A Comparison of Intravenous Propafenone and Flecainide in the Treatment of Tachycardias Associated with the Wolff-Parkinson-White Syndrome SEAN O'NUNAIN, CLIFFORD J. GARRATT, NICHOLAS J. LINKER, JASWINDER CILL, DAVID E. WARD, and A. JOHN CAMM From the Department of Cardiological Sciences, St. George's Hospital Medical School, London, United Kingdom
O'NUNAIN, S.. ET AL 1 A Comparison of Intravenous Propafenone and Flecainide in the Treatment of Tachycardias Associated with the Wolff-Parkinson-White Syndrome. We compared the alectrophysiologicai effects of intravenous propafenone and flecainide on accessory pathway conduction by a randomized crossover study in 16 patients with Wolff-Parkinson-White syndrome. The antegrade refractory period of the pathway increased from 256 ± 18 msec at baseline lo 288 ± 13 msec on propa/enone fP < 0.05) and to296 ± 27 msec on flecainide (P - 0.075). The minimum preexcited Rfi inten^a/during atriaJ/ibriilation or incremental atriaJ pacing was prolonged from 225 ± 37 msec to 262 ± 22 msec by propa/enone (P < 0.05] and to 301 ± 31 msec by/Jecainide (P < 0.005). The prolongation was significantly greater with flecainide than propafenone (P < 0.05). Both drugs increased tachycardia cycle length (TCL) from 310 ± 35 msec to 354 ± 37 msec (propafenone P < 0.005} and to 352 ± 37 msec (flecainide P < O.Olj. Both propafenone and flecainide blocked antegrade conduction in the pathway in five patients. Both drugs rendered atriaJ fibrillation noninducible in seven patients and orthodromic tachycardia noninducibie in five patients. Conclusions.- fl) Flecainide causes a greater prolongation of minimum preexcited HR interval than propa/enone; (2) There is no significant difference between propafenone and /Jecainide on the inducibility of arrhythmias, TCL, or incidence of antegrade conduction block. (PACE, VoJ. 14, November, Part II 1991} flecainide, propa/enone, Wol//-Parkinson-White syndrome
Introduction Flecainide and propafenone both possess potent Class lc antiarrhythmic activity. Propafenone in addition has weak beta-blocking and calcium channel-blocking activity which may contribute to its overall effectiveness. Both agents were first developed for the treatment of ventricular arrhythmias but it is now increasingly clear that they have
Address for reprints; Dr. S. O'Nunain. Department of Cardiological Sciences. St. George's Hospital Medical School, Cranmer Terrace. London SW17 ORE, England. Fax: 81-7677141.
2028
a significant role in the treatment of both atrial and junctional arrhythmias, particularly those associated with the Wolff-Parkinson-White (WPW) syndrome. Both agents individually have been shown to increase the antegrade and retrograde refractoriness of the accessory pathway and to be effective in the termination of atrioventricular reentrant tachycardia (AVRT).^""* In Britain, flecainide has been a first line agent for the treatment of tachycardias associated with WPW syndrome, particularly in those patients who present with preexcited atrial fibrillation with a rapid ventricular response. However, since the findings of the Cardiac Arrhythmia Suppression Trial, there has been a reluctance to use flecainide for the treatment of supraventricular
November 1991, Part II
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FLECAINIDE AND PROFAFENONE IN WOLFF-PARKINSON-WHITE SYNDROME
arrhythn:iias even in the absence of structural heart disease.''" This has developed despite the paucity of information on the proarrhythmic potential of flecainide in patients with supraventricular arrhythmias and structurally normal hearts." Although there has heen no formal double blind study investigating the relative proarrhythmic potential of flocainide and propafenone there is some uncontrolled data in patients with ventricular arrhythmias which suggests that propafenone may be less proarrhythmic. These factors have led to a growing interest in the use of propafenone in the treatment of tachycardias associated with WPW syndrome. In this study we assessed the relative effectiveness of intravenous flecainide and propafenone in a group of 16 patients presenting with symptomatic WPW syndrome. Methods Sixteen patients undergoing electrophysiological assessment of WPW syndrome with acces-
sory pathways capable of antegrade conduction were included in the study. Seven patients had documented episodes of spontaneous preexcited atrial fibrillation. The remainder had evidence of spontaneous AVRT. One patient with two accessory pathways had presented with antidromic AVRT. The protocol was approved by the Ethics Committee of St. George's Hospital and all patients gave informed consent (Table I). Patients were studied in the postabsorbtive, nonsedatod state. All antiarrhythmic drugs were discontinued for at least 5 half-lives before the haseline study. Patients who had received amiodarone within the previous 3 months were excluded. Standard multipoiar electrode catheters were introduced under local anaesthesia with 1% lidocaine. Two catheters were introduced via the femoral vein; one to pace and r(x:ord from the high right atrium and the second was placed across the tricuspid valve to record the His potential. Two further electrode catheters were introduced via the
Table 1.
