[Warfarin in the treatment of antiphospholipid syndrome].
OBJECTIVE
To assess efficacy and safety of warfarin therapy and its combination with low-dose acetylsalicylic acid (ASA) in antiphospholipid syndrome (APS).


METHODS
The trial enrolled 60 APS patients. They were divided into two groups: group 1 (n = 39) on antithrombotic therapy with warfarin; group 2 (n = 21) on combined therapy with warfarin and ASA. Efficacy of the treatments was assessed by the number and frequency of thrombosis recurrences and transient ischemic attacks (TIA) while safety was evaluated by frequency and number of hemorrhages during the study. Genetic variants of cytochrome P450 (CYP2C9*1, CYP2C9*2 and CYP2C9*3) were studied in 30 patients (25 females, 5 males) with APS. CYP2C9 gene genetic variants were determined by polymerase chain reaction and restrictase analysis.


RESULTS
The thrombosis rate was 19.6 per 100 man-day, TIA rate was not less than 8 per 100 man-day, total rate of thrombotic complications (thromboses and TIA) before warfarin individual dose adjustment--27.6 per 100 man-day. Doses of anticoagulant were adjusted and the patients on treatment were followed up for 15.7 months, on the average. For this period thrombosis occurred in 6 cases (7.6 per 100 man-day), TIA also in 6 cases (7.6 per 100 man-day). This corresponded to thrombotic complications rate 15.1 per 100 man-year. Hemorrhages (major and minor) occurred in 19 (48.7%) patients of group 1 and in 13 (61.9%) patients of group 2 (p = 0.33). Total rate of CYP2C9*2 and CYP2C9*3 carriage was 36.7%. The CYP2C9*2 variant was detected in 7 (23.3%) patients, who were all heterozygous carriers. The CYP2C9*3 variant was seen in 4 (13.3%) patients: 3 heterozygous and 1 homozygous. Females of reproductive age with mutations had more frequent menorrhagies than carriers of a wild-type variant. Patients with CYP2C9*3 had also more frequent nasal hemorrhages and gingival bleeding (p = 0.005) compared to carriers of CYP2C9*1 and CYP2C9*2. Episodes of MHO rise > 5.0 in warfarin therapy were observed in 50% carriers of CYP2C9*3 and in none homozygous carriers of CYP2C9*1 (p = 0.024). CYP2C9*3 patients needed lower maintenance doses of warfarin, in CYP2C9*1 and CYP2C9*2 patients anticoagulant doses were comparable. CONCLUSION; Efficacy of warfarin for secondary prophylaxis of thrombosis was found similar to that of warfarin use in combination with low-dose ASA (MHO 2.0-3.0). Safety of monotherapy was higher. Determination of CYP2C9 genotype in APS patients before treatment with oral anticoagulants may help in planning individual policy and in reducing the risk of warfarin overdosage at the start of therapy.
Reshetniak
T M
TM
Kondrat'eva
L V
LV
Patrusheva
N L
NL
Patrushev
L I
LI
D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016736:Antiphospholipid Syndrome / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001241:Aspirin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D001777:Blood Coagulation / Q000187:drug effects* / Q000235:genetics; D002560:Cerebrovascular Circulation / Q000187:drug effects; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D016133:Polymerase Chain Reaction; D013927:Thrombosis / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D016896:Treatment Outcome; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
D000925:Anticoagulants; D014859:Warfarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D001241:Aspirin