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

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 Perspective Cardiovascular and Renal Drugs Advisory Committee Bel

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  1. 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

  2. Vernakalant for AF: Points for Discussion Determination of benefit – spontaneous conversion from AF to sinus rhythm Limitations of data Special risks

  3. Drug P=? P=<0.05 No treatment Apparent Effect Size of Treatments for AF: Effect of Time Prior to Initiating Other Treatments

  4. 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)

  5. Generalizability of the Data: Subject Population in ACT I and ACT III Race: Caucasian 97.7% African Ancestry 0.8% Other 1.5%

  6. 21% 16% Probability of Converting vs. Duration of Atrial Fibrillation (ACT I) 63 40 13 7 10 8 4 N’s AF Duration (days)

  7. Probability of Converting – Sponsor’s Logistic Regression Model (ACT I)

  8. Probability of Converting – Sponsor’s Logistic Regression Model with Actual Data (ACT I) 21%

  9. ? 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?

  10. 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?

  11. 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)

  12. Need for post-marketing assessment? Effect of Vernakalant on Ventricular Defibrillation Threshold

  13. 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)

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