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Azimilide for the Treatment of Atrial Fibrillation, Atrial Flutter,
and Paroxysmal Supraventricular Tachycardia: Results of a
Randomized Trial and Insights on the Concordance of Symptoms
and Recurrent Arrhythmias
RICHARD L. PAGE, M.D.,∗ EDWARD L.C. PRITCHETT, M.D.,† STUART CONNOLLY, M.D.,‡,
and WILLIAM E. WILKINSON, PH.D.,† For the SVA-4 Investigators
From the ∗ University of Washington, Seattle, Washington; †Duke University Medical Center, Durham, North Carolina; ‡Hamilton Health
Sciences Center, Hamilton, Ontario, Canada
Azimilide Efficacy and Symptom Concordance. Introduction: Azimilide hydrochloride is an investigational antiarrhythmic medication that had shown evidence of efficacy in prolonging the time to
recurrence of atrial fibrillation (AF) or atrial flutter (AFL) and paroxysmal supraventricular tachycardia
(PSVT). This study was designed to confirm efficacy of 125 mg daily azimilide.
Methods and Results: The primary endpoint was ECG-documented recurrence of AF, AFL, or PSVT,
followed for a maximum of 180 days. Four hundred eighty-two patients were enrolled in the United States
and Canada (422 with AF or AFL and 60 with PSVT). The primary efficacy analysis included 402 patients
with AF-AFL and 56 patients with PSVT. There was no significant difference in the time to first recurrence
of symptomatic supraventricular arrhythmia in the AF-AFL stratum (median of 38 days for azimilide
versus 27 days for placebo; hazard ratio [HR] of 1.14, P = 0.29). Similarly, there was no difference in
time to recurrence in the PSVT stratum (>180 days for azimilide versus 135 days for placebo; HR = 1.28,
P = 0.55). There were three deaths in the azimilide group and one in the placebo group. Four patients had
nonsustained ventricular tachycardia (one torsades de pointes), all in the azimilide group. Asymptomatic
recurrence was frequent in the AF-AFL group (8% with azimilide and 11% with placebo), but was absent
in the PSVT group. False recurrence was common in both groups.
Conclusion: Azimilide 125 mg daily was not associated with significant prolongation of the time to recurrent symptomatic supraventricular arrhythmias. There was substantial discordance between symptoms
and recurrence. (J Cardiovasc Electrophysiol, Vol. pp. 1-6)
atrial fibrillation, azimilide, silent atrial fibrillation, asymptomatic, false recurrence, antiarrhythmic medication
Introduction
Atrial fibrillation is the most common arrhythmia that requires therapy, accounting for substantial health care costs in
the USA and elsewhere.1 Despite advances in nonpharmacologic therapy2 and the evidence that antiarrhythmic drug therapy does not improve survival, many patients receive medical
This study was sponsored by Procter & Gamble Pharmaceuticals, Mason,
Ohio. At the time it was conducted, all authors were members of the scientific
advisory committee for the trial and were either consultants or investigators
for Procter & Gamble Pharmaceuticals. At the time the manuscript was
written, Drs. Pritchett and Wilkinson were consultants for Procter & Gamble
Pharmaceuticals. Dr. Pritchett is also a consultant to Reliant Pharma. Dr. Page
received grant support from Procter & Gamble Pharmaceuticals through
the University of Washington. He has also received significant honoraria
from sanofi-aventis for consulting work. Dr. Connolly received funding from
sanofi-aventis as a principle investigator in an ACTIVE trial. He also received
significant honoraria and travel support from sanofi-aventis.
Address for correspondence: Richard L. Page, M.D., Division of Cardiology,
University of Washington School of Medicine, 1959 NE Pacific Street, Room
AA502, Health Sciences Bldg., Box 356422, Seattle, WA 98195-6422.
Fax: 206-616-4847; E-mail: [email protected]
Manuscript received 2 July 2007; Revised manuscript received 30 July 2007;
Accepted for publication 7 August 2007.
doi: 10.1111/j.1540-8167.2007.00985.x
therapy for atrial stabilization in an effort to reduce symptoms. Currently available antiarrhythmic agents are limited
due to modest efficacy and substantial risk of toxicity. Azimilide dihydrochloride (azimilide) is a novel Vaughn Williams
class III agent that was shown in previous studies to reduce
symptomatic arrhythmia recurrence in patients with a history
of atrial fibrillation (AF), atrial flutter (AFL),3-5 or paroxysmal supraventricular tachycardia (PSVT).6 This study was
designed to further evaluate the efficacy and safety of azimilide in patients with these symptomatic supraventricular
arrhythmias, employing a single dose that appeared in those
previous studies to have clinical efficacy.
