CASE REPORT An Unusual Case of Flecainide-induced QT Prolongation Leading to Cardiac Arrest Kevin N. Oguayo,1,2,* Ola O. Oyetayo,3,4 Steven M. Costa,2,5 and Timothy A. Mixon2,5 1
Department of Internal Medicine, Baylor Scott & White Healthcare, Temple, Texas; 2College of Medicine, Texas A&M University Health Science Center, Temple, Texas; 3Pharmacy Department, Baylor Scott & White Healthcare, Temple, Texas; 4College of Pharmacy, Texas A&M University Health Science Center, Temple, Texas; 5 Division of Cardiology, Baylor Scott & White Healthcare, Temple, Texas
Flecainide is recommended as a first-line antiarrhythmic drug to maintain normal sinus rhythm in patients with atrial fibrillation (AF) who have structurally normal hearts or hypertension without left ventricular hypertrophy. Flecainide is a sodium channel blocker with minimal effects expected on ventricular repolarization. We describe the case of a 32-year-old man with a structurally normal heart and persistent AF who was started on diltiazem and flecainide 50 mg twice/day approximately a year prior to presentation. Due to persistent and bothersome symptoms, his dose was increased to 150 mg twice/ day, which was associated with a progressive lengthening of his corrected QT interval. On the day of presentation, he underwent an exercise test as part of his job requirements. While running, he felt lightheaded and experienced a syncopal event and cardiac arrest. An automated external defibrillator was available that displayed polymorphic ventricular tachycardia. The patient was successfully resuscitated. Although rare, this case suggests that flecainide can induce QT prolongation leading to torsades de pointes. Clinicians should be aware and consider periodic evaluations with electrocardiograms. KEY WORDS atrial fibrillation, flecainide, antiarrhythmic drugs, torsades de pointes, QT interval. (Pharmacotherapy 2014;34(5):e30–e33) doi: 10.1002/phar.1403
Atrial fibrillation (AF) is the most common sustained arrhythmia seen in clinical practice. Compared with patients in normal rhythm, AF is associated with clinically important sequelae that include an increased risk of thromboembolic stroke, tachycardia-induced cardiomyopathy, and increased all-cause mortality.1 In patients managed with a rhythm control strategy, recurrence of AF commonly necessitates the initiation of antiarrhythmic drug therapy to maintain normal sinus rhythm.2 American and European guidelines on AF recommend flecainide as a first-line treatment for maintaining normal sinus Financial Support: No sources of financial support. Conflicts of Interest: The authors have no conflict of interest to disclose. *Author for correspondence: Kevin Oguayo, Scott & White Healthcare, 2401 South 31st Street, Temple, TX 76508; e-mail: [email protected]. Ó 2014 Pharmacotherapy Publications, Inc.
rhythm in patients who have structurally normal hearts or hypertension without left ventricular hypertrophy.1, 3, 4 Although flecainide is considered safe in the population just described, it is contraindicated in patients with diminished left ventricular function and prior myocardial infarction due to an increased risk of proarrhythmia and death, which was demonstrated in the Cardiac Arrhythmia Suppression Trial.5 Although flecainide-induced lethal cardiac arrhythmias are rare in patients with structurally normal hearts, we present a case of flecainide-induced cardiac arrest associated with a prolonged QT interval leading to torsades de pointes in a patient with a structurally normal heart.6, 7 Case Presentation A 32-year-old man with persistent AF was started on diltiazem 240 mg/day and flecainide 50 mg twice/day about 3 years prior to
UNUSUAL FLECAINIDE-INDUCED CARDIAC ARREST Oguayo et al presentation. His electrocardiogram (ECG) demonstrated AF with a rapid ventricular response, a QRS duration of 74 milliseconds (ms), and corrected QT of 367 ms. After initiation of flecainide, he underwent exercise ECG testing and achieved 92% of maximum predicted heart rate with isolated premature atrial contraction and no further arrhythmias or ischemia noted. The patient subsequently did well without recurrent symptoms and self-discontinued the medications after 2 years. The patient unfortunately experienced further AF-related symptoms ~15 months prior to his cardiac arrest, leading to reinitiation of flecainide 50 mg twice/day. Following a repeat stress test, the patient achieved 95% of predicted heart rate with rare premature atrial contractions and premature ventricular contractions but with no significant ectopy, arrhythmias, or ischemia noted. The patient continued to experience further symptomatic recurrent episodes of AF, which led to an increase in his flecainide dose from 50 to 100 mg twice/day 3 months prior to his presentation with cardiac arrest. His ECG at the time the dose was increased showed AF with a rapid ventricular response, a QRS duration of 92 ms, and a QTc of 367 ms. Approximately 12 days prior to presentation with cardiac arrest, he presented to his cardiologist with continuing bothersome symptoms. At that time his flecainide dose was further increased to 150 mg twice/day and his ECG then showed normal sinus rhythm with a QTc interval of 475 ms. An ECG performed about 2 days prior to his event showed that he was back in AF with a QRS duration of 90 ms and a prolonged QTc at 496 ms. This led to the scheduling of an elective
Figure 1. Patient’s rhythm.
