- Email: [email protected]
Radiofrequency ablation of atrial flutter due to administration of class IC antiarrhythmic drugs for atrial fibrillation
Radiofrequency Ablation of Atrial Flutter Due to Administration of Class IC Antiarrhythmic Drugs for Atrial Fibrillation Burghard Schumacher, MD, Werner Jung, Christian Vahlhaus, MD, Christian Wolpert,
MD, MD,
Thorsten Lewalter, MD, and Berndt Lu¨deritz, MD
In selected patients, atrial fibrillation (AF) converts to atrial flutter (AFl) due to treatment with class IC antiarrhythmic drugs. In this study, we prospectively investigated the effects of AFl ablation and continuation of drug therapy in patients with AF who developed AFl due to long-term administration of class IC antiarrhythmic drugs. The study population consisted of 187 patients from an AF registry with paroxysmal AF who were orally treated with flecainide (n 5 96) or propafenone (n 5 91). Twenty-four patients (12.8%) developed AFl during the course of treatment. In 20 of these patients (10.7%), electrophysiologic study revealed typical AFl. These patients underwent radiofrequency ablation of AFl. Ablation failed in 1 patient. All patients continued preexisting drug treatment. Recurrence of AF was assessed by ambulatory Holter monitoring and serial questionnaires. During a mean follow-up of 11 6 4 months, the incidence of AF episodes was significantly lower in patients with a combined therapy (2.7 6 3.6
per year) than in control subjects with a sole drug treatment (7.8 6 9.2 per year, p <0.05) and than before therapy (10.2 6 5.4 per year, p <0.001). Subgroup analysis revealed that 7 patients (36.8%) remained symptom free with no evidence of atrial tachyarrhythmia. Eight additional patients (42.1%) had ongoing paroxysmal AF, however, with a significantly lower incidence of AF episodes than before therapy (2.3 6 1.6 per year vs 11.5 6 5.0 per year, p <0.001). In the remaining 4 patients (14.7%), no beneficial effect of AFl ablation was found. It is concluded that in patients with AF who develop typical AFl due to administration of class IC antiarrhythmic agents, a combined therapy with catheter ablation of AFl and continuation of drug treatment is highly effective in reducing occurrence and duration of atrial tachyarrhythmias. Q1999 by Excerpta Medica, Inc. (Am J Cardiol 1999;83:710–713)
adiofrequency (RF) catheter ablation of typical atrial flutter (AFl) is well established, and its R acute and long-term efficacy is high. In contrast to
METHODS
1
2– 8
AFl, atrial fibrillation (AF) remains a therapeutic challenge. In selected patients, AF may be due to repetitive focal depolarization, which is susceptible to curative ablation approaches.9 Ablation approaches in other than “focal” AF are currently under investigation. Currently, in most patients with AF, long-term drug treatment with class IC antiarrhythmic agents remains the mainstay of therapy. In selected patients treated with class IC antiarrhythmic drugs, AF evolves to typical AFl.10 Because 1:1 atrioventricular conduction is facilitated by these drugs, the occurrence of AFl in patients with pharmacologically treated AF is generally believed to be a contraindication for maintaining class IC drug trials. In this study, we prospectively investigated the effects of AFl ablation and continuation of drug therapy in patients with AF who develop AFl due to long-term administration of class IC antiarrhythmic drugs. From the Department of Cardiology, University of Bonn, Bonn, Germany. Manuscript received August 24, 1998; revised manuscript received and accepted October 13, 1998. Address for reprints: Burghard Schumacher, MD, Department of Cardiology, University of Bonn, 25, Sigmund-Freud-Strasse, Bonn, 53105, Germany. E-mail: [email protected].
710
©1999 by Excerpta Medica, Inc. All rights reserved.
Patients: The study population consisted of 187 patients from a local AF registry with paroxysmal AF who were orally treated with 150 to 250 mg flecainide (n 5 96) or 300 to 900 mg propafenone (n 5 91). If a patient developed stable, documented AFl throughout the course of drug treatment, that patient was included in the study group. Twenty consecutive, randomized patients without evidence of AFl due to class IC drug trials formed the control group. All patients continued their preexisting drug treatment. Electrophysiologic study: All subjects gave informed written consent to a protocol approved by the institutional review board. Patients with AFl underwent electrophysiologic study to determine the AFl reentrant circuit by activation mapping around the tricuspid annulus, as described previously,8 and by entrainment mapping at the sub-Eustachian isthmus according to established criteria.11 Catheter ablation of atrial flutter: If a typical “isthmus-dependent” flutter circuit with a counterclockwise or clockwise activation sequence around the tricuspid annulus was identified, patients underwent RF catheter ablation. Ablation was performed by creating a linear lesion between the tricuspid annulus and either the inferior vena cava or the Eustachian ridge. If AFl terminated during RF application, pulse propagation at the targeted isthmus was determined during pacing at the coronary sinus and the low right atrium 0002-9149/99/$–see front matter PII S0002-9149(98)00975-8
adjacent to the ablation line. In addition, the occurrence of double potentials at the ablation line was documented. Catheter ablation was considered to be successful if a complete conduction block could be demonstrated by pacing and if a continuous line of double potentials was found at the ablation line. Otherwise, RF application was repeated. Follow-up: Patients were monitored for 48 hours after ablation. Antiarrhythmic drug treatment was continued after discharge. Patients were followed-up by a monthly questionnaire and ambulatory Holter monitoring 1 month, 3 months, 6 months, and 12 months after discharge. Palpitations for a time period ,30 seconds were not considered to be sustained AF. Data analysis: Data are reported as means 6 1 SD. Incidence of AF episodes throughout the previous year before class IC drug treatment were compared with those determined during follow-up. These variables were analyzed with Student’s t test for paired data. In addition, incidence of AF recurrence during follow-up were compared interindividually between patients with and without catheter ablation of AFl. These variables were analyzed with Student’s t test for unpaired data. Categorical variables were analyzed by Fisher’s exact test. A p value ,0.05 was considered statistically significant.
