- Email: [email protected]
Importance of left atrial diameter and atrial fibrillatory frequency for conversion of persistent atrial fibrillation with oral flecainide
3. Rasmussen C, Thiis JJ, Clemmensen P, Efsen F, Arendrup HC, Saunamaki K,
Madsen JK, Pettersson G. Significance and management of early graft failure after coronary artery bypass grafting: feasibility and results of acute angiography and re-re-vascularization. Eur J Cardiothorac Surg 1997;12:847–852. 4. Chaitman BR, Alderman EL, Sheffield LT, Tong T, Fisher L, Mock MB, Weins RD, Kaiser GC, Roitman D, Berger R, et al. Use of survival analysis to determine the clinical significance of new Q waves after coronary bypass surgery. Circulation 1983;67:302–309. 5. Alderman EL, Levy JH, Rich JB, Nili M, Vidne B, Schaff H, Uretzky G, Pettersson G, Thiis JJ, Hantler CB, Chaitman B, Nadel A. Analyses of coronary graft patency after aprotinin use: results from the International Multicenter
Aprotinin Graft Patency Experience (IMAGE) trial. J Thorac Cardiovasc Surg 1998;116:716 –730. 6. Kahn JK, Rutherford BD, McConahay DR, Giorgi LV, Johnson WL, Shimshak TM, Hartzler GO. Early postoperative balloon coronary angioplasty for failed coronary artery bypass grafting. Am J Cardiol 1990;66:943–946. 7. Dorogy ME, Highfill WT, Davis RC. Use of angioplasty in the management of complicated perioperative infarction following bypass surgery. Cathet Cardiovasc Diagn 1993;29:279 –282. 8. Piana RN, Adams MR, Orford JL, Popma JJ, Adams DH, Goldhaber SZ. Rescue percutaneous coronary intervention immediately following coronary artery bypass grafting. Chest 2001;120:1417–1420.
Importance of Left Atrial Diameter and Atrial Fibrillatory Frequency for Conversion of Persistent Atrial Fibrillation With Oral Flecainide Andreas Bollmann,
MD,
Karl-Heinz Binias, MD, Ines Toepffer, RN, Jochen Molling, Christoph Geller, MD, and Helmut U. Klein, MD
his study sought to evaluate the efficacy and tolerability of oral flecainide beginning with a T 300-mg bolus in patients with atrial fibrillation (AF)
lasting ⬎24 hours. The focus of this study, however, was to relate patient characteristics including echocardiographic parameters and fibrillatory frequency obtained from the surface electrocardiogram to conversion rate. Fibrillatory frequency was chosen as a marker of electrical remodeling, because it represents atrial refractoriness,1 thereby reflecting AF complexity.2 Furthermore, fibrillatory frequency obtained from intra-atrial recordings3 or the surface electrocardiogram4 has been shown to predict AF conversion success using intravenous ibutilide. •••
The subjects of this observational study were 18 consecutive patients with AF of ⬎24 hours in duration. Patients aged ⬎18 years were eligible when they were hemodynamically stable (ventricular rate between 50 and 120 beats/min and systolic pressure ⬎100 mm Hg), had no known or suspected coronary artery disease or dilated cardiomyopathy, had AF not associated with hyperthyroidism, electrolyte disturbances, or infection, and were not taking class I or III antiarrhythmic drugs at the time of the study. Clinical characteristics of the study group are listed in Table 1. All patients provided written informed consent for participation. Flecainide (Tambocor, 3 M, Borken, Germany) was initiated on an inpatient basis under continuous electrocardiographic monitoring as a single oral dose of 300 mg, followed by a maintenance therapy of 200 to 300 mg/day. Patients received concomitantly either oral anticoagulation therapy to maintain an international normalized ratio between 2.5 and 3.5 or weightFrom the Department of Cardiology, University Hospital Magdeburg, Magdeburg, Germany. Dr. Bollmann’s address is: Department of Cardiology, University Hospital Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany. E-mail: andreas.bollmann@ medizin.uni-magdeburg.de. Manuscript received March 20, 2002; revised manuscript received and accepted June 21, 2002. ©2002 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 90 November 1, 2002
MD,
TABLE 1 Characteristics of Study Group (n ⫽ 18) Men/Women Age (yrs) Underlying heart disease None Systemic hypertension Valvular heart disease Duration of AF (mo) Concomitant medication* Digitalis  blocker Calcium antagonist Left atrial diameter (mm) Left ventricular ejection fraction (%) Fibrillatory frequency (Hz) Flecainide plasma level (ng/ml)†
9/9 64 ⫾ 13 7 9 2 5.2 ⫾ 5.4 6 5 9 44 ⫾ 5 59 ⫾ 5 6.2 ⫾ 0.5 518 ⫾ 112
*More than 1 possible. † n ⫽ 12.
