The new heparins

Summary
Most of the new heparins are made from unfractionated heparin. They have a lower molecular weight and act differently from heparin. They are not interchangeable with heparin or necessarily with each other; however, they have similar adverse effects. The new heparins can be used for thromboprophylaxis in surgery and in the treatment of venous thromboembolism. They do not require routine monitoring and can be given once a day for some indications. Thromboprophylaxis and treatment of thromboembolism with these drugs is cost-effective compared with no treatment or treatment with anticoagulants requiring monitoring.

Introduction
Heparin has been used for over 50 years in the acute management of venous thromboembolism. It halves the risk of fatal pulmonary embolism when given as prophylaxis in general surgery.

Over the past decade, 'new' heparins have emerged. While these products may be compared to their ancestor for efficacy or cost-effectiveness, it must be emphasised that they are not interchangeable with heparin or necessarily with each other. Any decision to use anticoagulant therapy is based on risk and benefit considerations individualised to each patient. The decision to use a new heparin should be based on evaluable data for that preparation.

Biochemical and biophysical properties
The new heparins are prepared from unfractionated heparin by enzymatic or chemical depolymerisation methods. The fractions have a mean molecular weight of 4000-6000 IU (range 1000-10000) compared with heparin which has a mean molecular weight of 15000 IU (range 5000-30000)¹, hence the term low molecular weight heparin (LMWH).

The antithrombotic effect of heparin is achieved through its interaction with plasma antithrombin III which accelerates the inactivation of the coagulation enzymes thrombin (Factor IIa), Factor Xa and Factor IXa. Thrombin is inactivated only when it is bound to both antithrombin III and heparin.²

Heparin fragments can only bind to antithrombin III and thrombin when they exceed a molecular weight of 5000 IU.

Fragments of smaller size (LMWHs) cannot bind to antithrombin III and thrombin, but can bind to antithrombin III and Factor Xa. This catalyses the inactivation of Factor Xa.

The LMWHs presently marketed in Australia are dalteparin, enoxaparin and nadroparin. These are produced by differing physico-chemical methods from heparin. Danaparoid is an unrelated heparinoid which is derived from porcine gut mucosa. It also catalyses the inactivation of Factor Xa and has similar antithrombotic properties to LMWHs.

The different LMWHs have different mean molecular weights and consequently differing anti-IIa and anti-Xa activity profiles. LMWHs bind less than heparin to plasma and matrix proteins and platelets. This improves their bioavailability, already enhanced because of their smaller size, and the predictability of their anticoagulant responses. A predictable response allows doses to be 'fixed'.

Nadroparin has important differences from other LMWHs. It is recommended only for subcutaneous administration and the dosage for thromboprophylaxis is adjusted according to the weight of the patient.

The reduced binding of LMWHs to endothelium and platelets reduces vascular permeability and platelet dysfunction resulting in fewer bleeding complications than heparin. This has been shown clinically both in prophylaxis and in the treatment of venous thrombosis.^3,4

The clearance of LMWH is mainly renal, independent of dose and slower than the metabolic clearance of heparin. The longer half-life permits less frequent dosing.

Thromboprophylaxis in orthopaedic surgery

Risks of thrombosis and embolism
A risk of peri-operative deep venous thrombosis may be assigned to a patient according to the type of surgery and a patient's co-morbidity (Table 1).

Without prophylaxis, up to 50% of patients undergoing total hip replacement will have venographically proven deep venous thrombosis. Approximately 20% of patients will have popliteal and proximal venous thromboses (which are those more frequently complicated by symptomatic pulmonary embolism), with a mortality rate of up to 6%. Asymptomatic pulmonary embolism still occurs in up to 30% of patients given 5000 IU of subcutaneous heparin every 8 or 12 hours as prophylaxis.

By contrast, total knee replacement is complicated by deep venous thrombosis in 40-80% of patients, although most thromboses occur in the calf. Asymptomatic pulmonary embolism, as assessed by lung scan, is seen in up to 7%, symptomatic pulmonary embolism in 2% and death due to pulmonary embolism in less than 1%.

* _________ Thrombophilic states include inherited disorders such as antithrombin III deficiency and acquired disorders such as anti- phospholipid antibody syndromes

UFH ______ unfractionated heparin

LMWH ____ low molecular weight heparin

Deep venous thrombosis complicates hip fracture in 43% of patients with a mortality rate of up to 12% when no thromboprophylaxis is given.

Monitoring asymptomatic patients with Doppler ultrasonography of proximal veins has low sensitivity for the diagnosis of deep venous thrombosis and cannot be used as a diagnostic test to identify those patients requiring antithrombotic treatment.⁵ The risk of deep venous thrombosis with lower limb orthopaedic surgery, although reduced by regional or spinal anaesthesia, warrants prophylactic treatment.

What to use
There are many published studies comparing LMWH with fixed dose heparin, monitored dose heparin (the dose is adjusted according to the activated partial thromboplastin time (APTT)), and monitored dose warfarin therapy. There are no studies directly comparing dalteparin with enoxaparin or any other LMWH.