FIGURE 1. Incidence of AF episodes per year before enrollment (left bar) and during follow-up (right bar) in patients with drugrelated AFl who underwent AFl ablation and continued class IC drug treatment.
RESULTS
Incidence of atrial flutter: Twenty-four of 187 registered patients (12.8%) developed AFl during the course of class IC drug treatment. Thirteen of these patients received flecainide (13.5%) and 11 patients propafenone (12.1%) (p 5 NS). Common-type AFl with inverted flutter waves in leads II, III, and aVF was found in 18 patients and uncommon-type AFl with biphasic or upright flutter waves in 6 patients. In none of the patients was there documented AFl before drug treatment. Twenty consecutive, randomized patients without evidence of AFl due to class IC drug trials formed the control group. Both groups were matched regarding age, gender, history of AF, number and duration of episodes before ablation, and drug treatment. Electrophysiologic study and catheter ablation: All 24 patients with AFl underwent electrophysiologic study. In 20 patients, activation and entrainment mapping revealed counterclockwise (n 5 18) or clockwise (n 5 2) “isthmus-dependent” AFl. The 4 remaining patients had various reentrant circuits and were excluded from this study. The 20 patients with typical AFl underwent RF ablation of AFl at the isthmus between the tricuspid annulus and either the inferior vena cava (n 5 9) or the Eustachian ridge (n 5 11). Ablation failed in 1 patient. Recurrence of atrial fibrillation after ablation: All patients continued preexisting class IC drug treatment. During a mean follow-up of 11 6 4 months, the incidence of recurrent AF episodes was 2.7 6 3.6 per year (0 to 12) in patients with combined therapy and 7.8 6 9.2 per year (0 to 32) in control subjects with sole drug treatment. The differences were statistically significant (p ,0.05) (Figure 1). In addition, the dif-
FIGURE 2. Incidence of AF episodes per year during follow-up in patients with drug-related AFl who underwent AFl ablation (right bar) and control subjects (left bar). All patients received class IC drug treatment.
ferences were significantly lower than before therapy (10.2 6 5.4 episodes/year, 3 to 21 episodes/year, p ,0.001) (Figure 2). None of the patients experienced documented recurrence of AFl. Subgroup analysis revealed that 7 of the patients who had undergone AFl ablation (37.8%) remained symptom free with no evidence of sustained atrial arrhythmias. Eight additional patients (42.1%) had ongoing paroxysmal AF. However, in these patients, the incidence of AF episodes was significantly lower compared with that observed before therapy (2.8 6 1.6 vs 21 6 24 episodes/ year, p ,0.001) In addition, a strong tendency was found toward fewer episodes of AF (2.4 6 1.6 episodes/year) compared with control subjects undergoing single drug treatment (7.8 6 9.2 episodes/year). However, this difference did not reach statistical sig-
ARRHYTHMIAS AND CONDUCTION DISTURBANCES/HYBRID THERAPY FOR ATRIAL FIBRILLATION
711
FIGURE 3. Individual data and mean values 6 1 SD of episodes of AF per year before enrollment and during follow-up in patients who developed AFl due to administration of class IC antiarrhythmic drugs (left chart) and in control subjects without AFl (right chart). Patients with AFl due to class IC drugs underwent catheter ablation of AFl. All patients continued class IC drug treatment.
nificance (p 50.12). These 15 patients felt markedly improved with regard to their arrhythmia. In the remaining 4 patients (21.1%), no beneficial effect of AFl ablation was found. The individual data of AF recurrences is presented in Figure 3.
