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Circ J 2006; 70: 657–661

Pharmacological Conversion of Persistent Atrial Fibrillation Into Sinus Rhythm With Oral Pilsicainide Pilsicainide Suppression Trial for Persistent Atrial Fibrillation II

Kaoru Okishige, MD; Masatake Fukunami, MD*; Koichiro Kumagai, MD**; Hirotsugu Atarashi, MD†; Hiroshi Inoue, MD††; for the Pilsicainide Suppression Trial for Persistent Atrial Fibrillation II Investigators

Background The present study was conducted to determine the antiarrhythmic efficacy and safety of oral pilsicainide, a class Ic antiarrhythmic drug, in patients with persistent atrial fibrillation (AF). Methods and Results One hundred and eight patients (mean age, 58.9 years) with AF lasting ≥48h and ≤6 months were randomized to receive pilsicainide 50mg t.i.d. (n=58) or placebo (n=50) for 2 weeks in a double- blinded fashion. All patients underwent appropriate anticoagulation therapy with warfarin for ≥3 weeks prior to the study enrolment or after verification of the absence of left atrial thrombi by transesophageal echocardiography. After 2 weeks of treatment, an electrocardiogram was recorded to determine whether sinus rhythm was restored. Sinus rhythm was restored in 22.4% of patients treated with pilsicainide and in 2% treated with placebo (p=0.002). Cardioversion was less likely to occur with oral pilsicainide when the AF duration exceeded 2 months or if the left atrial diameter exceeded 45mm. There was no significant difference in the adverse cardiovascular event rate between the pilsicainide- and placebo-treated groups. One patient in the pilsicainide group developed an atrial flutter without any hemodynamic deterioration. Conclusion A 2-week oral administration of pilsicainide is well tolerated and moderately effective in convert- ing persistent AF into sinus rhythm. (Circ J 2006; 70: 657–661) Key Words: Cardioversion; Persistent atrial fibrillation; Pilsicainide; Randomized clinical trial

trial fibrillation (AF) has emerged as the most com- is effective in terminating recent-onset AF with a single oral mon cardiac arrhythmia leading to significant dosage.14,15 Our previous study16 showed that a 4-week A morbidity and possibly mortality, and affects oral treatment with pilsicainide terminated long-lasting (>6 approximately 5% of the population aged >65 years in the months) AF in 21% of patients, which is a similar conver- USA.1–3 For persistent AF, antiarrhythmic therapy has 2 sion rate to that of oral in patients with persis- main objectives; restoration of sinus rhythm and prevention tent or chronic AF.11 However, although conducted in a of AF recurrence. Restoration and maintenance of sinus randomized and placebo-controlled fashion, the study had rhythm have several benefits including alleviation of symp- some drawbacks.16 Hence, the Pilsicainide Suppression toms, hemodynamic improvement, and possible reduction Trial for Persistent Atrial Fibrillation II (PSTAF-II) was of thromboembolic risk.4 In a recent clinical trial the pres- conducted in a randomized, double-blinded, placebo-con- ence of sinus rhythm was associated with a considerable trolled fashion to determine the antiarrhythmic efficacy of reduction in the risk of death when the data were analyzed oral pilsicainide in patients with persistent AF. on an on-treatment basis.5 Several studies have been conducted to determine the effects of oral antiarrhythmic drugs in patients with recent- Methods onset AF.6–9 Pharmacologic conversion of persistent AF Twenty-seven hospitals in Japan participated in this with novel antiarrhythmic drugs has also been reported,10,11 multicenter study (Appendix 1). The study design was but available data are limited so far. Pilsicainide is a class Ic approved by the ethics committee of each participating antiarrhythmic drug or pure Na with slow hospital. Before entering the trial, each patient was in- recovery kinetics commercially available in Japan,12,13 and formed about the potential benefits and adverse effects of the drug, and gave consent. (Received November 29, 2005; revised manuscript received February Patients were eligible for entering the present study if they 22, 2006; accepted March 9, 2006) were aged between 20 and 75 years and had persistent AF Yokohama City Bay Red Cross Hospital, Yokohama, *Osaka General defined as AF lasting ≥48h but not exceeding 6 months. All Medical Center, Osaka, **Fukuoka University Hospital, Fukuoka, patients needed to undergo appropriate anticoagulation ther- †Nippon Medical School, Tama-Nagayama Hospital, Tokyo and ≥ ††University of Toyama, Toyama, Japan apy with warfarin for 3 weeks prior to the study enrolment Mailing address: Kaoru Okishige, MD, Division of Cardiology, Heart or after the verification of left atrial thrombi absence by Center, Yokohama City Bay Red Cross Hospital, 3-12-1 Shinyamashita, transesophageal echocardiography. Beta-blockers and anti- Naka-ku, Yokohama 231-8682, Japan. E-mail: [email protected] arrhythmic agents were discontinued for ≥2 pharmacokinetic

Circulation Journal Vol.70, June 2006 658 OKISHIGE K et al.