adapted low molecular weight heparin after exclusion of left atrial thrombus formation by transesophageal echocardiography. Flecainide plasma levels were measured in 12 randomly selected patients 4 hours after the first dose (trough level) using high-performance liquid chromatography. Before flecainide was given and 4 hours after drug initiation, a 2-minute, high-gain, high-resolution electrocardiogram (Predictor, Dr. Kaiser Medizintechnik GmbH, Bad Hersfeld, Germany) was recorded with all subjects relaxed in a supine position after a 5-minute equilibration period. Electrodes were applied in an orthogonal X (X⫹ ⫽ left midaxillary line at the fourth intercostal space, X⫺ ⫽ right midaxillary line at the fourth intercostal space), Y (Y⫹ ⫽ left manubrium sternum margin, Y⫺ ⫽ left xiphisternum margin), and Z (Z⫹ ⫽ fourth intercostal space at the left sternal margin, Z⫺ ⫽ directly opposite on the posterior chest wall) lead system. Signals were analog-to-digital converted at 2000 Hz, a 12-bit resolution, and a frequency response at 0.05 to 300 Hz. Electrograms were stored on optical disk and transferred to a personal computer for further 0002-9149/02/$–see front matter PII S0002-9149(02)02690-5
1011
FIGURE 1. Signal-processing technique used for the measurement of frequency content of the electrocardiogram. Top panel, electrocardiogram (ECG) with AF. Middle panel, typical appearance of the signal after filtering and subtraction of the QRST using a template-matching algorithm. Bottom panel, frequency power spectrum produced by Fourier transformation of the signal in the middle panel.
signal processing. Analysis of fibrillatory frequency was obtained from lead Z (corresponding with standard lead V1). After high-pass filtering, the QRST complexes were subtracted using a template-matching algorithm. The resulting fibrillatory baseline signal was subjected to Fourier transformation, displayed as a frequency power spectrum, and peak frequency was determined in the 3 to 12 Hz range (Figure 1). The algorithm4,5 and its reproducibility6,7 have been previously described in detail. The main outcome measure was achievement of sinus rhythm within 72 hours after drug initiation. Differences between converters and nonconverters were assessed using Student’s t test or Wilcoxon test for continuous variables and using the chisquare test for categoric variables. Sensitivities and specificities for predicting restoration of sinus rhythm were determined from receiver-operating characteristic curves. The t test for paired data was applied to compare fibrillatory frequencies before and after drug initiation. Linear regression was used to determine a possible relation between time to conversion and continuous variables (fibrillatory 1012 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 90
frequency, left atrial diameter, and flecainide plasma level). All results are presented as mean ⫾ 1 SD. A p value ⬍0.05 was considered statistically significant. •••
During the observation period, 9 patients (50%) achieved conversion to sinus rhythm 12 ⫾ 17 hours after flecainide was initiated (range 40 minutes to 48 hours). Of these 9, drug-induced conversion was observed in 7 patients within 4 hours after the flecainide bolus, and in 2 patients during maintenance therapy (after 24 and 48 hours, respectively). The remaining 9 patients were still in AF after 72 hours and underwent subsequent electrical cardioversion. The flecainide plasma level 4 hours after the 300-mg bolus was within the therapeutic range in all patients (288 to 641 ng/ml). Adverse reactions were observed in 3 patients. One patient developed asymptomatic sinus bradycardia (first-degree atrioventricular and right bundle branch block after drug-induced conversion requiring flecainide discontinuation). In 2 patients the maintenance dose was reduced because of asymptomatic pauses in NOVEMBER 1, 2002
