Download Vernakalant Hydrochloride for Rapid Conversion of

Vernakalant Hydrochloride for Rapid Conversion
of Atrial Fibrillation
A Phase 3, Randomized, Placebo-Controlled Trial
Denis Roy, MD; Craig M. Pratt, MD; Christian Torp-Pedersen, MD; D. George Wyse, MD, PhD;
Egon Toft, MD; Steen Juul-Moller, MD; Tonny Nielsen, MD; S. Lind Rasmussen, MD;
Ian G. Stiell, MD; Benoit Coutu, MD; John H. Ip, MD; Edward L.C. Pritchett, MD;
A. John Camm, MD; for the Atrial Arrhythmia Conversion Trial Investigators
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Background—The present study assessed the efficacy and safety of vernakalant hydrochloride (RSD1235), a novel
compound, for the conversion of atrial fibrillation (AF).
Methods and Results—Patients were randomized in a 2:1 ratio to receive vernakalant or placebo and were stratified by AF
duration of 3 hours to 7 days (short duration) and 8 to 45 days (long duration). A first infusion of placebo or vernakalant
(3 mg/kg) was given for 10 minutes, followed by a second infusion of placebo or vernakalant (2 mg/kg) 15 minutes later
if AF was not terminated. The primary end point was conversion of AF to sinus rhythm for at least 1 minute within 90
minutes of the start of drug infusion in the short-duration AF group. A total of 336 patients were randomized and
received treatment (short duration, n⫽220; long duration, n⫽116). Of the 145 vernakalant patients, 75 (51.7%) in the
short-duration AF group converted to sinus rhythm (median time, 11 minutes) compared with 3 of the 75 placebo
patients (4.0%; P⬍0.001). Overall, in the short- and long-duration AF groups, 83 of the 221 vernakalant patients
(37.6%) experienced termination of AF compared with 3 of the 115 placebo patients (2.6%; P⬍0.001). Transient
dysgeusia and sneezing were the most common side effects in vernakalant-treated patients. Four vernakalant-related
serious adverse events (hypotension [2 events], complete atrioventricular block, and cardiogenic shock) occurred in 3
patients.
Conclusion—Vernakalant demonstrated rapid conversion of short-duration AF and was well tolerated. (Circulation. 2008;
117:1518-1525.)
Key Words: antiarrhythmia agents 䡲 arrhythmia 䡲 fibrillation 䡲 vernakalant
C
urrently available antiarrhythmic agents have modest
efficacy in converting atrial fibrillation (AF) to sinus
rhythm, and the risk of proarrhythmia or hypotension is of
concern.1–3 Time to conversion with these drugs often is
unpredictable and may be long, especially with oral therapies.4 Although electric cardioversion is more effective than
drug administration, it is associated with adverse effects such
as skin burns, heart block, ventricular proarrhythmia, and
pacemaker or internal defibrillator malfunction.2,4,5 Electrical
cardioversion requires general anesthesia or conscious sedation from which patients must recover and may prolong
hospitalization. In addition, the procedure generally is de-
layed for at least 6 hours after meals.6 A rapidly acting,
efficacious, and safe drug that targets the fibrillating atria
would be a valuable alternative to current treatments for
patients with this common arrhythmia. Prompt pharmacological conversion of AF may prove to be a cost-saving strategy.
Clinical Perspective p 1525
Vernakalant hydrochloride (RSD1235), an investigational
compound, is a relatively atrium-selective, early-activating
K⫹ and frequency-dependent Na⫹ channel blocker with a
half-life of 2 to 3 hours.7,8 In animal models of AF and in a
recent clinical study, vernakalant selectively prolonged the
Received June 28, 2007; accepted January 4, 2008.
From the Montreal Heart Institute, University of Montreal, Montreal, Quebec, Canada (D.R.); Department of Cardiology, Methodist DeBakey Heart
Center, Methodist Hospital Research Institute, Houston, Tex (C.M.P.); Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark (C.T.-P.);
Libin Cardiovascular Institute of Alberta, Calgary, Alberta, Canada (D.G.W.); Department for Health Science and Technology, Aalborg University, and
Department of Cardiology, Aalborg Hospital, Aalborg, Denmark (E.T.); Universitetssjukhuset I Malmo, Malmo, Sweden (S.J.-M.); Centralsygehuset
Esbjerg Varde, Esbjerg, Denmark (T.N.); Hvidovre Hospital, Hvidovre, Denmark (S.L.R.); Department of Emergency Medicine, University of Ottawa,
Ottawa, Ontario, Canada (I.G.S.); Notre-Dame Hospital, Montreal, Quebec, Canada (B.C.); Thoracic and Cardiovascular Institute, Lansing, Mich (J.H.I.);
Duke University, Durham, NC (E.L.C.P.); and St George’s Hospital, London, UK (A.J.C.).
Clinical trial registration information—URL: http://Clinicaltrials.gov. Unique identifier: NCT00468767.
The online Data Supplement, which contains a list of the Atrial Arrhythmia Conversion Trial Investigators, can be found with this article at
http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.107.723866/DC1.