e31
cardioversion. Unfortunately, the patient did not keep the appointment. On the day of admission, he underwent an exercise test as part of his job requirements. While running, he felt lightheaded and experienced a syncopal event and cardiac arrest. Fortunately, immediate access to an automated external defibrillator was available, which recommended that a shock be delivered. Figure 1 shows the patient’s rhythm strip prior to and after his shock. Chest compressions were initiated. After 1 minute of chest compressions, return of spontaneous circulation occurred and he was transferred to our institution. Upon arrival to the hospital the patient denied chest pain, shortness of breath, or palpitations. He was afebrile with a blood pressure of 144/ 100 mm Hg, pulse of 102 beats per minute, and oxygen saturations of 100% on room air. On physical examination, the patient’s heart rate was regular with no obvious murmurs, rubs, or gallops, and he had an otherwise normal physical examination. Cardiac troponin I, total creatine kinase, creatine kinase myocardial band, and B-type natriuretic peptide were all within normal limits. Serum sodium, potassium, magnesium, and calcium were also within normal limits. Serum phosphorus was mildly decreased at 1.6 mg/dl (normal range 2.4–4.2), aspartate aminotransferase was 199 U/L (0–40), alanine aminotransferase 292 U/L (0–68), and lactate was 2.6 mmol/L (0.5–2.2). These liver enzyme elevations were attributed to his cardiac arrest, all of which normalized within days of admission. An ECG obtained at admission showed sinus
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tachycardia with a QTc of 504 ms and QRS duration of 96 ms. Flecainide was discontinued and he was continued on diltiazem. On day 2, the patient was back in AF, although with minimal symptoms. A transthoracic echocardiogram displayed upper limit of normal left and right ventricle size with preserved left ventricular ejection fraction of 55%, moderate left atrial enlargement, and mild mitral and tricuspid regurgitation. On day 3, the patient was still in AF with increased palpitations, and a decision was made to proceed with electrical cardioversion. A transesophageal echocardiogram displayed no new findings, with no evidence of thrombus within the left atrium or atrial appendage. Initially, cardioversion was attempted at 50 J biphasic with no success, but subsequently was successful at 150 J. He later underwent cardiac computed tomography with contrast, which showed variant pulmonary venous anatomy with an accessory right inferior pulmonary vein. On day 4, he underwent genetic counseling and subsequent testing for long QT syndrome with an extensive panel of known genetic causes of long QT syndrome. All genetic studies were ultimately found to be negative. The patient was discharged home on day 4 on metoprolol, enoxaparin, and warfarin. Six months later, the patient had continued recurrence of symptomatic AF. His ECG showed AF with a QTc of 408 ms and a QRS duration of 90 ms. Discussion Flecainide is a class IC antiarrhythmic agent by the Vaughn-Williams classification system of antiarrhythmics. It is a potent blocker of sodium channels leading to the depression of the maximum upstroke of phase 0 of the action potential (Vmax) and dissociates slowly, leading to an increase in action potential duration.8, 9 As with other sodium channel blockers, it exhibits usedependent characteristics and produces greater antiarrhythmic effects at higher heart rates.10, 11 The expected electrophysiologic effects of flecainide include the prolongation of the AH, HV, PR, and QRS intervals as well as the ventricular effective refractory period.8, 9, 12 There is a dose-dependent increase in both the PR and QRS intervals with a slightly non-dose-related increase in the JT interval (QT minus the QRS interval).8, 9 Although flecainide can increase the rate-corrected QT interval, the intrinsic