TABLE 2 Characteristics Associated With Drug-induced Conversion Conversion ⫹ Conversion ⫺ (n ⫽ 9) (n ⫽ 9) Men/Women Age (yrs) Underlying heart disease None Systemic hypertension Valvular heart disease Duration of AF (mo) Concomitant medication* Digitalis  blocker Calcium antagonist Left atrial diameter (mm) Left ventricular ejection fraction (%) Fibrillatory frequency (Hz) Flecainide plasma level (ng/ml)†
6/3 66 ⫾ 14
3/6 62 ⫾ 12
5 4 0 4.0 ⫾ 5.1
2 5 2 6.6 ⫾ 5.6
2 3 6 ⫾ ⫾ ⫾ ⫾
4 2 3 ⫾ ⫾ ⫾ ⫾
41 60 5.9 536
4 6 0.4 106
47 59 6.4 510
3‡ 5 0.4§ 122
*More than 1 possible. † n ⫽ 4 in converted patients, n ⫽ 8 in nonconverted patients. ‡ p ⫽ 0.004; §p ⫽ 0.007.
1, and new left bundle branch block and diarrhea in the other. Fibrillatory frequency measuring 6.2 ⫾ 0.5 Hz at baseline was reduced to 4.4 ⫾ 0.4 Hz (p ⬍0.001) after the flecainide bolus (frequency reduction 31 ⫾ 6%). The clinical characteristics of converters and nonconverters are compared in Table 2. The receiver-operating characteristic curves for predicting conversion to sinus rhythm as a function of fibrillatory frequency or echocardiographically determined left atrial diameter are plotted in Figure 2. Sensitivity and specificity were strongly related to fibrillatory frequency (area under the curve ⫽ 0.833) as well as left atrial diameter (area under the curve ⫽ 0.92). Conversion to sinus rhythm was predicted by a frequency ⬍6 Hz, with a sensitivity of 89% and a specificity of 78%. Sensitivity and specificity were 78% and 89%, respectively, when using a left atrial diameter ⬍45 mm. All patients (n ⫽ 6) with both a fibrillatory frequency ⬍6 Hz and a left atrial diameter ⬍45 mm achieved conversion to sinus rhythm, whereas no drug-induced conversion occurred in patients with greater fibrillatory frequencies and left atrial diameters (n ⫽ 6). Intermediate results (50% conversion) were obtained when either fibrillatory frequency measured ⬍6 Hz or left atrial diameter ⬍45 mm (n ⫽ 6). In the 9 patients with conversion, AF duration ranged from 2 days to 12 months, with 4 patients having AF for ⬎5 months. There was a trend toward a positive correlation between time to conversion and fibrillatory frequency (r ⫽ 0.626, p ⫽ 0.07). In contrast, left atrial diameter or flecainide plasma level were not related with time to conversion. •••
Oral flecainde loading (ⱕ400 mg in 3 hours) has been shown to convert AF lasting ⬍24 hours in 72%8 to 95% of patients.9 However, if this drug was administered to patients with longer-standing AF, conver-
sion occurred between 0%8 and 30%.10 Conversion rate, time to conversion, and adverse effects of this study, which lacks a placebo group, were within the range of previous investigations.9,11 As with 1 previous study,10 trough levels were not different between patients in whom sinus rhythm was restored and patients with persisting AF. In contrast, patients who had successful conversion had smaller left atria and lower fibrillatory frequencies. Although the former has been described in earlier investigations,11,12 the latter represents a new finding. Flecainide has been found to decrease fibrillatory frequency (increase atrial cycle length) before AF termination in both animals13 and induced human AF.14 Conduction slowing of fibrillatory wave fronts preferentially at pivot point (points of high curvature) may be responsible for this observation, resulting in both increased wavelet circuit size and excitable gap.15 This in turn would result in fewer wave fronts with a higher chance that all wavelets will extinguish simultaneously and AF will terminate. This study has found that flecainide has the potential to reduce fibrillatory frequency in a small range of approximately 30%. In patients who underwent successful conversion, the baseline fibrillatory frequency