Peter Kowey, MD Lankenau Hospital, Wynnewood, Pennsylvania

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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

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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 - PowerPoint PPT Presentation

Transcript of Peter Kowey, MD Lankenau Hospital, Wynnewood, Pennsylvania

Page 1: Peter Kowey, MD  Lankenau Hospital, Wynnewood, Pennsylvania

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

Page 2: Peter Kowey, MD  Lankenau Hospital, Wynnewood, Pennsylvania

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

Page 3: Peter Kowey, MD  Lankenau Hospital, Wynnewood, Pennsylvania

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.

Page 4: Peter Kowey, MD  Lankenau Hospital, Wynnewood, Pennsylvania

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

Page 5: Peter Kowey, MD  Lankenau Hospital, Wynnewood, Pennsylvania

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

Page 6: Peter Kowey, MD  Lankenau Hospital, Wynnewood, Pennsylvania

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.

Page 7: Peter Kowey, MD  Lankenau Hospital, Wynnewood, Pennsylvania

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

Page 8: Peter Kowey, MD  Lankenau Hospital, Wynnewood, Pennsylvania

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

Page 9: Peter Kowey, MD  Lankenau Hospital, Wynnewood, Pennsylvania

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)

Page 10: Peter Kowey, MD  Lankenau Hospital, Wynnewood, Pennsylvania

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.

Page 11: Peter Kowey, MD  Lankenau Hospital, Wynnewood, Pennsylvania

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

Page 12: Peter Kowey, MD  Lankenau Hospital, Wynnewood, Pennsylvania

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

Page 13: Peter Kowey, MD  Lankenau Hospital, Wynnewood, Pennsylvania

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

Page 14: Peter Kowey, MD  Lankenau Hospital, Wynnewood, Pennsylvania

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

Page 15: Peter Kowey, MD  Lankenau Hospital, Wynnewood, Pennsylvania

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

Page 16: Peter Kowey, MD  Lankenau Hospital, Wynnewood, Pennsylvania

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

Page 17: Peter Kowey, MD  Lankenau Hospital, Wynnewood, Pennsylvania

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.

Page 18: Peter Kowey, MD  Lankenau Hospital, Wynnewood, Pennsylvania

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.

Page 19: Peter Kowey, MD  Lankenau Hospital, Wynnewood, Pennsylvania

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).

Page 20: Peter Kowey, MD  Lankenau Hospital, Wynnewood, Pennsylvania

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

Page 21: Peter Kowey, MD  Lankenau Hospital, Wynnewood, Pennsylvania

Backup SlidesBackup Slides

Page 22: Peter Kowey, MD  Lankenau Hospital, Wynnewood, Pennsylvania

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

Page 23: Peter Kowey, MD  Lankenau Hospital, Wynnewood, Pennsylvania

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

Page 24: Peter Kowey, MD  Lankenau Hospital, Wynnewood, Pennsylvania

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.

*

*

*

**

* * *

Page 25: Peter Kowey, MD  Lankenau Hospital, Wynnewood, Pennsylvania

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

**

**

* * * *

Page 26: Peter Kowey, MD  Lankenau Hospital, Wynnewood, Pennsylvania

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

**