Reprint requests to Dr Denis Roy, Montreal Heart Institute, 5000 Belanger St, Montreal, Quebec H1T 1C8, Canada. E-mail [email protected]
© 2008 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.107.723866
1518
Roy et al
Vernakalant in Patients With Atrial Fibrillation
atrial refractory period without affecting ventricular refractoriness.7–9 Vernakalant effectively converted acute-onset AF
(AF lasting 3 to 72 hours) in a placebo-controlled phase 2 trial
(n⫽56).10
1519
Randomized
AF duration
3 hours to 45 days
(N=356)
Methods
Study Design
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This prospective, randomized, double-blind, placebo-controlled trial
was conducted in 44 centers in Canada, the United States, and
Scandinavia. Patients were stratified by duration of AF: 3 hours to 7
days (short duration) and 8 to 45 days (long duration). Patients
within the 2 strata were then randomized 2:1 to vernakalant or
placebo using block randomization and a computer-generated centralized list via an Interactive Voice Response System. This 2:1
randomization scheme was used to gather extra safety data for
vernakalant. The study protocol was developed by the Steering
Committee and the sponsor. Study oversight was provided by the
Steering Committee and an unblinded independent Data Safety
Monitoring Committee. The Data Safety Monitoring Committee held
monthly teleconferences, with 2 planned interim safety evaluations
once 90 and 180 patients, respectively, were enrolled. The protocol
was approved by the institutional or regional review board at each
site, and patients gave written informed consent before starting study
procedures. The Steering Committee approved the text of this
manuscript before publication.
Selection and Description of Participants
To be eligible, patients had to have sustained AF for 3 hours to 45
days, be ⱖ18 years of age, have a body weight of 45 to 136 kg, be
receiving adequate anticoagulation, and have a systolic blood pressure ⬎90 mm Hg and ⬍160 mm Hg and a diastolic blood pressure
⬍95 mm Hg. Women could not be pregnant or nursing and, if
premenopausal, had to use an effective form of birth control. Patients
were excluded if they had sick-sinus syndrome or QRS ⬎0.14
seconds without a pacemaker; ventricular rate of ⬍50 bpm; uncorrected QT ⬎0.440 seconds; typical atrial flutter; New York Heart
Association class IV heart failure; acute coronary syndrome, myocardial infarction, or cardiac surgery within 30 days before enrollment; an investigational drug within 30 days before enrollment; a
reversible cause of AF; end-stage disease; previously failed electric
conversion; uncorrected electrolyte imbalance; or digoxin toxicity.
Treatment initiation with ␤-blockers, calcium antagonists, and
digoxin for control of ventricular rate was permitted for up to 2 hours
before study drug infusion. Treatment with intravenous class I and
III antiarrhythmics was allowed up to 24 hours before study drug
infusion, and background therapy of oral antiarrhythmics was
allowed.
Treatment Plan
Patients received a 10-minute infusion of vernakalant (3.0 mg/kg) or
placebo, followed by a 15-minute observation period. If the patient
did not convert to sinus rhythm, an additional dose of vernakalant
(2.0 mg/kg) or placebo was administered. The infusion was to be
discontinued if the uncorrected QT interval increased to ⬎0.550
seconds or by ⬎25%; heart rate decreased between 40 and 50 bpm
with symptoms or to ⬍40 bpm; systolic blood pressure increased to
⬎190 mm Hg or decreased to ⬍85 mm Hg; new bundle-branch
block developed or QRS increased ⱖ50%; or polymorphic ventricular tachycardia, a sinus pause of ⱖ5 seconds, or intolerable side
effects occurred. The use of other antiarrhythmic medications and
electrical cardioversion was not recommended until at least 2 hours
after study drug infusion.
Patients were observed in the hospital for a minimum of 8 hours
after study drug infusion. ECGs were recorded and vital signs were
measured at screening; at baseline; every 5 minutes from the start of
infusion to 50 minutes after infusion; at 90 minutes and 2, 4, 8, and
24 hours; and at 1 week after dose. Lead II or V5 tracings were used
to measure ECG intervals by a central ECG laboratory. Generally,
the intervals were evaluated from 3 (consecutive if possible) com-
AF duration
3 hours to 7 days
(n=237)
AF duration
8 to 45 days
(n=119)
Did not receive drug*
(n=17)
Vernakalant (n=13)
Placebo (n=4)
Did not receive drug*
(n=3)
Vernakalant (n=3)
Placebo (n=0)
Treated
(n=220)
Vernakalant (n=145)
Placebo (n=75)
Treated
(n=116)
Vernakalant (n=76)
Placebo (n=40)
Completed study
through day 30
(n=215)
Vernakalant (n=141)
Placebo (n=74)
Completed study
through day 30
(n=115)
Vernakalant (n=75)
Placebo (n=40)
Figure 1. Patient disposition. *Reasons why subjects did not
receive study drug were spontaneous conversion to sinus
rhythm (n⫽14), violation of inclusion or exclusion criteria (n⫽2),
myocardial infarction (n⫽2), study drug unavailability (n⫽1), and
reason not specified (n⫽1).
plexes. QT intervals were corrected for heart rates with Bazett’s
(QTcB) and Fridericia’s (QTcF) formulas. A Holter continuously
monitored the cardiac rhythm from screening to 24 hours after dose.
