What Is the Optimal Dosage of LMW Heparin in the Sc Treatment of Deep Venous Thrombosis

Abstract

LMW heparin (LMWH) is better suited for subcutaneous (sc) administration than is UF heparin due to higher bioavailability and slower elimination. Optimal dosage for sc treatment of DVT has not been defined. Our previous study suggested that LMWH should be given in doses according to bodyweight (bw), and that sc injection of 100 anti-Xa U/kg bw/12 hrs might result in therapeutic plasma levels (Holm et al. Haemostasis 16, supl 2,30-37, 1986). This dosage is now being evaluated in an open study including patients with venographically proven DVT. Excluded were patients with pulmonary embolism, thrombosis in the IIiacal vein and females beyond 70 yrs of age. LMWH (Fragmin) is administered sc for at least 5 days. Venography is repeated the last day of treatment and evaluated blindly (Marder score). Compared to the previous study in which doses were given according to age and sex, the present protocol results in more uniform and predictable heparin plasma concentrations : Peak concentration day 2 now ranged 0.40-0.75 U/ml (mean 0.58) (n = ll) as compared to the three-fold wider range (0.261.20 U/ml)(mean 0.57)(n = 29) in the previous study. The 12 hrs plasma heparin profile was determined on day 3. Peak concentrations in the 0.44-0.72 U/ml range were found 2.5-4 hrs after injection. The plasma heparin activity was subtherapeutic (< 0.2 U/ml) the last 3-6 hrs of the 12 hrs period. The heparin activity at the next injection averaged 0.05 U/ml (range 0-0.ll). Day to day variation of peak heparin activity in the individual patient, expressed as CV, ranged 11-22% and there was no heparin accumulation.Conclusions: SC treatment of DVT with LMWH 100 anti-Xa U/kg bw/12 hrs results in peak plasma heparin activity in the 0.40-0.75 U/ml range. The plasma heparin activity was below therapeutic level 3-6 hrs of the 12 hrs period indicating that a larger dose (250 U/kg bw/ 24 hrs divided into 2 or perhaps 3 injections) is preferable.

Anticoagulant Effects of Low-Molecular-Weight Heparin following Thrombolytic Therapy in Acute Myocardial Infarction: A Dose-Finding Study

“…However, with the twice daily regi men, the trough levels of the corresponding dalteparin dose (0.51, 0.34-0.82 IU/ml) did not reach the minimum desired anti-FXa lev el implying that a s.c. dalteparin dose of 100 IU/ml administered b.i.d. is not sufficient to cover 12 h as regards proposed therapeutic levels of anti-FXa activity [ 18,19] In all patient groups in our study we ob served a transient increase of the APTT value, peaking during the first 24 h. This observa tion is probably explained by streptokinaseinduced depletion of fibrinogen, coagulation factors V and VIII. Also, the appearance of anticoagulant fibrin(ogen) degradation prod ucts can affect the APTT value [21].…”

“…Plasma concentra tions ranging between 0.4 and 2.0 anti-FXa IU/ml have been obtained following subcuta neous dalteparin doses of 240-480 IU/kg b.w./24 h [ 17], Other studies have shown that mean plasma levels in the range of 0.6-1.0 anti-FXa IU/ml are comparable to high-dose unfractionated heparin regarding antithrom botic effect without causing bleeding compli cations in patients with deep-venous throm bosis [18,19]. Another dose-finding study evaluating different doses (240-360 IU/kg b.w./24 h) of dalteparin in AMI verified the range of 0.6-1.0 anti-FXa IU/ml to be effec tive also regarding prevention of left-ventricu lar thrombi [20].…”

“…However, a larger patient popula tion is required to confirm the safety aspect of subcutaneous dalteparin following thrombo lytic therapy in AMI. In order to achieve the desired presumed therapeutic range of antiFXa (0.6-1.0 anti-FXa IU/ml) [18,19], our study indicates that a dalteparin dose slightly higher than 100 IU/kgb.w. s.c. b.i.d.…”

“…b.i.d., an anti-FXa level of 0.79 (0.59-1.00) IU/ml was obtained when mea sured 3-4 h after dalteparin administration. Assuming that the desired therapeutic range of anti-FXa activity as secondary prophylaxis after AMI is between 0.6 and 1.0 anti-FXa IU/ml, this dalteparin dose seems adequate [18,19]. However, with the twice daily regi men, the trough levels of the corresponding dalteparin dose (0.51, 0.34-0.82 IU/ml) did not reach the minimum desired anti-FXa lev el implying that a s.c. dalteparin dose of 100 IU/ml administered b.i.d.…”

Therapeutic Use of Low-Molecular-Weight Heparins

“…In recent years, low-molecular-weight (LMW) derivatives of commercial heparin have been prepared that have a mean molecu lar weight of 4,000-5,000 daltons in contrast to unfractionated heparin, which has a mean molecular weight of 12.000-16,000 daltons [19,20], Pharmacokinetic studies [21][22][23][24][25][26], and recent small clinical trials in selected patients with venous thrombosis [27][28][29][30][31], in dicate that the bioavailability of these LMW heparin fractions following subcutaneous in jection is very' high. For example, Bratt et al [23] reported that the bioavailability of LMW heparin after a subcutaneous injection of 120 factor Xa units per kilogram to healthy volun teers was approximately 90% of an equivalent intravenous dose.…”