was already low, although in 4 of 9 converted patients, AF had lasted for ⬎5 months. In these patients druginduced AF termination would not have been expected from previous studies.8,10 In cardioverted patients, the drug-induced frequency reduction was sufficient enough to reach the critical frequency threshold below which AF was terminated. Because 7 of 9 patients underwent conversion before a second electrocardiogram was recorded, the actual conversion frequency and subsequently their frequency reduction could not be determined in this study. However, from previous observations4,14 it can be assumed that this “AF conversion threshold” is in the range of 3.3 to 4 Hz (corresponding with a cycle length between 250 and 300 ms), with converters and nonconverters exhibiting similar amounts of drug-induced frequency reduction.4 The positive linear relation between baseline fibrillatory frequency and time to conversion is further support for this concept. In other words, the lower the initial fibrillatory frequency, the faster the frequency below which AF terminates will be reached. In contrast, although fibrillatory frequency was substantially reduced in those who had unsuccessful cardioversion, this reduction was not large enough to reach the critical threshold, and subsequently AF persisted. One previous study suggested that a stepped conversion regimen of first-line ibutilide followed by electrical cardioversion for patients who fail to achieve conversion is less expensive and has a higher conversion rate than first-line electrical cardioversion.16 Considering our study, which identifies subgroups with a high, intermediate, or low probability of pharmacologic cardioversion success, this approach may even be more cost effective. This study determined the efficacy and safety of an oral flecainide loading protocol (300-mg bolus BRIEF REPORTS
1013
FIGURE 2. Receiver operating characteristic curve of fibrillatory frequency (left panel) and left atrial diameter (right panel) for predicting conversion to sinus rhythm.
followed by 200 to 300 mg/day) in 18 patients with no overt structural heart disease having AF of >24 hours in duration. Sinus rhythm was restored in 50% of patients within a 72-hour observation period and was predicted by both echocardiographically determined left atrial diameter and fibrillatory frequency obtained from the surface electrocardiogram. Therefore, in patients with small left atria and/or a low fibrillatory frequency, a conversion attempt with oral flecainide may be warranted irrespective of AF duration. 1. Capucci A, Biffi M, Boriani G, Ravelli F, Nollo G, Sabbatani P, Orsi C, Magnani B. Dynamic electrophysiological behavior of human atria during paroxysmal atrial fibrillation. Circulation 1995;92:1193–1202. 2. Konings KT, Kirchhof CJ, Smeets JR, Wellens HJ, Penn OC, Allessie MA. High-density mapping of electrically induced atrial fibrillation in humans. Circulation 1994;89:1665–1680. 3. Stambler BS, Wood MA, Ellenbogen KA. Antiarrhythmic actions of intravenous ibutilide compared with procainamide during human atrial flutter and fibrillation: electrophysiological determinants of enhanced conversion efficacy. Circulation 1997;96:4298 –4306. 4. Bollmann A, Kanuru NK, McTeague KK, Walter PF, DeLurgio DB, Langberg JJ. Frequency analysis of human atrial fibrillation using the surface electrocardiogram and its response to ibutilide. Am J Cardiol 1998;81:1439 –1445. 5. Holm M, Pehrson S, Ingemansson M, Sornmo L, Jahansson R, Sandhall L, Sunemark M, Smideberg B, Olsson C, Olsson SB. Non-invasive assessment of the atrial cycle length during atrial fibrillation in man: introducing, validating and illustrating a new ECG method. Cardiovasc Res 1998;38:69 –81. 6. Bollmann A, Wodarz K, Esperer HD, Toepffer I, Klein HU. Response of atrial
