Efficacy and Safety of Vernakalant Hydrochloride Injection for the Treatment of Atrial Fibrillation After
Valvular or Coronary Artery Bypass Surgery
Efficacy and Safety of Vernakalant Hydrochloride Injection for the Treatment of Atrial Fibrillation After
Valvular or Coronary Artery Bypass Surgery
Peter Kowey, MD Lankenau Hospital, Wynnewood, PennsylvaniaDenis Roy, MD University of Montréal, Montréal, Canada
Craig Pratt, MD The Methodist DeBakey Heart Center, Houston, TexasPeter J. Schwartz, MD University of Pavia, Pavia, ItalyPaul Dorian, MD University of Toronto, Toronto, Canada
L. Brent Mitchell, MD University of Calgary, Calgary, CanadaEgon Toft, MD Aalborg University, Aalborg, Denmark
Presenter Disclosure InformationPresenter Disclosure Information
The following relationships exist related to this presentation:
Vernakalant hydrochloride injection (RSD1235) is under investigation for the treatment of atrial fibrillation.
Peter Kowey, MD
Honoraria from and consultant, advisory board member, and speaker’s bureau member for Cardiome Pharma Corp. and Astellas Pharma US, Inc.
Denis Roy, MD
Honoraria from and consultant for Astellas Pharma US, Inc. Consultant and advisory board member for and ownership interest in Cardiome Pharma Corp.
Craig Pratt, MD
Consultant and advisory board member for Cardiome Pharma Corp. and Astellas Pharma US, Inc. Speaker’s bureau member for Cardiome Pharma Corp.
Peter J. Schwartz, MD
None
Paul Dorian, MD
Honoraria from Cardiome Pharma Corp. and Astellas Pharma US, Inc. Research grant received from and consultant and advisory board member for Cardiome Pharma Corp.
L. Brent Mitchell, MD
Honoraria and research grant received from, ownership interest in, and consultant, advisory board member, and speaker’s bureau member for Cardiome Pharma Corp.
Egon Toft, MD
None
BackgroundBackground
• Atrial fibrillation (AF) is the most common clinically significant arrhythmia, affecting an estimated 2.3 million US adults
• AF develops after cardiothoracic surgery in up to 40% of patients
• Antiarrhythmic drugs are used often in patients with recent-onset AF to restore sinus rhythm (SR)
– Available agents are suboptimal due to effects on ventricular tissue; they prolong ventricular refractoriness or slow conduction velocity in ventricle
• Vernakalant (RSD1235) is a novel antiarrhythmic that blocks multiple ion channels, which preferentially prolongs atrial refractoriness and rapidly converts AF to SR
– Blocks early-activating K+ channels and frequency-dependent Na+ channels
Go AS, et al. JAMA. 2001;285:2370-2375; Allessie MA, et al. Circulation. 2001;103:769-777; Dorian P, et al. J Cardiovasc Pharmacol. 2007;50:35-40; Fedida D, et al. J Cardiovasc Eletrophysiol. 2005;16:1227-1238.
ACT II (Atrial arrhythmia Conversion Trial II) Study ObjectivesACT II (Atrial arrhythmia Conversion Trial II) Study Objectives
Primary objective:
• To evaluate the efficacy of vernakalant, compared with placebo, in converting AF or atrial flutter (AFL) to SR after recent coronary artery bypass graft (CABG) or valvular surgery
Secondary objective:
• To evaluate the safety of vernakalant in this patient population
ACT IIStudy DesignACT IIStudy Design
Randomized, double-blind, placebo-controlled, parallel-group, multinational, multicenter study
In-Hospital Observation
0 24 h10 25 90 min
1st Infusion: vernakalant (3 mg/kg)
or placebo
2nd Infusion (if in AF/AFL):
vernakalant (2 mg/kg) or placebo
35
Hour 24 VisitEfficacy Period
Discharge(up to 14 d)
Follow-upVisit
Time 2 h
Continuous Holter Monitoring
Randomization (2:1)
Electrical cardioversion and other drugs permitted
Pre- and Post-Surgery
Screening
TelephoneFollow-up
30 d
ACT IIKey Inclusion and Exclusion CriteriaACT IIKey Inclusion and Exclusion Criteria
Inclusion criteria:
• Age 18 y
• CABG or valvular surgery within 7 days
• ECG showing normal SR prior to surgery
• ECG showing AF or AFL (3–72 h duration) with onset occurring within 24 hours to 7 days after surgery
Exclusion criteria:
• Prolonged QT interval, long QT syndrome, previous torsade de pointes, Brugada syndrome
• Unstable New York Heart Association (NYHA) class IV heart failure
• Bradycardia or sick-sinus syndrome*
• ECG evidence of 2/3 AV block*
• Intravenous class I or III antiarrhythmic drug given postsurgery
• Hemodynamically unstable
*Unless controlled by pacemaker.