Table 1 Baseline Clinical Characteristics of Patients Table 2 Clinical Characteristics of Responders and Non-Responders in the Pilsicainide Group Pilsicainide Placebo p value (n=58) (n=50) Responders Non-responders p value (n=13) (n=45) Male sex 45 (77.6) 39 (78.0) 0.959 Age (years) 58±9 60±10 0.245 Male sex 11 (84.6) 34 (75.6) 0.711 Cardiac diseases 29 (50.0) 29 (58.0) 0.406 Age (years) 57±10 58±9 0.715 Previous AADs 13 (22.4) 20 (40.0) 0.048 Cardiac diseases 4 (30.8) 25 (55.6) 0.115 AF duration (months) 0.180 Previous AADs 4 (30.8) 9 (20.0) 0.460 ≤2 44 (75.9) 32 (64.0) AF duration (months) 0.407 >2–6 14 (24.1) 18 (36.0) ≤2 11 (84.6) 33 (73.3) AF duration (days) 43±34 58±46 0.052 >2–6 2 (15.4) 12 (26.7) LAD (mm) 42±6 41±7 0.469 AF duration (days) 33±33 45±34 0.274 LVEF (%) 62±9 64±10 0.327 LAD (mm) 40±7 43±6 0.067 ANP (pg/ml) 72±44 71±43 0.838 LVEF (%) 63±7 61±9 0.675 BNP (pg/ml) 100±85 100±77 0.993 ANP (pg/ml) 71±41 73±46 0.885 BNP (pg/ml) 112±104 97±80 0.589 Data are mean ± standard deviation or number (%) of patients. AADs, antiarrhythmic drugs; AF, atrial fibrillation; LAD, left atrial diame- Data are mean ± standard deviation or number (%) of patients. ter; LVEF, left ventricular ejection fraction; ANP, atrial natriuretic peptide; Abbreviations see Table1. BNP, brain natriuretic peptide. half-lives before entry. Patients were excluded from the vs placebo group and responders vs non-responders) were present study if they met any of the following criteria: (1) evaluated by using a Student’s t-test for parametric data. no necessity of digitalis administration for the appropriate Chi-square analysis or Fisher’s exact test was used as rate control of AF; (2) sick sinus syndrome, intraventricular appropriate for the comparison of differences in categorical conduction disturbance, high degree atrioventricular block, variables between the groups. A p<0.05 was considered to or bifascicular block; (3) congestive heart failure or remark- be statistically significant. able cardiomegaly; (4) myocardial infarction within the pre- vious 28 days; (5) hypertrophic or dilated cardiomyopathy; (6) renal dysfunction (creatinine clearance <50ml/min) or Results on hemodialysis; (7) prior administration of pilsicainide; Of the 117 patients registered in the study, 9 were with- (8) contra-indication of digitalization or anticoagulation drawn because of protocol violation. Thus, 108 patients with warfarin; and (9) were pregnant or lactating. constituted the study group. Fifty-eight patients were assigned to pilsicainide treatment and 50 to placebo. In Study Protocol 46% of patients, no underlying cardiac disease was present. Patients were randomized to receive oral pilsicainide Although there was a slight tendency for a relatively 50mg t.i.d. or placebo for 2 weeks in a double-blinded shorter duration of AF in the pilsicainide than in the control manner. Baseline demographic data including all relevant group, clinical characteristics were comparable between cardiac diagnosis, history, physical examination, and labo- the 2 groups, with the exception of previous antiarrhythmic ratory results (electrolytes, renal and liver function tests, drug treatment (p=0.048; Table1). No patient was followed and prothrombin time) were obtained. Plasma concentra- up beyond 2 weeks. tions of atrial natriuretic peptide and brain natriuretic pep- tide were also determined. For echocardiographic variables, Restoration of Sinus Rhythm left atrial dimension (LAD) and left ventricular ejection Two weeks after starting the treatment, sinus rhythm fraction were determined. Patients received oral warfarin to was restored in 13 of 58 patients (22.4%) in the pilsicainide maintain the international normalized ratio of prothrombin group. In contrast, it was restored