Tedisamil for Conversion of Atrial Fibrillation

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Tedisamil for Conversionof Atrial Fibrillation

• Thomas A. Marciniak, M.D.
• Division of Cardiovascular and Renal Products
• U.S. Food Drug Administration

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Fundamental question

• Not whether tedisamil works, BUT
• Is the benefit/risk tradeoff favorable enough to
  justify approval?

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Fundamental benefit question

• What is the NET benefit?
• Issue Most recent onset afib converts
  spontaneously (although not in the first 1-2
  hours.)

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Spontaneous conversion rates in the medical
literature

• Annals Int Med 03 0-76
• The Lancet 06 20 _at_ 3h
• (onset lt 48h) 60 _at_ 24h
• 80 _at_ 48h
• JACC 03 35-64 _at_ 24h
• (onset lt48h-7d meta-analysis of
• amiodarone studies)

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Success rates _at_24h for onset 48h
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Success rates _at_24h for onset gt 48h
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Success rates _at_24h by gender
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Success rates _at_24h for flutter
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What is the NET benefit?

• For atrial fibrillation
• In men, 20-30 with onset 48h
• 10-20 with onset gt 48h
• Less in women
• For atrial flutter
• No clear evidence of benefit

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Fundamental safety questions

• What is the impact of the pro-arrhythmic effects?
• Are there any other safety concerns?

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One death temporally associated with tedisamil

• an Asian female, aged 80, with AFib died of an
  AE of AFib, cardiac arrest, electromechanical
  dissociation and hypotension NOS. According to
  the investigators judgment the events were found
  to be unrelated to the drug treatment. The
  subject had a history of coronary artery disease
  NOS and age indeterminate myocardial infarction
  and essential hypertension. Ten minutes after the
  initiation of infusion, the subject experienced
  bradycardia, asystole and low blood pressure and
  the infusion was stopped. During the infusion a
  wide QRS complex occurred. The subject underwent
  cardiopulmonary resuscitation and was intubated
  and never recovered.

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Ventricular tachycardia, fibrillation, or arrest
on day 1
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Bradycardia and hypotension on day 1
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Thromboembolic events within 2 weeks
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There could be mechanisms for delayed
thromboembolism

• Antonelli et al., Am J Card 99
• We studied left atrial function in 55 patients
  undergoing electrical (n 23) or chemical
  (intravenous administration of propafenone, n
  32) attempts at cardioversion from atrial
  fibrillation. Chemical attempts at cardioversion
  revealed a significant increase in spontaneous
  echo contrast and a significant decrease in left
  atrial appendage Doppler flow, even in patients
  who did not have successful conversion to sinus
  rhythm.

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Dosing
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Safety concerns

• With widespread use if approved
• There will be deaths from ventricular
  arrhythmias.
• There will be deaths from bradycardia and
  hypotension.
• Is there an increased thromboembolic risk?
• What will happen to safety in real world use,
  particularly considering the complex dosing?

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Benefit/Risk?