Transcript 6577 Vernakalant 2007 AHA ACT II Slide

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, Pennsylvania
Denis Roy, MD University of Montréal, Montréal, Canada
Craig Pratt, MD The Methodist DeBakey Heart Center, Houston, Texas
Peter J. Schwartz, MD University of Pavia, Pavia, Italy
Paul Dorian, MD University of Toronto, Toronto, Canada
L. Brent Mitchell, MD University of Calgary, Calgary, Canada
Egon Toft, MD Aalborg University, Aalborg, Denmark
Presenter Disclosure Information
The following relationships exist related to this presentation:
Peter Kowey, MD
Peter J. Schwartz, MD
Honoraria from and consultant, advisory
board member, and speaker’s bureau
member for Cardiome Pharma Corp.
and Astellas Pharma US, Inc.
None
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.
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
Vernakalant hydrochloride injection (RSD1235) is under investigation for the treatment of atrial fibrillation.
Background
• 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
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 II
Study Design
Randomized, double-blind, placebo-controlled,
parallel-group, multinational, multicenter study
Randomization
(2:1)
In-Hospital Observation
Pre- and PostSurgery
Screening
Time
Telephone
Follow-up
Efficacy Period
0
10
25
1st Infusion:
vernakalant (3 mg/kg)
or placebo
35
Hour 24 Visit
90 min 2 h
2nd Infusion (if in AF/AFL):
vernakalant (2 mg/kg)
or placebo
Continuous Holter Monitoring
24 h
Follow-up
Visit
Discharge 30 d
(up to 14 d)
Electrical cardioversion
and other drugs permitted
ACT II
Key Inclusion and Exclusion Criteria
Inclusion criteria:
Exclusion criteria:
• Age 18 y
• Prolonged QT interval, long QT
syndrome, previous torsade de
pointes, Brugada syndrome
• 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
• 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 II
Concomitant 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 II
Endpoints
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 II
Patient Disposition
Randomized
(N=190)
Placebo
(n=63)
Vernakalant
(n=127)
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)
Treated
(n=54; 86%)
Vernakalant
(n=107; 84%)
Discontinued (n=1)
• Withdrew consent (n=1)
Completed Study
(n=54)
Completed Study
(n=106)
ACT II
Demographics and Baseline Characteristics
Placebo
(n=54)
Vernakalant
(n=107)
Male
40 (74%)
81 (76%)
Caucasian
50 (93%)
101 (94%)
Age, y: mean (SD)
68 (6.4)
68 (7.7)
≥65 y
40 (74%)
79 (74%)
≥75 y
7 (13%)
25 (23%)
CABG
37 (69%)
71 (66%)
Valvular surgery
10 (18%)
28 (26%)
7 (13%)
8 (8%)
AF
50 (93%)
100 (93%)*
AFL
4 (7%)
6 (6%)*
Both
*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 II
Percentage Demonstrating Conversion of AF/AFL to SR
Within 90 Min
P=.0002
AF/AFL Responders, %
50
45%
40
30
20
15%
10
8/54
48/107
Placebo
Vernakalant
(n=54)
(n=107)
0
ACT II
Median Time to Conversion of AF/AFL to SR
60
45%
responders
50
Percentage
Vernakalant
40
P=.0002
30
Median time to conversion
among responders=12 min
20
Placebo
10
0
0
10
20
30
40
50
60
70
Time to Conversion, min
80
90
100
ACT II
Percentage Demonstrating Conversion of AF to SR Within
90 Min
P=.0001
47%
AF Responders, %
50
40
30
20
14%
10
0
7/50
47/100
Placebo
Vernakalant
(n=50)
(n=100)
ACT II
Median Time to Conversion of AF to SR
60
47%
responders
50
Percentage
Vernakalant
40
P=.0001
30
Median time to conversion
among responders=12 min
20
Placebo
10
0
0
10
20
30
40
50
60
70
Time to Conversion, min
80
90
100
ACT II
Responders Demonstrating
Conversion to SR After 1 Dose, %
Conversion to SR After 1 Dose of Vernakalant
80
75%
74%
36/48
35/47
AF/AFL
AF
60
40
20
0
(n=48)
(n=47)
• 75% of responders given vernakalant demonstrated
conversion after the first dose
ACT II
Maintenance of SR Among Responders*
Patients in SR, %
80
60%
57%
24 Hours
7 Days
60
40
20
0
AF/AFL
(n=48)
*Based on life table estimates.