DISCUSSION
Impact on therapy for atrial fibrillation: Currently, long-term antiarrhythmic drug administration remains the mainstay of therapy in patients with paroxysmal AF. However, recurrence rates are still high. In this study, we investigated the effects of AFl ablation and continuation of drug therapy on AF recurrence rates in patients with AFl due to administration of class IC antiarrhythmic drugs. It was found that catheter ablation of drug-related AFl and continuation of drug therapy is highly effective in reducing AF episodes in these patients. Altogether, nearly 80% of the enrolled patients experienced a marked improvement of the natural course of AF during a 1-year follow-up. Of note, 1/3 of the treated patients were completely symptom free during follow-up. These results support the findings published recently by Huang and coworkers.12 These authors reported a benefit of hybrid therapy in 8 of 9 treated patients. Incidence of drug-related atrial flutter: Development of AFl due to administration of class IC antiarrhythmic drugs for AF is a well-known phenomenon.13 It gained special attention because 1:1 atrioventricular conduction with potentially life-treatening consequences was facilitated.10,14,15 Published data on the incidence of class IC-related AFl focused on AFl with a fast ventricular response. In safety studies with class IC drugs, an incidence of 5% to 10% has been shown.10,13,16 –19 The overall incidence of conversion of AF to AFl due to class IC antiarrhythmic drugs, which is not necessarily associated with a fast ventricular response, has not been investigated systematically. In our study, the incidence of drug-related AFl was determined in a population of 187 patients who had undergone class IC antiarrhythmic drug therapy for AF. In 12.8% of these patients, AF had evolved to AFl. No differences were found between patients taking flecainide and those taking propafenone. AFl had 712 THE AMERICAN JOURNAL OF CARDIOLOGYT
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not been documented before in any of the patients. These data might indicate a slightly higher incidence of drug-induced AFl than previously recognized. This assumption is supported by the observation of Bianconi et al,19 who found a conversion of AF in AFl in 22.4% of patients in a prospective study on the effects of oral propafenone administration (750 mg/day). Because the incidence of drug-related AFl was approximately 12% in our patient cohort and the efficacy of a combined treatment about 80%, it might be calculated from these data that up to 10% of unselected patients with AF may benefit from this therapy. However, this study was not prospectively designed to assess the incidence of class IC-mediated AFl, but rather an analysis of consecutive cases with long-term followup. Therefore, some concern exists regarding the accuracy of the denominator in this study despite all the patients being followed thoroughly through a local AF registry. Larger prospective studies are needed to clarify this issue. Mechanism of drug-related atrial flutter: It is well established that AFl is a macroreentrant rhythm localized to the right atrium20 –22 that is determined by anatomic barriers.23–26 In contrast, the mechanism of AF has not been fully elucidated up to now. Recent studies support the multiple wavelet hypothesis of Moe27 and the concept that AF involves a critical number of reentrant wavelets. The antiarrhythmic effect of class IC antiarrhythmic drugs results from a decrease of intraatrial conduction velocity. The slowing and organization of AF to AFl is almost likely due to the depression of atrial conduction velocity with a consecutive transfer of conduction delay into conduction block. This prevents the simultaneous occurrence of the multiple reentrant circuits necessary for the perpetuation of AF and results in a single “atrial flutter” reentrant circuit, in which the area of slow conduction, that is, the sub-Eustachian isthmus, can be transformed into an area of conduction block by RF ablation. Study limitations: Following AFl ablation and class IC drug treatment, the incidence of AF episodes was low in patients with drug-related AFl. To qualify a beneficial effect of the “hybrid” therapy, the recurMARCH 1, 1999
rence rates during follow-up were compared intraindividually as well as interindividually, that is, in comparison to the incidence of AF episodes throughout the last year before class IC drug treatment and in comparison to patients with sole drug treatment. The intraindividual analysis basically demonstrated that hybrid therapy is superior to no antiarrhythmic therapy. This has clinical implications, because drug-related AFl is usually considered a contraindication for continuation of class IC drug treatment. It was concluded that drug-related AFl need not result in a discontinuation of class IC drug treatment, but rather can result in concomitant catheter ablation of AFl. However, the intraindividual analysis could not clarify whether the reduction of AF episodes was the result of the antiarrhythmic action of class IC drugs, of AFl ablation, or of both. To answer this, the hybrid therapy would have to be compared with a continuation of class IC drug treatment, which cannot be performed for obvious ethical reasons in patients with drug-related AFl. Therefore, the incidence of AF episodes during follow-up was compared interindividually between patients with drug-related AFl, who were treated with the hybrid therapy, and control subjects without drugrelated AFl, who were exclusively treated with class IC drugs. It was found that the incidence of AF episodes was significantly lower in patients undergoing the hybrid therapy. This suggests a beneficial effect of AFl ablation. However, it cannot be excluded that the differences are exclusively the result of a different susceptibility to the antiarrhythmic action of class IC drugs. 