Study designs differ, but LMWH, adjusted-dose heparin and adjusted-dose 'low-intensity' warfarin (INR 2.0-3.0) thromboprophylaxis are all effective in reducing the risk of total and proximal deep venous thrombosis to approximately 15% and 7% respectively.

A recent meta-analysis shows that LMWH is probably the most effective of these, without differences in bleeding complications, symptomatic or fatal pulmonary embolism.⁶

Joint replacements
Total hip or total knee replacements require fixed, once daily, subcutaneous injections of either enoxaparin 40 mg or dalteparin 5000 IU. This therapy is independent of a patient's weight and does not require laboratory monitoring. Any differences in deep venous thrombosis risk reduction between starting LMWH before or after the operation are likely to be small.⁷ Whether intermittent pneumatic compression plus LMWH is more efficacious than either alone is not yet established.

Trauma
There are no randomised studies comparing different antithrombotic therapies in inpatients with fractures.

Once daily prophylaxis with a LMWH has been studied in outpatients with minor traumatic injuries who had plaster cast immobilisation of the leg and otherwise low risks of deep venous thrombosis development.⁸ Their incidence of deep venous thrombosis was reduced from 4.3% to 0%, the 'baseline' figure highlighting the risks of immobilisation. Further studies, including health economic analyses, are required.

Duration
The optimum duration of thromboprophylaxis post-operatively is not known. It is recommended that patients continue prophylaxis for at least 10 days post-operatively, but longer-term antithrombotic therapy may well be appropriate, particularly if the patient is slow to mobilise.

Thromboprophylaxis in non-orthopaedic conditions
General surgery
When patients undergo general surgery, it is possible to assign a level of risk of deep venous thrombosis according to the age of the patient, complexity and duration of surgery and the presence of malignancy or other predisposing co-morbidities (Table 1).

Both subcutaneous low-dose heparin (5000 IU every 8 or 12 hours) and LMWH are effective in preventing deep venous thrombosis/pulmonary embolism in general surgical patients.⁹ Absorption of subcutaneous unfractionated heparin is very variable between patients. Whether this explains the development of thrombosis in patients given prophylaxis is not yet known. The convenience of once daily LMWH (20 mg enoxaparin, 2500 IU dalteparin) should be offset against their increased cost compared with heparin. It should be noted that these doses are lower than those recommended for lower limb arthroplasty.

Laparoscopic surgery with pneumoperitoneum creates femoral vein stasis. Its clinical significance and the optimum thromboprophylaxis are yet to be determined.

Acute spinal cord injury
Deep venous thrombosis is commonly seen (15% clinically, 40% venographically) following acute spinal cord injury. Pulmonary emboli are most common within the first 3 months. LMWH, or adjusted-dose heparin, followed by warfarin for 3 months is effective in reducing deep venous thrombosis.

Ischaemic stroke
Although a meta-analysis¹⁰ of antithrombotic therapies (heparin, LMWH and heparinoids) has shown a reduction in the incidence of deep venous thrombosis in acute ischaemic stroke, there has been no reduction in pulmonary embolism or mortality. A recent placebo controlled study of a 10-day course of nadroparin commenced within 48 hours of stroke symptoms showed that the LMWH-treated patients had a lower incidence of death and disability at 6 months without any increase in haemorrhagic complications.¹¹ These interesting findings, whilst requiring confirmation, may offer support to the frequent, but so far unproven, practice of anticoagulation in stroke patients. Anticoagulants are contraindicated if a CT scan shows evidence of haemorrhage.

Arterial thrombosis
Arterial thromboses develop at sites of high shear rate such as stenoses. Animal models of arterial thromboses show that clot-bound thrombin and Factor Xa are resistant to both LMWH and heparin-bound antithrombin III complexes.¹² No clinical data yet show LMWH to be more effective than heparin in maintaining post-angioplasty vessel patency and the therapeutic role of LMWHs in arterial thrombotic disease is not known.

Treatment of established venous thromboembolism
Two recent meta-analyses^4,13 have compared heparin with LMWH in the treatment of deep venous thrombosis. They show that LMWH is both a more effective antithrombotic agent, as shown venographically by thrombus reduction, and a safer anticoagulant, with fewer major bleeding complications than heparin. Studies using enoxaparin and dalteparin were included, although no study compared the different LMWHs or subcutaneous heparin.

The Australian product information for treatment of venous thromboembolism recommends twice daily dosing for enoxaparin, dalteparin and nadroparin.¹⁴ A major breakthrough would be once daily outpatient therapy with potentially major savings on inpatient bed costs. This has been trialled using dalteparin (200 IU/kg subcutaneously). These patients were carefully selected, wanted outpatient therapy and were reviewed daily. The safety and efficacy of this once daily protocol had already been compared with continuous heparin.¹⁵ This was for the short-term use of LMWH overlapping with the introduction of warfarin therapy. Preliminary results of a pharmacokinetic study of a daily subcutaneous dose of 1.5 mg/kg enoxaparin have been reported.¹⁶ Clinical confirmatory studies of this compared with twice daily enoxaparin or heparin are underway.

