What is the clinical support for the use of low-molecular-weight heparin in pulmonary embolism and

Fråga: What is the clinical support for the use of low-molecular-weight heparin in pulmonary embolism and which preparation should be used?

Sammanfattning: Low-molecular-weight heparins are at least as effective and safe as unfractionated heparin in the prevention and treatment of deep vein thrombosis with a trend in favour of low-molecular-weight heparins. Evidence is accumulating that low-molecular-weight heparins can also be used safely to treat acute, submassive pulmonary embolism.

Their advantages over unfractionated heparin are that they can be given once or twice daily by subcutaneous injection without the need for monitoring of the anticoagulant effect. The possibility of outpatient treatment of uncomplicated deep vein thrombosis is also a significant advantage of low-molecular-weight heparins because of the better cost-effectiveness ratio and the improved quality of life.

Svar: Prevention and therapy of venous thromboembolism is of major importance since deep vein thrombosis is an economic burden and presents a threat to health and life (1).

Heparin was used during the last six decades in prevention and treatment of venous thromboembolism causing a significant decrease of deaths from pulmonary embolism and the morbidity of deep vein thrombosis (2). Low-molecular-weight heparins were developed in the late 1970´s and are progressively replacing unfractionated heparin for preventing postoperative thromboembolism and for treating established deep vein thrombosis and pulmonary embolism (3).

Unfractionated heparin is a heterogeneous mixture of polysaccharide chains ranging in molecular weight from about 3000 to 30000 (4).

Low-molecular-weight heparins are fragments of unfractionated heparin produced by controlled enzymatic or chemical depolymerization processes that yield chains with a mean molecular weight of about 5000 (5).

Unfractionated heparin has two major limitations compared to low-molecular-weight heparin: a narrow therapeutic window and a highly variable dose-response relation (6). Another important limitation is its inability to inactivate thrombin bound to fibrin (7) and factor Xa bound to activated platelets trapped within the thrombus (8); this could cause thrombus growth during heparin treatment and reactivate the thrombotic process once treatment is stopped.

Low-molecular-weight heparins, produce a more predictable anticoagulant response than unfractionated heparin reflecting their better bioavailability, longer half-life, and dose-independent clearance (9). The pharmacokinetic advantages of low-molecular-weight heparin over unfractinated heparin can be explained by the decreased propensity of the former to bind to plasma proteins, endothelial cells and macrophages.

A meta-analysis of 16 randomised controlled trials, enrolling more than 2000 patients with established deep vein thrombosis and treated with low-molecular-weight heparin or unfractionated heparin, revealed a significant reduction in the incidence of thrombus extension in favour of low-molecular-weight heparin, but non-significant trends in favour of low-molecular-weight heparin were observed for the recurrence of thromboembolic events, major haemorrhages and total mortality (10).

A meta-analysis of randomised trials, conducted during the period 1980-1994, classified studies as level one if they were double-blind or if there was blinded assessment of outcome measures, and level two if they did not provide assurance of blinded outcome assessment (11). The relative risk of recurrent venous thromboembolism or major bleeding was in favour of low-molecular-weight heparin treatment only in level one studies. The relative risk for overall mortality was lower in the low-molecular-weight heparin treatment, particularly in the subgroup of patients with cancer.

Another meta-analyses (12) selected only 10 studies because they used unfractionated heparin dosage adjustments; the relative risk reductions for symptomatic recurrent venous thromboembolic disease, clinically important bleeding, and mortality were all statistically significant in favour of low-molecular-weight heparin.

These studies showed that subcutaneous, low-molecular-weight heparin is likely to be at least as effective and safe as unfractionated heparin in treating patients with uncomplicated deep vein thrombosis; the follow up was limited to the initial hospital stay, which rarely exceeded 10 days and the primary end point was the extension of the thrombus and not a real clinical outcome. The results of these meta-analyses are based mainly on the findings of just two trials (13, 14) using two different low-molecular-weight heparins (Fraxiparine and Logiparin) that may not be interchangeable. Furthermore, the results were almost entirely attributable to differences in the subgroup of patients with cancer (5).

Because these trials did not include patients with pulmonary embolism the findings may not translate directly to clinical practice. In recent years, two clinical trials (15, 16) were carried out to determine the effectiveness and safety of low-molecular-weight heparin in the treatment of acute symptomatic pulmonary embolism. After a three months follow up, the evaluation of outcomes such as symptomatic recurrent thromboembolism, major bleeding, and death, revealed that low-molecular-weight heparin is as effective and safe as unfractionated heparin in patients with acute pulmonary embolism. In addition, low-molecular-weight heparin permits treatment regimens to be simplified so that hospital stay can be shortened and suitable patients can be treated outside the hospital.

Since the longer plasma half-life, better bioavailability after subcutaneous administration, and more predictable anticoagulant response of low-molecular-weight heparins made them attractive for possible home use, two recent clinical trials (17, 18) compared low-molecular-weight heparins administered primarily at home with unfractionated heparin administered in the hospital, in the treatment of deep vein thrombosis. Both studies showed that low-molecular-weight heparins are at least as effective and safe as standard unfractionated heparin for the initial treatment of deep vein thrombosis.

The introduction of a new treatment modality should be reviewed not only in terms of its safety and efficacy, but also in terms of its relative cost. The cost of medication with low-molecular-weight heparins is 10 to 20 times as expensive as unfractionated heparin (19).

In Sweden, the daily cost of the treatment with Fragmin is SEK 100-110/day, compared with SEK 14-18/day for a treatment with unfractionated heparin (FASS, 1999).

To justify the added drug cost, there must be a compensatory decrease in indirect costs. The greatest potentials for economic advantage of low-molecular-weight heparins lie in the outpatient treatment of deep vein thrombosis and pulmonary embolism (5).

All studies evaluating the cost-effectiveness of low-molecular-weight heparins, concluded that they had a lower rate of complications, had shorter nursing time, and required less laboratory monitoring than unfractionated heparin (20). An economic evaluation of replacing inpatient care with unfractionated heparin by outpatient care with subcutaneous low-molecular-weight heparin, in the treatment of deep vein thrombosis, demonstrated a cost reduction of 64 per cent with the outpatient management with low-molecular-weight heparin (21).

However the relative cost-effectiveness ratio is centre and country specific because it is critically dependent on the price ratio between the two drugs (22), and on the public sources provided (23); it is also suggested that some specific subgroups of patients could influence the final cost-effective evaluation (24).

Tinzaparin and Reviparin are the two low-molecular-weight heparins that have been proven to be efficient and safe in the treatment of pulmonary embolism (15, 16), while Enoxaparin, Dalteparin, Nadroparin and Tinzaparin were used in most trials for the prevention and treatment of venous thrombosis (10, 11, 12).

The possibility to interchange different low-molecular-weight heparins is not yet proven. However the clinical effects of low-molecular-weight heparins are remarkably similar, and any differences between the preparations are likely to be clinically unimportant (25). A prospective trial comparing two different low-molecular-weight heparins would be the only clear resolution of this question. Since low-molecular-weight heparins are highly effective against deep vein thrombosis, such a trial would be limited by the statistical problem of inadequate power and for this reason it is unlikely that it will be performed (26). However, a Medline and Current Content literature search (27), revealed that one-daily enoxaparin is more cost-effective than twice-daily danaparoid, in the prophylactics of deep vein thromboo