1. Schumacher B, Lewalter T, Wolpert C, Jung W, Lu¨deritz B. Radiofrequency catheter ablation of atrial flutter. J Cardiovasc Electrophysiol 1998;9:S139 – S146. 2. Fischer B, Jais P, Shah D, Chouairi S, Haissaguerre M, Garrigues S, Poquet F, Gencel L, Clementy J, Marcus FI. Radiofrequency catheter ablation of common atrial flutter in 200 patients. J Cardiovasc Electrophysiol 1996;7:1225–1233. 3. Poty H, Saoudi N, Nair M, Anselme F, Letac B. Radiofrequency catheter ablation of atrial flutter. Further insights into the various types of isthmus block: application to ablation during sinus rhythm. Circulation 1996;94:3204 –3213. 4. Tai CT, Chen SA, Chiang CE, Lee SH, Ueng KC, Wen ZC, Chen YJ, Yu WC, Huang JL, Chiou CW, Chang MS. Electrophysiologic characteristics and radiofrequency catheter ablation in patients with clockwise atrial flutter. J Cardiovasc Electrophysiol 1997;8:24 –34. 5. Cosio FG, Lopez Gil M, Arribas F, Goicolea A. Radiofrequency catheter ablation for the treatment of human type 1 atrial. Circulation 1993;88:804 – 805. 6. Feld GK, Fleck RP, Chen PS, Boyce K, Bahnson TD, Stein JB, Calisi CM,
Ibarra M. Radiofrequency catheter ablation for the treatment of human type 1 atrial flutter. Identification of a critical zone in the reentrant circuit by endocardial mapping techniques. Circulation 1992;86:1233–1240. 7. Schwartzman D, Callans DJ, Gottlieb CD, Dillon SM, Movsowitz C, Marchlinski FE. Conduction block in the inferior vena caval-tricuspid valve isthmus: association with outcome of radiofrequency ablation of type I atrial flutter. J Am Coll Cardiol 1996;28:1519 –1531. 8. Schumacher B, Tebbenjohanns J, Pfeiffer D, Lewalter T, Jung W, Lu¨deritz B. Acute and long-term effects of consecutive radiofrequency applications on conduction properties of the inferior vena cava to tricuspid annulus isthmus in type 1 atrial flutter. J Cardiovasc Electrophysiol 1998;9:152–163. 9. Jais P, Haissaguerre M, Shah DC, Chouairi S, Gencel L, Hocini M, Clementy J. A focal source of atrial fibrillation treated by discrete RF ablation. Circulation 1997;95:572–576. 10. Feld GH, Chen PS, Nicod P, Fleck RP, Mezer D. Atrial proarrhythmic effects of class IC antiarrhythmic drugs. Am J Cardiol 1990;66:378 –382. 11. Waldo AL, Carlson MD, Henthorn RW. Atrial Flutter: Transient Entrainment and Related Phenomena. Philadelphia: WB Saunders Co., 1990;530 –536. 12. Huang DT, Monahan KM, Zimetbaum P, Papageorgiou P, Epstein LM, Josephson ME. Hybrid pharmacological and ablative therapy: a novel and effective approach for the management of atrial fibrillation. J Cardiovasc Electrophysiol 1998;9:462– 469. 13. Marcus FI. The hazards of using type 1C antiarrhythmic drugs for the treatment of paroxysmal atrial fibrillation. Am J Cardiol 1990;66:366 –367. 14. Crijns HJ, van Gelder IC, Lie KI. Supraventricular tachycardia mimicking ventricular tachycardia during flecainide treatment. Am J Cardiol 1988;62:1303– 1306. 15. De Meester A, Machiels JP, Rousseau L, Luwaert R, Chaudron JM. Unusual atrial proarrhythmic effect of flecainide: a contemporary review. Acta Cardiol 1996;51:529 –534. 16. Capucci A, Boriani G, Botto GL, Della Casa S, Sanguinetti M, Magnani B. Conversion of recent onset atrial fibrillation by a single oral loading dose of propafenone or flecainide. Am J Cardiol 1994;74:503–505. 17. Capucci A, Boriani G, Rubino I, Della Casa S, Sanguinetti M, Magnani B: A controlled study on oral propafenone versus digoxin plus quinidine in converting recent onset atrial fibrillation to sinus rhythm. Int J Cardiol 1994;43:305–313. 18. Murdock CJ, Kyles AE, Yeung-lai-Wah JA, Qi A, Vorderbrugge S, Kerr CR. Atrial flutter in patients treated for atrial fibrillation with propafenone. Am J Cardiol 1990;66:755–757. 19. Bianconi L, Mennuni M, Lukic V, Castro A, Chieffi M, Santini M. Effects of oral propafenone administration before electrical cardioversion of chronic atrial fibrillation: a placebo-controlled study. J Am Coll Cardiol 1996;28:700 –706. 20. Waldo AL. Atrial flutter: new directions in management and mechanism. Circulation 1990;81:1142–1143. 21. Cosio FG, Lopez GM, Goicolea A, Arribas F. Electrophysiologic studies in atrial flutter. Clin Cardiol 1992;15:667– 673. 22. Olshansky B, Wilber DJ, Hariman RJ. Atrial flutter: update on the mechanism and treatment. Pacing Clin Electrophysiol 1992;15:2308 –2335. 23. Boyden PA, Frame LH, Hoffman BF. Activation mapping of reentry around an anatomic barrier in the canine atrium: observations during entrainement and termination. Circulation 1989;79:406 – 416. 24. Schoels W, Kuebler W, Yang H, Gough WB, El Sherif N. A unified functional/anatomic substrate for circus movement atrial flutter: activation and refractory patterns in the canine right atrial enlargement model. J Am Coll Cardiol 1993;21:73– 84. 25. Frame LH, Page RL, Hoffman BF. Atrial reentry around an anatomic barrier with a partially refractory excitable gap: a canine model of atrial flutter. Circ Res 1986;58:495– 511. 26. Kalman JM, Olgin JE, Saxon LA, Fisher WG, Lee RJ, Lesh MD. Activation and entrainment mapping defines the tricuspid annulus as the anterior barrier in typical atrial flutter. Circulation 1996;94:398 – 406. 27. Moe G. On the multiple wavelet hypothesis of atrial fibrillation. Arch Int Pharmacodyn Ther 1962;140:183–188.
