Europace Advance Access originally published online on February 7, 2006
Europace 2006 8(3):211-215; doi:10.1093/europace/euj051
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ATRIAL FIBRILLATION
Utility of adjunctive single oral bolus propafenone therapy in patients with atrial defibrillators
1 University of PittsburghUPMC Presbyterian, B535 Pittsburgh, PA 15213-2582 USA ; 2 Oklahoma Foundation for Cardiovascular ResearchOklahoma City, OK USA ; 3 Iowa Heart CenterIowa City, IA USA ; 4 Medtronic Inc.Minneapolis, MN USA
Manuscript submitted 1 September 2005. Accepted after revision 22 November 2005.
* Corresponding author. Tel: +1 412 647 2762; fax: +1 412 647 7979. E-mail address: schwartzmand{at}upmc.edu
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Abstract |
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Aims Previous studies have demonstrated that ambulatory atrial defibrillation shocks delivered by an implantable cardioverter-defibrillator (ICD) are safe and effective, but poorly tolerated. Separate studies have demonstrated the utility of single oral bolus propafenone for conversion of recent-onset atrial fibrillation (AF); however, most patients were hospitalized, had no structural heart disease, were taking no other antiarrhythmic drugs, and were not exposed to concomitant shock. We hypothesized that a single oral bolus dose of propafenone given early after onset would be a safe and effective adjunct to ICD-based AF therapy and improve overall therapy tolerance.
Methods and results A randomized three-way crossover study design was used to compare three strategies, deployed in the ambulatory setting early after AF episode onset in 35 ICD patients with advanced, drug refractory episodic/persistent syndromes, many of whom had structural heart disease and were taking other antiarrhythmic drugs: (i) single oral bolus propafenone (600 mg), followed by ICD shock if necessary; (ii) single oral bolus placebo, followed by ICD shock if necessary; and (iii) no oral bolus therapy and ICD shock if necessary (no bolus). Antiarrhythmic efficacy, defined by the restoration of sinus rhythm within 24 h, was similar during propafenone (81%) and no-bolus strategies (84%); both were significantly higher than during placebo strategy (62%). Propafenone was well tolerated and not associated with proarrhythmia. Shock use was significantly lower during propafenone strategy (19%) than during no-bolus strategy (55%); this was correlated with improved patient tolerance.
Conclusion Adjunctive use of single oral bolus propafenone is safe and effective in patients with an ICD and improves patient tolerance of device-based AF therapy.
Key Words: Atrial fibrillation, Antiarrhythmic drug, Implantable cardioverter-defibrillator, Atrial defibrillator, Pacing
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Introduction |
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Ablation and implantable devices are non-pharmacological approaches that assist in the maintenance of sinus rhythm in a substantial portion of patients with atrial fibrillation (AF).1
One such device is the implantable cardioverter-defibrillator (ICD); this device has dedicated atrial tachyarrhythmia detection and treatment capability.2 Embedded treatment options include pacing and defibrillation; the latter may be programmed as automatic or patient-elicited. The device has undergone clinical trials and has been shown to be safe and effective in treating AF in patients with and without concomitant ventricular tachyarrhythmias.2–7 However, the not-infrequent need for atrial defibrillation therapy, which is poorly tolerated, limits its widespread use.
Previous studies have demonstrated the efficacy of a strategy of single oral bolus propafenone for conversion of recent-onset AF. However, these studies involved patients not typical of those with an ICD, including infrequent AF, structurally normal hearts, no concomitant antiarrhythmic drug therapy, and hospital-based drug administration; in addition, early shock was not used if the drug failed to convert the AF.8–17 We thus wondered about the use of a single oral bolus propafenone strategy as an adjunct to ambulatory, device-based AF therapy. In this report, we detail the results of a feasibility study intended to evaluate the safety and efficacy of a strategy of ambulatory administration of single oral bolus propafenone followed by early atrial defibrillation shocks as needed. We hypothesized that propafenone would reduce the need for shocks and thus improve treatment tolerance.
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Methods |
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Patients
Patients underwent ICD implantation specifically for the management of highly symptomatic episodic/persistent AF; there was no ventricular tachyarrhythmia indication. In each patient, type I and/or III antiarrhythmic drug therapy was insufficient to maintain sinus rhythm: AF burden exceeded two persistent episodes in the 3 month period prior to implantation on the optimal regimen. Key exclusions included active ischaemic heart disease, NYHA class III/IV heart failure, inability to maintain sinus rhythm for at least 1 h after cardioversion, and prior implanted device. Each participant gave written informed consent in advance, according to a protocol approved by the Human Subjects Committee of each participating institution.