Study End Points
The primary efficacy end point was the proportion of patients in the
short-duration AF (3 hours to 7 days) group who had conversion to
sinus rhythm for at least 1 minute within 90 minutes of drug
initiation. Secondary and exploratory efficacy end points in the
short-duration AF group included the time to conversion from first
exposure to study drug and the proportion of patients who remained
in sinus rhythm at 24 hours, respectively. Other secondary efficacy
end points included the proportion of patients with AF duration of 3
hours to 45 days and 8 to 45 days who had termination of AF
(defined as the absence of AF or atrial flutter, which included
conversion to sinus rhythm and a paced rhythm).
Conversion to sinus rhythm and termination of AF were adjudicated by a Clinical Events Committee blinded to treatment assignment. The Clinical Events Committee also reviewed all episodes of
suspected torsade de pointes. All 12-lead ECGs and 24-hour Holter
recordings were reviewed by a cardiologist at the central ECG
laboratory who was blinded to treatment assignment. Ventricular
tachycardia was defined as ⱖ3 wide complex beats with a rate of
ⱖ100 bpm.
A serious adverse event was defined as any adverse event
occurring from the start of the infusion through the 30 days after
study treatment that, at any dose of study drug, was fatal or life
threatening, required or prolonged hospitalization, was significantly
incapacitating, or required medical or surgical intervention.
Statistical Considerations
All randomized patients who received any amount of study drug
were included in the efficacy and safety analyses (prespecified
1520
Circulation
March 25, 2008
Table 1.
Baseline Clinical Characteristics
Short Duration
Placebo
(n⫽75)
Long Duration
Vernakalant
(n⫽145)
Placebo
(n⫽40)
Overall Study Population
Vernakalant
(n⫽76)
Placebo
(n⫽115)
Vernakalant
(n⫽221)
Male sex, n (%)
48 (64.0)
102 (70.3)
27 (67.5)
57 (75.0)
75 (65.2)
159 (71.9)
White, n (%)
73 (97.3)
138 (95.2)
40 (100)
74 (97.4)
113 (98.3)
212 (95.9)
Age (mean⫾SD), y
59.9⫾11.8
60.4⫾14.0
64.6⫾9.7
65.9⫾12.5
61.5⫾11.3
62.3⫾13.7
28.4 (1.2–165)
28.2 (1.2–372)
465.2 (18.2–1081.6)
613.0 (130.4–1040.8)
41.8 (1.2–1082)
59.1 (1.2–1041)
Atrial fibrillation duration
(median range), h
History of significant medical
conditions, n (%)
Hypertension*
32 (43)
57 (39)
21 (52)
34 (45)
53 (46)
91 (41)
Ischemic heart disease*
13 (17)
22 (15)
11 (28)
22 (29)
24 (21)
44 (20)
Myocardial infarction*
4 (5)
12 (8)
5 (12)
12 (16)
9 (8)
24 (11)
Diabetes*
4 (5)
10 (7)
4 (10)
9 (12)
8 (7)
19 (9)
14 (10)
13 (32)
18 (24)
Heart failure*
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Current smoker, n (%)
5 (7)
12 (16.0)
18 (16)
32 (14)
20 (13.8)
5 (12.5)
9 (11.8)
17 (14.8)
29 (13.1)
128 (57.9)
Concomitant therapy, n (%)
␤-Blockers
42 (56.0)
80 (55.2)
29 (72.5)
48 (63.2)
71 (61.7)
Calcium channel blockers
19 (25.3)
27 (18.6)
8 (20.0)
13 (17.1)
27 (23.5)
40 (18.1)
Digoxin
15 (20.0)
26 (17.9)
21 (52.5)
29 (38.2)
36 (31.3)
55 (24.9)
Class I antiarrhythmic
drugs†
8 (10.7)
9 (6.2)
0
5 (6.6)
8 (7.0)
14 (6.3)
Class III antiarrhythmic
drugs†
2 (2.7)
10 (6.9)
3 (7.5)
2 (2.6)
5 (4.3)
12 (5.4)
*Derived from verbatim terms in medical history after the study database was locked and unblinded.
†Class I antiarrhythmics included procainamide, quinidine, propafenone, and flecainide. Class III antiarrhythmics included dofetilide and amiodarone.
modified intention-to-treat population). Baseline characteristics were
compared between groups by use of a 1-way ANOVA with a fixed
effect for treatment for continuous variables and a ␹2 test or Fisher’s
exact test for categorical variables. The primary end point was
analyzed with the Cochran-Mantel-Haenszel test stratified by center;
this test also was used in the analysis of the secondary end point in
the group of patients with AF duration of 3 hours to 45 days. Fisher’s
exact test was used in the analysis of the secondary end point in the
group with AF duration of 8 to 45 days. The Kaplan-Meier method
was used to summarize time to conversion, with the log-rank test
used to compare the distributions. The sample sizes were based on
assumed conversion rates of 25% and 50% for the placebo and active
groups, respectively, in the short-duration AF group and 5% and
30% in the long-duration AF group. Based on a 2-sided ␹2 test
(significance level, P⫽0.05), 240 patients in the short-duration AF
group and 120 patients in the long-duration AF group, each allocated
in a 2:1 ratio of vernakalant to placebo, provided ⬎90% power to
detect a 25% difference between treatments. Except for AF duration,
data are given as mean⫾SD.