1014 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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fibrillatory activity to carotid sinus massage in patients with atrial fibrillation. Pacing Clin Electrophysiol 2001;24:1363–1368. 7. Meurling CJ, Ingemansson MP, Roijer A, Carlson J, Lindholm CJ, Smideberg B, Sorno L, Stridh M, Olsson SB. Attenuation of electrical remodelling in chronic atrial fibrillation following oral treatment with verapamil. Europace 1999;1:234 – 241. 8. Crijns HJ, van Wijk LM, van Gilst WH, Kingma JH, van Gelder IC, Lie KI. Acute conversion of atrial fibrillation to sinus rhythm: clinical efficacy of flecainide acetate. Comparison of two regimens. Eur Heart J 1988;9:634 –638. 9. Capucci A, Lenzi T, Boriani G, Trisolino G, Binetti N, Cavazza M, Fontana G, Magnani B. Effectiveness of loading oral flecainide for converting recent-onset atrial fibrillation to sinus rhythm in patients without organic heart disease or with only systemic hypertension. Am J Cardiol 1992;70:69 –72. 10. Kuhlkamp V, Schmid F, Risler T, Seipel L. Randomized comparison of flecainide and cibenzoline in the conversion of atrial fibrillation. Int J Cardiol 1991;31:65–69. 11. Goy JJ, Kaufmann U, Kappenberger L, Sigwart U. Restoration of sinus rhythm with flecainide in patients with atrial fibrillation. Am J Cardiol 1988;62: 38D–40D. 12. Carr B, Hawley K, Channer KS. Cardioversion of atrial fibrillation of recent onset with flecainide. Postgrad Med J 1991;67:659 –662. 13. Wijffels MC, Dorland R, Allessie MA. Pharmacologic cardioversion of chronic atrial fibrillation in the goat by class IA, IC, and III drugs: a comparison between hydroquinidine, cibenzoline, flecainide, and d-sotalol. J Cardiovasc Electrophysiol 1999;10:178 –193. 14. Biffi M, Boriani G, Bronzetti G, Capucci A, Branzi A, Magnani B. Electrophysiological effects of flecainide and propafenone on atrial fibrillation cycle and relation with arrhythmia termination. Heart 1999;82:176 –182. 15. Wijffels MC, Dorland R, Mast F, Allessie MA. Widening of the excitable gap during pharmacological cardioversion of atrial fibrillation in the goat: effects of cibenzoline, hydroquinidine, flecainide, and d-sotalol. Circulation 2000;102: 260 –267. 16. Zarkin GA, Bala MV, Calingaert B, VanderLugt JT. The cost-effectiveness of ibutilide versus electrical cardioversion in the conversion of atrial fibrillation and flutter to normal rhythm. Am J Managed Care 1997;3:1387–1394.
NOVEMBER 1, 2002
Madsen JK, Pettersson G. Significance and management of early graft failure after coronary artery bypass grafting: feasibility and results of acute angiography and re-re-vascularization. Eur J Cardiothorac Surg 1997;12:847–852. 4. Chaitman BR, Alderman EL, Sheffield LT, Tong T, Fisher L, Mock MB, Weins RD, Kaiser GC, Roitman D, Berger R, et al. Use of survival analysis to determine the clinical significance of new Q waves after coronary bypass surgery. Circulation 1983;67:302–309. 5. Alderman EL, Levy JH, Rich JB, Nili M, Vidne B, Schaff H, Uretzky G, Pettersson G, Thiis JJ, Hantler CB, Chaitman B, Nadel A. Analyses of coronary graft patency after aprotinin use: results from the International Multicenter
Aprotinin Graft Patency Experience (IMAGE) trial. J Thorac Cardiovasc Surg 1998;116:716 –730. 6. Kahn JK, Rutherford BD, McConahay DR, Giorgi LV, Johnson WL, Shimshak TM, Hartzler GO. Early postoperative balloon coronary angioplasty for failed coronary artery bypass grafting. Am J Cardiol 1990;66:943–946. 7. Dorogy ME, Highfill WT, Davis RC. Use of angioplasty in the management of complicated perioperative infarction following bypass surgery. Cathet Cardiovasc Diagn 1993;29:279 –282. 8. Piana RN, Adams MR, Orford JL, Popma JJ, Adams DH, Goldhaber SZ. Rescue percutaneous coronary intervention immediately following coronary artery bypass grafting. Chest 2001;120:1417–1420.
