Late positive flecainide challenge test for Brugada syndrome Belinda Gray, BSc(Med), MBBS,*†‡ Mark McGuire, MBBS, PhD,*† Christopher Semsarian, MBBS, PhD, FHRS,*†‡ Caroline Medi, BMed, PhD*†‡ From the *Department of Cardiology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia, †Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia, and ‡Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Newtown, New South Wales, Australia. The flecainide challenge is an important investigation in the diagnosis of individuals with Brugada syndrome (BrS). Published protocols on the use of the flecainide test recommend a 10–30-minute waiting period if the test has a negative result.1,2 We report a case where type 1 electrocardiogram (ECG) changes occurred more than 90 minutes postinfusion after an initial apparently negative test. A 23-year-old woman with baseline type 2 Brugada ECG pattern (Figure 1) and a history of palpitations and syncope was admitted for a diagnostic flecainide study (Figure 2A). There was no structural heart disease on echocardiography, and no family history of sudden cardiac death. Renal function and liver function tests were normal, and the patient was not taking any other medications. A flecainide challenge test was performed by using a standard protocol,3 and ECGs were performed in the high precordial position. Serial ECGs were performed every 10 minutes until 60-minute postinfusion and remained negative for type 1 Brugada pattern (Figure 2B). Approximately 100 minutes after the flecainide infusion ceased, the patient complained of palpitations, dizziness, and nausea, with sinus tachycardia evident on single ECG lead monitoring. A repeat 12-leads ECG showed a classic type 1 Brugada pattern in lead V1 and V2 as well as significant broadening of the QRS interval (Figure 3). These changes completely reversed with the administration of intravenous isoprenaline, and the ECG spontaneously normalized after a further 5 hours. We believe this to be the first documented case of a “late positive” flecainide challenge test. There are currently no specific guidelines on the recommendation of a minimum monitoring period of patients after a negative sodiumchannel blocker challenge test. Meregalli et al4 described KEYWORDS Brugada syndrome; Flecainide challenge ABBREVIATIONS BrS ¼ Brugada syndrome; CYP2D6 ¼ cytochrome P450 2D6; ECG ¼ electrocardiogram (Heart Rhythm 2014;11:898–900) Address reprint requests and correspondence: Dr Caroline Medi, Department of Cardiology, Royal Prince Alfred Hospital, Missenden Rd, Camperdown, NSW 2050, Australia. E-mail address: c.medi@centenary. org.au.

1547-5271/$-see front matter B 2014 Heart Rhythm Society. All rights reserved.

flecainide challenge tests in a large cohort of 160 patients determined to be at risk of BrS. They monitored patients until the ECG normalized or for 30 minutes in the case of a negative study. An early study of sodium-channel challenge tests by Wolpert et al1 used a protocol in which patients were monitored for 10 minutes after the infusion of flecainide or ajmaline. In this study, they found discordance between patient’s responses to flecainide compared with ajmaline and concluded flecainide to be less sensitive as a sodiumchallenge drug. However, it is plausible that some of the discrepancies associated with flecainide were false-negative results related to the short duration of postinfusion monitoring. Our department’s protocol is based on Zorzi et al,5 who studied 153 patients with a baseline type 2 or 3 Brugada ECG pattern. Patients were given flecainide or ajmaline and monitored until ST-segment elevation returned to baseline or for a minimum of 60 minutes after the infusion. The present case highlights the potential for the underdiagnosis of BrS after negative provocative testing with a short monitoring period. Our patient developed late-onset typical changes at a time beyond generally accepted waiting times after a negative test. One may speculate that the symptoms that prompted the additional ECG recordings may have been due to the side effects of flecainide, which also manifested late. The plasma pharmacokinetics of flecainide has been previously well described. After intravenous administration, plasma levels of flecainide decrease rapidly within 15–30 minutes owing to uptake from the systemic circulation to the tissues.6 After this initial phase of rapid distribution, the plasma half-life of the terminal clearance phase ranges from 7 to 19 hours after a single intravenous dose.6 Flecainide is renally excreted both as an unchanged active drug and as its inactive metabolites. The plasma protein binding of flecainide is low. Approximately 40% of flecainide is bound to plasma proteins and is independent of the total drug level. Flecainide binding is related predominantly to α-1 glycoprotein as well as to albumin, and the degree of dependence is such that large changes in serum protein levels are required to alter serum binding of flecainide to a clinically significant extent.6 http://dx.doi.org/10.1016/j.hrthm.2014.02.020

