Orthopedics

Low-Molecular-Weight Heparin: From the Bench to the Orthopedic Patient

A G G Turpie, MD

Abstract

Standard heparin is widely used for the prevention and treatment of venous thromboembolism; however, it has several limitations including variable dose response, dose-dependent clearance and inhibition of platelet function. To overcome these disadvantages, standard heparin, which is composed of glycosaminoglycans of various molecular weights, has been fractionated into its low-molecular-weight component. Low-molecularweight heparin (LMWH) exhibits less binding to plasma proteins and endothelial cells than standard heparin resulting in a more predictable dose response profile, a dose-independent mechanism of clearance and a longer plasma half-life. LMWH also has a lower binding affinity for platelets and produces less microvascular bleeding. Evidence from randomized clinical trials demonstrates that LMWH is effective in the prevention of deep vein thrombosis (DVT) in high-risk orthopedic patients. There is also considerable evidence of its efficacy and safety in the initial treatment of proximal DVT. Recent studies have demonstrated the feasibility of home treatment with LMWH, which offers the advantage of greater clinical utility compared with current antithrombotic regimens and hence the possibility of cost savings.

Abstract

Standard heparin is widely used for the prevention and treatment of venous thromboembolism; however, it has several limitations including variable dose response, dose-dependent clearance and inhibition of platelet function. To overcome these disadvantages, standard heparin, which is composed of glycosaminoglycans of various molecular weights, has been fractionated into its low-molecular-weight component. Low-molecularweight heparin (LMWH) exhibits less binding to plasma proteins and endothelial cells than standard heparin resulting in a more predictable dose response profile, a dose-independent mechanism of clearance and a longer plasma half-life. LMWH also has a lower binding affinity for platelets and produces less microvascular bleeding. Evidence from randomized clinical trials demonstrates that LMWH is effective in the prevention of deep vein thrombosis (DVT) in high-risk orthopedic patients. There is also considerable evidence of its efficacy and safety in the initial treatment of proximal DVT. Recent studies have demonstrated the feasibility of home treatment with LMWH, which offers the advantage of greater clinical utility compared with current antithrombotic regimens and hence the possibility of cost savings.

Standard heparin is an effective anticoagulant that is widely used in the prevention and treatment of venous thromboembolism. ' However, there are several limitations of standard heparin related to its pharmacokinetic, antihemostatic and biophysical properties that reduce its clinical utility. Standard heparin binds to a number of plasma proteins that compete with its binding to antithrombin, and thus contributes to a variable dose response and the phenomenon of heparin resistance. In addition, standard heparin binds to endothelial cells and macrophages, which are responsible for its dose-dependent mechanism of clearance.

As many of the heparin-binding proteins are phase-reactant proteins, there is not only inter-patient variation in response to standard heparin, but also a variable response within individual patients depending on their state of health. This variation in response contributes to the complexity of managing standard heparin treatment. Thrombin bound to fibrin and factor Xa in the prothrombin complex on the platelet surface are both relatively resistant to inactivation by the combination of heparin and antithrombin. This limits the anticoagulant activity of standard heparin in some circumstances. In addition to its inhibitory effects on coagulation, standard heparin binds to platelets and inhibits their function thus contributing to the hemorrhagic side effects of standard heparin.

ADVANTAGES OF LOW-MOLECULAR-WEIGHT HEPARIN

To overcome these limitations, standard heparin, which is a mixture of glycosaminoglycans of various molecular weights ranging from 2-30 kD, has been fractionated into various components. The component of heparin with a molecular weight from 4.0-5.5 kD, the low-molecular-weight fraction, has pharmacological and pharmacokinetic advantages over the parent compound mat translate into potential efficacy and safety benefits. Low-molecular weight heparin (LMWH) exhibits less binding to plasma proteins and endothelial cells, and therefore has a much more predictable dose response, and a dose-independent mechanism of clearance. Reduced endothelial cell binding at least partially contributes to the longer plasma half-life of LMWH.2 In experimental models of thrombosis, LMWH retains the ability to inhibit thrombus development, but at equipotent antithrombotic doses to standard heparin produces much less bleeding, in part because of less platelet binding and less microvascular bleeding.3

Table

TABLE 1Different types of LMWH

TABLE 1

Different types of LMWH

The pharmacologic and pharmacokinetic properties of LMWH in comparison to standard heparin result in a number of differences that are clinically important. Even in therapeutic doses, LMWH has little or no effect on standard tests of blood coagulation.2 This is an important difference because the effectiveness of anticoagulant therapy in the past has been related to therapeutic prolongation of standard coagulation tests such as the prothrombin time with oral anticoagulants or the activated partial thromboplastin time with standard heparin. In addition, because LMWH has a lower platelet binding affinity and produces less microvascular bleeding with an equivalent antithrombotic effect in experimental animals, there is potential for less bleeding in the perioperative period.

