Low molecular weight heparins: are they interchangeable? Yes
Article first published online: 3 JAN 2003
Journal of Thrombosis and Haemostasis
Volume 1, Issue 1, pages 10–11, January 2003
How to Cite
Prandoni, P. (2003), Low molecular weight heparins: are they interchangeable? Yes. Journal of Thrombosis and Haemostasis, 1: 10–11. doi: 10.1046/j.1538-7836.2003.00014.x
- Issue published online: 3 JAN 2003
- Article first published online: 3 JAN 2003
Low molecular weight heparins (LMWHs) are derivatives of unfractionated heparin (UFH). They are prepared either by enzymatic degradation of UFH or by chemical processes. In contrast to UFH, LMWH preparations have a more homogeneous molecular weight (mean ∼5000 Da). They present a number of potential advantages over UFH: a longer plasma half-life, improved subcutaneous bioavailability, and a more predictable dose–response relationship . As a result of these pharmacokinetic properties, a stable and sustained anticoagulant effect is achieved when these drugs are administered subcutaneously, either once or twice daily, without any laboratory monitoring . These compounds have the potential to greatly simplify the initial treatment of venous thromboembolism, making the treatment of suitable patients feasible in an outpatient setting with considerable saving in costs and improvement in patients' quality of life . In addition, LMWHs have become the standard of care for prevention of venous thromboembolism in high-risk medical and surgical patients . Finally, following the demonstration that LMWHs are at least as effective and safe as UFH for the therapeutic approach of unstable angina and non-Q-wave myocardial infarction, they are increasingly being used in patients with acute coronary artery disease .
A number of pharmaceutical companies have marketed preparations of LMWH both in Europe and in the USA. The available LMWHs differ in physico-chemical properties, in vitro activity and pharmacodynamics [1,2]. Potential differences among these agents include the number of available antithrombin III binding sites, glycosaminoglycan content, affinity for circulating and cellular proteins, and their effects on platelets. Remarkable differences already observed among LMWHs include anti-Xa and anti-IIa activities; release of tissue factor pathway inhibitor, inhibition of plasminogen activator inhibitor type 1; interactions with platelets, endothelial cells, and inflammatory modulators; and effects on angiogenesis . However, although LMWHs are distinct compounds and possess distinct profiles, it is not yet known what effect, if any, these differences exert on clinical efficacy and safety in the various fields of application.
As far as the treatment of venous thromboembolism is concerned, at least five LMWHs (dalteparin, enoxaparin, nadroparin, reviparin and tinzaparin) have been shown to be at least as effective as UFH when administered once or twice daily for prevention of clinically relevant recurrent thromboembolism, with a trend in favor of LMWHs when the investigated compound was enoxaparin, nadroparin, reviparin, or tinzaparin, and in favor of UFH when dalteparin was being investigated . A statistically significant reduction in major bleeding was observed only in one study using tinzaparin , whereas no appreciable differences in terms of tolerability were recorded between LMWHs and UFH when the investigated compound was dalteparin, enoxaparin, nadroparin, or reviparin. As no direct clinical comparison between different LMWH preparations is available, it cannot be excluded that there are differences regarding clinical efficacy and safety between LMWH treatment regimens. As it is very unlikely that such studies will be conducted, the question about the differences between LMWHs for the treatment of venous thromboembolism may never be adequately answered. Indirect evidence coming from comparative studies between LMWH preparations and UFH suggests that it is reasonable to use any of the available products in the dosages evaluated in the respective clinical trials.
LMWHs have become the standard of care for primary prevention of venous thromboembolism in high-risk medical and surgical patients. In major orthopedic surgery, the superiority of LMWHs over UFH and oral anticoagulants has emerged in almost all clinical trials dealing with this issue . Although in general surgery no selective advantage of LMWHs over UFH has been shown , the need for prolonging prophylaxis beyond hospital stay, at least in oncologic surgery, makes the once daily administration of a fixed dose of LMWH a more attractive option. In the field of primary prevention of venous thromboembolism, all available agents have shown similar efficacy and safety profiles. In addition, two comparative trials conducted in major orthopedic surgery between enoxaparin and either tinzaparin or reviparin failed to show any appreciable differences between the treatment groups either in terms of efficacy or safety [8,9]. In conclusion, when administered at the dosages used in the reviewed clinical trials, the available LMWHs are basically indistinguishable.
Addition of UFH or LMWH to aspirin for up to 7 days in patients with unstable angina or non-Q-wave myocardial infarction reduces the incidence of non-fatal myocardial infarction or death by about 50%. The benefits of UFH and LMWH emerge during treatment in all available studies . Selective emphasis on two comparative trials between the two categories of drugs has led many clinicians to believe that enoxaparin might be more effective than all other LMWHs as, in this setting, enoxaparin is the only agent for which a statistically significant superiority over UFH has been demonstrated . However, it should be considered that indirect comparisons are unreliable and potentially misleading on account of differences in the kinds of patients randomized, in outcome definitions, and in treatment regimens. For example, on completion of treatments of equal duration, neither trial comparing enoxaparin with UFH showed a significant reduction in the irreversible outcome of death and myocardial infarction, which represents the true aim of the treatment of patients with acute coronary syndromes .
In conclusion, although there is no doubt that LMWHs show considerable variations in their pharmacodynamic and pharmacological profiles, there are no data to suggest that these variable properties translate into differences in clinical outcome. The consistency of clinical results between different compounds in both venous and arterial trials does not support the concept of a superiority of one LMWH over any other. Thus, provided they are administered at the dosages recommended by manufacturers according to the results of available clinical trials, we may state that LMWHs are interchangeable.