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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

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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

presenter disclosure information
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.

Presenter Disclosure Information

The following relationships exist related to this presentation:

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

Vernakalant hydrochloride injection (RSD1235) is under investigation for the treatment of atrial fibrillation.

background
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 a trial arrhythmia c onversion t rial ii study objectives
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 studyACT IIStudy Design

Randomization

(2:1)

TelephoneFollow-up

In-Hospital Observation

Pre- and Post-

Surgery

Screening

Follow-upVisit

Efficacy Period

Hour 24 Visit

Discharge(up to 14 d)

Time

0

10

35

90 min

2 h

24 h

30 d

25

1st Infusion:

vernakalant (3 mg/kg)

or placebo

2nd Infusion (if in AF/AFL):

vernakalant (2 mg/kg) or placebo

Electrical cardioversion and other drugs permitted

Continuous Holter Monitoring

act ii key 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

ACT IIKey Inclusion and Exclusion Criteria

*Unless controlled by pacemaker.

act ii concomitant therapy
ACT 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 ii endpoints
ACT 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 ii patient disposition
ACT IIPatient 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 concomitantmedication (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
ACT IIDemographics and Baseline Characteristics

*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
ACT IIPercentage Demonstrating Conversion of AF/AFL to SR Within 90 Min

P=.0002

50

45%

40

30

AF/AFL Responders, %

20

15%

10

8/54

48/107

0

Placebo

Vernakalant

(n=54)

(n=107)

act ii median time to conversion of af afl to sr
ACT IIMedian Time to Conversion of AF/AFL to SR

60

45%responders

50

Vernakalant

40

P=.0002

Percentage

30

Median time to conversion among responders=12 min

20

Placebo

10

0

0

10

20

30

40

50

60

70

80

90

100

Time to Conversion, min

act ii percentage demonstrating conversion of af to sr within 90 min
ACT IIPercentage Demonstrating Conversion of AF to SR Within 90 Min

P=.0001

47%

50

40

30

AF Responders, %

20

14%

10

7/50

47/100

0

Placebo

Vernakalant

(n=50)

(n=100)

act ii median time to conversion of af to sr
ACT IIMedian Time to Conversion of AF to SR

60

47%

responders

50

Vernakalant

40

P=.0001

Percentage

30

Median time to conversion among responders=12 min

20

Placebo

10

0

0

20

40

60

80

100

10

30

50

70

90

Time to Conversion, min

act ii conversion to sr after 1 dose of vernakalant
ACT IIConversion to SR After 1 Dose of Vernakalant

80

75%

74%

60

Responders Demonstrating Conversion to SR After 1 Dose, %

40

20

36/48

35/47

0

AF/AFL

AF

(n=48)

(n=47)

  • 75% of responders given vernakalant demonstrated conversion after the first dose
act ii maintenance of sr among responders
ACT IIMaintenance of SR Among Responders*

80

60%

57%

60

Patients in SR, %

40

20

0

24 Hours

7 Days

AF/AFL

(n=48)

*Based on life table estimates.

act ii most common aes
ACT IIMost Common 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
ACT IISummary of Key Safety Events

*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
ACT 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
act ii percentage of responders by surgery type
ACT IIPercentage of Responders by Surgery Type

P=.562

P=.002

60

60

48%

50

50

40

40

36%

AF/AFL Responders, %

AF/AFL Responders, %

30

30

20%

20

20

14%

10

10

5/37

34/71

2/10

10/28

0

0

Placebo

Vernakalant

Placebo

Vernakalant

(n=37)

(n=71)

(n=10)

(n=28)

CABG Surgery

Valvular Surgery

act ii maintenance of sr among responders1
ACT IIMaintenance of SR Among Responders*

80

71%

71%

70

60

50

Patients, %

40

30

20

10

34/48

34/48

0

24 Hours

7 Days

AF/AFL

(n=48)

*Based on a review of 12-lead ECG data by the CEC.

act ii qrs duration over time all patients excluding those with pacemakers
ACT IIQRS Duration Over Time(all patients, excluding those with pacemakers)

130

120

110

100

90

80

70

Placebo

Vernakalant

*

*

*

*

*

*

*

*

QRS Duration, ms

Infusion #1

Infusion #2

Baseline

10

25

35

50

1.5

2

4

6

24

Follow-up

Minutes

Hours

Time

*P<.05 vs placebo.

act ii qtcf interval over time all patients excluding those with pacemakers
ACT IIQTcF Interval Over Time (all patients, excluding those with pacemakers)

500

450

400

350

300

Placebo

Vernakalant

*

*

*

*

*

*

*

*

QT Fridericia Correction, ms

Infusion #1

Infusion #2

Baseline

10

25

35

50

1.5

2

4

6

24

Follow-up

Minutes

Hours

Time

*P<.05 vs placebo.

act ii qtcb interval over time all patients excluding those with pacemakers
ACT IIQTcB Interval Over Time (all patients, excluding those with pacemakers)

550

500

450

400

350

300

Placebo

Vernakalant

*

*

QT Bazett Correction, ms

Infusion #1

Infusion #2

Baseline

10

25

35

50

1.5

2

4

6

24

Follow-up

Minutes

Hours

Time

*P<.05 vs placebo.

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