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Vernakalant for Conversion of Atrial Fibrillation: FDA Perspective Cardiovascular and Renal Drugs Advisory Committee Bel

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Vernakalant for Conversion of Atrial Fibrillation: FDA Perspective Cardiovascular and Renal Drugs Advisory Committee Beltsville, MD December 11, 2007. Ellis F. Unger, M.D. Deputy Director Division of Cardiovascular and Renal Products Center for Drug Evaluation and Research

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Vernakalant for Conversion of Atrial Fibrillation:FDA PerspectiveCardiovascular and Renal Drugs Advisory CommitteeBeltsville, MDDecember 11, 2007

Ellis F. Unger, M.D.

Deputy Director

Division of Cardiovascular and Renal Products

Center for Drug Evaluation and Research

U.S. Food and Drug Administration

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Vernakalant for AF:

Points for Discussion

Determination of benefit – spontaneous conversion from AF to sinus rhythm

Limitations of data

Special risks

apparent effect size of treatments for af effect of time prior to initiating other treatments

Drug

P=?

P=<0.05

No treatment

Apparent Effect Size of Treatments for AF: Effect of Time Prior to Initiating Other Treatments

slide4

Generalizability of the Data: Patient Population in ACT III

Congestive heart failure (CHF):

NYHA Functional Class I 5.3%

NYHA Functional Class II 8.3%

NYHA Functional Class III 1.1%

NYHA Functional Class ?? 2.3%

Any CHF 17% (n=23)

slide5

Generalizability of the Data: Subject Population in ACT I and ACT III

Race:

Caucasian 97.7%

African Ancestry 0.8%

Other 1.5%

probability of converting vs duration of atrial fibrillation act i

21%

16%

Probability of Converting vs. Duration of

Atrial Fibrillation (ACT I)

63

40

13

7

10

8

4

N’s

AF Duration (days)

probability of converting sponsor s logistic regression model with actual data act i
Probability of Converting – Sponsor’s Logistic Regression Model with Actual Data (ACT I)

21%

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? Need for Additional Study of Vernakalant in Patients with CHF

Cardiovascular depression in animals at supratherapeutic doses

Hypotension in some patients, ? mechanism

hemodynamic effect

negative inotropism?

direct myocardial depression?

vernakalant and monitoring for qt prolongation how long is long enough

1 hour after 1 dose; 90 minutes after 2?

  • Until QT is normal?
  • Until peak period of QT prolongation has passed?
  • A hybrid approach (consider time and QT interval)?

Vernakalant and Monitoring for QT Prolongation: How Long is Long Enough?

lack of effect of vernakalant on atrial defibrillation threshold

before 4 hours

after 4 hours

Lack of Effect of Vernakalant on

Atrial Defibrillation Threshold

<100 100-199 200-299 300-360

<100 100-199 200-299 300-360

energy (j)

energy (j)

effect of vernakalant on ventricular defibrillation threshold

Need for post-marketing assessment?

Effect of Vernakalant on

Ventricular Defibrillation Threshold

vernakalant for conversion of atrial fibrillation fda perspective summary

Vernakalant for Conversion of Atrial Fibrillation:FDA Perspective: Summary

Evidence of Efficacy:

Substantiated in two independent RCTs; results robust to exploration

Apparent effect size is largely a function of study design

Safety Concerns:

Torsades de pointes

Hypotension

Bradycardia

QT prolongation

More Data Would be Helpful:

More advanced heart disease; non-whites

Ventricular defibrillation threshold (pre-clinical)