The authors had full access to and take responsibility for the
integrity of the data. All authors have read and agree to the
manuscript as written.
Results
Patient Disposition
A total of 356 patients were randomized to either vernakalant
or placebo. Twenty patients did not receive study drug and
were withdrawn: 14 spontaneously converted to sinus
rhythm; 2 violated inclusion or exclusion criteria; 2 were
diagnosed with myocardial infarction; 1 could not obtain the
study drug; and 1 discontinued for an unspecified reason.
Thus, the efficacy and safety evaluable populations included
220 patients in the short-duration AF group and 116 patients
in the long-duration AF group (Figure 1).
Baseline Characteristics
There were no statistical differences in patient demographics
between the 2 treatment arms in the short-duration AF,
long-duration AF, or overall groups (Table 1). The median
AF duration at baseline in the placebo and vernakalant groups
was 28.4 and 28.2 hours, respectively, in the short-duration
AF group, and 465.2 and 613.0 hours, respectively, in the
long-duration group.
Efficacy End Points
In the primary efficacy analysis, 75 of the 145 vernakalant
patients (51.7%) in the short-duration AF (3 hours to 7 days)
group converted to sinus rhythm within 90 minutes compared
with 3 of the 75 placebo patients (4.0%; P⬍0.001; Figure 2).
Figure 3 shows the cumulative success of conversion relative
to time after the start of the infusion. Patients with AF lasting
3 to 48 hours given vernakalant demonstrated the highest
conversion rate (62.1% versus 4.9% with placebo; P⬍0.001;
Table 2). Of the 75 patients who demonstrated conversion, 57
(76.0%) did so with a single dose. The median time to
conversion to sinus rhythm for the 75 patients receiving
vernakalant who converted was 11 minutes. Only 1 of the 75
vernakalant-treated patients who converted to sinus rhythm
relapsed to AF at 24 hours.
Six of the 76 vernakalant patients (7.9%) in the longduration AF group had termination of AF (5 demonstrated
Roy et al
P<0.001
60
Vernakalant in Patients With Atrial Fibrillation
Placebo
Vernakalant
51.7
Table 2. Success Rates in Patients With AF Lasting 3 to 48
Hours and 3 to 7 Days
50
P<0.001
Percentage
40
1521
37.6
Conversion
to Sinus
Rhythm, n (%)
Difference
of Success
(95% CI), %
P
64 (62.1)
57.2 (46.4–68.0)
⬍0.001
23.8 (10.9–36.7)
0.048
AF lasting 3 to 48 h
30
Vernakalant (n⫽103)
Placebo (n⫽61)*
20
AF lasting 3 to 7 d
P=0.09
10
Vernakalant (n⫽42)
7.9
4.0
Placebo (n⫽16)*
2.6
0
0
(n=75)
(n=145)
Short-Duration
AF*
(n=40)
(n=76)
(n=115)
Long-Duration
AF†
Overall
Population†
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conversion to sinus rhythm, 1 had paced rhythm) compared
with 0 of the 40 placebo patients (P⫽0.09; Figure 2). In the
overall population, 83 of the 221 vernakalant patients
(37.6%) experienced termination of AF compared with 3 of
the 115 placebo patients (2.6%; P⬍0.001). An additional 2 of
4 vernakalant patients with pacemakers in the short-duration
AF group converted to a paced rhythm but were considered
treatment failures in the prespecified primary analysis of
conversion to sinus rhythm.
Nineteen vernakalant patients (8.6%) displayed atrial flutter in the first 90 minutes, 5 of whom subsequently converted
to sinus rhythm. Each of the 19 patients had AF confirmed at
baseline. None of these episodes of atrial flutter were associated with 1:1 atrioventricular conduction.
Safety Results
Deaths were assessed up to 30 days after study drug infusion.
Three patients died; all 3 had received vernakalant. None of
these deaths were considered to be related to study drug. A
Vernakalant
Placebo
0.5
Proportion of Patients
With Conversion to SR
10 (23.8)
0
*Two patients given placebo in the long-duration AF group were reassigned
after randomization for this nonprespecified analysis based on actual AF
duration.
(n=221)
Figure 2. Success rates in the short-duration, long-duration,
and overall AF populations. *Success rate defined as the percentage of patients who demonstrated conversion to sinus
rhythm within 90 minutes of the first infusion. †Success rate
defined as the percentage of patients who demonstrated termination of AF within 90 minutes of the first infusion.