only in 1 of 50 patients time within a target range of 1.5–2.0, and such a low inten- (2%) in the placebo group (p=0.002). sity of anticoagulation caused by warfarin had been proved to have a favorable effect in terms of prevention of embolic Determinants of Pharmacological Defibrillation events in Japanese patients with non-valvular AF.17,18 Atrio- Because only 1 patient receiving placebo had restored ventricular nodal blocking agents, for example, sinus rhythm, clinical characteristics were compared be- alone or in combination with blockers, tween responders and non-responders in the pilsicainide- initiated to obtain adequate ventricular rate control were treated group only. No clinical variables were found to continued at the same dosage throughout the study period. discriminate responders vs non-responders; however, LAD Treatment of underlying heart disease was optimized and showed borderline significance (p=0.067; Table2). Fig1 kept constant, if necessary, in all patients throughout the shows the relationships of conversion rate with AF duration study. After 2 weeks of treatment, patients underwent 12- (Fig1A) and LAD (Fig1B). When AF duration exceeded 2 lead electrocardiography and clinical laboratory tests at the months or when LAD exceeded 45mm, pharmacological outpatient clinic. defibrillation with oral pilsicainide seemed unlikely in our cohort of patients who had persistent AF. Statistical Analysis The sample size was based on an estimate of a placebo Adverse Effects conversion rate of 4%,10 pilsicainide conversion rate of With oral pilsicainide, QRS duration increased slightly 25%,16 an α level of 0.05, and a power of 0.8. Data are but significantly from 91±18 to 98±21ms (p<0.001); how- expressed as mean ± standard deviation. Differences in ever, the QT interval and blood pressure did not change clinical characteristics between the 2 groups (pilsicainide significantly. In the pilsicainide group, 1 patient developed

Circulation Journal Vol.70, June 2006 Persistent AF and Oral Pilsicainide 659

Fig1. (A) Conversion rate plotted against duration (≤days) of atrial fibrillation (AF). The abscissa indicates the cut-off value to determine the conversion rate. For example, patients with an AF duration ≤60 days had a conversion rate of 19%. (B) Conversion rate plotted against left atrial diameter (≤mm), determined by transthoracic echocardiography. The format is the same as that in (A). an atrial flutter but did not need treatment due to relatively conversion of persistent AF in a placebo-controlled, dou- slow ventricular responses. ble-blind fashion. The conversion rate of these studies ranged at 20–50%. Amiodarone (400 mg b.i.d.) treatment for 2 weeks Discussion restored sinus rhythm in 21% of patients with persistent AF A 2-week treatment with oral pilsicainide restored sinus (>72h), but placebo did not do so in any patients who had rhythm in 22.4% of patients with persistent AF. In contrast, been scheduled for cardioversion.11 This conversion rate placebo therapy restored sinus rhythm only in 2% of was quite similar to the rate shown in other studies with patients. Only 1 patient showed conversion into atrial oral amiodarone19,20 and also in the present study. Oral flutter with pilsicainide treatment, but the heart rate did not could also restore sinus rhythm in approximately increase to the critical level that might require prompt treat- 30% of patients with AF or atrial flutter lasting 2–26 weeks; ment. These findings are in agreement with those previous- however, placebo did so only in 1% of these patients.10 ly reported,16 in that pilsicainide is more effective than Dofetilide might be superior to pilsicainide because placebo in converting persistent AF into sinus rhythm. dofetilide does not suppress