Importance of Left Atrial Diameter and Atrial Fibrillatory Frequency for Conversion of Persistent Atrial Fibrillation With Oral Flecainide Andreas Bollmann,
MD,
Karl-Heinz Binias, MD, Ines Toepffer, RN, Jochen Molling, Christoph Geller, MD, and Helmut U. Klein, MD
his study sought to evaluate the efficacy and tolerability of oral flecainide beginning with a T 300-mg bolus in patients with atrial fibrillation (AF)
lasting ⬎24 hours. The focus of this study, however, was to relate patient characteristics including echocardiographic parameters and fibrillatory frequency obtained from the surface electrocardiogram to conversion rate. Fibrillatory frequency was chosen as a marker of electrical remodeling, because it represents atrial refractoriness,1 thereby reflecting AF complexity.2 Furthermore, fibrillatory frequency obtained from intra-atrial recordings3 or the surface electrocardiogram4 has been shown to predict AF conversion success using intravenous ibutilide. •••
The subjects of this observational study were 18 consecutive patients with AF of ⬎24 hours in duration. Patients aged ⬎18 years were eligible when they were hemodynamically stable (ventricular rate between 50 and 120 beats/min and systolic pressure ⬎100 mm Hg), had no known or suspected coronary artery disease or dilated cardiomyopathy, had AF not associated with hyperthyroidism, electrolyte disturbances, or infection, and were not taking class I or III antiarrhythmic drugs at the time of the study. Clinical characteristics of the study group are listed in Table 1. All patients provided written informed consent for participation. Flecainide (Tambocor, 3 M, Borken, Germany) was initiated on an inpatient basis under continuous electrocardiographic monitoring as a single oral dose of 300 mg, followed by a maintenance therapy of 200 to 300 mg/day. Patients received concomitantly either oral anticoagulation therapy to maintain an international normalized ratio between 2.5 and 3.5 or weightFrom the Department of Cardiology, University Hospital Magdeburg, Magdeburg, Germany. Dr. Bollmann’s address is: Department of Cardiology, University Hospital Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany. E-mail: andreas.bollmann@ medizin.uni-magdeburg.de. Manuscript received March 20, 2002; revised manuscript received and accepted June 21, 2002. ©2002 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 90 November 1, 2002
MD,
TABLE 1 Characteristics of Study Group (n ⫽ 18) Men/Women Age (yrs) Underlying heart disease None Systemic hypertension Valvular heart disease Duration of AF (mo) Concomitant medication* Digitalis  blocker Calcium antagonist Left atrial diameter (mm) Left ventricular ejection fraction (%) Fibrillatory frequency (Hz) Flecainide plasma level (ng/ml)†
9/9 64 ⫾ 13 7 9 2 5.2 ⫾ 5.4 6 5 9 44 ⫾ 5 59 ⫾ 5 6.2 ⫾ 0.5 518 ⫾ 112
*More than 1 possible. † n ⫽ 12.
adapted low molecular weight heparin after exclusion of left atrial thrombus formation by transesophageal echocardiography. Flecainide plasma levels were measured in 12 randomly selected patients 4 hours after the first dose (trough level) using high-performance liquid chromatography. Before flecainide was given and 4 hours after drug initiation, a 2-minute, high-gain, high-resolution electrocardiogram (Predictor, Dr. Kaiser Medizintechnik GmbH, Bad Hersfeld, Germany) was recorded with all subjects relaxed in a supine position after a 5-minute equilibration period. Electrodes were applied in an orthogonal X (X⫹ ⫽ left midaxillary line at the fourth intercostal space, X⫺ ⫽ right midaxillary line at the fourth intercostal space), Y (Y⫹ ⫽ left manubrium sternum margin, Y⫺ ⫽ left xiphisternum margin), and Z (Z⫹ ⫽ fourth intercostal space at the left sternal margin, Z⫺ ⫽ directly opposite on the posterior chest wall) lead system. Signals were analog-to-digital converted at 2000 Hz, a 12-bit resolution, and a frequency response at 0.05 to 300 Hz. Electrograms were stored on optical disk and transferred to a personal computer for further 0002-9149/02/$–see front matter PII S0002-9149(02)02690-5
1011
FIGURE 1. Signal-processing technique used for the measurement of frequency content of the electrocardiogram. Top panel, electrocardiogram (ECG) with AF. Middle panel, typical appearance of the signal after filtering and subtraction of the QRST using a template-matching algorithm. Bottom panel, frequency power spectrum produced by Fourier transformation of the signal in the middle panel.