Gray et al

Late Positive Flecainide Challenge Test

Figure 1

Twelve-lead electrocardiogram showing baseline type 2 Brugada pattern.

Flecainide is metabolized predominantly by cytochrome P450 2D6 (CYP2D6), and CYP2D6 polymorphisms have been associated with a 40% reduction in flecainide clearance, as well as higher serum concentrations and an increase in the area under the curve for flecainide.7 Genetic polymorphisms in CYP2D6 resulting in poor metabolism occurs in up to 10% of the Caucasian population, seen rarely in the Asian population.8 The activity of CYP2D6 shows wide variability between individuals, with a greater than 10-fold variance found between poor metabolizers and extensive metabolizers, and a 5-fold variance within the group of patients who are classified as poor metabolizers.7 In addition, polymorphisms in other cytochrome P450 pathways may also affect

Figure 2

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flecainide pharmacokinetics. In particular, polymorphisms of CYP3A5 and CYP1A2 may affect flecainide metabolism, with significantly decreased clearance and higher plasma concentrations of flecainide seen especially in patients who have less active variants of CYP2D6.8 This patient subsequently underwent CYP2D6 genotyping and was found to be heterozygous for a mutation resulting in the reduction in the function of CYP2D6 (genotype *1/*41). This genotype is known to reduce enzyme function by approximately 30% owing to the presence of 1 normal allele (*1) and 1 reduced functioning allele (*41). This abnormality may at least in part explain the delayed pharmacologic effects, resulting from an accumulation in the plasma of unchanged flecainide.9

Twelve-lead electrocardiogram at the (A) commencement of flecainide infusion and (B) negative flecainide challenge test result at 60 minutes.

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Figure 3

Twelve-lead electrocardiogram showing classic type 1 Brugada pattern at 100 minutes after the infusion.

Other contributory mechanisms for the late positive flecainide challenge test can also been postulated; however, they are not relevant in this case. Flecainide may interact with other drugs metabolized through the CYP2D6 pathway10; the impairment of renal function and congestive cardiac failure may prolong the half-life of flecainide6; and electrolyte abnormalities, specifically hypo- or hyperkalemia, may alter the pharmacokinetics of flecainide.11 However, our patient was an otherwise healthy young woman with normal serum electrolytes measured on the morning of the test. It is also a possibility that the late positive test was unrelated to the earlier administration of flecainide. In patients with BrS, ECG patterns are known to fluctuate between diagnostic and nondiagnostic ECG patterns, even over the course of a few minutes.12,13 Other physiological factors such as deep inspiration or transient changes in autonomic tone have also been shown to lead to type 1 ECG patterns appearing and may affect the outcome of the test.14,15 When performing provocative testing with flecainide in cases of potential BrS, patients are typically monitored for 10–30 minutes. This case highlights the potential for the ECG changes to appear nearly 2 hours after the administration of flecainide. A short (o30 minutes) monitoring period may lead to false-negative results in patients with sodium-channel abnormalities and who are also poor metabolizers of flecainide. By increasing the duration of monitoring in all patients, there is the potential of increasing the sensitivity of the sodium-channel challenge test in this subgroup, although the majority of patients who have an early negative test result will likely remain negative. Ajmaline has a higher sensitivity and specificity than flecainide when used as a provocative drug in assessing patients for BrS. However, in many countries, including the authors’, ajmaline is unavailable. The clinical implications of this case suggest that owing to the population incidence of cytochrome polymorphisms leading to poor drug metabolism, when flecainide is used for provocative testing in BrS, a more prolonged period of monitoring after flecainide infusion may be warranted to avoid underdiagnosis of late positive tests.