The difference in the plasma clearance of LMWH and standard heparin results in greater clinical utility through a more stable and predictable dose response. Thus, LMWH may be given subcutaneously in a fixed dose for thrombosis prophylaxis and subcutaneously in a fixed weight-adjusted dose for the treatment of thrombosis. Several LMWHs have been evaluated in clinical trials in the management of thromboembolic diseases (Table 1). There are major chemical and pharmacological differences between these agents and because of these differences regulatory authorities have required testing of each LMWH for all indications for which approval is sought.

Table

TABLE 2Comparison of LMWH and heparin as DVT prophylaxis in general surgery: results of a meta-analysis

TABLE 2

Comparison of LMWH and heparin as DVT prophylaxis in general surgery: results of a meta-analysis

LMWH AND THROMBOEMBOLIC DISEASE

The most extensive clinical evaluation of LMWH has been carried out in the prevention and treatment of thromboembolic disease. Venous thromboembolism is a common complication in surgical patients. In the absence of prophylaxis, patients undergoing major general surgery have a 10%-40% incidence of calf-vein thrombosis, a 2%8% incidence of proximal deep vein thrombosis (DVT) and a 0.1%-0.8% incidence of fatal pulmonary embolism (PE). Patients undergoing orthopedic procedures who do not receive prophylaxis are at higher risk for venous thromboembolism, with 40%-80% developing calf- vein thrombosis, 10%20% proximal DVT and l%-5% fatal PE.4 Thus, the morbidity and mortality associated with thromboembolic disease is a major problem in hospitalized patients.

Several methods of thrombosis prophylaxis have been evaluated including the use of low-dose standard heparin, dose-adjusted standard heparin, oral anticoagulants, antiplatelet drugs, intermittent pneumatic compression devices, and LMWH. Low-dose heparin prophylaxis is a commonly recommended and utilized form of prophylaxis for moderate and high-risk patients. In one meta-analysis, low-dose heparin was shown to be effective in reducing the risk of venous thrombosis in general surgery patients, orthopedic patients, and patients undergoing urological procedures, with a risk reduction in each category of approximately 65%.5 Different LMWHs have recently been evaluated for the prevention of venous thromboembolism in randomized clinical trials in high-risk surgery patients. The data from the general surgery studies demonstrate that LMWHs are effective in preventing DVT (Table If and, in doses that give an equivalent antithrombotic effect to standard unfractionated standard heparin, the risk of bleeding complications is much less. Thus, these relative safety and efficacy data favor the use of LMWH over unfractionated standard heparin in general surgery patients.

Patients undergoing orthopedic procedures provide a much more rigorous test of the efficacy and safety of prophylactic regimens. Before the introduction of LMWH, a number of methods of thrombosis prophylaxis were evaluated in patients undergoing orthopedic procedures, but none was ideal. Low-dose subcutaneous standard heparin is only 50% effective and aspirin has been shown to be of no benefit when venography is used to detect venous thrombosis. Dextran, which provides about a 50% risk reduction, is not widely used because of the high frequency of side effects associated with its use, including heart failure and allergic reactions.

Table

TABLE 3DVT prophylaxis in elective hip surgery: results of a meta-analysis

TABLE 3

DVT prophylaxis in elective hip surgery: results of a meta-analysis

Table

TABLE 4Comparison of LMWH and standard heparin prophylaxis for DVT in orthopedic patients: results of a meta-analysis

TABLE 4

Comparison of LMWH and standard heparin prophylaxis for DVT in orthopedic patients: results of a meta-analysis