ACT II
Summary of Deaths, Discontinuations, and AEs
Entire Study
Event, no. (%)
Placebo
(n=54)
Vernakalant
(n=107)
First 24 Hours
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)
24 (44)
61 (57)
Any AEs
AE=adverse event.
17 (32)
41 (38)
ACT II
Most Common AEs
Entire Study
First 24 Hours
Placebo
(n=54)
Vernakalant
(n=107)
Placebo
(n=54)
Vernakalant
(n=107)
Atrial fibrillation
8 (15)
22 (20)
5 (9)
9 (8)
Nausea
3 (6)
6 (6)
2 (4)
6 (6)
Constipation
1 (2)
5 (5)
1 (2)
0
Weight increase
2 (4)
5 (5)
2 (4)
0
Dyspnea
0
5 (5)
0
2 (2)
Atrial fibrillation
0
3 (3)
0
1 (1)
1st-degree atrioventricular block
0
3 (3)
0
3 (3)
Nausea
0
3 (3)
0
3 (3)
Event, no. (%)
Most common AEs*
Most common drug-related AEs†
*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 II
Summary of Key Safety Events
Entire Study
Event, no. (%)
Any ventricular arrhythmia
event*
Ventricular tachycardia
Ventricular fibrillation
Torsade de pointes
First 24 Hours
Placebo
(n=54)
Vernakalant
(n=107)
Placebo
(n=54)
Vernakalant
(n=107)
9 (17%)
19 (18%)
9 (17%)
19 (18%)
7 (13%)
18 (17%)
7 (13%)
18 (17%)
0
0
0
0
0
0
0
0
Any bradycardia event†
8 (15%)
20 (19%)
Any hypotension event‡
15 (28%)
27 (25%)
2 (4%)
13
(24%)
15 (14%)
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 II
Conclusions
• 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 Slides
ACT II
Percentage of Responders by Surgery Type
P=.002
48%
50
40
30
20
14%
10
5/37
P=.562
60
34/71
0
AF/AFL Responders, %
AF/AFL Responders, %
60
50
40
36%
30
20%
20
10
2/10
10/28
0
Placebo
Vernakalant
Placebo
Vernakalant
(n=37)
(n=71)
(n=10)
(n=28)
CABG Surgery
Valvular Surgery
ACT II
Maintenance of SR Among Responders*
80
71%
71%
70
Patients, %
60
50
40
30
20
10
0
34/48
34/48
24 Hours
*Based on a review of 12-lead ECG data by the CEC.
7 Days
AF/AFL
(n=48)
ACT II
QRS Duration Over Time (all patients, excluding those with pacemakers)
130
*
QRS Duration, ms
120
Placebo
Vernakalant
*
*
*
*
*
*
*
2
4
6
110
100
90
80
Infusion #1
Infusion #2
70
Baseline
10
25
35
50
1.5
Minutes
*P<.05 vs placebo.
Hours
Time
24 Follow-up
ACT II
QTcF Interval Over Time (all patients, excluding those with pacemakers)
QT Fridericia Correction, ms
500
Placebo
Vernakalant
*
*
450
*
*
*
*
*
*
1.5
2
4
6
400
350
Infusion #1
Infusion #2
300
Baseline
10
25
35
50
Minutes
*P<.05 vs placebo.
Hours
Time
24 Follow-up
ACT II
QTcB Interval Over Time (all patients, excluding those with pacemakers)
QT Bazett Correction, ms
550
Placebo
Vernakalant
*
500
*
450
400
350
Infusion #1
Infusion #2
300
Baseline
10
25
35
50
1.5
Minutes
*P<.05 vs placebo.
2
4
Hours
Time
6
24 Follow-up