References 1. Wolpert C, Echternach C, Veltmann C, Antzelevitch C, Thomas GP, Spehl S, Streitner F, Kuschyk J, Schimpf R, Haase KK, Borggrege M. Intravenous drug challenge using flecainide and ajmaline in patients with Brugada syndrome. Heart Rhythm 2005;2:254–260. 2. Obeyesekere MN, Klein GJ, Modi S, Leong-Sit P, Gula LJ, Yee R, Skanes AC, Krahn AD. How to perform and interpret provocative testing for the diagnosis of Brugada syndrome, long-QT syndrome, and catecholaminergic polymorphic ventricular tachycardia. Circ Arrhythm Electrophysiol 2011;4:958–964. 3. Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation 2005;111:659–670. 4. Meregalli PG, Ruijter JM, Hofman N, Bezzina CR, Wilde AA, Tan HL. Diagnostic value of flecainide testing in unmasking SCN5A-related Brugada syndrome. J Cardiovasc Electrophysiol 2006;17:857–864. 5. Zorzi A, Migliore F, Marras E, et al. Should all individuals with a nondiagnostic Brugada-electrocardiogram undergo sodium-channel blocker test? Heart Rhythm 2012;9:909–916. 6. Conard GJ, Ober RE. Metabolism of flecainide. Am J Cardiol 1984;53:41B–51B. 7. Mikus G, Gross AS, Beckmann J, Hertrampf R, Gundert-Remy U, Eichelbaum M. The influence of the sparteine/debrisoquin phenotype on the disposition of flecainide. Clin Pharmacol Ther 1989;45:562–567. 8. Hu M, Yang YL, Fok BS, Chan SW, Chu TT, Poon EW, Yin OQ, Lee VH, Tomlinson B. Effects of CYP2D6*10, CYP3A5*3, CYP1A2*1F, and ABCB1 C3435T polymorphisms on the pharmacokinetics of flecainide in healthy Chinese subjects. Drug Metabol Drug Interact 2012;27:33–39. 9. Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I. Clin Pharmacokinet 2009;48:689–723. 10. Birgersdotter UM, Wong W, Turgeon J, Roden DM. Stereoselective geneticallydetermined interaction between chronic flecainide and quinidine in patients with arrhythmias. Br J Clin Pharmacol 1992;33:275–280. 11. MIMS Online. Full Product Information: Flecainide acetate. December 12, 2013. https://www-mimsonline-com-au.ezproxy2.library.usyd.edu.au/Search/FullPI.aspx? ModuleName=Product%20Info&searchKeyword=flecainide&PreviousPage=  /Search/QuickSearch.aspx&SearchType=&ID=1900002_2. Accessed December 12, 2013. 12. Veltmann C, Schimpf R, Echternach C, Eckardt L, Kuschyk J, Streitner F, Spehl S, Borggrefe M, Wolpert C. A prospective study on spontaneous fluctuations between diagnostic and non-diagnostic ECGs in Brugada syndrome: implications for correct phenotyping and risk stratification. Eur Heart J 2006;27:2544–2552. 13. Ariyarajah V, Smith H, Hodge S, Khadem A. Spontaneous alternans in Brugada ST-segment morphology within minutes. J Electrocardiol 2008;41:302–305. 14. Mizumaki K, Fujiki A, Tsuneda T, Sakabe M, Nishida K, Sugao M, Inoue H. Vagal activity modulates spontaneous augmentation of ST elevation in the daily life of patients with Brugada syndrome. J Cardiovasc Electrophysiol 2004;15: 667–673. 15. Yamawake N, Nishizaki M, Shimizu M, Fujii H, Sakurada H, Hiraoka M. Unmasking Brugada-type electrocardiogram on deep inspiration. Circ J 2014;78:360–365.

Late positive flecainide challenge test for Brugada syndrome.

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