Coagulometric units:15.500 U correspond to about 6000–6500 chromogenic units.
Low molecular weight heparins: are they interchangeable? No
Version of Record online: 3 JAN 2003
Journal of Thrombosis and Haemostasis
Volume 1, Issue 1, pages 12–13, January 2003
How to Cite
Nenci, G. G. (2003), Low molecular weight heparins: are they interchangeable? No. Journal of Thrombosis and Haemostasis, 1: 12–13. doi: 10.1046/j.1538-7836.2003.00017.x
- Issue online: 3 JAN 2003
- Version of Record online: 3 JAN 2003
Besides the well-known effect of molecular weight (MW) distribution of the heparin chains of the different low molecular weight heparins (LMWHs) on the relative inhibition of thrombin (IIa) and of factor Xa (fXa), several chemical differences can influence the biological activity of the various commercial fractionated heparins.
Random cleavage of glycosidic bonds used to prepare LMWHs will inevitably degrade some of the pentasaccharide units during depolymerization of the parent heparin chains with high affinity to antithrombin III. Therefore, LMWHs prepared for clinical use have a lower proportion of high-affinity chains than unfractionated heparin (UFH)  and thus a lower specific activity. This adds to decreased activity due to loss of sulfate ester groups during depolymerization. The extent of activity loss may very well depend on the cleavage procedure adopted for the individual commercial product. Thus, even if differences in terminal residues  do not influence bioequivalence and if the same is true for the final ion-exchange clean-up applied to dalteparin, the loss of sulfate ester groups or the resulfatation of some LMWHs can alter the activity spectrum of the product .
Mean MW varies from 3800 Da for certoparin to 6500 Da for tinzaparin, and the (a-Xa/a-IIa) ratio can range from 2 for ardeparin to 3.3–3.5 for enoxaparin . In addition to these differences, denaturation during depolymerization may add variability to the pharmacological characteristics and the clinical effects of the various LMWHs, and offer an answer to the question of why prophylactic doses of LMWHs result in different anti-Xa anti-IIa activity in blood of patients.
UFH 2000 U injected subcutaneously gave a-Xa values of 0.03–0.13 U mL−1 from 2 to 4 h after administration across most of the comparative studies cited in Table 1. Similar a-Xa levels (as well as similar efficacy and safety) were shown after dalteparin 2500 U, parvaparin 7500 U, reviparin 1750 U or tinzaparin 2500–3500 U. nadroparin 2850 U was associated with an a-Xa level of 0.38 U mL−1 (and the same bleeding rate as the placebo); dalteparin 5000 U gave comparable plasma a-Xa activity (together with an excess of major bleeds with respect to UFH 5000 IU × 2), as did 40 mg and 30 mg × 2 enoxaparin (with an excess of local hematomas for the latter dosage), 4200 U reviparin, and as much as parvaparin 15 500 coagulometric a-Xa U. In other hands, dalteparin 5000 U resulted in 0.13 U mL−1 a-Xa activity after 2 h and no excess bleeding when compared with UFH. In one of the few comparative trials in 440 hip surgery patients, reviparin 4200 U and enoxaparin 40 mg resulted in equal efficacy and safety, but a-Xa levels were consistently lower in reviparin-treated patients (all the above studies have been reported by Sarret et al. ).
|LMWH||mg or a-Xa U administered||Plasma a-Xa (U mL−1)||Hours after injection|
|Trials in general surgery|
|2500||0.11–0.15 (2 studies)||4|
|Parnaparin*||15 500||0.26||‘at peak’|
|Trials in orthopedic surgery|
|40 mg||1.50||4 (at day 14)|
|30 mg × 2||0.31||4|
|Parnaparin *||7500 × 2||0.23 (mean)||‘at peak’|
It is clear that standardization of a-Xa assays is far from perfect. However, most studies show not only that similar plasma aXa levels are obtained with a broad range of dosages for the different LMWHs, but also that clinical efficacy and safety are largely independent of the a-Xa levels attained by the different LMWHs used for thromboprophylaxis.
Several meta-analyses have failed to show a superiority of LMWHs on UFH for thromboprophylaxis in general surgery. However, meta-analyses on a drug class may fail to document a clinical effect in terms of efficacy/safety ratio when the different drugs behave differently in the various studies. In effect, when compared to UFH, some LMWHs showed better efficacy but equal safety [4,5], others better safety but equal efficacy [6–8], and still others equal efficacy but lower safety . Halving the dose of the latter LMWH proved safer but less effective [10,11]; incidentally, this half-dosage had been shown to be equally efficacious but safer than UFH · Such conflicting results may annihilate one another when pooled in a meta-analysis.
Different results on the treatment of acute coronary syndromes (ACS) with LMWHs have been shown by several trials. In contrast to dalteparin and nadroparin studies, ESSENCE and TIMI 11 B independently showed the superiority of enoxaparin over UFH. Interestingly, enoxaparin but not dalteparin was able to suppress the serious rise of von Willebrand factor seen in ACS patients treated with UFH . It is not clear if at least some of differences in the results of the above trials are due to chance or bias. A possible explanation could be the varying lower number of events or differences in the severity of illness, or in the rates of revascularization  as well as the pharmacological profile of the different drugs. In any case, for the time being a difference in the clinical results does exist and must be taken into account.
Differences in efficacy and safety between LMWHs probably exist also in the treatment of venous thromboembolism (VTE). When the log odds ratio for bleeding is plotted against that for recurrent VTE of an LMWH used for the treatment of a venous thromboembolic event, there appears to be some variations among six currently available LMWHs . For example, dalteparin proves to be associated with a statistically significant difference in efficacy (which was lower) and safety (which was higher), with respect to the other LMWHs. The results of two of the three studies with Enoxaparin fall near the indifference point, while all three studies with Nadroparin fell in the advantageous area. The particular risk profile in terms of bleeding or recurrences of a given patient could thus orient the choice of the drug to be used for him or her.
In conclusion, are all LMWHs created equal?
It is clear that there are significant differences between the various LMWHs concerning their physical, biochemical, pharmacological and clinical properties.
Their in vitro potency measures only one aspect of the product and even the units used for this (a-Xa units, milligrams) are not strictly comparable. Neither the resulting a-Xa levels in vivo nor their clinical efficacy or safety seem to be strictly correlated with the drug's label activity and its pharmacological profile.
Direct comparisons between LMWHs are scanty. However, five studies and their meta-analyses  comparing Enoxaparin with Fondaparinux (which can be considered a synthetic very low MW heparin) in major orthopaedic surgery showed a marked difference in efficacy (55.2% odds reduction of VTE in favor of Fondaparinux), while the bleeding incidence was comparable.
Indirect comparison shows that efficacy and safety in prophylaxis and treatment are sometimes different for various LMWHs at their own dose regimens.
Differences could be due in part to chance, error or different experimental designs. In any case, they are great enough to suggest for each indication the choice of product and the relevant dosage that has given the best clinical results.
- 1Low Molecular Weight Heparin. Chichester: John Wiley & Sons, 1992., ,
- 3Low Molecular Weight Heparin Therapy: An Evaluation of Clinical trials Evidence. New York, Basel: Marcel Dekker, Inc., 1999., ,