Author's Accepted Manuscript
A refined protocol of flecainide testing in Brugada Syndrome: from ambiguous assessment towards definite diagnosis Yuka Mizusawa MD, Hanno L. Tan MD, Ph.D.
www.elsevier.com/locate/buildenv
PII: DOI: Reference:
S1547-5271(14)01318-6 http://dx.doi.org/10.1016/j.hrthm.2014.11.021 HRTHM6018
To appear in:
Heart Rhythm
Cite this article as: Yuka Mizusawa MD, Hanno L. Tan MD, Ph.D., A refined protocol of flecainide testing in Brugada Syndrome: from ambiguous assessment towards definite diagnosis, Heart Rhythm, http://dx.doi.org/10.1016/j.hrthm.2014.11.021 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
A refined protocol of flecainide testing in Brugada Syndrome: from ambiguous assessment towards definite diagnosis.
Yuka Mizusawa, MD, Hanno L. Tan, MD, PhD
Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
Total word count:1507/1500 Corresponding to: H.L. Tan, MD, PhD Academic Medical Center, University of Amsterdam Clinical and Experimental Cardiology, Heart Center Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands E-mail: [email protected] Phone: +31-20-5663264 Fax:
+31-20-6975458 0
Brugada syndrome (BrS) is diagnosed in individuals with ≥2mm ST elevation with coved-type (type1) morphology in the right precordial leads1. This typical ECG pattern often fluctuates in time, from a diagnostic to a non-diagnostic pattern or vice versa, modulated by several factors such as autonomic tones, fever and sodium channel blocking drugs. Consequently, in suspected BrS cases with a non-diagnostic ECG pattern, drug-challenge testing is required to unmask BrS1. Various sodium channel blocking drugs are used to provoke type1 ECG while these agents also block other cardiac ion channels such as Ito, leading to varied effects on ST-segment and eventually, to different diagnostic yields2. A study comparing the effect of intravenous ajmaline vs. flecainide reported that flecainide failed to induce type1 ECG in 32% of the individuals with ajmaline-positive BrS2. Therefore, ajmaline should ideally be used in every drug-challenge testing to avoid false negative results. However, flecainide remains a diagnostic tool in clinical practice as ajmaline is not available in every country. The current standard protocol of flecainide testing is its intravenous infusion of 2mg/kg body weight over 10 minutes3. Yet, recent case reports showed that type1 ECG may appear 100 to 120 minutes after flecainide infusion4, 5. This points out that a 10 to 30-minute monitoring time of the test may be too short in some cases. In this issue of Heart Rhythm, Calvo et al. presented their effort to work out this problem6. They studied 59 patients with non-diagnostic BrS ECG pattern at baseline (but only at the 3rd and 2nd intercostal space) and performed flecainide testing. For 30 minutes from the start of flecainide infusion, 12-lead ECG was continuously monitored with the right precordial leads placed at the 3rd intercostal space. Two other ECGs were also made at 30 minutes and 90 minutes using the 3rd and 2nd intercostal space. Overall, 11 of the 59 patients (18.6%) showed a positive test: one-thirds at an early time period (0-10 minutes), another one-thirds at a ‘delayed’ period (10-30 minutes) and the remaining one-thirds at a ‘late’ period (90 minutes). Further, ECG parameters during the 1st 30 minutes were compared between 4 late responders and non-responders (48 patients). A QRS width exceeding 110 ms could differentiate the late responders from the non-responders (sensitivity 100%,
1
specificity 86%, positive predictive value 88% and negative predictive value 100%). The authors also attempted to find pharmacogenetic backgrounds to explain diverse responses to flecainide by screening polymorphisms in CYP2D6 and CYP3A5, liver enzymes involved in flecainide metabolism7. Although the study methods (only 3rd intercostal space was used for continuous monitoring during flecainide testing) possibly limited the authors’ ability to reveal the true ratio of delayed and late responders as well as to study pharmacogenetics in flecainide testing of BrS, several interesting points merit discussion. First, two-thirds of the flecainide-positive subjects failed to develop a positive test in 10 minutes, meaning these patients would have fallen into the false-negative category if the standard monitoring period