0.6
3 (4.9)
0.4
0.3
P<.001 (Log-rank Test)
0.2
68-year-old woman received vernakalant and died 28 hours
later during a gastroscopy procedure; an autopsy revealed
rupture of a dissecting aneurysm of the ascending aorta. A
90-year-old woman died of pulmonary edema and congestive
heart failure 26 days after receiving vernakalant. A 67-yearold man with lung cancer died of pneumonia and respiratory
arrest 8 days after successful conversion with vernakalant.
Serious Adverse Events
In the overall study population, investigator-reported serious
adverse events were recorded from the time of study drug
infusion through the 30-day follow-up assessment. There
were 21 placebo patients (18.3%) and 29 vernakalant patients
(13.1%) with serious adverse events. Most events were of
cardiac origin, with the most common being recurrent AF
requiring hospitalization (placebo, 12.2%; vernakalant,
5.9%). Four serious adverse events occurring in 3 patients
were considered to be possibly or probably related to vernakalant. One patient developed hypotension 14 minutes after
receiving a partial second infusion (mean baseline blood
pressure, 120/81 mm Hg; lowest recorded blood pressure,
88/53 mm Hg), which responded to a saline intravenous bolus
infusion. A second patient had hypotension (mean baseline
blood pressure, 113/83 mm Hg; lowest recorded blood pressure, 82/68 mm Hg) after the first infusion, which responded
to a saline intravenous bolus infusion, and he did not receive
the second infusion; he underwent electrical cardioversion a
few hours later and then developed cardiogenic shock. He
was successfully treated and later diagnosed as having a
tachyarrhythmia-induced cardiomyopathy. The previously
mentioned 90-year-old woman had complete heart block after
electrical cardioversion, which was performed ⬇2.5 hours
after the second vernakalant infusion.
Ventricular Arrhythmia During the First 24 Hours
0.1
0.0
0
20
40
60
80
100
Time From First Infusion of Study Drug, min
Figure 3. Cumulative success rates (proportion) based on time
after the start of study drug infusion for the short-duration AF
primary efficacy set.
A full characterization of possible ventricular arrhythmia
events during the 24-hour period after the administration of
vernakalant included investigator-reported adverse events
(such as syncope), 12-lead ECGs, and Holter recordings. The
incidence of ventricular arrhythmia from all sources was
17.4% for placebo and 9.0% for vernakalant. Confirmed
nonsustained ventricular tachycardia was reported in 14.8%
of the placebo patients and 6.3% of the vernakalant patients.
1522
Circulation
March 25, 2008
There were no reports of sustained ventricular tachycardia
during this 24-hour interval.
Torsade de Pointes
There were no reports of torsade de pointes or ventricular
fibrillation during the first 24 hours after infusion. The
90-year-old woman referenced above experienced an episode
of torsade de pointes 32 hours after vernakalant administration. Another patient had 3 episodes of torsade de pointes, 2
of which occurred 16 days after treatment with vernakalant (2
days after cardiac surgery). The third episode occurred 17
days after treatment and resulted in cardiac arrest, for which
the patient received an internal defibrillator.
patients was 12 minutes for dysgeusia, 3 minutes for sneezing, 7 minutes for paresthesia, 12.5 minutes for nausea, and
15 minutes for hypotension.
A total of 5 patients, 4 vernakalant and 1 placebo, had
study drug discontinued because of adverse events. Adverse
events that led to study drug discontinuation in 3 of the 4
vernakalant patients were bradycardia (n⫽1), hypotension
(n⫽1), and prolonged uncorrected QT (⬎25%, as per protocol; n⫽1); 1 of the 4 patients discontinued as a result of
ventricular bigeminy and multiple other minor complaints.
The placebo patient discontinued study drug prematurely
because of prolonged QT.
Effects of Vernakalant on ECG
Other Adverse Events
Placebo
Vernakalant
Vernakalant—patients
with termination of AF
140
120
100
80
60
C
Baseline 5
10
15
20
25
30
Placebo
Vernakalant
550
500
450
400
Infusion 2
Infusion 1
40
ECG effects of vernakalant were compared with those of
placebo in patients who remained in AF. Except for a
transient 4.5-bpm increase at 10 minutes, the effect of
vernakalant on heart rate was unremarkable (Figure 4A).
Patients given vernakalant who demonstrated termination of
AF had higher mean heart rates at baseline (110⫾26 versus
91⫾22 bpm in those who remained in AF). There was a
correlation between AF duration and baseline heart rate (log
Mean (±SD) QT Bazett Correction, ms
Mean (±SD) Heart Rate, beats/min
A
Infusion 2
Infusion 1
35
40
45
50
Minutes
1.5
350
2
Baseline 5
10
15
20
Hours
140
Placebo
Vernakalant
120
100
80
D
Mean (±SD) QT Fridericia Correction, ms
B
10
15
20
25
30
40
45
Minutes
50
1.5
2
Hours
Time
40
45
50
1.5
2
Hours
Placebo
Vernakalant
500
450
400
Infusion 2
Infusion 1
35
35
550
350
Baseline 5
30
Time
Infusion 2
Infusion 1
60
25
Minutes
Time
Mean (±SD) QRS, ms
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The most common treatment-emergent adverse events reported during the first 24 hours in patients given vernakalant
were dysgeusia (29.9% vernakalant, 0.9% placebo), sneezing
(16.3% vernakalant, 0% placebo), paresthesia (10.9% vernakalant, 0% placebo), nausea (9.0% vernakalant, 0.9%
placebo), and hypotension (6.3% vernakalant, 3.5% placebo).