signal processing. Analysis of fibrillatory frequency was obtained from lead Z (corresponding with standard lead V1). After high-pass filtering, the QRST complexes were subtracted using a template-matching algorithm. The resulting fibrillatory baseline signal was subjected to Fourier transformation, displayed as a frequency power spectrum, and peak frequency was determined in the 3 to 12 Hz range (Figure 1). The algorithm4,5 and its reproducibility6,7 have been previously described in detail. The main outcome measure was achievement of sinus rhythm within 72 hours after drug initiation. Differences between converters and nonconverters were assessed using Student’s t test or Wilcoxon test for continuous variables and using the chisquare test for categoric variables. Sensitivities and specificities for predicting restoration of sinus rhythm were determined from receiver-operating characteristic curves. The t test for paired data was applied to compare fibrillatory frequencies before and after drug initiation. Linear regression was used to determine a possible relation between time to conversion and continuous variables (fibrillatory 1012 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 90
frequency, left atrial diameter, and flecainide plasma level). All results are presented as mean ⫾ 1 SD. A p value ⬍0.05 was considered statistically significant. •••
During the observation period, 9 patients (50%) achieved conversion to sinus rhythm 12 ⫾ 17 hours after flecainide was initiated (range 40 minutes to 48 hours). Of these 9, drug-induced conversion was observed in 7 patients within 4 hours after the flecainide bolus, and in 2 patients during maintenance therapy (after 24 and 48 hours, respectively). The remaining 9 patients were still in AF after 72 hours and underwent subsequent electrical cardioversion. The flecainide plasma level 4 hours after the 300-mg bolus was within the therapeutic range in all patients (288 to 641 ng/ml). Adverse reactions were observed in 3 patients. One patient developed asymptomatic sinus bradycardia (first-degree atrioventricular and right bundle branch block after drug-induced conversion requiring flecainide discontinuation). In 2 patients the maintenance dose was reduced because of asymptomatic pauses in NOVEMBER 1, 2002
TABLE 2 Characteristics Associated With Drug-induced Conversion Conversion ⫹ Conversion ⫺ (n ⫽ 9) (n ⫽ 9) Men/Women Age (yrs) Underlying heart disease None Systemic hypertension Valvular heart disease Duration of AF (mo) Concomitant medication* Digitalis  blocker Calcium antagonist Left atrial diameter (mm) Left ventricular ejection fraction (%) Fibrillatory frequency (Hz) Flecainide plasma level (ng/ml)†
6/3 66 ⫾ 14
3/6 62 ⫾ 12
5 4 0 4.0 ⫾ 5.1
2 5 2 6.6 ⫾ 5.6
2 3 6 ⫾ ⫾ ⫾ ⫾
4 2 3 ⫾ ⫾ ⫾ ⫾
41 60 5.9 536
4 6 0.4 106
47 59 6.4 510
3‡ 5 0.4§ 122
*More than 1 possible. † n ⫽ 4 in converted patients, n ⫽ 8 in nonconverted patients. ‡ p ⫽ 0.004; §p ⫽ 0.007.