There have been reports evaluating the longer-term treatment of deep venous thrombosis/pulmonary embolism with LMWHs. Dalteparin (5000 IU twice daily) is as safe and effective as heparin (10 000 IU twice daily) in patients with contraindications to warfarin.¹⁷ Enoxaparin (40 mg once daily) has been compared with adjusted-dose warfarin as secondary thromboprophylaxis. There was a higher rate of recurrent venous thromboembolism at one year in the enoxaparin group.¹⁸ More studies assessing dosage, frequency and duration of LMWH in the longer-term treatment of deep venous thrombosis are necessary.

Complications of low molecular weight heparins

Bleeding
Although projections from animal studies predicted that LMWH would be less anticoagulant than heparin for equal antithrombotic potency, this has not been reflected in an observed reduction in bleeding in most clinical trials. The bleeding risk of LMWHs is generally considered 'acceptable'. It is increased in patients taking antiplatelet medication such as aspirin and non-steroidal anti-inflammatory drugs or with renal impairment. Non-surgical bleeding due to overdose of LMWH is not easily reversed. Protamine sulphate, 50-100 mg intravenously, may neutralise the higher molecular weight forms. Infusion of fresh frozen plasma, which carries serious allergic and infectious risks, is not of established benefit.

Heparin-induced thrombocytopenia
Heparin-induced thrombocytopenia is defined by a platelet count <150 x 10⁹/L and a positive test for platelet-associated heparin-dependent antibodies in a patient receiving heparin. Mild thrombocytopenia (platelets 100-150 x 10⁹/L) commonly occurs within 1-2 days of starting heparin therapy and is of no clinical consequence. Heparin-induced thrombocytopenia typically appears 5 or more days after the start of treatment, but may occur earlier if the patient has previously received heparin. While it occurs in up to 3% of all patients on heparin, it is much less common with subcutaneous thromboprophylaxis. About 10-30% of patients develop further venous or arterial thromboses, thought to be secondary to platelet and/or endothelial activation. This is a potentially fatal complication if unrecognised as a 'paradoxical' adverse effect of anticoagulant treatment.

Heparin-induced thrombocytopenia is much more commonly induced by unfractionated heparin than LMWH and is a risk factor for the development of both arterial and venous thrombosis.¹⁹ If a patient on heparin/LMWH has a falling platelet count, the diagnosis of heparin-induced thrombocytopenia should be considered. This is frequently a clinical diagnosis as diagnostic tests are often unreliable or unavailable. It is not appropriate to change from heparin to LMWH therapy as the cross-reactivity is high.

The heparinoid, danaparoid, because of its more marked chemical differences, has far less likelihood (10%) of cross-reactivity and has been used safely and effectively in over 90% of patients with heparin-induced thrombocytopenia and thromboembolism.²⁰ Currently, danaparoid is only registered in Australia for thromboprophylaxis.

Osteoporosis
There are insufficient clinical data to ascribe a lesser risk of osteoporosis to LMWHs than heparin. A lower incidence of spinal fractures was seen in long-term follow-up of elderly (>75 years) patients on LMWH (dalteparin 5000 IU twice daily) compared with heparin (10 000 IU twice daily).¹⁷

Pregnancy
LMWHs and heparinoids, like heparin, do not cross the placenta. When anticoagulant therapy is required, 'standard' treatment during at least the first and latter part of the third trimesters is twice daily subcutaneous heparin. Warfarin may be used as an alternative at other times in the pregnancy, although many clinicians continue heparin throughout. Possible advantages of LMWH are reduced osteoporotic changes and once daily administration. Current clinical experience is limited and further studies are required.²¹

Monitoring of LMWH therapy
Clinicians accept that heparin therapy of deep venous thrombosis/pulmonary embolism requires monitoring because efficacy and risks are related to its biologic effects, and these are unpredictable. The APTT is a simple reproducible test which can guide the dose of heparin.²² While it sensitively reflects anti-IIa activity, it cannot be used to measure LMWH therapy because it has poor sensitivity to the effects of LMWHs on Factor Xa.

The anti-Xa assay is sensitive to the effect of LMWHs. Monitoring of anti-Xa levels and dose adjustment of LMWH can maintain an appropriate target concentration within the plasma. However, the treatment outcomes of weight-adjusted protocols without monitoring are similar.²³ Measurement of the anti-Xa activity assay is usually unnecessary, except in patients on LMWH therapy who have renal impairment such as those undergoing acute haemodialysis or haemofiltration, or in those patients in whom overdose is suggested clinically by bleeding. Monitoring of prophylactic dose therapy is inappropriate.

Conclusion
LMWHs are effective in the prevention and treatment of venous thromboembolism. There is convenience and simplicity in once daily administration of fixed doses for prophylaxis and weight-adjusted, unmonitored doses for treatment. Outpatient therapy of deep venous thrombosis is safe, efficacious and cost-effective in carefully selected patients. The incidence of heparin-induced thrombocytopenia with complicating thromboembolism is also reduced.

The role of LMWHs in arterial disease is not established and it is likely that other antithrombotics which do not bind to antithrombin III will be more efficacious.

Further reading
Chong BH. Heparin-induced thrombocytopenia. Br J Haematol 1995;89: 431-9.