ACT IIConcomitant TherapyACT IIConcomitant Therapy
• Rate-control drugs, including -blockers, calcium channel antagonists, or digoxin were allowed, providing
– Heart rate >50 bpm
– Loading dose or bolus of these drugs was given at least 2 hours before study treatment
• Electrical cardioversion or additional antiarrhythmic medication was withheld until ≥2 hours after study drug administration, unless deemed medically necessary
• Alcohol, caffeine, smoking, and over-the-counter medications not allowed from postsurgery screening until 24 hours after dosing
ACT IIEndpointsACT IIEndpoints
Primary efficacy endpoint:
• Percentage of patients with treatment-induced conversion of AF/AFL to SR occurring within 90 min of first exposure to study medication and lasting for a minimum duration of 1 min
– “Responders”
Secondary endpoints:
• Time to conversion of all responders
• Percentage of treatment-induced conversion of AF to SR within 90 min for 1 min
• Time to conversion of AF to SR
ACT IIPatient DispositionACT IIPatient Disposition
Randomized(N=190)
Placebo(n=63)
Vernakalant(n=127)
Treated(n=54; 86%)
Vernakalant(n=107; 84%)
Completed Study (n=54)
Completed Study(n=106)
Not Treated (n=9)• Spontaneous conversion
to SR (n=7)• Investigator decision
(n=1)• Erroneously entered (n=1)
Not Treated (n=20)• Spontaneous conversion
to SR (n=17)• Withdrew consent (n=2)• Prohibited concomitant
medication (n=1)
Discontinued (n=1)• Withdrew consent (n=1)
ACT IIDemographics and Baseline CharacteristicsACT IIDemographics and Baseline Characteristics
Placebo(n=54)
Vernakalant(n=107)
Male 40 (74%) 81 (76%)
Caucasian 50 (93%) 101 (94%)
Age, y: mean (SD)
≥65 y
≥75 y
68 (6.4)
40 (74%)
7 (13%)
68 (7.7)
79 (74%)
25 (23%)
CABG
Valvular surgery
Both
37 (69%)
10 (18%)
7 (13%)
71 (66%)
28 (26%)
8 (8%)
AF
AFL
50 (93%)
4 (7%)
100 (93%)*
6 (6%)*
*One patient in the vernakalant group was judged by the Clinical Events Committee (CEC) to be in SR on all baseline and postbaseline ECGs.
ACT IIPercentage Demonstrating Conversion of AF/AFL to SR Within 90 Min
ACT IIPercentage Demonstrating Conversion of AF/AFL to SR Within 90 Min
AF
/AF
L R
esp
on
der
s, %
P=.0002
(n=107)
45%
0
10
20
30
40
50
Vernakalant
48/107
15%
(n=54)Placebo
8/54
ACT IIMedian Time to Conversion of AF/AFL to SRACT IIMedian Time to Conversion of AF/AFL to SR
Time to Conversion, min
Per
cen
tag
e
0 20 40 60 80 100 0
20
40
60
Placebo
45%responders
P=.0002
Median time to conversion among responders=12 min
Vernakalant
10 30 50 70 90
50
30
10
ACT IIPercentage Demonstrating Conversion of AF to SR Within 90 Min
ACT IIPercentage Demonstrating Conversion of AF to SR Within 90 Min
AF
Res
po
nd
ers,
%
P=.0001
47%
14%
0
10
20
30
40
50
(n=50) (n=100)
7/50 47/100
Placebo Vernakalant
ACT IIMedian Time to Conversion of AF to SRACT IIMedian Time to Conversion of AF to SR
Time to Conversion, min
Per
cen
tag
e
0 20 40 60 80 100 0
20
40
60
P=.0001
Placebo
47%responders
Vernakalant
Median time to conversion among responders=12 min
10 30 50 70 90
50
30
10
ACT IIConversion to SR After 1 Dose of VernakalantACT IIConversion to SR After 1 Dose of Vernakalant
• 75% of responders given vernakalant demonstrated conversion after the first dose
Res
po
nd
ers
Dem
on
stra
tin
g
Co
nve
rsio
n t
o S
R A
fter
1 D
ose
, %
(n=48) (n=47)
75% 74%
0
20
40
60
80
36/48 35/47
AF/AFL AF
ACT IIMaintenance of SR Among Responders*ACT IIMaintenance of SR Among Responders*
Pat
ien
ts i
n S
R,
%
AF/AFL(n=48)
*Based on life table estimates.
60% 57%
0
20
40
60
80
24 Hours 7 Days
ACT IISummary of Deaths, Discontinuations, and AEsACT IISummary of Deaths, Discontinuations, and AEs
Entire Study First 24 Hours
Event, no. (%)Placebo(n=54)
Vernakalant(n=107)
Placebo(n=54)
Vernakalant(n=107)
Death 0 0 0 0
Discontinuation due to AEs
0 3 (3) 0 3 (3)
Serious AEs 6 (11) 10 (9) 0 2 (2)
Any AEs 24 (44) 61 (57) 17 (32) 41 (38)
AE=adverse event.