1, and new left bundle branch block and diarrhea in the other. Fibrillatory frequency measuring 6.2 ⫾ 0.5 Hz at baseline was reduced to 4.4 ⫾ 0.4 Hz (p ⬍0.001) after the flecainide bolus (frequency reduction 31 ⫾ 6%). The clinical characteristics of converters and nonconverters are compared in Table 2. The receiver-operating characteristic curves for predicting conversion to sinus rhythm as a function of fibrillatory frequency or echocardiographically determined left atrial diameter are plotted in Figure 2. Sensitivity and specificity were strongly related to fibrillatory frequency (area under the curve ⫽ 0.833) as well as left atrial diameter (area under the curve ⫽ 0.92). Conversion to sinus rhythm was predicted by a frequency ⬍6 Hz, with a sensitivity of 89% and a specificity of 78%. Sensitivity and specificity were 78% and 89%, respectively, when using a left atrial diameter ⬍45 mm. All patients (n ⫽ 6) with both a fibrillatory frequency ⬍6 Hz and a left atrial diameter ⬍45 mm achieved conversion to sinus rhythm, whereas no drug-induced conversion occurred in patients with greater fibrillatory frequencies and left atrial diameters (n ⫽ 6). Intermediate results (50% conversion) were obtained when either fibrillatory frequency measured ⬍6 Hz or left atrial diameter ⬍45 mm (n ⫽ 6). In the 9 patients with conversion, AF duration ranged from 2 days to 12 months, with 4 patients having AF for ⬎5 months. There was a trend toward a positive correlation between time to conversion and fibrillatory frequency (r ⫽ 0.626, p ⫽ 0.07). In contrast, left atrial diameter or flecainide plasma level were not related with time to conversion. •••
Oral flecainde loading (ⱕ400 mg in 3 hours) has been shown to convert AF lasting ⬍24 hours in 72%8 to 95% of patients.9 However, if this drug was administered to patients with longer-standing AF, conver-
sion occurred between 0%8 and 30%.10 Conversion rate, time to conversion, and adverse effects of this study, which lacks a placebo group, were within the range of previous investigations.9,11 As with 1 previous study,10 trough levels were not different between patients in whom sinus rhythm was restored and patients with persisting AF. In contrast, patients who had successful conversion had smaller left atria and lower fibrillatory frequencies. Although the former has been described in earlier investigations,11,12 the latter represents a new finding. Flecainide has been found to decrease fibrillatory frequency (increase atrial cycle length) before AF termination in both animals13 and induced human AF.14 Conduction slowing of fibrillatory wave fronts preferentially at pivot point (points of high curvature) may be responsible for this observation, resulting in both increased wavelet circuit size and excitable gap.15 This in turn would result in fewer wave fronts with a higher chance that all wavelets will extinguish simultaneously and AF will terminate. This study has found that flecainide has the potential to reduce fibrillatory frequency in a small range of approximately 30%. In patients who underwent successful conversion, the baseline fibrillatory frequency was already low, although in 4 of 9 converted patients, AF had lasted for ⬎5 months. In these patients druginduced AF termination would not have been expected from previous studies.8,10 In cardioverted patients, the drug-induced frequency reduction was sufficient enough to reach the critical frequency threshold below which AF was terminated. Because 7 of 9 patients underwent conversion before a second electrocardiogram was recorded, the actual conversion frequency and subsequently their frequency reduction could not be determined in this study. However, from previous observations4,14 it can be assumed that this “AF conversion threshold” is in the range of 3.3 to 4 Hz (corresponding with a cycle length between 250 and 300 ms), with converters and nonconverters exhibiting similar amounts of drug-induced frequency reduction.4 The positive linear relation between baseline fibrillatory frequency and time to conversion is further support for this concept. In other words, the lower the initial fibrillatory frequency, the faster the frequency below which AF terminates will be reached. In contrast, although fibrillatory frequency was substantially reduced in those who had unsuccessful cardioversion, this reduction was not large enough to reach the critical threshold, and subsequently AF persisted. One previous study suggested that a stepped conversion regimen of first-line ibutilide followed by electrical cardioversion for patients who fail to achieve conversion is less expensive and has a higher conversion rate than first-line electrical cardioversion.16 Considering our study, which identifies subgroups with a high, intermediate, or low probability of pharmacologic cardioversion success, this approach may even be more cost effective. This study determined the efficacy and safety of an oral flecainide loading protocol (300-mg bolus BRIEF REPORTS
1013
FIGURE 2. Receiver operating characteristic curve of fibrillatory frequency (left panel) and left atrial diameter (right panel) for predicting conversion to sinus rhythm.
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