Propafenone test dose
Tolerance of a test dose (600 mg) of oral bolus propafenone (in addition to the chronic drug regimen) was assessed in-hospital in each patient prior to enrolment. At baseline and every 30 min for 3 h after drug administration, blood pressure, sinus rate, and electrocardiographic intervals were assessed; this interval encompassed the development of peak propafenone concentrations with single oral bolus dosing.18 Patients were enrolled in the study only if systolic blood pressure was >95 mmHg, QRS duration <140 ms, no evidence of ventricular proarrhythmia, and no significant symptoms during the monitoring session. One patient was withdrawn from the study because of hypotension during the test dose procedure. No proarrhythmia was observed in any prospective patient.
Device
Standard endovascular leads were placed in the right atrium and ventricle. Reproducible atrial and ventricular defibrillation at 
18 J (maximum device energy output 27 J) was confirmed. Leads were attached to a Jewel® device (model 7250, Medtronic, Inc., Minneapolis, MN, USA) that was inserted subcutaneously in the left or right pre-pectoral space. The device is capable of bradycardia pacing as well as detecting and treating episodes of atrial and ventricular tachyarrhythmias. Device functions as well as clinical safety and efficacy data have been described previously in detail.2–7 Elements of device function of particular importance in the present study included:
- AF detection: initial detection of an episode required interatrial electrogram intervals to be within the programmed detection zone for 32 consecutive ventricular cycles.
- AF therapies: 10 min after AF detection, the following therapies were delivered or available for delivery:
- Pacing: standard antitachycardia and high-frequency pacing were automatically delivered.2 If AF persisted after delivery, no further pacing therapies could be delivered until redetection of sinus rhythm.
- Defibrillation: shocks could be elicited only by the patient using an external hand-held device (Medtronic model 9464).
- Pacing: standard antitachycardia and high-frequency pacing were automatically delivered.2
- Ventricular tachyarrhythmia detection and therapy: detection was programmed into separate ‘ventricular tachycardia’ and ‘ventricular fibrillation’ zones. Ventricular tachycardia detection was programmed on, without therapy, to provide surveillance for proarrhythmia. All patients had ventricular fibrillation detection and therapies programmed on.
Study design
When AF symptoms occurred, patients were instructed to call a transtelephonic monitoring (TTM) service immediately for each AF recurrence. The TTM service acquired a rhythm strip and administered a symptom questionnaire. If AF was not diagnosed, then the patient was managed at the discretion of the physician. If AF was diagnosed, then the TTM technician instructed the patient to execute the treatment protocol (discussed subsequently). The service re-contacted the patient 24 h later to evaluate rhythm status, symptoms, therapy compliance, and therapy comfort. Patients were asked whether their symptoms had improved, stayed the same, or worsened compared with the initial call. Patients were also asked to score their comfort with the therapy from 1 (very uncomfortable) to 7 (very comfortable). Cardiovascular drug and device programming regimens were held constant for each individual throughout the study. Devices were interrogated and data downloaded at least every 4 months, with additional interrogations as needed.
A randomized three-way crossover design was used to compare, within patients, propafenone, placebo, and no oral bolus (no bolus) strategies. The propafenone and placebo strategy periods were double-blinded (the pills had identical appearances). Each treatment strategy lasted for 4 months. During the propafenone and placebo strategies, patients were instructed by the TTM service to swallow two pills immediately, each of which either contained propafenone (300 mg) or no active drug; propafenone and placebo tablets were physically identical. Patients were also instructed to wait at least 8 h after swallowing the pills before proceeding to manual shock therapy, unless symptoms were intolerable, in which case, they could elicit shock at any time. If at 8 h AF symptoms were still present, patients were instructed to elicit a defibrillation shock. During no-bolus strategy, patients were instructed by the TTM service to elicit a defibrillation shock at their earliest convenience, within 24 h.
Analysis
The analysis is confined to the 24 h period after a TTM-confirmed AF episode. Efficacy of the therapy was defined by the 24 h TTM recording; if this was not performed, the episode was excluded from the analysis. Analyses were performed on an intention-to-treat basis. Data were reported as mean±standard deviation or when they did not follow a normal distribution as median plus 25th–75th percentiles. A Wilcoxon rank-sum test was used to compare continuous variables. Event rates were compared using the generalized estimating equation.19 Two prospectively determined, paired comparisons were made for each variable: propafenone strategy vs. placebo strategy and propafenone strategy vs. no-bolus strategy. The Bonferroni method was used to correct the P-value for multiple comparisons. The null hypothesis was rejected when P0.05.
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Results |
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Thirty-five patients were enrolled; Table 1 summarizes their clinical data; key elements include the high prevalence of structural heart disease and concomitant use of other type I/III antiarrhythmic drugs. Table 2 summarizes device programming; bradycardia pacing and tachyarrhythmia detection intervals and therapy delays were similar among the treatment strategies. There was one death during follow-up, occurring 127 days after implantation, and this was attributed to lung cancer. Three other patients were withdrawn from the study, attributed to intractable AF (n=2, withdrawal at 167 days and 171 days) or psychopathology (n=1, withdrawal at 239 days). Data generated by these patients were included in the analysis until the time of their withdrawal.