Clinical Details and Inducibility of Atrioventricular Reentrant Tachycardia Inducibility and Cycle Length of AVRT Baseline Patient No.
Age/Sex
1. 2.
48 M 24 M
3. 4. 5. 6. 7. 8, 9. 10. 11. 12. 13. 14. 15. 16.
47 M 45 F 46 F 39 M 37 M 44 M 26 F 40 M 44 M 31 F 37 M 56 M 39 M 26 M
Arrhythmia AVRT AVRT (ADT) AVRT/AF AVRT/AF AVRT AVRT AVRT/AF AF AVRT AVRT AF AVRT AVRT AVRT/AF AF AVRT
IND
TCL
iND
TCL
LPS LFW/LPS
ADT
290 320
I/S 1 ODT 1 ODT 1/NS 1 1
350 440 400 360 350 340
LFW AS LPS LFW LPS LFW LFW LFW RPS LFW LFW LFW LFW RPS
270 310 300 310 320 300 350 320 NI 240 310 380 NI 260
Fiecainide
Propafenone
Position of Pathway
NI 1
Ni 1 I/NS NI NI 1 1 NI 1
380 385 300 355 420 300
iND
TCL
1 ODT
330 460
1 1 1
340 300 320
1
NI 1 1 1 NI NI NI
1 1 NI 1
360
420 370 — 330 400 350
AF = atrial fibrillation; ADT = antidromic tachycardia; AVRT = atrioventricular reentrant tachycardia; AS = anteroseptal; Ind (1) = inducible,/S = sustained./NS = non sustained; LFW = left free wall; LPS = left posteroseptal; ND = not determined; NI = non-inducible; TCL = tachycardia cycle length.
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O'NUNAIN, ET AL.
left subclavian vein; a quadripolar catheter was placed in the coronary sinus and a bipolar catheter in the right ventricular apex. All traces were recorded on a Siemens-Elema Mingograf chart recorder (Siemens-Elema. Solna, Sweden) at a paper speed of 100 mm/sec. The antegrade and retrograde refractory periods of the accessory pathway were assessed at a pacing cycie length (PCL) of 600 and 400 msec using the standard extrastimulus technique. Stimuli of 2 msec duration were delivered at twice diastolic threshold using a programmable stimulator (Medtronic Inc., Minneapolis, MN, USA). Localization of the accessory pathway was performed by retrograde mapping of atrial activation during orthodromic AVRT and/or ventricular mapping during atrial pacing. The antegrade effective refractory period of the accessory pathway was determined at the site closest to the atrial insertion of the pathway (e.g., distal coronary sinus pacing for left free-wall pathways). Attempts were made to induce atrial fibrillation using incremental atrial pacing from a PCL just above sinus cycle length to a PCL of 200 msec. If this was unsuccessful, burst atrial pacing at a PCL of 200 msec was used on three occasions for 10 sec each. The minimum preexcited RR interval during atrial fibrillation or minimum preexcited RR interval during incremental or burst atrial pacing was assessed in each case. At the end of the baseline study, as is standard procedure in our institution, the catheters were removed from the femoral vein and the pacing leads which had been introduced via the subclavian approach left in situ. In the one patient with an anteroseptal pathway, a quadripolar J electrode was introduced to the right atrial appendage instead of the coronary sinus catheter to allow easier estimation of the refractory periods of the pathway. On the day following the procedure the patient returned to the electrophysiology laboratory and the first restimulation was performed. Baseline antegrade and retrograde refractory periods of the pathway and inducibility of tachycardia were estimated (but not inducibility of atrial fibrillation). Flecainide or propafenone (chosen in random order) in a dose of 2 mg/kg to a maximum of 150 mg was administered by constant infusion over 10 minutes. After a further 10 minutes wait stimulation was repeated and an attempt was made to induce atrial fibrillation.