left ventricular function and Atarashi et al demonstrated that a single oral dosage may be used in patients with depressed ejection fraction;21 (150 mg) of pilsicainide converted recent-onset AF (<7 pilsicainide should not be given to patients with left ven- days) to sinus rhythm in 45% of patients within 90min, tricular dysfunction.13 Because of severe proarrhythmic whereas placebo did so only in 8.6% of patients.14 In 1 pa- events associated with dofetilide, initiation of treatment tient treated with pilsicainide, an atrial flutter with 2:1 should be performed in hospital, hampering the ease of atrioventricular conduction developed without any hemo- providing this therapy.21,22 Recently, Fujiki et al demon- dynamic deterioration, as in the present study. Further- strated that the class IV , , is more, a single oral dose of pilsicainide (100–150mg) had a very effective in terms of pharmacological conversion and similar conversion rate to that of intravenous maintenance of sinus rhythm in patients with long-lasting (2mg/kg up to a maximum dose of 100mg) in patients with persistent AF.23 Bepridil prolongs action potential duration recent-onset AF.15 as well as refractory periods of normal ventricular myocar- Okishige et al determined the efficacy of pilsicainide dium and thus presents a comparable potential risk for (50mg t.i.d.) and placebo in patients with long-lasting AF developing torsades de pointes to that of class III antiar- (>6 months) in whom electrical cardioversion had been rhythmic agents. Pilsicainide may also have proarrhythmic scheduled.16 After 4 weeks of treatment at the outpatient effects to convert AF into atrial flutter because of its potent clinic, 21% of patients in the pilsicainide group recovered class Ic effect as seen in 1 patient of the present study as sinus rhythm while none of the placebo group did so. well as in the results of our previous study.14 However, that study had some drawbacks. Patients were The factors previously identified to predict response of randomized to the active drug group or the placebo group AF to antiarrhythmic treatment were analyzed.19,24 None of by a 5:1 ratio. Additionally, treatment was not blinded. the variables including LAD, ejection fraction, concomitant Previous studies investigating the effects of oral class I cardiac diseases, age, and duration of AF were found to antiarrhythmic drug therapy (, cibenzoline, discriminate responders from non-responders in the pilsi- flecainide, and ) on recent-onset AF have shown cainide group. However, restoration of sinus rhythm with moderate conversion rates (29, 25, 57, and 60%, respec- oral pilsicainide seems less likely to occur when LAD tively).6–9 However, the duration of AF in these studies was exceeds 45mm or if the AF duration exceeds 2 months much shorter (<72h, <130h on average, <2 weeks, and (Fig1). Association of AF duration with successful car- <24 h, respectively) compared with that in the present dioversion was not consistently observed in previous study, in which the average duration was 50 days. Previous studies.11,19 A high plasma level of brain natriuretic peptide reports have also compared the efficacy of class III drugs and a relatively low plasma level of atrial natriuretic including ,9 dofetilide,10 and amiodarone11,19,20 for peptide were independent determinants of antiarrhythmic