ACT IIMost Common AEsACT IIMost Common AEs
Entire Study First 24 Hours
Event, no. (%)Placebo(n=54)
Vernakalant(n=107)
Placebo(n=54)
Vernakalant(n=107)
Most common AEs*
Atrial fibrillation
Nausea
Constipation
Weight increase
Dyspnea
8 (15)
3 (6)
1 (2)
2 (4)
0
22 (20)
6 (6)
5 (5)
5 (5)
5 (5)
5 (9)
2 (4)
1 (2)
2 (4)
0
9 (8)
6 (6)
0
0
2 (2)
Most common drug-related AEs†
Atrial fibrillation
1st-degree atrioventricular block
Nausea
0
0
0
3 (3)
3 (3)
3 (3)
0
0
0
1 (1)
3 (3)
3 (3)
*Occurring in 5% of patients given vernakalant and at a higher rate than with placebo.†Occurring in 3% of patients given vernakalant and at a higher rate than with placebo.
ACT IISummary of Key Safety EventsACT IISummary of Key Safety Events
Entire Study First 24 Hours
Event, no. (%)Placebo(n=54)
Vernakalant(n=107)
Placebo(n=54)
Vernakalant(n=107)
Any ventricular arrhythmia event*
Ventricular tachycardia
Ventricular fibrillation
Torsade de pointes
9 (17%)
7 (13%)
0
0
19 (18%)
18 (17%)
0
0
9 (17%)
7 (13%)
0
0
19 (18%)
18 (17%)
0
0
Any bradycardia event† 8 (15%) 20 (19%) 2 (4%) 15 (14%)
Any hypotension event‡ 15 (28%) 27 (25%)13 (24%)
23 (22%)
*Derived from AE reports, 12-lead-ECG, and Holter monitoring (ventricular tachycardia defined as wide complex events 3 beats with heart rate 100 bpm).
†Derived from AE reports, 12-lead-ECG, and Holter monitoring (bradycardia defined as heart rate <40 bpm [<60 bpm for sinus bradycardia]).
‡Derived from AE reports and vital signs (hypotension defined as a decrease from baseline in systolic pressure 30 mm Hg, decrease in diastolic pressure 15 mm Hg, or systolic pressure <90 mm Hg).
ACT IIConclusionsACT IIConclusions
• Vernakalant was significantly more effective than placebo in converting AF to SR after CABG, valvular surgery, or both– Conversion rate: 47% vs 14%, P=.0001
• Seventy-five percent of patients who responded did so after the first vernakalant infusion– Median time to conversion: 12 min
• Vernakalant was well tolerated in this patient population– 2 serious AEs in 1st 24 hours– 3% discontinued treatment due to AEs– No deaths or cases of torsade de pointes– Overall incidences of ventricular arrhythmia, bradycardia,
and hypotension events similar to those with placebo
• Vernakalant is a new option for converting AF/AFL to SR after CABG or valvular surgery
Backup SlidesBackup Slides
ACT IIPercentage of Responders by Surgery TypeACT IIPercentage of Responders by Surgery Type
AF
/AF
L R
esp
on
der
s, %
AF
/AF
L R
esp
on
der
s, %
(n=10)(n=71)(n=37)
P=.002 P=.562
CABG Surgery Valvular Surgery
20%
36%
0
10
20
30
40
50
60
Placebo Vernakalant(n=28)
10/282/1034/715/37
14%
48%
0
10
20
30
40
50
60
Placebo Vernakalant
ACT IIMaintenance of SR Among Responders*ACT IIMaintenance of SR Among Responders*
Pat
ien
ts,
%
AF/AFL(n=48)
*Based on a review of 12-lead ECG data by the CEC.
34/4834/48
71% 71%
0
10
20
30
40
50
60
70
80
24 Hours 7 Days
ACT IIQRS Duration Over Time (all patients, excluding those with pacemakers)
ACT IIQRS Duration Over Time (all patients, excluding those with pacemakers)
Minutes Hours
Time
QR
S D
ura
tio
n,
ms
Infusion #1 Infusion #2
130
120
110
100
90
80
70Baseline 10 25 35 50 1.5 2 4 6 24 Follow-up
PlaceboVernakalant
*P<.05 vs placebo.
*
*
*
**
* * *
ACT IIQTcF Interval Over Time (all patients, excluding those with pacemakers)
ACT IIQTcF Interval Over Time (all patients, excluding those with pacemakers)
Minutes Hours
Time
QT
Fri
der
icia
Co
rrec
tio
n,
ms
Infusion #1 Infusion #2
Baseline 10 25 35 50 1.5 2 4 6 24 Follow-up
*P<.05 vs placebo.
500
450
400
350
300
PlaceboVernakalant
**
**
* * * *
ACT IIQTcB Interval Over Time (all patients, excluding those with pacemakers)
ACT IIQTcB Interval Over Time (all patients, excluding those with pacemakers)
Minutes Hours
Time
QT
Baz
ett
Co
rrec
tio
n,
ms
Infusion #1 Infusion #2
Baseline 10 25 35 50 1.5 2 4 6 24 Follow-up
*P<.05 vs placebo.
550
500
450
400
350
300
PlaceboVernakalant
**
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