Xa inhibition and coagulation activity--the influence of prolonged dalteparin treatment and gender in patients with acute coronary syndrome and healthy individuals.
BACKGROUND
We evaluated coagulation activity in relation to gender in patients with acute coronary syndromes and in healthy individuals of similar age, and related coagulation activity to levels of Xa inhibition during dalteparin treatment.


METHODS
Serial blood samples were obtained from 555 (172 women) of 2267 patients in the Scandinavian FRISC II study, and a single sample in 457 (151 women) apparently healthy age- and sex-matched individuals. After randomization, all patients received dalteparin 120 IU/kg s.c. (maximum 10,000 IU) twice daily for 5 to 7 days inhospital and thereafter placebo (n = 285) or sex- and weight-adjusted doses of dalteparin (5000 or 7500 IU) twice daily (n = 270) for 3 months.


RESULTS
Before randomization, 96% of the patients had open-label anticoagulation with unfractionated heparin or dalteparin. Therapeutic anti-Xa levels (> 0.5 IU/mL) were found in 74%, 55%, 58%, and 33% of the dalteparin-treated patients at randomization, 2 days, 4 to 7 weeks, and 3 months, respectively, and were significantly related to lower levels of coagulation activity, ie, factor VIIa, prothrombin fragment 1+2, and D-dimer, during prolonged treatment. Female patients had higher anti-Xa levels than men at randomization (median 0.69 vs 0.60 IU/mL, P = .01) and at 2 days (0.65 vs 0.59 IU/mL, P < .001). Female patients had also significantly higher levels of all 3 coagulation markers at randomization, 2 days, 4 to 7 weeks, and 3 and 6 months. Similarly, healthy women had higher prothrombin fragment 1+2 levels (median 1.19 vs 0.94 nmol/L) and D-dimer levels than men (26 vs 21 microg/L) (both P < .001).


CONCLUSIONS
Despite weight-adjusted dosing, female patients reached higher anti-Xa levels, suggesting increased sensitivity to dalteparin treatment. Healthy women and female patients also had higher coagulation activity, which might increase the risk of thrombus formation. The large proportion of patients with subtherapeutic anti-Xa during prolonged dalteparin treatment may reflect poor compliance and could thus contribute to the gradual loss of clinical efficacy.
Oldgren
Jonas
J
Uppsala Clinical Research Center, Uppsala University Hospital, Uppsala, Sweden. Jonas.Oldgren@ucr.uu.se
Johnston
Nina
N
Siegbahn
Agneta
A
D000208:Acute Disease; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects*; D017985:Dalteparin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography; D004797:Enzyme-Linked Immunosorbent Assay; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000097:blood / Q000188:drug therapy* / Q000453:epidemiology; D015995:Prevalence; D011446:Prospective Studies; D013548:Sweden / Q000453:epidemiology; D013577:Syndrome; D013997:Time Factors; D016896:Treatment Outcome
D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D015951:Factor Xa; D017985:Dalteparin