Anticoagulant effects of Idraparinux after termination of therapy for prevention of recurrent venous thromboembolism: observations from the van Gogh trials
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To gather information on anticoagulant effects after the termination of long-term therapy with idraparinux.
The anticoagulant effects of idraparinux, a synthetic polymethylated analogue of its pentasaccharide, were analysed in 23 patients after termination of a 6- or 12-month therapy period for the prevention of recurrent venous thromboembolism (VTE). Plasma samples of patients initially randomized to 2.5 mg idraparinux (normal creatinine clearance) or 1.5 mg idraparinux (creatinine clearance <30 ml/min) were investigated in the van Gogh trials. At 3-month intervals for up to 15 months following the termination of the therapy, the factor Xa-specific S2222 chromogenic substrate (aXa) assay and Heptest were used to determine various pharmacokinetic parameters and prothrombin-induced clotting time (PiCT), activated partial thromboplastin time (aPTT) and prothrombin time (PT) were determined.
Based on the aXa assay and Heptest, the half lives (t1/2) were 60.2 days and 107.7 days (p < 0.0001), maximum drug concentrations (Cmax) were 0.30 and 0.39 μg/l (p = 0.0016), areas under the activity time curve (AUC) were 33.7 and 38.0 μg/l per day (p = 0.0002), plasma clearances were 0.09 and 0.06 ml/min (p < 0.0001), mean residence times (MRT) were 75.4 and 121.9 (p < 0.0001) and volumes of distribution (Vdiss) were 7.4 and 8.6 l (p = 0.1336), respectively. After 12 months of treatment (n = 18), the S2222 and Heptest results showed significantly higher Cmax and AUC, lower Vdiss and clearance and unchanged t1/2 and MRT values compared to 6 months of treatment (n = 5). The PiCT was prolonged for a period of 9 months. Coagulation times of aPTT and PT were not influenced. The results of these parameters did not differ between 12 and 6 months of treatment.
The data support reports on a non-ionic binding of idraparinux to antithrombin and other proteins. We suggest that these findings may explain some of the findings of the van Gogh Extension trial.
KeywordsAnticoagulants Anticoagulation Idraparinux Pharmacodynamics Thrombosis Venous thromboembolism
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