2030
Following a wash-out period of at least 3 halflives, a repeat electrophysiological assessment was performed as above using the second drug on this occasion. Statistics All data is expressed as mean ± standard deviations. Data obtained in the same patient at baseline and following drug therapy was compared using paired t-tests. A P value of
O'NUNAIN, S.. ET AL 1 A Comparison of Intravenous Propafenone and Flecainide in the Treatment of Tachycardias Associated with the Wolff-Parkinson-White Syndrome. We compared the alectrophysiologicai effects of intravenous propafenone and flecainide on accessory pathway conduction by a randomized crossover study in 16 patients with Wolff-Parkinson-White syndrome. The antegrade refractory period of the pathway increased from 256 ± 18 msec at baseline lo 288 ± 13 msec on propa/enone fP < 0.05) and to296 ± 27 msec on flecainide (P - 0.075). The minimum preexcited Rfi inten^a/during atriaJ/ibriilation or incremental atriaJ pacing was prolonged from 225 ± 37 msec to 262 ± 22 msec by propa/enone (P < 0.05] and to 301 ± 31 msec by/Jecainide (P < 0.005). The prolongation was significantly greater with flecainide than propafenone (P < 0.05). Both drugs increased tachycardia cycle length (TCL) from 310 ± 35 msec to 354 ± 37 msec (propafenone P < 0.005} and to 352 ± 37 msec (flecainide P < O.Olj. Both propafenone and flecainide blocked antegrade conduction in the pathway in five patients. Both drugs rendered atriaJ fibrillation noninducible in seven patients and orthodromic tachycardia noninducibie in five patients. Conclusions.- fl) Flecainide causes a greater prolongation of minimum preexcited HR interval than propa/enone; (2) There is no significant difference between propafenone and /Jecainide on the inducibility of arrhythmias, TCL, or incidence of antegrade conduction block. (PACE, VoJ. 14, November, Part II 1991} flecainide, propa/enone, Wol//-Parkinson-White syndrome
Introduction Flecainide and propafenone both possess potent Class lc antiarrhythmic activity. Propafenone in addition has weak beta-blocking and calcium channel-blocking activity which may contribute to its overall effectiveness. Both agents were first developed for the treatment of ventricular arrhythmias but it is now increasingly clear that they have
Address for reprints; Dr. S. O'Nunain. Department of Cardiological Sciences. St. George's Hospital Medical School, Cranmer Terrace. London SW17 ORE, England. Fax: 81-7677141.
2028
a significant role in the treatment of both atrial and junctional arrhythmias, particularly those associated with the Wolff-Parkinson-White (WPW) syndrome. Both agents individually have been shown to increase the antegrade and retrograde refractoriness of the accessory pathway and to be effective in the termination of atrioventricular reentrant tachycardia (AVRT).^""* In Britain, flecainide has been a first line agent for the treatment of tachycardias associated with WPW syndrome, particularly in those patients who present with preexcited atrial fibrillation with a rapid ventricular response. However, since the findings of the Cardiac Arrhythmia Suppression Trial, there has been a reluctance to use flecainide for the treatment of supraventricular
November 1991, Part II
PACE. Vol. 14
FLECAINIDE AND PROFAFENONE IN WOLFF-PARKINSON-WHITE SYNDROME
arrhythn:iias even in the absence of structural heart disease.''" This has developed despite the paucity of information on the proarrhythmic potential of flecainide in patients with supraventricular arrhythmias and structurally normal hearts." Although there has heen no formal double blind study investigating the relative proarrhythmic potential of flocainide and propafenone there is some uncontrolled data in patients with ventricular arrhythmias which suggests that propafenone may be less proarrhythmic. These factors have led to a growing interest in the use of propafenone in the treatment of tachycardias associated with WPW syndrome. In this study we assessed the relative effectiveness of intravenous flecainide and propafenone in a group of 16 patients presenting with symptomatic WPW syndrome. Methods Sixteen patients undergoing electrophysiological assessment of WPW syndrome with acces-
sory pathways capable of antegrade conduction were included in the study. Seven patients had documented episodes of spontaneous preexcited atrial fibrillation. The remainder had evidence of spontaneous AVRT. One patient with two accessory pathways had presented with antidromic AVRT. The protocol was approved by the Ethics Committee of St. George's Hospital and all patients gave informed consent (Table I). Patients were studied in the postabsorbtive, nonsedatod state. All antiarrhythmic drugs were discontinued for at least 5 half-lives before the haseline study. Patients who had received amiodarone within the previous 3 months were excluded. Standard multipoiar electrode catheters were introduced under local anaesthesia with 1% lidocaine. Two catheters were introduced via the femoral vein; one to pace and r(x:ord from the high right atrium and the second was placed across the tricuspid valve to record the His potential. Two further electrode catheters were introduced via the
Table 1.
