-15

Our patient likely developed acute flecainide toxicity from a combination of an acute ingestion of 900 mg of oral flecainide acetate over an 8-hour period with concomitant acute renal failure, resulting in an excess sodium channel blockade, organization of atrial fibrillation to atrial flutter, and severe widening of his QRS complex. Although he took his flecainide at a dose of 300 mg as prescribed, and which he had tolerated before, he was not given clear instructions by his prescribing physician on the daily limit, and proceeded to take 2 additional 300 mg doses within 8 hours of his initial dose due to the refractory nature of his atrial fibrillation. It is possible that a pharmacist-run antiarrhythmic drug clinic may have clarified instructions for drug use and reduced the risk of these accidental drug overdoses.¹⁶ 

His initial presentation was initially confused with acute myocardial injury. There was discussion for activation of the catheterization lab for urgent coronary angiogram, but after a detailed history and discussion with the on-call cardiologist, it was clear that the patient’s diagnosis was acute flecainide toxicity and prompt treatment with intravenous sodium bicarbonate was initiated. 

Summary

This case of acute flecainide toxicity illustrates several key points. First, prompt recognition of clinical and ECG manifestations of flecainide toxicity is important in order to establish the correct diagnosis and treatment protocol, as well as to avoid unnecessary treatments for acute myocardial infarction and ventricular tachycardia. Next, initial treatment should include a high concentration sodium bicarbonate infusion to acutely reverse flecainide effect and prevent life-threatening arrhythmias. A QRS duration >200 ms with flecainide toxicity is associated with adverse outcomes and may require early activation of the mechanical circulatory support team. Finally, pill-in-the-pocket flecainide can be safely used in select patients with normal renal function and without structural heart disease; however, providers must be cautious in elderly populations who are at risk for renal impairment, and should consider working closely with a pharmacist-run antiarrhythmic drug clinic to give clear dosing instructions in order to avoid inadvertent flecainide toxicity. 

Contact the author on Twitter at @GVenkataramanEP.

Disclosures: Dr. Venkataraman has no conflicts of interest to report regarding the content herein.

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For more information on direct oral anticoagulation:

Rivaroxaban or Apixaban?

How Can We Stop Heparin Bridging in Patients Taking NOACs?

To see more cases in EP Lab Digest, please visit here.