Circulation Journal Vol.70, June 2006 660 OKISHIGE K et al. efficacy in patients with mild heart failure.25 However, tion-based cohort study: The Framingham Heart Study. JAMA 1994; these 2 variables also could not differentiate the responders 271: 840–844. 2. Krahn AD, Manfreda J, Tate RB, Mathewson FA, Cuddy TE. The and non-responders in the present study from patients who natural history of atrial fibrillation: Incidence, risk factors, and prog- did not have heart failure. nosis in the Manitoba Follow-up Study. Am J Med 1995; 98: 476– A fixed dosage of 50mg t.i.d. pilsicainide was used in 484. the present study because this dosage is routinely used in 3. Feinberg WM, Blackshear JL, Laupacis A, Kronmal R, Hart RG. 16 Prevalence, age distribution, and gender of patients with atrial fibril- Japan and the benefit of using higher dosages is partially lation: Analysis and implications. Arch Intern Med 1995; 155: 469– outweighed by a higher incidence of adverse effects. In the 473. present study, the number of cardiovascular adverse events 4. Carlsson J, Miketic S, Windeler J, Cuneo A, Haun S, Micus S, et al was small. In 1 patient, AF was converted to sustained for the STAF Investigators. Randomized trial of rate-control versus atrial flutter without rapid ventricular responses, which did rhythm-control in persistent atrial fibrillation: The Strategies of Treatment of Atrial Fibrillation (STAF) Study. J Am Coll Cardiol not necessitate treatment. Patients with AF plus organic 2003; 41: 1690–1696. heart disease, particularly those with recent myocardial 5. The AFFIRM Investigators. Relationship between sinus rhythm, infarction and impaired left ventricular function, are at risk treatment, and survival in the atrial fibrillation follow-up investigation of lethal proarrhythmic effects.26 In the present study, of rhythm management (AFFIRM) study. Circulation 2004; 109: 1509–1513. recent myocardial infarction and severe left ventricular 6. Stroobandt R, Stiels B, Hoebrechts R, on behalf of the Propafenone dysfunction were exclusion criteria. Therefore, the results Atrial Fibrillation Trial Investigators. Propafenone for conversion of the present study cannot be extrapolated to the general and prophylaxis of atrial fibrillation. Am J Cardiol 1997; 79: 418– population who have persistent AF. 423. 7. Kuhlkamp V, Schmid F, Risler T, Seipel L. Randomized comparison The present study was conducted in a randomized, dou- of flecainide and cibenzoline in the conversion of atrial fibrillation. ble-blinded, placebo-controlled fashion, but was limited for Int J Cardiol 1991; 31: 65–69. several reasons. First, persistent AF was defined in the 8. Donovan KD, Dobb GJ, Coombs LJ, Lee KY, Weekes JN, Murdock present study as that lasting ≥48 h but not exceeding 6 CJ, et al. Efficacy of flecainide for the reversion of acute onset atrial fibrillation. Am J Cardiol 1992; 70: A50–A55. months. This definition was different from that of the 9. Hohnloser SH, van de Loo A, Baedeker F. Efficacy and proarrhyth- 27 current guideline. Second, antiarrhythmic efficacy was de- mic hazards of pharmacologic cardioversion of atrial fibrillation: termined at the outpatient clinic 2 weeks after the initiation Prospective comparison of sotalol versus quinidine. J Am Coll of treatment, as in a previous amiodarone study.11 There- Cardiol 1995; 26: 852–858. fore, it is quite impossible to determine when AF was 10. Singh S, Zoble RG, Yellen L, Brodsky MA, Feld GK, Berk M, et al for the Dofetilide Atrial Fibrillation Investigators. Efficacy and converted into sinus rhythm. Some patients might have safety of oral dofetilide in converting to and maintaining sinus actually experienced restored sinus rhythm but AF recurred rhythm in patients with chronic atrial fibrillation or atrial flutter: The before their visit to the outpatient clinic and they were Symptomatic Atrial Fibrillation Investigative Research on Dofetilide regarded as “non-responders”, which may have underesti- (SAFIRE-D) Study. Circulation 2000; 102: 2385–2390. 