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Tedisamil for Conversionof Atrial Fibrillation

Thomas A. Marciniak, M.D.Division of Cardiovascular

and Renal ProductsU.S. Food & Drug Administration

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Fundamental question:

Not whether tedisamil works, BUTIs 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% @ 3h

(onset < 48h) 60% @ 24h80% @ 48h

• JACC ’03: 35-64% @ 24h(onset <48h-7d – meta-analysis of amiodarone studies)

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Success rates @24h for onset ≤ 48h

study n placebodose

0.16 0.24 0.32 0.48 0.64107 140 28% 17% 17%

112 109 34% 21% 32% 25%

114 84 55% 1% 20% 5%

116 102 42% 11% 3%

117 55 26% 34%

118 36 39% 11%

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Success rates @24h for onset > 48h

study n placebodose

0.16 0.24 0.32 0.48 0.64107 2 0% 0% 0%

112 95 4% 6% 26% 43%

114 115 0% 4% 15% 16%

116 217 1% 4% 13%

117 41 0% 4%

118 100 0% 6%

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Success rates @24h by gender

study sex placebo

dose

0.32 0.48 0.64

107 F 25% 7% 10%

M 31% 19% 21%

112 F 13% 8% -1% 16%

M 23% 8% 28% 36%

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Success rates @24h for flutter

study placebo

dose

0.16 0.24 0.32 0.48 0.64

% p % p % p % p % p

107 0% 9% 0.3 7% 0.3

112 22% -11%

0.5 3% 0.9 28% 0.3

114 17% 8% 0.7 17% 0.5 -4% 0.8

116 23% 10% 0.6 8% 0.7

117 25% -25%

0.08

118 38% -38%

0.04*

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What is the NET benefit?

• For atrial fibrillation:– In men, 20-30% with onset ≤ 48h– 10-20% with onset > 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 investigator’s 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

dose

F M

subjects % subjects %

placebo 239 2.9% 231 5.6%

0.16 1 0.0% 66 0.0%

0.24 122 3.3% 6 0.0%

0.32 225 3.1% 172 7.6%

0.32-0.48 7 28.6% 10 10.0%

0.48 34 8.8% 207 11.1%

0.48-0.72 4 0.0% 15 20.0%

0.64 10 20.0% 52 23.1%

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Bradycardia and hypotension on day 1

dose

F M Both

No BB BB No BB BB No BB BB

0 0% 0% 0% 0% 0% 0%

0.16 0% 0% 0% 0%

0.24 0% 0% 0% 0%

0.32 0% 1% 0% 0% 0% 0%

0.32-0.48 0% 20% 0% 0% 0% 8%

0.48 0% 0% 1% 0% 1% 0%

0.48-0.72 0% 33% 0% 11% 0% 17%

0.64 0% 0% 0% 5% 0% 5%

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Thromboembolic events within 2 weeks

dose F M Both

0 0.8% 0.4% 0.6%

0.16 0.0% 1.5% 1.5%

0.24 1.6% 0.0% 1.6%

0.32 3.6% 1.2% 2.5%

0.32-0.48 0.0% 0.0% 0.0%

0.48 0.0% 1.0% 0.8%

0.48-0.72 0.0% 0.0% 0.0%

0.64 10.0% 5.8% 6.5%

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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?