Methods
Entry Criteria
Male and female patients 18 years or older were eligible if they had a history of symptomatic AF, AFL, or
PSVT and were candidates for antiarrhythmic medication
in the judgment of their physician. An institutional review board at each site approved the protocol. Patients
were required to give written informed consent for participation in the trial. Enrolling investigators were obligated
to provide either 12-lead ECG or transtelephonic ECG of
the arrhythmia recorded within 24 months of enrollment.
The patients were required to demonstrate sinus rhythm
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Vol. No.
immediately before initial dosing. Important exclusion criteria were: supraventricular arrhythmia (SVA) due to acute
electrolyte disturbance, hyperthyroidism, pericarditis, or
other reversible cause; NYHA class IV congestive heart
failure; unstable angina; history of polymorphic ventricular tachycardia (including torsades de pointes) or sustained
ventricular tachycardia; Wolff-Parkinson-White syndrome;
resting heart rate below 50 beats per minute; history of Mobitz type II or complete heart block; current use of class I
or class III antiarrhythmic drugs (and no amiodarone for 1
month); unresolved organ toxicity due to amiodarone; use of
other agents that prolong QTc within five half-lives of the
agent; QTc (Bazett’s) >440 ms during sinus rhythm; elevated blood pressure (systolic >160 and diastolic >100 mm
Hg); severe valvular disease; history of syncope, angina, congestive failure, or sudden death associated with any arrhythmia; acute myocardial infarction, cardiothoracic surgery, or
neurologic event within 2 months; implantable cardioverter–
defibrillator; underlying terminal illness with life expectancy
<1 year; current pregnancy or breast feeding, or plan for pregnancy within 1 year; recreational drug use or alcohol abuse;
current psychosis; or significant laboratory abnormality (ALT
or AST > 2 times normal, BUN > 50 mg/dL, creatinine >
2.0 mg/dL, potassium < 3.8 mEq/L, or > 5.5 mEq/L).
Randomization and Follow-Up
The investigator classified patients at the time of study
entry as manifesting AF, AFL, or PSVT as their “index arrhythmia.” Patients with AF or AFL were assigned to a single
stratum (AF-AFL stratum) for randomization and patients
with PSVT were assigned to a separate stratum (PSVT stratum). Patients in both strata were randomly assigned in a
1:1 fashion to receive azimilide 125 mg tablets or matching
placebo. The first dose was administered after confirmation
that the patient was in sinus rhythm. Dosing was twice daily
(10–12 hours apart) for 3 days (the “loading period”). On
day 4 and thereafter, dosing was once daily. The “efficacy
period” commenced on day 4 unless an arrhythmia was evident; the beginning of the efficacy period was delayed up
to 7 days until sinus rhythm returned (either spontaneously
or with electrical cardioversion). If sinus rhythm was not restored within 10 days, the patient was withdrawn from the
study and was not included in the primary efficacy analysis.
Drug dosage was not adjusted at any time.
Patients were provided nonlooping transtelephonic electrocardiogram monitors (TTM) and were instructed to document the rhythm at the time of symptoms that they believed
were indicative of an arrhythmia and to transmit the recording to a central monitoring service (Premier Research Worldwide, Philadelphia, PA, USA). They were also asked to respond to a brief standardized symptom questionnaire at the
time of these calls. The patients transmitted an ECG every
2 weeks at a time when there was no evidence of an arrhythmia. When a patient experienced a completion event (symptoms associated with documented AF, AFL, or PSVT), that
patient was removed from the study. The study was otherwise
complete after 180 days of treatment during the efficacy period without a completion event. Asymptomatic arrhythmias
were not considered to be endpoints; the study continued until
completion. All electrograms were sent to the investigator and
those that were associated with symptoms were forwarded to
the event committee consisting of five electrophysiologists
who were blinded as to treatment. Two members reviewed
each tracing to assign a diagnosis; if there was disagreement
between the reviewers, the ECG was adjudicated by the entire
committee.
Data Analysis
Statistical analyses were identical for the AF-AFL stratum and the PSVT stratum. The primary outcome variable
was the time to the first ECG-documented, symptomatic arrhythmia. The tachycardia-free period was defined as the time
from the beginning of the efficacy period until that first event.