The median duration of related adverse events in vernakalant
Baseline 5
10
15
20
25
30
35
40
45
Minutes
50
1.5
2
Hours
Time
Figure 4. Change in heart rate, QRS, QTcB, and QTcF intervals over time for vernakalant-treated patients vs placebo-treated patients.
Data are shown for patients who remained in AF. Vernakalant-treated patients who demonstrated termination of AF (wide error bars)
are included in A.
Roy et al
Table 3. QT, QTcB, and QTcF at Baseline and at the End of
the First Infusion (Minute 10)
Time Point
Treatment Group
n
Mean
SD
P
Baseline
Placebo
107
359.7
45.62
0.72
Baseline
Vernakalant
212
361.5
38.91
Minute 10
Placebo
104
363.1
47.49
Minute 10
Vernakalant
203
386.0
38.33
Baseline
Placebo
107
451.4
33.27
Baseline
Vernakalant
212
449.3
31.31
Minute 10
Placebo
104
455.3
40.91
Minute 10
Vernakalant
203
473.8
39.92
Baseline
Placebo
107
417.3
29.74
Baseline
QT interval
⬍0.001
Vernakalant in Patients With Atrial Fibrillation
1523
(3.5%). Hypotensive episodes occurred within 15 minutes of
the end of either infusion of vernakalant, were transient, and
resolved without pharmacological intervention. Two previously described hypotensive events were reported as serious;
both cases responded to saline, and 1 led to discontinuation of
treatment.
Discussion
[AF duration], P⬍0.001) so that patients with shorter AF
durations had higher baseline heart rates. Vernakalant prolonged QRS intervals from 100.1⫾16.6 ms (mean⫾SD) at
baseline to a peak of 106.9⫾21.4 ms at the end of the first
infusion, whereas QRS intervals remained unchanged in
placebo patients (Figure 4B). Maximum mean increases in
QT, QTcB, and QTcF intervals in vernakalant patients who
remained in AF were observed near the end of each infusion
(Figure 4C and 4D).
Similar changes in QT, QTcB, and QTcF intervals were
observed in the overall population (converters to sinus
rhythm and those who remained in AF; Table 3). At the end
of the first infusion, 24% of all patients given vernakalant had
QTcB ⬎500 ms compared with 15% of all patients given
placebo. If patients with baseline QTcB ⬎500 ms are excluded, these percentages fall to 22% with vernakalant and
12% with placebo. For QTcF, 3% of all vernakalant patients
and 1% of all placebo patients had values ⬎500 ms at the end
of the first infusion, all of whom had baseline values ⬍500
ms. Within 90 minutes, the percentages of patients with
QTcB or QTcF ⬎500 ms in the 2 treatment groups were
essentially the same (QTcB, 11% vernakalant versus 14%
placebo; QTcF, 1% vernakalant versus 2% placebo at 90
minutes).
In patients given vernakalant who demonstrated conversion to sinus rhythm, QRS intervals increased from
95.1⫾11.9 ms at baseline to 99.1⫾12.3 ms at the end of the
first infusion, and QTcF intervals were 408.6⫾24.1 ms at
baseline compared with 422.4⫾22.1 ms after the first
infusion.
The identification of an intravenous antiarrhythmic drug that
can provide reliable, safe, and prompt pharmacological cardioversion is highly desirable. Vernakalant was effective in
converting AF to sinus rhythm. Vernakalant was especially
effective in treating short-duration AF. Fifty-two percent of
vernakalant patients in the short-duration AF group converted
to sinus rhythm compared with only 4% of placebo patients,
and patients with the shortest duration of AF demonstrated
the highest rate of conversion. The majority (76%) converted
after receiving only the first infusion. Additionally, conversion to sinus rhythm was rapid; the median time to conversion
was 11 minutes. These findings are consistent with results
from the phase 2 study, which provided the first clinical
evidence of effective intravenous cardioversion with vernakalant.10 Vernakalant was associated with a minimal risk of
early recurrence of AF.
Efficacy comparisons with other drugs used for acute
cardioversion of AF must be made with caution because the
drugs are used in different patient populations. The most
relevant comparison to vernakalant is ibutilide, a class III
agent and the only intravenous drug approved by the Food
and Drug Administration for the conversion of AF.5 Results
from 3 large, randomized, placebo-controlled ibutilide trials
indicate placebo-subtracted conversion rates of 28% to 31%
for AF.11–13 Studies comparing ibutilide with other agents
have reported AF conversion rates of 32% to 51%.14 –16 In this
study, vernakalant displayed an AF conversion rate that
exceeded that reported for ibutilide.