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MD, MD,
Thorsten Lewalter, MD, and Berndt Lu¨deritz, MD
In selected patients, atrial fibrillation (AF) converts to atrial flutter (AFl) due to treatment with class IC antiarrhythmic drugs. In this study, we prospectively investigated the effects of AFl ablation and continuation of drug therapy in patients with AF who developed AFl due to long-term administration of class IC antiarrhythmic drugs. The study population consisted of 187 patients from an AF registry with paroxysmal AF who were orally treated with flecainide (n 5 96) or propafenone (n 5 91). Twenty-four patients (12.8%) developed AFl during the course of treatment. In 20 of these patients (10.7%), electrophysiologic study revealed typical AFl. These patients underwent radiofrequency ablation of AFl. Ablation failed in 1 patient. All patients continued preexisting drug treatment. Recurrence of AF was assessed by ambulatory Holter monitoring and serial questionnaires. During a mean follow-up of 11 6 4 months, the incidence of AF episodes was significantly lower in patients with a combined therapy (2.7 6 3.6
per year) than in control subjects with a sole drug treatment (7.8 6 9.2 per year, p <0.05) and than before therapy (10.2 6 5.4 per year, p <0.001). Subgroup analysis revealed that 7 patients (36.8%) remained symptom free with no evidence of atrial tachyarrhythmia. Eight additional patients (42.1%) had ongoing paroxysmal AF, however, with a significantly lower incidence of AF episodes than before therapy (2.3 6 1.6 per year vs 11.5 6 5.0 per year, p <0.001). In the remaining 4 patients (14.7%), no beneficial effect of AFl ablation was found. It is concluded that in patients with AF who develop typical AFl due to administration of class IC antiarrhythmic agents, a combined therapy with catheter ablation of AFl and continuation of drug treatment is highly effective in reducing occurrence and duration of atrial tachyarrhythmias. Q1999 by Excerpta Medica, Inc. (Am J Cardiol 1999;83:710–713)
adiofrequency (RF) catheter ablation of typical atrial flutter (AFl) is well established, and its R acute and long-term efficacy is high. In contrast to
METHODS
1
2– 8
AFl, atrial fibrillation (AF) remains a therapeutic challenge. In selected patients, AF may be due to repetitive focal depolarization, which is susceptible to curative ablation approaches.9 Ablation approaches in other than “focal” AF are currently under investigation. Currently, in most patients with AF, long-term drug treatment with class IC antiarrhythmic agents remains the mainstay of therapy. In selected patients treated with class IC antiarrhythmic drugs, AF evolves to typical AFl.10 Because 1:1 atrioventricular conduction is facilitated by these drugs, the occurrence of AFl in patients with pharmacologically treated AF is generally believed to be a contraindication for maintaining class IC drug trials. In this study, we prospectively investigated the effects of AFl ablation and continuation of drug therapy in patients with AF who develop AFl due to long-term administration of class IC antiarrhythmic drugs. From the Department of Cardiology, University of Bonn, Bonn, Germany. Manuscript received August 24, 1998; revised manuscript received and accepted October 13, 1998. Address for reprints: Burghard Schumacher, MD, Department of Cardiology, University of Bonn, 25, Sigmund-Freud-Strasse, Bonn, 53105, Germany. E-mail: [email protected].
710
©1999 by Excerpta Medica, Inc. All rights reserved.
Patients: The study population consisted of 187 patients from a local AF registry with paroxysmal AF who were orally treated with 150 to 250 mg flecainide (n 5 96) or 300 to 900 mg propafenone (n 5 91). If a patient developed stable, documented AFl throughout the course of drug treatment, that patient was included in the study group. Twenty consecutive, randomized patients without evidence of AFl due to class IC drug trials formed the control group. All patients continued their preexisting drug treatment. Electrophysiologic study: All subjects gave informed written consent to a protocol approved by the institutional review board. Patients with AFl underwent electrophysiologic study to determine the AFl reentrant circuit by activation mapping around the tricuspid annulus, as described previously,8 and by entrainment mapping at the sub-Eustachian isthmus according to established criteria.11 Catheter ablation of atrial flutter: If a typical “isthmus-dependent” flutter circuit with a counterclockwise or clockwise activation sequence around the tricuspid annulus was identified, patients underwent RF catheter ablation. Ablation was performed by creating a linear lesion between the tricuspid annulus and either the inferior vena cava or the Eustachian ridge. If AFl terminated during RF application, pulse propagation at the targeted isthmus was determined during pacing at the coronary sinus and the low right atrium 0002-9149/99/$–see front matter PII S0002-9149(98)00975-8
adjacent to the ablation line. In addition, the occurrence of double potentials at the ablation line was documented. Catheter ablation was considered to be successful if a complete conduction block could be demonstrated by pacing and if a continuous line of double potentials was found at the ablation line. Otherwise, RF application was repeated. Follow-up: Patients were monitored for 48 hours after ablation. Antiarrhythmic drug treatment was continued after discharge. Patients were followed-up by a monthly questionnaire and ambulatory Holter monitoring 1 month, 3 months, 6 months, and 12 months after discharge. Palpitations for a time period ,30 seconds were not considered to be sustained AF. Data analysis: Data are reported as means 6 1 SD. Incidence of AF episodes throughout the previous year before class IC drug treatment were compared with those determined during follow-up. These variables were analyzed with Student’s t test for paired data. In addition, incidence of AF recurrence during follow-up were compared interindividually between patients with and without catheter ablation of AFl. These variables were analyzed with Student’s t test for unpaired data. Categorical variables were analyzed by Fisher’s exact test. A p value ,0.05 was considered statistically significant.
