The first evaluation of a novel vitamin K antagonist, tecarfarin (ATI-5923), in patients with atrial fibrillation.
BACKGROUND
Tecarfarin (ATI-5923) is a novel oral vitamin K antagonist. Unlike warfarin, it is metabolized by esterases, escaping metabolism by the cytochrome P450 system and thereby avoiding cytochrome P450-mediated drug-drug or drug-food interactions as well as genetic variations found in the cytochrome P450 system. Both tecarfarin and warfarin can be monitored with the international normalized ratio. We hypothesized that the time in therapeutic range for tecarfarin will exceed values usually experienced with warfarin.


RESULTS
This was a 6- to 12-week open-label, multicenter, phase IIA study of 66 atrial fibrillation patients with a mild to moderate risk of stroke to determine the safety and tolerability of tecarfarin and to ascertain an optimal tecarfarin dosing regimen. Sixty-four subjects (97%) were taking warfarin at enrollment and were switched to tecarfarin. After the initial 3 weeks of tecarfarin treatment, the mean interpolated time in therapeutic range was 71.4%. Only 10.9% of patients had time in therapeutic range of <45%. Times in extreme international normalized ratio ranges of <1.5 and >4.0 were 1.2% and 1.2%, respectively. The median daily dose (for an individual patient) to maintain an international normalized ratio between 2 and 3 was 15.6 mg (range, 6 to 29 mg).


CONCLUSIONS
This is the first study of tecarfarin in patients with atrial fibrillation. It appears that tecarfarin may possess advantages over the currently available standard of care, warfarin, by improving time in therapeutic range. Adequately powered prospective trials are warranted to definitively compare tecarfarin with warfarin in clinical settings for which warfarin is indicated.
Ellis
David J
DJ
ARYx Therapeutics Inc, Fremont, Calif, USA.
Usman
Mohammed Haris
MH
Milner
Peter G
PG
Canafax
Daniel M
DM
Ezekowitz
Michael D
MD
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001281:Atrial Fibrillation / Q000188:drug therapy*; D001779:Blood Coagulation Factors / Q000032:analysis; D065729:Cytochrome P-450 CYP2C9; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics; D014812:Vitamin K / Q000037:antagonists & inhibitors*; D064417:Vitamin K Epoxide Reductases
D000925:Anticoagulants; D001779:Blood Coagulation Factors; D014812:Vitamin K; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D064417:Vitamin K Epoxide Reductases