change in the JT interval is small, and increases in the QT interval can be mostly explained by the considerable increase in QRS duration.9 Like other antiarrhythmics, flecainide is proarrhythmic.9 In patients with AF, flecainide can lead to conversion to atrial flutter with one-toone ventricular conduction. In patients with structural heart disease, flecainide can lead to both nonsustained and sustained ventricular arrhythmias.5, 13 Flecainide-induced ventricular tachycardia is believed to be caused by its conduction slowing properties leading to the formation of a reentrant tachyarrhythmia.10, 14 One hypothesis suggests that flecainide, by inducing excessive conduction slowing, alters the balance between conduction velocity and refractoriness.10 This hypothesis is best illustrated using an example of a patient with an existing reentrant circuit. Conduction in the circuit could be slowed by flecainide to a point where conduction time exceeds refractory period, thereby leading to a reentrant arrhythmia.10, 14 Essential to the development of such an arrhythmia is the presence of a preexisting substrate that can support the reentry and the magnitude of the druginduced conduction slowing. As such in patients with structural heart disease or preexisting substrates, the enhancement of flecainide’s activity by exercise might be sufficient to lead to the development of ventricular arrhythmia.15 Other researchers studied the effect of flecainide in 24 patients with structurally normal hearts similar to our patient.14 They compared rest and peak exercise ECG intervals between flecainide-treated patients and those who received placebo. They reported QRS duration on flecainide versus placebo at rest to be 81 versus 68 ms (p
Department of Internal Medicine, Baylor Scott & White Healthcare, Temple, Texas; 2College of Medicine, Texas A&M University Health Science Center, Temple, Texas; 3Pharmacy Department, Baylor Scott & White Healthcare, Temple, Texas; 4College of Pharmacy, Texas A&M University Health Science Center, Temple, Texas; 5 Division of Cardiology, Baylor Scott & White Healthcare, Temple, Texas
Flecainide is recommended as a first-line antiarrhythmic drug to maintain normal sinus rhythm in patients with atrial fibrillation (AF) who have structurally normal hearts or hypertension without left ventricular hypertrophy. Flecainide is a sodium channel blocker with minimal effects expected on ventricular repolarization. We describe the case of a 32-year-old man with a structurally normal heart and persistent AF who was started on diltiazem and flecainide 50 mg twice/day approximately a year prior to presentation. Due to persistent and bothersome symptoms, his dose was increased to 150 mg twice/ day, which was associated with a progressive lengthening of his corrected QT interval. On the day of presentation, he underwent an exercise test as part of his job requirements. While running, he felt lightheaded and experienced a syncopal event and cardiac arrest. An automated external defibrillator was available that displayed polymorphic ventricular tachycardia. The patient was successfully resuscitated. Although rare, this case suggests that flecainide can induce QT prolongation leading to torsades de pointes. Clinicians should be aware and consider periodic evaluations with electrocardiograms. KEY WORDS atrial fibrillation, flecainide, antiarrhythmic drugs, torsades de pointes, QT interval. (Pharmacotherapy 2014;34(5):e30–e33) doi: 10.1002/phar.1403
Atrial fibrillation (AF) is the most common sustained arrhythmia seen in clinical practice. Compared with patients in normal rhythm, AF is associated with clinically important sequelae that include an increased risk of thromboembolic stroke, tachycardia-induced cardiomyopathy, and increased all-cause mortality.1 In patients managed with a rhythm control strategy, recurrence of AF commonly necessitates the initiation of antiarrhythmic drug therapy to maintain normal sinus rhythm.2 American and European guidelines on AF recommend flecainide as a first-line treatment for maintaining normal sinus Financial Support: No sources of financial support. Conflicts of Interest: The authors have no conflict of interest to disclose. *Author for correspondence: Kevin Oguayo, Scott & White Healthcare, 2401 South 31st Street, Temple, TX 76508; e-mail: [email protected]. Ó 2014 Pharmacotherapy Publications, Inc.