of 10 minutes had been applied. This is a surprisingly large number. In our series of 159 subjects with non-type1 BrS ECG at baseline who underwent flecainide testing, no patient developed type1 ECG during a 10 to 30-minute monitoring period8. In addition, the overall positive rate is quite low (18.6%) in the study by Calvo et al.6 compared to ours (40%, 64/159)8. This may be explained by differences in the methods between the two studies, such as selection of study subjects (number and age of subjects, symptoms or family history of BrS, more symptomatic and familial cases in our series), different ECG-lead use for continuous monitoring (3rd intercostal space in the study by Calvo et al. vs. 4th and 3rd intercostal space in ours) and the proportion of SCN5A mutation carriers (3% in the study by Calvo et al. vs. 27% in ours)6, 8. Another reason may be the metabolism of flecainide. When flecainide is intravenously injected in healthy men, its mean plasma half-life is 11 hours (range, 7-15 hours) and its pharmacokinetics appears to be linear9. Several factors contribute to its wide range of half-life. Aging, liver and kidney dysfunction, heart failure or polymorphisms of liver enzymes (e.g. CYP2D6) are known to delay its metabolism10. Given that BrS patients are usually young with normal liver or kidney function, polymorphisms of liver enzymes are attractive candidates to evaluate. So, how do we find individuals with a delayed response to flecainide testing and how long do we need to monitor them after flecainide infusion? The authors attempted to answer these questions by 1) seeking for ECG parameters indicative of late responders (at 90 minutes) and 2) screening
2
polymorphisms of liver enzymes (CYP2D6 and CYP3A5) to find subjects with poor flecainide metabolism. As to ECG parameters, the authors reported that a QRS width exceeding 110 ms during the 1st 30 minutes after flecainide infusion was useful to distinguish late responders from non-responders. However, the analysis included too small a number of cases (4 late responders vs. 48 non-responders) to draw a definite conclusion. Of note, in our series, by using logistic regression analysis, we also attempted to find baseline ECG parameters which may predict the outcome of flecainide testing8. Our results showed that QRS width in V1, J point elevation in V2, S wave duration in II significantly contributed to the prediction8. In a future study, ECG parameters measured both before and after flecainide should be tested to find any ECG parameters useful for prediction of the outcome of flecainide testing. Finally, with regard to flecainide metabolism as a possible factor of delayed/late response to the drug, the association between the time of occurrence of type1 ECG and CYP2D6 polymorphisms was inconclusive. As for CYP3A5, all patients were homozygous for a minor allelle6. One of the reasons may be that a limited number of ECG leads for continuous monitoring led to underestimation of the development of type1 ECG and to misclassification of CYP2D6 polymorphisms related to the time points of type1 ECG appearance. In fact, although CYP2D6 is known to be the major metabolizer of flecainide, little is known about the effects of CYP2D6 polymorphisms and their interaction with other liver enzymes10. Current knowledge is drawn from few clinical studies with a small number of patients who are treated not only with flecainide but other antiarrhythmic drugs7, 11. The results of these studies are also discordant10. The effects of CYP2D6 polymorphisms on flecainide metabolism certainly need to be re-evaluated, and actually, a study population consisting of BrS patients seems quite ideal to test the pure effect of CYP2D6 polymorphisms because it is a rather young cohort without concomitant diseases. The results shown by Calvo et al. are certainly intriguing and call on revision of the flecainide testing protocol to improve its diagnostic yield in BrS. To do so, it is encouraged to create a large
3
international registry of flecainide testing so that the questions raised here are re-evaluated before a refined protocol of flecainide testing is finally established.
References
1.
Priori SG, Wilde AA, Horie M et al. HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes: Document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 2013;12:1932-1963.