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On the basis of the device interrogation, in aggregate 1108 AF episodes lasting
10 min each occurred during follow-up; these were thus treated with automatic pacing therapies. These episodes were equally distributed among the three treatment strategies. The incidence of pace termination was not significantly different among the treatment strategies (Table 3). Defibrillation shocks were elicited during 118 episodes, almost half of which occurred during no-bolus strategy (Table 3). Per-shock defibrillation efficacy was not significantly different among treatment strategies.
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On the basis of the TTM transmission, in aggregate 304 sustained AF episodes occurred during follow-up (Table 4). These episodes were not equally distributed among the three treatment strategies: the number was lower during no-bolus strategy than either propafenone or placebo strategies (Table 4). In response to these episodes, the patient compliance rate with pill ingestions exceeded 70% during both propafenone and placebo strategies (Table 4). The patient compliance rate with shock administration was higher during no-bolus strategy (81%) than during either propafenone (55%) or placebo (42%) strategies (Table 4). No ventricular tachyarrhythmias were detected during any strategy. The antiarrhythmic therapy efficacy rate, defined by sinus rhythm on the 24 h follow-up TTM, was higher during propafenone (81%) and no-bolus (84%) strategies than during placebo strategy (62%); this was correlated with the incidence of symptomatic improvement (Table 4). Shock was administered more frequently during no-bolus strategy (55%) than during propafenone (19%) or placebo (26%) strategies; this was correlated with a worse therapy comfort score (Table 4).
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Discussion |
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The key observation of this study was that single oral bolus propafenone strategy could be used safely and efficaciously as an adjunct to device-based AF therapy and was more effective and better tolerated than adjunctive oral bolus placebo or no oral bolus strategies. Our data confirm and extend previous evaluations of oral bolus propafenone.8
–17 Confirming prior studies, our patients experienced a high rate of conversion with good tolerance and no proarrhythmia. Extending prior studies, our cohort (i) was ambulatory; (ii) had an aggressive/drug-resistant AF syndrome; (iii) frequently had structural heart disease; (iv) was commonly taking other antiarrhythmic drugs; and (v) sometimes delivered shock at a time when high propafenone blood and tissue levels would be expected. The discrepancy between the number of device and the TTM-reported AF episodes is of interest. As demonstrated in Table 3, this cannot be explained solely by the rate of pace termination. It is possible that some of these events occurred during sleep or were otherwise asymptomatic or terminated spontaneously prior to the patient deciding to make the TTM call. However, patient compliance was also a contributor, as evidenced by the lower proportion of TTM calls made during no bolus than either pill strategy. We attribute this to trepidation over shock-related pain, because patients knew that during their no-bolus strategy period, they would be instructed to deliver a shock. We attribute the difference in antiarrhythmic efficacy between placebo and no-bolus strategies to similar trepidation: relative to no-bolus strategy (in which patients called knowing they would be instructed to deliver a shock), shock compliance during placebo strategy (in which shock was not assured) was significantly diminished. The lower therapy comfort score during no-bolus strategy supports this notion.
We note several limitations of this study. First, the cohort size was small. Second, these patients were carefully screened for tolerance of the 600 mg propafenone bolus. Despite our experience in this study (only one patient excluded because of intolerance), it is worth emphasizing that the potential for haemodynamic and proarrhythmic events after ingestion of this dose of propafenone is significant.14,15 Third, although many patients had structural heart disease, the degree of left ventricular systolic dysfunction was not typical of a population of patients for which the ICD was implanted primarily for a ventricular tachyarrhythmia indication. It is important to emphasize that the indication for ICD implantation in this study was AF alone, which is presently not regarded as a conventional treatment. Fourth, the imbalance in the number of TTM-reported AF episodes among strategies introduces a clear bias. However, we have no reason to suspect that this bias affects the veracity of our findings. Fifth, although patients were instructed to delay shock during propafenone and placebo strategies and to expedite shock during no-bolus strategy, we were unable to quantify the duration of AF prior to shock in each arm. This was due to a transcription oversight that left us unable to correlate TTM events with device-stored events. Given the short window (<24 h) in which all shocks were to be delivered, we have no reason to expect that differences discovered here would have altered our conclusions. Sixth, propafenone was taken after automatic delivery of atrial tachypacing therapies, and thus we cannot address the safety and efficacy of this combination. It is conceivable that properly timed single oral bolus propafenone therapy would create a more favourable milieu for pace termination. Far less likely would be an enhanced risk for ventricular proarrhythmia due to ventricular rate acceleration associated with atrial tachypacing. Seventh, we note the high mean body weight of the patients in this cohort. It is conceivable that obesity could somehow have biased our data. Finally, the study did not routinely assess how episodes of AF which were ongoing at the 24 h TTM were resolved.
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Acknowledgement |
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This work was supported by a grant from Medtronic, Inc.
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References |
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