rhythm in patients who have structurally normal hearts or hypertension without left ventricular hypertrophy.1, 3, 4 Although flecainide is considered safe in the population just described, it is contraindicated in patients with diminished left ventricular function and prior myocardial infarction due to an increased risk of proarrhythmia and death, which was demonstrated in the Cardiac Arrhythmia Suppression Trial.5 Although flecainide-induced lethal cardiac arrhythmias are rare in patients with structurally normal hearts, we present a case of flecainide-induced cardiac arrest associated with a prolonged QT interval leading to torsades de pointes in a patient with a structurally normal heart.6, 7 Case Presentation A 32-year-old man with persistent AF was started on diltiazem 240 mg/day and flecainide 50 mg twice/day about 3 years prior to
UNUSUAL FLECAINIDE-INDUCED CARDIAC ARREST Oguayo et al presentation. His electrocardiogram (ECG) demonstrated AF with a rapid ventricular response, a QRS duration of 74 milliseconds (ms), and corrected QT of 367 ms. After initiation of flecainide, he underwent exercise ECG testing and achieved 92% of maximum predicted heart rate with isolated premature atrial contraction and no further arrhythmias or ischemia noted. The patient subsequently did well without recurrent symptoms and self-discontinued the medications after 2 years. The patient unfortunately experienced further AF-related symptoms ~15 months prior to his cardiac arrest, leading to reinitiation of flecainide 50 mg twice/day. Following a repeat stress test, the patient achieved 95% of predicted heart rate with rare premature atrial contractions and premature ventricular contractions but with no significant ectopy, arrhythmias, or ischemia noted. The patient continued to experience further symptomatic recurrent episodes of AF, which led to an increase in his flecainide dose from 50 to 100 mg twice/day 3 months prior to his presentation with cardiac arrest. His ECG at the time the dose was increased showed AF with a rapid ventricular response, a QRS duration of 92 ms, and a QTc of 367 ms. Approximately 12 days prior to presentation with cardiac arrest, he presented to his cardiologist with continuing bothersome symptoms. At that time his flecainide dose was further increased to 150 mg twice/day and his ECG then showed normal sinus rhythm with a QTc interval of 475 ms. An ECG performed about 2 days prior to his event showed that he was back in AF with a QRS duration of 90 ms and a prolonged QTc at 496 ms. This led to the scheduling of an elective
Figure 1. Patient’s rhythm.