FIGURE 1. Incidence of AF episodes per year before enrollment (left bar) and during follow-up (right bar) in patients with drugrelated AFl who underwent AFl ablation and continued class IC drug treatment.
RESULTS
Incidence of atrial flutter: Twenty-four of 187 registered patients (12.8%) developed AFl during the course of class IC drug treatment. Thirteen of these patients received flecainide (13.5%) and 11 patients propafenone (12.1%) (p 5 NS). Common-type AFl with inverted flutter waves in leads II, III, and aVF was found in 18 patients and uncommon-type AFl with biphasic or upright flutter waves in 6 patients. In none of the patients was there documented AFl before drug treatment. Twenty consecutive, randomized patients without evidence of AFl due to class IC drug trials formed the control group. Both groups were matched regarding age, gender, history of AF, number and duration of episodes before ablation, and drug treatment. Electrophysiologic study and catheter ablation: All 24 patients with AFl underwent electrophysiologic study. In 20 patients, activation and entrainment mapping revealed counterclockwise (n 5 18) or clockwise (n 5 2) “isthmus-dependent” AFl. The 4 remaining patients had various reentrant circuits and were excluded from this study. The 20 patients with typical AFl underwent RF ablation of AFl at the isthmus between the tricuspid annulus and either the inferior vena cava (n 5 9) or the Eustachian ridge (n 5 11). Ablation failed in 1 patient. Recurrence of atrial fibrillation after ablation: All patients continued preexisting class IC drug treatment. During a mean follow-up of 11 6 4 months, the incidence of recurrent AF episodes was 2.7 6 3.6 per year (0 to 12) in patients with combined therapy and 7.8 6 9.2 per year (0 to 32) in control subjects with sole drug treatment. The differences were statistically significant (p ,0.05) (Figure 1). In addition, the dif-
FIGURE 2. Incidence of AF episodes per year during follow-up in patients with drug-related AFl who underwent AFl ablation (right bar) and control subjects (left bar). All patients received class IC drug treatment.
ferences were significantly lower than before therapy (10.2 6 5.4 episodes/year, 3 to 21 episodes/year, p ,0.001) (Figure 2). None of the patients experienced documented recurrence of AFl. Subgroup analysis revealed that 7 of the patients who had undergone AFl ablation (37.8%) remained symptom free with no evidence of sustained atrial arrhythmias. Eight additional patients (42.1%) had ongoing paroxysmal AF. However, in these patients, the incidence of AF episodes was significantly lower compared with that observed before therapy (2.8 6 1.6 vs 21 6 24 episodes/ year, p ,0.001) In addition, a strong tendency was found toward fewer episodes of AF (2.4 6 1.6 episodes/year) compared with control subjects undergoing single drug treatment (7.8 6 9.2 episodes/year). However, this difference did not reach statistical sig-
ARRHYTHMIAS AND CONDUCTION DISTURBANCES/HYBRID THERAPY FOR ATRIAL FIBRILLATION
711
FIGURE 3. Individual data and mean values 6 1 SD of episodes of AF per year before enrollment and during follow-up in patients who developed AFl due to administration of class IC antiarrhythmic drugs (left chart) and in control subjects without AFl (right chart). Patients with AFl due to class IC drugs underwent catheter ablation of AFl. All patients continued class IC drug treatment.
nificance (p 50.12). These 15 patients felt markedly improved with regard to their arrhythmia. In the remaining 4 patients (21.1%), no beneficial effect of AFl ablation was found. The individual data of AF recurrences is presented in Figure 3.