Within each stratum, the primary efficacy analysis included
all patients who met inclusion criteria and entered the efficacy period. All patients who were randomized and received
study medication were included in safety analyses. Patients
withdrawn from the study or who completed 180 days of the
efficacy period without a completion event were censored at
the last day in the study. The time-to-event data were summarized by treatment group using a plot of Kaplan–Meier estimates of the survival curves.7 The median time to event and
its standard error were estimated for each treatment group.
The log rank test was used to evaluate the statistical significance of observed differences between treatment groups. A
proportional hazards model was used to estimate the hazard
ratio (azimilide:placebo) between the two treatment groups.7
The secondary efficacy endpoint was the heart rate during
a qualifying arrhythmia (during the efficacy period). Mean
heart rates were compared using linear models. In order to
study drug action during the loading period, additional analyses included the time to first event as measured from the first
day of the loading period and the time to first event during
the loading period.
Adverse events were monitored from the time the
patient received the first dose of study drug until exit from
the trial. Adverse events were counted if they occurred within
30 days of withdrawal from the trial for any reason. Safety
variables reported here include deaths, occurrences of torsades de pointes, occurrences of other ventricular tachycardias, withdrawal from the study because of adverse events,
neutropenia, and the adverse events most commonly reported
by patients. Deaths were classified by the event committee using a variant of the Hinkle system.8 Serious adverse
events were defined according to industry guidelines. The
Data Safety Monitoring Board reviewed unblinded safety
data, primarily serious adverse events, at periodic intervals.
Further analysis of the concordance of symptoms and
recurrent supraventricular arrhythmias was performed for the
patients who met inclusion criteria and entered the efficacy
period. Asymptomatic recurrence was defined as the occurrence of supraventricular arrhythmia as recorded on the routine 30-second recording. False recurrence was defined as
symptoms that were reported by the patient to represent recurrent supraventricular arrhythmia but another rhythm was documented by TTM. Both asymptomatic recurrence and false
recurrence were categorized by cohort (AF-AFL or PSVT)
and by treatment group (azimilide or placebo).
Study Chronology
The first and last patients were enrolled on July 2, 1998,
and November 30, 1998, respectively. The last patient observation took place on June 30, 1999, and the database was
locked on July 31, 1999.
Page et al.
Results
Study Population
A total of 482 patients were enrolled. There were 422 patients in the AF-AFL stratum; of these, 66% had a history of
AF alone, 5% AFL alone, 20% both AF and AFL; 8% had
a history of PSVT also. There were 60 patients with PSVT;
17% had a history of atrial fibrillation as well. The first dose
was administered while the patient was in the hospital in 38
(9%) of the AF-AFL group and none of those with PSVT. Demographic and baseline characteristics for both the AF-AFL
and PSVT strata were similar among the treatment groups, as
were concomitant medications. Mean age was 61 years; 63%
were men. A history of congestive heart failure was reported
in 13%, cardiomyopathy in 6%, and valvular heart disease in
42%. Left ventricular ejection fraction measurement was not
available. The only differences observed were in the PSVT
stratum, where smaller numbers allowed for disproportion-
Figure 1. Kaplan–Meier plot of the time to
completion event (recurrence of SVA during
the efficacy period). A. AF/FL stratum. B.
PSVT stratum.
Azimilide Efficacy and Symptom Concordance
3
ately higher percentage of male patients, black patients, and
those with structural heart disease in the azimilide group.
Efficacy Analyses
Among the 422 AF-AFL patients, 409 entered the efficacy period, as did 57 of the 60 PSVT patients. Among the
patients who entered the efficacy period, seven AF-FL patients and one PSVT patient failed to meet inclusion criteria,
so they were not included in the primary efficacy analysis.
Their data were included in analyses that examined all randomized patients and in safety analyses.
Primary and other efficacy analyses for the AF-FL stratum
The median time to symptomatic arrhythmia occurrence
was 38 days in the azimilide group and 27 days for placebo,
yielding a placebo-to-azimilide hazard ratio of 1.14 (P =
0.29, 95% confidence interval = 0.89, 1.47) (see Fig. 1A).
Further analyses that measured recurrence from the first day
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Vol. No.
of the loading period (all randomized patients) showed no
difference between the two groups, nor did a comparison of
the number of events that occurred during the loading period
(27 events on azimilide and 34 on placebo, P = NS).
The secondary analysis of heart rate during a recurrent
arrhythmia demonstrated no significant difference (119 beats
per minute for azimilide vs 122 for placebo; P = 0.32).