Other antiarrhythmic drugs are used for pharmacological
cardioversion of AF. Patterns of usage vary in different
countries.17–19 Amiodarone generally is considered of limited
value for the acute cardioversion of AF because prolonged
infusions generally are required for efficacy.17,18,20,21 Intravenous flecainide and propafenone reportedly successfully terminate recent-onset AF in ⬎50% to 60% of patients.22–28
These formulations are not available in North America,4,19
however, and they have significant proarrhythmic and negative inotropic potential.22,23,25,26 Procainamide is used despite
a risk-to-benefit profile that is inferior to ibutilide or flecainide.15,28 Studies of intravenous dofetilide have shown modest
results.29 –31 Tedisamil, an investigational class III drug,
successfully converted 57% of patients with recent-onset AF
to sinus rhythm in a preliminary trial; however, an increased
risk of proarrhythmia was seen.32
Hemodynamic Effects of Vernakalant
Safety Considerations of Vernakalant
There were no significant changes from baseline in mean
systolic or diastolic blood pressure in vernakalant patients
compared with those given placebo. In the 24 hours from the
start of drug infusion, hypotension was reported as an adverse
event in 14 vernakalant patients (6.3%) and 4 placebo patients
Vernakalant was well tolerated in most patients. A transient
alteration in taste, sneezing, paresthesia, and nausea were the
most common adverse reactions with vernakalant. Hypotension may occur; however, most episodes of hypotension in
this study were transient. The exception was the patient with
QTcB
0.59
⬍0.001
QTcF
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Vernakalant
212
416.8
24.84
Minute 10
Placebo
104
420.8
32.73
Minute 10
Vernakalant
203
441.5
29.61
0.86
⬍0.001
1524
Circulation
March 25, 2008
tachyarrhythmic cardiomyopathy previously described. Atrial
flutter may occur with vernakalant, and atrioventricular
nodal-blocking drugs for rate control may be needed.
Vernakalant-treated patients who remained in AF showed
statistically significant increases in QRS duration, QT, QTcB,
and QTcF. In those who remained in AF, vernakalant had
little effect on heart rate. Patients given vernakalant who were
successfully treated had a higher baseline heart rate, which
was likely related to a shorter duration of AF. Two patients
had torsade de pointes: 1 patient 32 hours after treatment with
vernakalant and the second patient 16 to 17 days after
treatment. These episodes were not considered to be due to
vernakalant because the half-life of vernakalant is 2 to 3
hours. There were 3 deaths during the study, none of which
were considered to be related to vernakalant because they
occurred 28 hours and 8 and 26 days after study drug
infusion.
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
Conclusion
Vernakalant demonstrated rapid conversion of short-duration
AF and was well tolerated.
Acknowledgments
We would like to thank the nurse coordinators at the participating
sites for their cooperation with this study and the scientific teams at
Astellas, including Therese Kitt and Bo Yan, and at Cardiome,
including Gregory Beatch, Garth Dickinson, Sheila Grant, and Brian
Mangal.
Sources of Funding
This study was sponsored by Astellas Pharma US, Deerfield, Ill, and
Cardiome Pharma Corp, Vancouver, Canada.
Disclosures
Dr Roy has received consultant fees from and is an advisory board
member for Cardiome Pharma Corp, Astellas Pharma US, Inc,
Sanofi-aventis, and CryoCath Technologies Inc. Dr Roy also held
stock in Cardiome Pharma Corp and is fully divested. Dr Pratt has
received consultant fees and honoraria from Astellas Pharma US, Inc
and Cardiome Pharma Corp. Dr Torp-Pedersen has received grant
support and honoraria from Astellas Pharma US, Inc and Cardiome
Pharma Corp. Dr Wyse has received consultant fees from Astellas
Pharma US, Inc, Boehringer Ingelheim, Cardiome Pharma Corp, CV
Therapeutics, Medtronic, Novartis, Sanofi-aventis, and Transoma
Medical; grant support from Astellas Pharma US, Inc, Cardiome
Pharma Corp, and Medtronic; and speaker’s fees from Astellas
Pharma US, Inc, Cardiome Pharma Corp, and Eisai Inc. Dr Stiell has
received research support from the Canadian Institutes of Health
Research and the National Institutes of Health. Dr Ip has received
grant support from Aryx Therapeutics, Astellas Pharma US, Inc,
Biotronik, Cardiome Pharma Corp, Guidant, Reliant Pharmaceuticals, Inc, SCTR/NIH, St Jude, and Vitatron. Dr Pritchett has received
consultant fees from Astellas Pharma US, Inc, Cardiome Pharma
Corp, NovaCardia Inc, Procter & Gamble, Reliant Pharmaceuticals,
Inc, Sanofi-aventis, and Solvay Pharma BV. Dr Camm has received
consultant fees, honoraria, and speaker’s fees from Astellas Pharma
US, Inc and Cardiome Pharma Corp. The remaining authors report
no conflicts.