DISCUSSION
Impact on therapy for atrial fibrillation: Currently, long-term antiarrhythmic drug administration remains the mainstay of therapy in patients with paroxysmal AF. However, recurrence rates are still high. In this study, we investigated the effects of AFl ablation and continuation of drug therapy on AF recurrence rates in patients with AFl due to administration of class IC antiarrhythmic drugs. It was found that catheter ablation of drug-related AFl and continuation of drug therapy is highly effective in reducing AF episodes in these patients. Altogether, nearly 80% of the enrolled patients experienced a marked improvement of the natural course of AF during a 1-year follow-up. Of note, 1/3 of the treated patients were completely symptom free during follow-up. These results support the findings published recently by Huang and coworkers.12 These authors reported a benefit of hybrid therapy in 8 of 9 treated patients. Incidence of drug-related atrial flutter: Development of AFl due to administration of class IC antiarrhythmic drugs for AF is a well-known phenomenon.13 It gained special attention because 1:1 atrioventricular conduction with potentially life-treatening consequences was facilitated.10,14,15 Published data on the incidence of class IC-related AFl focused on AFl with a fast ventricular response. In safety studies with class IC drugs, an incidence of 5% to 10% has been shown.10,13,16 –19 The overall incidence of conversion of AF to AFl due to class IC antiarrhythmic drugs, which is not necessarily associated with a fast ventricular response, has not been investigated systematically. In our study, the incidence of drug-related AFl was determined in a population of 187 patients who had undergone class IC antiarrhythmic drug therapy for AF. In 12.8% of these patients, AF had evolved to AFl. No differences were found between patients taking flecainide and those taking propafenone. AFl had 712 THE AMERICAN JOURNAL OF CARDIOLOGYT
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not been documented before in any of the patients. These data might indicate a slightly higher incidence of drug-induced AFl than previously recognized. This assumption is supported by the observation of Bianconi et al,19 who found a conversion of AF in AFl in 22.4% of patients in a prospective study on the effects of oral propafenone administration (750 mg/day). Because the incidence of drug-related AFl was approximately 12% in our patient cohort and the efficacy of a combined treatment about 80%, it might be calculated from these data that up to 10% of unselected patients with AF may benefit from this therapy. However, this study was not prospectively designed to assess the incidence of class IC-mediated AFl, but rather an analysis of consecutive cases with long-term followup. Therefore, some concern exists regarding the accuracy of the denominator in this study despite all the patients being followed thoroughly through a local AF registry. Larger prospective studies are needed to clarify this issue. Mechanism of drug-related atrial flutter: It is well established that AFl is a macroreentrant rhythm localized to the right atrium20 –22 that is determined by anatomic barriers.23–26 In contrast, the mechanism of AF has not been fully elucidated up to now. Recent studies support the multiple wavelet hypothesis of Moe27 and the concept that AF involves a critical number of reentrant wavelets. The antiarrhythmic effect of class IC antiarrhythmic drugs results from a decrease of intraatrial conduction velocity. The slowing and organization of AF to AFl is almost likely due to the depression of atrial conduction velocity with a consecutive transfer of conduction delay into conduction block. This prevents the simultaneous occurrence of the multiple reentrant circuits necessary for the perpetuation of AF and results in a single “atrial flutter” reentrant circuit, in which the area of slow conduction, that is, the sub-Eustachian isthmus, can be transformed into an area of conduction block by RF ablation. Study limitations: Following AFl ablation and class IC drug treatment, the incidence of AF episodes was low in patients with drug-related AFl. To qualify a beneficial effect of the “hybrid” therapy, the recurMARCH 1, 1999
rence rates during follow-up were compared intraindividually as well as interindividually, that is, in comparison to the incidence of AF episodes throughout the last year before class IC drug treatment and in comparison to patients with sole drug treatment. The intraindividual analysis basically demonstrated that hybrid therapy is superior to no antiarrhythmic therapy. This has clinical implications, because drug-related AFl is usually considered a contraindication for continuation of class IC drug treatment. It was concluded that drug-related AFl need not result in a discontinuation of class IC drug treatment, but rather can result in concomitant catheter ablation of AFl. However, the intraindividual analysis could not clarify whether the reduction of AF episodes was the result of the antiarrhythmic action of class IC drugs, of AFl ablation, or of both. To answer this, the hybrid therapy would have to be compared with a continuation of class IC drug treatment, which cannot be performed for obvious ethical reasons in patients with drug-related AFl. Therefore, the incidence of AF episodes during follow-up was compared interindividually between patients with drug-related AFl, who were treated with the hybrid therapy, and control subjects without drugrelated AFl, who were exclusively treated with class IC drugs. It was found that the incidence of AF episodes was significantly lower in patients undergoing the hybrid therapy. This suggests a beneficial effect of AFl ablation. However, it cannot be excluded that the differences are exclusively the result of a different susceptibility to the antiarrhythmic action of class IC drugs. 