2.
Wolpert C, Echternach C, Veltmann C, Antzelevitch C, Thomas GP, Spehl S, Streitner F, Kuschyk J, Schimpf R, Haase KK, Borggrefe M. Intravenous drug challenge using flecainide and ajmaline in patients with Brugada syndrome. Heart Rhythm 2005;3:254-260.
3.
Antzelevitch C, Brugada P, Borggrefe M et al. Brugada syndrome: report of the second consensus conference. Heart Rhythm 2005;4:429-440.
4.
Gray B, McGuire M, Semsarian C, Medi C. Late positive flecainide challenge test for Brugada syndrome. Heart Rhythm 2014;5:898-900.
5.
de-Riva-Silva M, Montero-Cabezas JM, Fontenla-Cerezuela A, Salguero-Bodes R, Lopez-Gil M, Arribas-Ynsaurriaga F. Delayed positive response to a flecainide test in a patient with suspected Brugada syndrome: a worrisome finding. Rev Esp Cardiol (Engl Ed) 2014;8:674-675.
6.
Calvo D, Rubín JM, Pérez D, Gómez J, Flórez JP, Avanzas P, García-Ruíz JM, de la Hera JM, Reguero J, Coto E, Morís C. Time dependent responses to provocative testing with flecainide in the diagnosis of Brugada Syndrome. Heart Rhythm. 2014.
4
7.
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;1:33-39.
8.
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;8:857-864.
9.
Conard GJ, Carlson GL, Frost JW, Ober RE, Leon AS, Hunninghake DB. Plasma concentrations of flecainide acetate, a new antiarrhythmic agent, in humans. Clin Ther 1984;5:643-652.
10.
Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev 2009;2:89-295.
11.
Doki K, Homma M, Kuga K, Aonuma K, Kohda Y. Effects of CYP2D6 genotypes on agerelated change of flecainide metabolism: involvement of CYP1A2-mediated metabolism. Br J Clin Pharmacol 2009;1:89-96.
5
A refined protocol of flecainide testing in Brugada Syndrome: from ambiguous assessment towards definite diagnosis Yuka Mizusawa MD, Hanno L. Tan MD, Ph.D.
www.elsevier.com/locate/buildenv
PII: DOI: Reference:
S1547-5271(14)01318-6 http://dx.doi.org/10.1016/j.hrthm.2014.11.021 HRTHM6018
To appear in:
Heart Rhythm
Cite this article as: Yuka Mizusawa MD, Hanno L. Tan MD, Ph.D., A refined protocol of flecainide testing in Brugada Syndrome: from ambiguous assessment towards definite diagnosis, Heart Rhythm, http://dx.doi.org/10.1016/j.hrthm.2014.11.021 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
A refined protocol of flecainide testing in Brugada Syndrome: from ambiguous assessment towards definite diagnosis.