Clinical Details and Inducibility of Atrioventricular Reentrant Tachycardia Inducibility and Cycle Length of AVRT Baseline Patient No.
Age/Sex
1. 2.
48 M 24 M
3. 4. 5. 6. 7. 8, 9. 10. 11. 12. 13. 14. 15. 16.
47 M 45 F 46 F 39 M 37 M 44 M 26 F 40 M 44 M 31 F 37 M 56 M 39 M 26 M
Arrhythmia AVRT AVRT (ADT) AVRT/AF AVRT/AF AVRT AVRT AVRT/AF AF AVRT AVRT AF AVRT AVRT AVRT/AF AF AVRT
IND
TCL
iND
TCL
LPS LFW/LPS
ADT
290 320
I/S 1 ODT 1 ODT 1/NS 1 1
350 440 400 360 350 340
LFW AS LPS LFW LPS LFW LFW LFW RPS LFW LFW LFW LFW RPS
270 310 300 310 320 300 350 320 NI 240 310 380 NI 260
Fiecainide
Propafenone
Position of Pathway
NI 1
Ni 1 I/NS NI NI 1 1 NI 1
380 385 300 355 420 300
iND
TCL
1 ODT
330 460
1 1 1
340 300 320
1
NI 1 1 1 NI NI NI
1 1 NI 1
360
420 370 — 330 400 350
AF = atrial fibrillation; ADT = antidromic tachycardia; AVRT = atrioventricular reentrant tachycardia; AS = anteroseptal; Ind (1) = inducible,/S = sustained./NS = non sustained; LFW = left free wall; LPS = left posteroseptal; ND = not determined; NI = non-inducible; TCL = tachycardia cycle length.
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O'NUNAIN, ET AL.
left subclavian vein; a quadripolar catheter was placed in the coronary sinus and a bipolar catheter in the right ventricular apex. All traces were recorded on a Siemens-Elema Mingograf chart recorder (Siemens-Elema. Solna, Sweden) at a paper speed of 100 mm/sec. The antegrade and retrograde refractory periods of the accessory pathway were assessed at a pacing cycie length (PCL) of 600 and 400 msec using the standard extrastimulus technique. Stimuli of 2 msec duration were delivered at twice diastolic threshold using a programmable stimulator (Medtronic Inc., Minneapolis, MN, USA). Localization of the accessory pathway was performed by retrograde mapping of atrial activation during orthodromic AVRT and/or ventricular mapping during atrial pacing. The antegrade effective refractory period of the accessory pathway was determined at the site closest to the atrial insertion of the pathway (e.g., distal coronary sinus pacing for left free-wall pathways). Attempts were made to induce atrial fibrillation using incremental atrial pacing from a PCL just above sinus cycle length to a PCL of 200 msec. If this was unsuccessful, burst atrial pacing at a PCL of 200 msec was used on three occasions for 10 sec each. The minimum preexcited RR interval during atrial fibrillation or minimum preexcited RR interval during incremental or burst atrial pacing was assessed in each case. At the end of the baseline study, as is standard procedure in our institution, the catheters were removed from the femoral vein and the pacing leads which had been introduced via the subclavian approach left in situ. In the one patient with an anteroseptal pathway, a quadripolar J electrode was introduced to the right atrial appendage instead of the coronary sinus catheter to allow easier estimation of the refractory periods of the pathway. On the day following the procedure the patient returned to the electrophysiology laboratory and the first restimulation was performed. Baseline antegrade and retrograde refractory periods of the pathway and inducibility of tachycardia were estimated (but not inducibility of atrial fibrillation). Flecainide or propafenone (chosen in random order) in a dose of 2 mg/kg to a maximum of 150 mg was administered by constant infusion over 10 minutes. After a further 10 minutes wait stimulation was repeated and an attempt was made to induce atrial fibrillation.
2030
Following a wash-out period of at least 3 halflives, a repeat electrophysiological assessment was performed as above using the second drug on this occasion. Statistics All data is expressed as mean ± standard deviations. Data obtained in the same patient at baseline and following drug therapy was compared using paired t-tests. A P value of