Subgroup analyses were conducted according to the protocol, with analysis performed for the following subgroups:
gender, age, blood pressure, weight, congestive heart failure, ischemic heart disease, hypertension, valvular disease,
atrial enlargement, structural heart disease, prior cardioversion, digoxin, and smoking. All results were consistent with
the primary efficacy analysis.
Primary efficacy and secondary analyses
for the PSVT stratum
The median time to symptomatic arrhythmia occurrence
was >180 days in the azimilide group and 135 days for
placebo, yielding a placebo-to-azimilide hazard ratio of
1.28 (P = 0.55, 95% confidence interval = 0.57, 2.89)
(see Fig. 1B). As in the AF/FL group, further analyses that
included the loading phase demonstrated no difference in
overall time to recurrence and no difference in risk during
the loading period.
The secondary analysis of heart rate during a recurrent
arrhythmia demonstrated a significant difference with rate of
130 beats per minute on azimilide and 171 on placebo (P =
0.003).
Safety
Safety data were collected for all patients who received
study drug and data were collected for 30 days after withdrawal from the study. Three patients receiving azimilide
(1.2%) and one receiving placebo (0.4%) died during the
study. Three of the deaths were classified as cardiac arrhythmic (two azimilide and one placebo). Considering time on
treatment, the mortality rates were 5.7 versus 2.0 deaths per
100 years for azimilide and placebo, respectively (P = NS).
Adverse events were reported in 66% of azimilide and
58% of placebo patients. Investigators withdrew 15 (6%) az-
Figure 2. Frequency of asymptomatic and
false recurrence in study groups.
imilide patients and six (2%) of placebo patients from the
study due to adverse events (P = NS). The most frequent
events for both groups were asthenia, headache, and respiratory infection (each reported in 10% of azimilide-treated
patients). Serious adverse events (including the four deaths
described above) were reported in 17 azimilide patients and
nine placebo patients. There was one documented episode of
torsades de pointes, occurring in an azimilide patient during
surgery to repair an abdominal aortic aneurysm; this resulted
in ventricular fibrillation that was treated satisfactorily with
countershock. Three azimilide patients were reported to experience nonsustained ventricular tachycardia. Symptomatic
ventricular ectopic beats were reported in one patient taking
azimilide and one receiving placebo. Syncope was reported
in only one patient receiving placebo. Agranulocytosis was
observed in one patient receiving azimilide; this resolved after withdrawal of the drug.
Prolongation of the QTc (as measured by routine 12-lead
ECG) beyond baseline was observed throughout the study
in the patients receiving azimilide, with mean prolongation
of 10.6% at 6 months, compared with 0.8% in patients receiving placebo. Four patients (all receiving azimilide) were
withdrawn for QTc prolongation, with QTc intervals ranging
from 499 to 608 ms, as measured in a blinded fashion post
hoc by the event committee.
Asymptomatic and False Recurrence
Asymptomatic recurrence of a supraventricular arrhythmia in the AF-FL group was seen in 17 of 202 patients (8%)
on azimilide and in 22 of 200 (11%) receiving placebo. In
contrast, there were no episodes of asymptomatic recurrence
in the PSVT stratum, with 29 patients receiving azimilide and
27 receiving placebo (see Fig. 2).
False recurrence was common in all groups, as shown in
Figure 2. Among patients with AF-AFL receiving placebo,
62 of 200 (31%) provided such recordings. Similar frequency
of false recurrence was observed among the patients receiving azimilide, with 72 of 202 (36%) providing a total of 192
events where recurrence was reported but no index supraventricular arrhythmia was reported. Most of these patients (49
of 72) and most recordings (101 of 192) demonstrated sinus
Page et al.
rhythm without ectopic beats. Next most common rhythms
recorded were sinus with premature supraventricular beats
(26 patients) and sinus with premature ventricular beats (11
patients). The most common symptom was palpitations, reported in 81% of the patients receiving placebo and 74% of
those receiving azimilide. Patients in the PSVT cohort also
manifested false recurrence. Among the combined azimilide
and placebo patients, 32 of 56 (57%) reported a total of 110
false recurrences. As with the AF/AFL cohort, the most frequent symptom was palpitations, reported in 91% of patients
with false recurrence.
Discussion
Main Study Results
The primary result of this study is that azimilide failed to
reduce the recurrence of AF/FL or PSVT. Trends toward prolongation of the time to symptomatic recurrence were seen,
but the degree of effect was not clinically important.