Yuka Mizusawa, MD, Hanno L. Tan, MD, PhD
Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
Total word count:1507/1500 Corresponding to: H.L. Tan, MD, PhD Academic Medical Center, University of Amsterdam Clinical and Experimental Cardiology, Heart Center Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands E-mail: [email protected] Phone: +31-20-5663264 Fax:
+31-20-6975458 0
Brugada syndrome (BrS) is diagnosed in individuals with ≥2mm ST elevation with coved-type (type1) morphology in the right precordial leads1. This typical ECG pattern often fluctuates in time, from a diagnostic to a non-diagnostic pattern or vice versa, modulated by several factors such as autonomic tones, fever and sodium channel blocking drugs. Consequently, in suspected BrS cases with a non-diagnostic ECG pattern, drug-challenge testing is required to unmask BrS1. Various sodium channel blocking drugs are used to provoke type1 ECG while these agents also block other cardiac ion channels such as Ito, leading to varied effects on ST-segment and eventually, to different diagnostic yields2. A study comparing the effect of intravenous ajmaline vs. flecainide reported that flecainide failed to induce type1 ECG in 32% of the individuals with ajmaline-positive BrS2. Therefore, ajmaline should ideally be used in every drug-challenge testing to avoid false negative results. However, flecainide remains a diagnostic tool in clinical practice as ajmaline is not available in every country. The current standard protocol of flecainide testing is its intravenous infusion of 2mg/kg body weight over 10 minutes3. Yet, recent case reports showed that type1 ECG may appear 100 to 120 minutes after flecainide infusion4, 5. This points out that a 10 to 30-minute monitoring time of the test may be too short in some cases. In this issue of Heart Rhythm, Calvo et al. presented their effort to work out this problem6. They studied 59 patients with non-diagnostic BrS ECG pattern at baseline (but only at the 3rd and 2nd intercostal space) and performed flecainide testing. For 30 minutes from the start of flecainide infusion, 12-lead ECG was continuously monitored with the right precordial leads placed at the 3rd intercostal space. Two other ECGs were also made at 30 minutes and 90 minutes using the 3rd and 2nd intercostal space. Overall, 11 of the 59 patients (18.6%) showed a positive test: one-thirds at an early time period (0-10 minutes), another one-thirds at a ‘delayed’ period (10-30 minutes) and the remaining one-thirds at a ‘late’ period (90 minutes). Further, ECG parameters during the 1st 30 minutes were compared between 4 late responders and non-responders (48 patients). A QRS width exceeding 110 ms could differentiate the late responders from the non-responders (sensitivity 100%,
1
specificity 86%, positive predictive value 88% and negative predictive value 100%). The authors also attempted to find pharmacogenetic backgrounds to explain diverse responses to flecainide by screening polymorphisms in CYP2D6 and CYP3A5, liver enzymes involved in flecainide metabolism7. Although the study methods (only 3rd intercostal space was used for continuous monitoring during flecainide testing) possibly limited the authors’ ability to reveal the true ratio of delayed and late responders as well as to study pharmacogenetics in flecainide testing of BrS, several interesting points merit discussion. First, two-thirds of the flecainide-positive subjects failed to develop a positive test in 10 minutes, meaning these patients would have fallen into the false-negative category if the standard monitoring period of 10 minutes had been applied. This is a surprisingly large number. In our series of 159 subjects with non-type1 BrS ECG at baseline who underwent flecainide testing, no patient developed type1 ECG during a 10 to 30-minute monitoring period8. In addition, the overall positive rate is quite low (18.6%) in the study by Calvo et al.6 compared to ours (40%, 64/159)8. This may be explained by differences in the methods between the two studies, such as selection of study subjects (number and age of subjects, symptoms or family history of BrS, more symptomatic and familial cases in our series), different ECG-lead use for continuous monitoring (3rd intercostal space in the study by Calvo et al. vs. 4th and 3rd intercostal space in ours) and the proportion of SCN5A mutation carriers (3% in the study by Calvo et al. vs. 27% in ours)6, 8. Another reason may be the metabolism of flecainide. When flecainide is intravenously injected in healthy men, its mean plasma half-life is 11 hours (range, 7-15 hours) and its pharmacokinetics appears to be linear9. Several factors contribute to its wide range of half-life. Aging, liver and kidney dysfunction, heart failure or polymorphisms of liver enzymes (e.g. CYP2D6) are known to delay its metabolism10. Given that BrS patients are usually young with normal liver or kidney function, polymorphisms of liver enzymes are attractive candidates to evaluate. So, how do we find individuals with a delayed response to flecainide testing and how long do we need to monitor them after flecainide infusion? The authors attempted to answer these questions by 1) seeking for ECG parameters indicative of late responders (at 90 minutes) and 2) screening