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CLINICAL PERSPECTIVE
Pharmacological cardioversion often is used to restore sinus rhythm in patients with hemodynamically stable and
recent-onset atrial fibrillation. However, currently available antiarrhythmic agents have modest efficacy, and the risk of
proarrhythmia is of concern. Vernakalant is a new and relatively atrium-selective antiarrhythmic agent undergoing
investigation for the conversion of atrial fibrillation to sinus rhythm. The results of this placebo-controlled trial demonstrate
the efficacy of intravenous vernakalant in terminating recent-onset atrial fibrillation. Moreover, conversion was rapid and
not associated with ventricular proarrhythmia. The clinical implication is that intravenous vernakalant may represent a
valuable new antiarrhythmic drug for the acute conversion of atrial fibrillation to sinus rhythm, and it may be particularly
useful in patients with recent-onset atrial fibrillation in the emergency room setting.
Vernakalant Hydrochloride for Rapid Conversion of Atrial Fibrillation: A Phase 3,
Randomized, Placebo-Controlled Trial
Denis Roy, Craig M. Pratt, Christian Torp-Pedersen, D. George Wyse, Egon Toft, Steen
Juul-Moller, Tonny Nielsen, S. Lind Rasmussen, Ian G. Stiell, Benoit Coutu, John H. Ip,
Edward L.C. Pritchett and A. John Camm
for the Atrial Arrhythmia Conversion Trial Investigators
Downloaded from http://circ.ahajournals.org/ by guest on June 15, 2017
Circulation. 2008;117:1518-1525; originally published online March 10, 2008;
doi: 10.1161/CIRCULATIONAHA.107.723866
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2008 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/117/12/1518
Data Supplement (unedited) at:
http://circ.ahajournals.org/content/suppl/2009/02/27/CIRCULATIONAHA.107.723866.DC1
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CIRCULATIONAHA/2007/723866/R35
APPENDIX
Steering Committee—D. Roy (chair), C. Pratt (co-chair), S. Juul-Möller, E. Toft, C. TorpPedersen, D.G. Wyse; Data Safety Monitoring Board—A.J. Camm, D. DeMets, L. Kober,
J.Y. Le Heuzey, A. Waldo; Clinical Events Committee—K. Egstrup, L. Erhardt, M. Hamer,
E. Pritchett; Hospital name, City, Investigator—Centralsygehuset Esbjerg Varde,
Esbjerg, T. Neilsen – Hvidovre Hospital, Hvidovre, Rasmussen – H:S Bispebjerg Hospital,
København, Torp-Pedersen – Montreal Heart Institute, Montreal, Roy – Notre Dame
Hospital, Montreal, Coutu – Thoracic and Cardiovascular Institute, Lansing, Ip –
Akademiska Sjukhuset Uppsala, Uppsala, Blomstrom – Universityetssjukhuset Örebro,
Örebro, Englund – Libin Cardiovascular Institute of Alberta, Calgary, Wyse – Herlev
Amtssygehus, Herlev, Skagen – Centre Hospitalier Le Gardeur, Terrebonne, Costi –
Marshfield Clinic, Marshfield, Vidaillet – Hjørring-Brønderslev Sygehus, Hjørring, Petersen
– Gentofte Amtssygehus, Hellerup, Hassager – Ottawa Hospitals (Civic and General sites),
Ottawa, Stiell – CHUM-Hotel-Dieu de Montreal, Montreal, Phaneuf – Universitetssjukhuset
Mölndal/Sahlgrenska, Mölndal, Klintberg – Aalborg Sygehus Syd, Aalborg, Toft – Århus
Amtssygehus, Århus C, Frost – Roskilde Amts Sygehus, Køge, Klarlund –
Universitetssjukhuset MAS Malmö, Juul-Moller – Glostrup Amtssygehus, Glostrup,
Rokkedal – Heart Health Institute, Calgary, Ma – Danderyds sjukhus, Stockholm, Persson
– Holstebro Centralsygehus, Holstebro, Nyvad – Amager Hospital, København, H. Nielsen
– University of Alberta Hospital, Edmonton, Rowe – Hamilton Health Sciences, Hamilton,
Connolly – Regional Cardiology Associates, Sacramento, O’Neill – Centrallasarettet
Västerås, Västerås, Bandh – Fredericia Sygehus, Fredericia, Markenvard – Institute de
Cardiologie de Quebec, Ste Foy, O’Hara – Frederikssund Sygehus, Frederikssund, McNair
CIRCULATIONAHA/2007/723866/R36
– Sygehus Fyn Svendborg, Svendborg, Egstrup – Sunnybrook Health Sciences Centre,
Toronto, Lee – Horsens Sygehus, Horsens, Vigholt – Kolding Sygehus, Kolding, Asklund –
Hillerød Sygehus, Hillerød, Launbjerg – Helsingør Sygehus, Helsingør, Agner – Cardiac
Arrhythmia Trials, Victoria, Sterns – Central Florida Cardiology Group, Orlando, Pollak –
McGuire VA Medical Center, Richmond, Vijayraman – Cardiac Arrhythmia Service, Boston,
Singh