1. Schumacher B, Lewalter T, Wolpert C, Jung W, Lu¨deritz B. Radiofrequency catheter ablation of atrial flutter. J Cardiovasc Electrophysiol 1998;9:S139 – S146. 2. Fischer B, Jais P, Shah D, Chouairi S, Haissaguerre M, Garrigues S, Poquet F, Gencel L, Clementy J, Marcus FI. Radiofrequency catheter ablation of common atrial flutter in 200 patients. J Cardiovasc Electrophysiol 1996;7:1225–1233. 3. Poty H, Saoudi N, Nair M, Anselme F, Letac B. Radiofrequency catheter ablation of atrial flutter. Further insights into the various types of isthmus block: application to ablation during sinus rhythm. Circulation 1996;94:3204 –3213. 4. Tai CT, Chen SA, Chiang CE, Lee SH, Ueng KC, Wen ZC, Chen YJ, Yu WC, Huang JL, Chiou CW, Chang MS. Electrophysiologic characteristics and radiofrequency catheter ablation in patients with clockwise atrial flutter. J Cardiovasc Electrophysiol 1997;8:24 –34. 5. Cosio FG, Lopez Gil M, Arribas F, Goicolea A. Radiofrequency catheter ablation for the treatment of human type 1 atrial. Circulation 1993;88:804 – 805. 6. Feld GK, Fleck RP, Chen PS, Boyce K, Bahnson TD, Stein JB, Calisi CM,
Ibarra M. Radiofrequency catheter ablation for the treatment of human type 1 atrial flutter. Identification of a critical zone in the reentrant circuit by endocardial mapping techniques. Circulation 1992;86:1233–1240. 7. Schwartzman D, Callans DJ, Gottlieb CD, Dillon SM, Movsowitz C, Marchlinski FE. Conduction block in the inferior vena caval-tricuspid valve isthmus: association with outcome of radiofrequency ablation of type I atrial flutter. J Am Coll Cardiol 1996;28:1519 –1531. 8. Schumacher B, Tebbenjohanns J, Pfeiffer D, Lewalter T, Jung W, Lu¨deritz B. Acute and long-term effects of consecutive radiofrequency applications on conduction properties of the inferior vena cava to tricuspid annulus isthmus in type 1 atrial flutter. J Cardiovasc Electrophysiol 1998;9:152–163. 9. Jais P, Haissaguerre M, Shah DC, Chouairi S, Gencel L, Hocini M, Clementy J. A focal source of atrial fibrillation treated by discrete RF ablation. Circulation 1997;95:572–576. 10. Feld GH, Chen PS, Nicod P, Fleck RP, Mezer D. Atrial proarrhythmic effects of class IC antiarrhythmic drugs. Am J Cardiol 1990;66:378 –382. 11. Waldo AL, Carlson MD, Henthorn RW. Atrial Flutter: Transient Entrainment and Related Phenomena. Philadelphia: WB Saunders Co., 1990;530 –536. 12. Huang DT, Monahan KM, Zimetbaum P, Papageorgiou P, Epstein LM, Josephson ME. Hybrid pharmacological and ablative therapy: a novel and effective approach for the management of atrial fibrillation. J Cardiovasc Electrophysiol 1998;9:462– 469. 13. Marcus FI. The hazards of using type 1C antiarrhythmic drugs for the treatment of paroxysmal atrial fibrillation. Am J Cardiol 1990;66:366 –367. 14. Crijns HJ, van Gelder IC, Lie KI. Supraventricular tachycardia mimicking ventricular tachycardia during flecainide treatment. Am J Cardiol 1988;62:1303– 1306. 15. De Meester A, Machiels JP, Rousseau L, Luwaert R, Chaudron JM. Unusual atrial proarrhythmic effect of flecainide: a contemporary review. Acta Cardiol 1996;51:529 –534. 16. Capucci A, Boriani G, Botto GL, Della Casa S, Sanguinetti M, Magnani B. Conversion of recent onset atrial fibrillation by a single oral loading dose of propafenone or flecainide. Am J Cardiol 1994;74:503–505. 17. Capucci A, Boriani G, Rubino I, Della Casa S, Sanguinetti M, Magnani B: A controlled study on oral propafenone versus digoxin plus quinidine in converting recent onset atrial fibrillation to sinus rhythm. Int J Cardiol 1994;43:305–313. 18. Murdock CJ, Kyles AE, Yeung-lai-Wah JA, Qi A, Vorderbrugge S, Kerr CR. Atrial flutter in patients treated for atrial fibrillation with propafenone. Am J Cardiol 1990;66:755–757. 19. Bianconi L, Mennuni M, Lukic V, Castro A, Chieffi M, Santini M. Effects of oral propafenone administration before electrical cardioversion of chronic atrial fibrillation: a placebo-controlled study. J Am Coll Cardiol 1996;28:700 –706. 20. Waldo AL. Atrial flutter: new directions in management and mechanism. Circulation 1990;81:1142–1143. 21. Cosio FG, Lopez GM, Goicolea A, Arribas F. Electrophysiologic studies in atrial flutter. Clin Cardiol 1992;15:667– 673. 22. Olshansky B, Wilber DJ, Hariman RJ. Atrial flutter: update on the mechanism and treatment. Pacing Clin Electrophysiol 1992;15:2308 –2335. 23. Boyden PA, Frame LH, Hoffman BF. Activation mapping of reentry around an anatomic barrier in the canine atrium: observations during entrainement and termination. Circulation 1989;79:406 – 416. 24. Schoels W, Kuebler W, Yang H, Gough WB, El Sherif N. A unified functional/anatomic substrate for circus movement atrial flutter: activation and refractory patterns in the canine right atrial enlargement model. J Am Coll Cardiol 1993;21:73– 84. 25. Frame LH, Page RL, Hoffman BF. Atrial reentry around an anatomic barrier with a partially refractory excitable gap: a canine model of atrial flutter. Circ Res 1986;58:495– 511. 26. Kalman JM, Olgin JE, Saxon LA, Fisher WG, Lee RJ, Lesh MD. Activation and entrainment mapping defines the tricuspid annulus as the anterior barrier in typical atrial flutter. Circulation 1996;94:398 – 406. 27. Moe G. On the multiple wavelet hypothesis of atrial fibrillation. Arch Int Pharmacodyn Ther 1962;140:183–188.
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