Tolerability of azimilide was generally good, with predictable QT prolongation and infrequent torsades de pointes.
Of the four deaths reported, three were sudden and two of
these were in the azimilide group. A previous study in highrisk patients postmyocardial infarction demonstrated no effect of azimilide on mortality.9
Prior studies, entitled SVA 1, 2, and 3, had shown variable
efficacy of azimilide,3,5,10 although SVA-3, the only study
that had previously studied the effect of azimilide 125 mg
daily, showed a significant effect with a hazard ratio of 1.58.5
Partial results of the study presented in this article previously were incorporated into a combined analysis of all four
SVA studies, showing a dose-dependent benefit of azimilide
in prolonging the time to recurrence of AF/FL.3 That article included a combined subgroup analysis suggesting that
patients who had ischemic heart disease and/or congestive
heart failure might derive the greatest benefit from azimilide
therapy. Since that high-risk group of patients has limited options for antiarrhythmic drug action and had previously been
shown to derive a neutral mortality effect from azimilide,9
further study was undertaken to further define the drug effect
in this population. Studies in patients with and without structural heart disease and those post cardioversion did not show
significant benefit to azimilide.11,12
This is the second study to evaluate the antiarrhythmic effect of azimilide on the recurrence of SVA in patients with
symptomatic PSVT. The previous report of 193 patients with
PSVT provided a hazard ratio of 2.35 at 100 mg and 1.28 at
125 mg; although only the 100 mg comparison was statistically significant, a combined analysis (100 mg with 125 mg)
showed a significant prolongation of time to recurrence (P =
0.02).6 Our data provide an identical hazard ratio as the previous experience with 125 mg daily, confirming a modest (but
not significant) effect on recurrence. The secondary analysis,
demonstrating a significant slowing of the heart rate during
recurrent arrhythmia, is of questionable clinical significance.
Concordance of Symptoms with Arrhythmia Recurrence
Asymptomatic, or silent, AF has become well recognized in recent years. In a population of patients with established symptomatic AF, asymptomatic recurrence has been
shown to occur up to 12 times more frequently than symptomatic recurrence.6 In the first three azimilide trials, asymp-
Azimilide Efficacy and Symptom Concordance
5
tomatic recurrence was evaluated in similar fashion with this
study, with 17% on placebo and 11% on azimilide (100 or
125 mg) demonstrating asymptomatic AF before having a
documented symptomatic recurrence. This study confirms
frequent asymptomatic recurrence, although somewhat lower
at 11% on placebo and 8% on azimilide. The lower rates in
this study may relate to the shorter follow-up that resulted
from earlier symptomatic recurrence or may suggest a lower
overall frequency of silent AF. Even the lower event rate
observed in this study suggests that a far greater frequency
would be documented if monitoring were continuous (as opposed to just 30 seconds every 2 weeks). It should be noted
that asymptomatic recurrence has been reported in patients
following ablation for AF. Although one study suggested that
this was uncommon,13 further studies suggest that asymptomatic recurrence occurs frequently following ablation.14,15
False recurrence in patients with AF and PSVT has been
described.16 In SOPAT (Suppression of Paroxysmal Atrial
Tachyarrhythmias Trial), using a protocol that included daily
TTM recordings, AF was only present in 37% of symptomtriggered ECG recordings.17 False recurrence has also been
reported in patients post ablation; one study that included
daily and symptomatic TTM transmissions for 6 months post
ablation, 11% of the recordings in sinus rhythm were accompanied by symptoms consistent with recurrence AF.18 Our
study provides additional insight regarding patients who have
not undergone ablation. ECG documentation was available
for all episodes (assuming a functional ECG event recorder)
and demonstrated that one patient in three who has AF or
AFL will report a false recurrence before a true symptomatic
recurrence would be experienced. This phenomenon of false
recurrence should dictate prudence in considering changes
in therapy based on self-reported recurrence. It is noteworthy
that patients with PSVT who previously and in this study have
been shown to be free of silent recurrence, nevertheless have
false recurrence before they demonstrate true recurrence in
over half of the patients studied, suggesting that clinicians
should not make therapeutic decisions about PSVT recurrence based on symptom reporting alone.
Conclusion
The SVA-4 trial did not show a statistically significant or
clinically important effect in reducing recurrence of symptomatic AF/FL or PSVT. The results expand our understanding of the concordance of symptoms and recurrence of
supraventricular arrhythmias.
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