e31
cardioversion. Unfortunately, the patient did not keep the appointment. On the day of admission, he underwent an exercise test as part of his job requirements. While running, he felt lightheaded and experienced a syncopal event and cardiac arrest. Fortunately, immediate access to an automated external defibrillator was available, which recommended that a shock be delivered. Figure 1 shows the patient’s rhythm strip prior to and after his shock. Chest compressions were initiated. After 1 minute of chest compressions, return of spontaneous circulation occurred and he was transferred to our institution. Upon arrival to the hospital the patient denied chest pain, shortness of breath, or palpitations. He was afebrile with a blood pressure of 144/ 100 mm Hg, pulse of 102 beats per minute, and oxygen saturations of 100% on room air. On physical examination, the patient’s heart rate was regular with no obvious murmurs, rubs, or gallops, and he had an otherwise normal physical examination. Cardiac troponin I, total creatine kinase, creatine kinase myocardial band, and B-type natriuretic peptide were all within normal limits. Serum sodium, potassium, magnesium, and calcium were also within normal limits. Serum phosphorus was mildly decreased at 1.6 mg/dl (normal range 2.4–4.2), aspartate aminotransferase was 199 U/L (0–40), alanine aminotransferase 292 U/L (0–68), and lactate was 2.6 mmol/L (0.5–2.2). These liver enzyme elevations were attributed to his cardiac arrest, all of which normalized within days of admission. An ECG obtained at admission showed sinus
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tachycardia with a QTc of 504 ms and QRS duration of 96 ms. Flecainide was discontinued and he was continued on diltiazem. On day 2, the patient was back in AF, although with minimal symptoms. A transthoracic echocardiogram displayed upper limit of normal left and right ventricle size with preserved left ventricular ejection fraction of 55%, moderate left atrial enlargement, and mild mitral and tricuspid regurgitation. On day 3, the patient was still in AF with increased palpitations, and a decision was made to proceed with electrical cardioversion. A transesophageal echocardiogram displayed no new findings, with no evidence of thrombus within the left atrium or atrial appendage. Initially, cardioversion was attempted at 50 J biphasic with no success, but subsequently was successful at 150 J. He later underwent cardiac computed tomography with contrast, which showed variant pulmonary venous anatomy with an accessory right inferior pulmonary vein. On day 4, he underwent genetic counseling and subsequent testing for long QT syndrome with an extensive panel of known genetic causes of long QT syndrome. All genetic studies were ultimately found to be negative. The patient was discharged home on day 4 on metoprolol, enoxaparin, and warfarin. Six months later, the patient had continued recurrence of symptomatic AF. His ECG showed AF with a QTc of 408 ms and a QRS duration of 90 ms. Discussion Flecainide is a class IC antiarrhythmic agent by the Vaughn-Williams classification system of antiarrhythmics. It is a potent blocker of sodium channels leading to the depression of the maximum upstroke of phase 0 of the action potential (Vmax) and dissociates slowly, leading to an increase in action potential duration.8, 9 As with other sodium channel blockers, it exhibits usedependent characteristics and produces greater antiarrhythmic effects at higher heart rates.10, 11 The expected electrophysiologic effects of flecainide include the prolongation of the AH, HV, PR, and QRS intervals as well as the ventricular effective refractory period.8, 9, 12 There is a dose-dependent increase in both the PR and QRS intervals with a slightly non-dose-related increase in the JT interval (QT minus the QRS interval).8, 9 Although flecainide can increase the rate-corrected QT interval, the intrinsic
change in the JT interval is small, and increases in the QT interval can be mostly explained by the considerable increase in QRS duration.9 Like other antiarrhythmics, flecainide is proarrhythmic.9 In patients with AF, flecainide can lead to conversion to atrial flutter with one-toone ventricular conduction. In patients with structural heart disease, flecainide can lead to both nonsustained and sustained ventricular arrhythmias.5, 13 Flecainide-induced ventricular tachycardia is believed to be caused by its conduction slowing properties leading to the formation of a reentrant tachyarrhythmia.10, 14 One hypothesis suggests that flecainide, by inducing excessive conduction slowing, alters the balance between conduction velocity and refractoriness.10 This hypothesis is best illustrated using an example of a patient with an existing reentrant circuit. Conduction in the circuit could be slowed by flecainide to a point where conduction time exceeds refractory period, thereby leading to a reentrant arrhythmia.10, 14 Essential to the development of such an arrhythmia is the presence of a preexisting substrate that can support the reentry and the magnitude of the druginduced conduction slowing. As such in patients with structural heart disease or preexisting substrates, the enhancement of flecainide’s activity by exercise might be sufficient to lead to the development of ventricular arrhythmia.15 Other researchers studied the effect of flecainide in 24 patients with structurally normal hearts similar to our patient.14 They compared rest and peak exercise ECG intervals between flecainide-treated patients and those who received placebo. They reported QRS duration on flecainide versus placebo at rest to be 81 versus 68 ms (p