11. Channer KS, Birchall A, Steeds RP, Walters SJ, Yeo WW, West JN, mated the conversion rate. Third, all patients in this trial et al. A randomized placebo-controlled trial of pre-treatment and received digoxin. It is unlikely, however, that digoxin short- or long-term maintenance therapy with amiodarone supporting significantly affected the outcome of the study.28 In addi- DC cardioversion for persistent atrial fibrillation. Eur Heart J 2004; tion, , which could attenuate the progression of 25: 144–150. 29 12. Hattori Y, Hidaka T, Aisaka K, Satoh F, Ishihara T. Effect of SUN atrial electrical remodeling, was given to approximately 1165, a new potent antiarrhythmic agent, on the kinetics of the rate- 10% of the patients in both groups; therefore, it also seems dependent block of Na channel and ventricular conduction of extra- unlikely that verapamil affected the present results. Fourth, systoles. J Cardiovasc Pharmacol 1988; 11: 407–412. patients were randomly assigned to the 2 treatment arms; 13. Kodama I, Ogawa S, Inoue H, Kasanuki H, Kato T, Mitamura H, et al. The Guideline Committee for Clinical Use of Antiarrhythmic however, the number of patients receiving antiarrhythmic Drugs in Japan: Profiles of , cibenzoline, pilsicainide and drugs prior to entry into the study was lower in the pilsi- pirmenol in the framework of the Sicilian Gambit. Jpn Circ J 1999; cainide group than in the placebo group. Therefore, there 63: 1–12. might have been more patients in the placebo group whose 14. Atarashi H, Inoue H, Hiejima K, Hayakawa H, for the PSTAF In- AF was refractory to antiarrhythmic drugs as compared vestigators. Conversion of recent-onset atrial fibrillation by a single oral dose of pilsicainide (Pilsicainide Suppression Trial on Atrial with the pilsicainide group. Finally, AF duration tended to Fibrillation). Am J Cardiol 1996; 78: 694–697. be shorter in the pilsicainide group than in the placebo 15. Kumagai K, Abe H, Hiraki T, Nakashima H, Oginosawa Y, Ikeda H, group (p=0.052). This could affect the present study et al. Single oral administration of pilsicainide versus infusion of result;19 however, more than half of responders had an AF disopyramide for termination of paroxysmal atrial fibrillation. Pacing Clin Electrophysiol 2000; 23: 1880–1882. duration of >1 month. 16. Okishige K, Nishizaki M, Azegami K, Igawa M, Yamawaki N, Isolation of pulmonary veins could be an option of treat- Aonuma K. Pilsicainide for conversion and maintenance of sinus ment for patients with persistent AF who desire a cure for rhythm in chronic atrial fibrillation: A placebo-controlled, multicen- their AF.30 As for pharmacological treatment, pilsicainide ter study. Am Heart J 2000; 140: 437–444. 17. Yasaka M, Minematsu K, Yamaguchi T. Optimal intensity of interna- might be useful for terminating persistent AF when its tional normalized ratio in warfarin therapy for secondary prevention duration does not exceed 2 months or when LAD does not of stroke in patients with non-valvular atrial fibrillation. Intern Med exceed 45mm. 2001; 40: 1183–1188. 18. Nozawa T, Inoue H, Iwasa A, Okumura K, Jong-dae L, Shimizu A, Acknowledgments et al. Effects of anticoagulation intensity on hemostatic markers in patients with non-valvular atrial fibrillation. Circ J 2004; 68: 29–34. The authors wish to acknowledge the Daiichi Pharmaceutical Co, Ltd 19. Tielman RG, Gosselink ATM, Crijns HJGM, van Gelder IC, van den (Tokyo, Japan) and Daiichi Asubio Pharma Co, Ltd (Tokyo, Japan) for berg MP, de Kam PJ, et al. Efficacy, safety, and determinants of con- providing the test drugs and placebo for use in the present study. version of atrial fibrillation and flutter with oral amiodarone. Am J Cardiol 1997; 79: 53–57. References 20. Kochiadakis GEK, Igoumenidis NE, Solomou MC, Kaleboubas MD, Chlouverakis GI, Vardas PE. Efficacy of amiodarone for the termina- 1. Benjamin EJ, Levy D, Vaziri SM, D’Agostino RB, Belanger AJ, tion of persistent atrial fibrillation. Am J Cardiol 1999; 83: 58–61. Wolf PA. Independent risk factors for atrial fibrillation in a popula- 21. Torp-Pedersen C, Moller M, Kober L, Camm AJ. Dofetilide for the