2
polymorphisms of liver enzymes (CYP2D6 and CYP3A5) to find subjects with poor flecainide metabolism. As to ECG parameters, the authors reported that a QRS width exceeding 110 ms during the 1st 30 minutes after flecainide infusion was useful to distinguish late responders from non-responders. However, the analysis included too small a number of cases (4 late responders vs. 48 non-responders) to draw a definite conclusion. Of note, in our series, by using logistic regression analysis, we also attempted to find baseline ECG parameters which may predict the outcome of flecainide testing8. Our results showed that QRS width in V1, J point elevation in V2, S wave duration in II significantly contributed to the prediction8. In a future study, ECG parameters measured both before and after flecainide should be tested to find any ECG parameters useful for prediction of the outcome of flecainide testing. Finally, with regard to flecainide metabolism as a possible factor of delayed/late response to the drug, the association between the time of occurrence of type1 ECG and CYP2D6 polymorphisms was inconclusive. As for CYP3A5, all patients were homozygous for a minor allelle6. One of the reasons may be that a limited number of ECG leads for continuous monitoring led to underestimation of the development of type1 ECG and to misclassification of CYP2D6 polymorphisms related to the time points of type1 ECG appearance. In fact, although CYP2D6 is known to be the major metabolizer of flecainide, little is known about the effects of CYP2D6 polymorphisms and their interaction with other liver enzymes10. Current knowledge is drawn from few clinical studies with a small number of patients who are treated not only with flecainide but other antiarrhythmic drugs7, 11. The results of these studies are also discordant10. The effects of CYP2D6 polymorphisms on flecainide metabolism certainly need to be re-evaluated, and actually, a study population consisting of BrS patients seems quite ideal to test the pure effect of CYP2D6 polymorphisms because it is a rather young cohort without concomitant diseases. The results shown by Calvo et al. are certainly intriguing and call on revision of the flecainide testing protocol to improve its diagnostic yield in BrS. To do so, it is encouraged to create a large
3
international registry of flecainide testing so that the questions raised here are re-evaluated before a refined protocol of flecainide testing is finally established.
References
1.
Priori SG, Wilde AA, Horie M et al. HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes: Document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 2013;12:1932-1963.
2.
Wolpert C, Echternach C, Veltmann C, Antzelevitch C, Thomas GP, Spehl S, Streitner F, Kuschyk J, Schimpf R, Haase KK, Borggrefe M. Intravenous drug challenge using flecainide and ajmaline in patients with Brugada syndrome. Heart Rhythm 2005;3:254-260.
3.
Antzelevitch C, Brugada P, Borggrefe M et al. Brugada syndrome: report of the second consensus conference. Heart Rhythm 2005;4:429-440.
4.
Gray B, McGuire M, Semsarian C, Medi C. Late positive flecainide challenge test for Brugada syndrome. Heart Rhythm 2014;5:898-900.
5.
de-Riva-Silva M, Montero-Cabezas JM, Fontenla-Cerezuela A, Salguero-Bodes R, Lopez-Gil M, Arribas-Ynsaurriaga F. Delayed positive response to a flecainide test in a patient with suspected Brugada syndrome: a worrisome finding. Rev Esp Cardiol (Engl Ed) 2014;8:674-675.
6.
Calvo D, Rubín JM, Pérez D, Gómez J, Flórez JP, Avanzas P, García-Ruíz JM, de la Hera JM, Reguero J, Coto E, Morís C. Time dependent responses to provocative testing with flecainide in the diagnosis of Brugada Syndrome. Heart Rhythm. 2014.
4
7.
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;1:33-39.
8.
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;8:857-864.
9.
Conard GJ, Carlson GL, Frost JW, Ober RE, Leon AS, Hunninghake DB. Plasma concentrations of flecainide acetate, a new antiarrhythmic agent, in humans. Clin Ther 1984;5:643-652.
10.
Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev 2009;2:89-295.
11.
Doki K, Homma M, Kuga K, Aonuma K, Kohda Y. Effects of CYP2D6 genotypes on agerelated change of flecainide metabolism: involvement of CYP1A2-mediated metabolism. Br J Clin Pharmacol 2009;1:89-96.
5
