Morris Timothy A, Jacobson Alan, Marsh James J, Lane James R
Division of Pulmonary and Critical Care Medicine, University of California, San Diego, 200 West Arbor Drive, San Diego, CA 92103-8380, USA.
Thromb Res. 2005;115(1-2):45-51. doi: 10.1016/j.thromres.2004.07.010.
The ability to administer low molecular weight heparins (LMWH) subcutaneously without laboratory monitoring contributes to their popularity for the treatment of thrombotic disorders. Subcutaneous unfractionated heparin, although less expensive, is deemed to require routine laboratory monitoring on the basis of more variability in drug effect compared to LMWH. However, the more predictable pharmacokinetic profiles of low molecular weight heparins are largely based on anti-Xa activity, while antithrombin activity may be at least as important to their mechanisms of action.
We performed a clinical pharmacokinetic trial to compare the variability in peak antithrombin effect between subcutaneous unfractionated heparin and various LMWHs, all given in recommended weight-adjusted treatment doses. Sixty-one patients enrolled in a warfarin clinic were randomized to receive one of four different weight-adjusted subcutaneous heparin doses: unfractionated heparin, 250 units/kg (n=15); tinzaparin, 175 units/kg (n=15); dalteparin, 200 units/kg (n=15); or enoxaparin, 1 mg/kg (n=16). The areas under the curves of antithrombin levels during the first 3 h after administration were determined for each patient, and the coefficients of variation (CV) and 95% confidence intervals of the AUCs were compared among the treatment groups.
There was no statistically significant difference in the coefficients of variation of antithrombin effect between unfractionated heparin (52.8, 95% CI: 32.6-72.9) and enoxaparin (56.5, 95% CI: 35.7-77.4) or dalteparin (43.5, 95% CI 25.4-61.6). Tinzaparin had statistically significant decrease in coefficients of variation (21.6, 95% CI: 12.2-30.9) relative to unfractionated heparin, dalteparin and enoxaparin.
LMWHs, as a class of drugs, are no more predictable in antithrombin effect after subcutaneous injection than unfractionated heparin. There were considerable differences among LMWHs in the observed variability of antithrombin effects, with tinzaparin being somewhat more predictable than the other drugs tested.
无需实验室监测即可皮下注射低分子量肝素（LMWH），这使得它们在血栓性疾病治疗中广受欢迎。皮下注射普通肝素虽然成本较低，但与低分子量肝素相比，由于药物效果变异性更大，被认为需要进行常规实验室监测。然而，低分子量肝素更可预测的药代动力学特征很大程度上基于抗Xa活性，而抗凝血酶活性对其作用机制可能至少同样重要。
我们进行了一项临床药代动力学试验，比较皮下注射普通肝素与各种低分子量肝素在抗凝血酶峰值效应方面的变异性，所有药物均按推荐的体重调整治疗剂量给药。华法林诊所的61名患者被随机分配接受四种不同体重调整的皮下肝素剂量之一：普通肝素，250单位/千克（n = 15）；亭扎肝素，175单位/千克（n = 15）；达肝素，200单位/千克（n = 15）；或依诺肝素，1毫克/千克（n = 16）。测定每位患者给药后前3小时抗凝血酶水平曲线下面积，并比较各治疗组曲线下面积的变异系数（CV）和95%置信区间。
普通肝素（52.8，95%置信区间：32.6 - 72.9）与依诺肝素（56.5，95%置信区间：35.7 - 77.4）或达肝素（43.5，95%置信区间25.4 - 61.6）之间，抗凝血酶效应的变异系数无统计学显著差异。与普通肝素、达肝素和依诺肝素相比，亭扎肝素的变异系数有统计学显著降低（21.6，95%置信区间：12.2 - 30.9）。
作为一类药物，低分子量肝素皮下注射后的抗凝血酶效应并不比普通肝素更可预测。在观察到的抗凝血酶效应变异性方面，低分子量肝素之间存在相当大的差异，亭扎肝素比其他受试药物在某种程度上更可预测。