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treatment of atrial fibrillation in patients with congestive heart fail- induced electrical and mechanical remodeling of the atrium. Circ J ure. Eur Heart J 2000; 21: 1204–1206. 2004; 68: 494–500. 22. Prystowsky EN, Freeland S, Branyas NA, Rardon DP, Fogel RI, 30. Oral H, Knight BP, Tada H, Ozaydin M, Chugh A, Hassan S, et al. Padanilam BJ, et al. Clinical experience with dofetilide in the treat- Pulmonary vein isolation for paroxysmal and persistent atrial fibrilla- ment of patients with atrial fibrillation. J Cardiovasc Electrophysiol tion. Circulation 2002; 105: 1077–1081. 2003; 14: S287–S290. 23. Fujiki A, Tsuneda T, Sakabe M, Nakagawa K, Mizumaki K, Hirai T, Appendix 1 et al. Maintenance of sinus rhythm and recovery of atrial mechanical function after cardioversion with bepridil or in combination with In addition to the authors, the following investigators (and the centers from aprindine in long-lasting persistent atrial fibrillation. Circ J 2004; 68: where they are from) also participated in the Pilsicainide Suppression Trial 834–839. for Atrial Fibrillation II (PSTAF-II) study: M Sakurai, MD (Hokko 24. Reisinger J, Gatterer E, Heinze G, Wiesinger K, Zeindlhofe E, Memorial Hospital, Sapporo), K Okumura, MD (Hirosaki University, Gattermeier M, et al. Prospective comparison of flecainide versus Hirosaki), K Ikeda, MD (Yamagata Saiseikai Hospital, Yamagata), K sotalol for immediate cardioversion of atrial fibrillation. Am J Kuga, MD (University of Tsukuba, Tsukuba), K Takayanagi, MD (Dokkyo Cardiol 1998; 81: 1450–1454. Medical University Koshigaya Hospital, Koshigaya), Y Murakawa, MD 25. Mabuchi N, Tsutamoto T, Maeda K, Kinoshita M. Plasma cardiac (Teikyo University School of Medicine Mizonokuchi Hospital, Kawasaki), natriuretic peptides as biochemical markers of recurrence of atrial Y Kobayashi, MD (Showa University, Tokyo), H Hamamoto, MD fibrillation in patients with mild congestive heart failure. Jpn Circ J (Sakakibara Memorial Hospital, Tokyo), K Sagara, MD and T Yamashita, 2000; 64: 765–771. MD (The Cardiovascular Institute, Tokyo), S Ogawa, MD (Keio Univer- 26. Flaker GC, Blackshear JL, McBride R, Kronmal RA, Halperin JL, sity, Tokyo), K Sugi, MD (Toho University, Tokyo), H Sakurada, MD Hart RG. Antiarrhythmic drug therapy and cardiac mortality in atrial (Tokyo Metropolitan Hiroo Hospital, Tokyo), Y Nakazato, MD (Juntendo fibrillation. J Am Coll Cardiol 1992; 20: 527–532. University, Tokyo), T Tanabe, MD (Tokai University, Isehara), M 27. Gallagher MM, Camm AJ. Classification of atrial fibrillation. Pacing Nishizaki, MD (Yokohama Minamikyosai Hospital, Yokohama), A Itoh, Clin Electrophysiol 1997; 20: 1603–1605. MD and N Tsuboi, MD (Nagoya Daini Red Cross Hospital, Nagoya), R 28. Falk RH, Knowlton AA, Bernard SA, Gottlieb NE, Battinelli NJ. Katoh, MD (Nagoya Ekisaikai Hospital, Nagoya), O Igawa, MD (Tottori Digoxin for converting recent-onset atrial fibrillation to sinus University, Tottori), H Abe, MD (University of Occupational and Envi- rhythm: A randomized double-blind trial. Ann Intern Med 1987; 106: ronmental Health, Kitakyushu), M Ohga, MD, T Hiraki, MD (Kurume 503–506. University, Kurume), T Honda, MD (Kumamoto Saiseikai Hospital, 29. Kinebuchi O, Mitamura H, Shiroshita-Takeshita A, Kurita Y, Ieda M, Kumamoto), H Odakura, MD (Sendai City Hospital, Sendai), and Y Ohashi N, et al. Oral verapamil attenuates the progression of pacing- Nakata, MD (Juntendo University, Shizuoka Hospital, Izunokuni).

Circulation Journal Vol.70, June 2006