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Low Molecular Weight Heparin

Introduction

After several years of intensive basic and clinical research, low-molecular-weight heparins (LMWH) clearly have been established as efficacious in several clinical settings, including the treatment and prevention of venous thromboembolic disease, the treatment of unstable coronary ischemic disease, and treatment of acute cerebrovascular ischemia. In most parts of Europe, LMWH has replaced unfractionated heparin, and they are now increasingly being utilized in this country because it has demonstrated that many patients with venous thromboembolic disease (VTE) can

Mechanisms of Action of Low Molecular Weight Heparin

Standard unfractionated heparin (UH) is a heterogeneous mixture of highly sulfated polysaccharide chains ranging in MW from 3000 to 30,000 daltons. Low molecular weight hepafins are fragments of unfractionated heparin produced by

Pharmacokinetics of LMWH

LMW heparins produce a more predictable anticoagulant response than UH which reflects their better bioavailability, longer half-life, and dose independent clearance. The plasma half-life of LMWH is 2-4 times as long as UH (2-4 hrs after IV injection and 3-6 hrs after SC injection). The pharmacokinetic differences between LMWH and UH is explained by the decreased binding of LMWH to plasma proteins, endothelial cells and macrophages, whereas UH binds to proteins

Treatment of Venous Thromboembolic Disease with LMWH

There is very litfie doubt now that LMWH is effective and safe in treating patients with venous thromboembolic disease. Four meta-analyses company UF to LMWH have been published. The results of these meta-analyses are illustrated below:

The above meta-analyses contrast to recent large randomized controlled clinical trials by the Columbus, Dutch and Canadian investigators.

It is clear from the evidence illustrated above that LM'WH is at least as effective as unfracdonated heparin in the treatment of acute venous thromboemboic disease. In the majority of trials, LMWH was given in f'txed or weight-adjusted doses without laboratory monitoring. In two well-controlled randomized

- trials noted above (Levine and Tasman) the safety and efficacy of LMWH "at home" therapy were compared to the standard "in-hospital' treatment with intravenous unfractionated heparin. The results of these two studies are

Prophylaxis

LMWH is effective prophylaxis of VTE in patients undergoing major orthopedic and general surgery. Moreover, they have been shown to be efficacious in preventing VTE in patients with acute spinal cord injury, patients with major trauma, and patients with a variety of medical conditions associated with prolonged immobility. However, in many instances where it has been used for prophylaxis, it has not been shown to be that much better than low dose UH, and thus, because of its expense, it has not gained a great deal of favor. Those conditions where low dose UH appears to be as efficacious and safe include general surgery patients and medical patients with prolonged immobility.

In patients undergoing major hip surgery, LMWH is only marginally better than warfarin or adjusted dose UH, but they do Eave an advantage in that no monitoring is required. Although the incidence of DVT in total knee replacement remains quite high, LMWH appears to be more efficacious than low intensity warfarin in reducing the incidence. However, LMWH should not be given until 12 hrs after surgery because of an increased incidence of bleeding.

Unstable Angina

The combination of aspirin and heparin is the standard treatment of choice for unstable coronary syndromes. Two large studies comparing LMWI-I with UH resulted in disparate findings. In the Fragmin in Unstable Coronary Artery Disease (Fric) Study LMWH and UH were equivalent, whereas in the Enoxaparin in Non-Q-Wave Coronary Events Study Group (Essence) trial, there was a significant reduction in the primary end point of death,

^{Whether the difference between the two trials is due to the use of two different preparations of LMWH or whether it is due to other variables is not clear. However, because LMWH is at least equivalent and doesn't require monitoring, it is useful for outpatient administration.}

^{Ischemic Stroke}

^{A randomized double-blind, placebo controlled trial of LMWH in ischemic stroke demonstrated better outcomes at 6 months. However, more recent clinical trials have failed to corroborate these results but several other trials are. ongoing.}

^{Use During Pregnancy}

^{LMWH does not cross the placenta and there is accumulating data that they are efficacious and safe ,:luting pregnancy and are easier to use since they don't require monitoring. However, there is a lack of information regarding the proper dosing of LMWH in pregnancy either for acute treatment or for prophylaxis. Other advantages for the use of LMWH in pregnancy is the lower incidence of heparin-induced thrombocytopenia and probably less osteoporosis. Unfortunately, no randomized trials compaing LMWH to UF have been published to date, and LMWH has not been approved for use in pregnancy.}

^{Heparin-Induced Thrombocytopenla and Osteoporosis}

^{There is sisgnificant evidence that heparin-induced thrombocytopenia with or without thrombosis is less frequent with LMWH.}

^{Although there is not a very large amount of data regarding osteoporosis, this complication appears to be less frequent in}