Table

TABLE 5ACCP consensus conference on antithrombotic therapy

TABLE 5

ACCP consensus conference on antithrombotic therapy

Oral anticoagulants, which are widely used but require careful monitoring, result in an approximately 60% risk reduction in venous thrombosis.7 The absolute rates of thrombosis in randomized trials in patients undergoing total hip replacement are shown in Table 3. Several studies in patients undergoing elective and emergency orthopedic procedures have demonstrated the safety and efficacy of LMWH. In a metaanalysis of studies comparing LMWHs with standard heparin in orthopedic patients, LMWHs were shown to be either as effective as, or superior to, standard heparin in the prevention of DVT and were not associated with an increased risk of bleeding (Table 4).6

The Fourth Consensus Conference of the American College of Chest Physicians (ACCP) reviewed the evidence from randomized clinical trials of thrombosis prophylaxis in high-risk orthopedic patients and, based on the results of the studies, developed a series of guidelines for the prevention of venous thromboembolism in this patient population.8 It is important to note that these guidelines are not the standard of care, but contribute to the standard of care, and data from the comparative trials should be assessed to determine the optimal management of individual patients at risk. The guidelines developed by the ACCP for prophylaxis in orthopedic patients are shown in Table 5.

TREATMENT OF VENOUS THROMBOEMBOLISM

Venous thromboembolism is the third most common vascular disease associated with thrombosis after ischemic heart disease and stroke. Despite the advances in prevention and recommendations for primary prophylaxis, DVT remains a problem in postoperative patients and requires active treatment. In addition, venous thromboembolism may occur in ambulant patients without an obvious predisposing cause. The treatment of choice for most patients with venous thromboembolism is intravenous standard heparin followed by secondary prophylaxis with warfarin for up to 6 months, depending on associated risk factors for recurrence.9 The pharmacokinetic and pharmacologic properties of LMWH make it an excellent candidate for the treatment of venous thromboembolism, enabling weight-adjusted fixed-dose LMWH given subcutaneously to be used in the initial treatment. Recent studies have shown that LMWH is as effective or more effective than doseadjusted intravenous standard heparin in the treatment of DVT.10 The data from an overview of the studies comparing fixed-dose LMWH with unfractionated standard heparin is shown in Table 6.

OUTPATIENT TREATMENT WITH LMWH

Because LMWH is effective when given in fixed doses by the subcutaneous route, home treatment for patients with DVT who are not severely ill may be possible with LMWH. This issue has been addressed in two clinical trials, one performed in Canada11 and the other in Europe and Australia (the Tasman Study)12, involving a total of 900 patients with acute proximal DVT who were randomized to fixed-dose LMWH, given mainly at home, or continuous intravenous standard heparin administered in hospital. The results of both studies showed nonsignificant reductions in recurrent venous thromboembohsm in patients treated with LMWH with no difference in bleeding comphcations. There were no deaths due to PE in patients managed at home. The results of both studies11,12 were consistent with the conclusions of a meta-analysis of earlier trials10 and a combined analysis of data from these three analyses indicates significantly greater efficacy and safety of LMWH compared with standard heparin (Table 7).

Both studies demonstrated the feasibility of home treatment and it is likely that these data, along with results of ongoing clinical trials, will result in a shift of management of most patients with venous thromboembohsm to the outpatient setting resulting in greater clinical utility and potential cost savings. This will have an added advantage in patients who develop venous thrombosis in hospital as a complication of surgery or other illnesses reducing the need for prolongation of the hospital stay and allowing uninterrupted convalescence. Based on the solid scientific evidence for efficacy and safety of LMWH, the ACCP has recommended the use of LMWH as an alternative to standard heparin in the treatment of DVT.9

CONCLUSION

LMWH represents an important advance in the prevention and treatment of venous thromboembolism. Data from randomized clinical trials have demonstrated its effectiveness and safety and, because of its improved clinical utility with fixed-dose subcutaneous administration, LMWH is likely replace standard heparin in clinical practice.

Table

TABLE 6Comparison of LMVVH and standard heparin In the treatment of DVT: a meta-analysis

TABLE 6

Comparison of LMVVH and standard heparin In the treatment of DVT: a meta-analysis

Table

TABLE 7Comparison of LMVVH and standard heparin in the treatment of venous thrombosis

TABLE 7

Comparison of LMVVH and standard heparin in the treatment of venous thrombosis

REFERENCES

1 - Hirsh J. Drug therapy. Heparin. N Engl J Med. 1991;324:1565-1574.

2. Hirsh J, Levine M. Low molecular weight heparin. Blood. 1992; 79:1-17.

3. Cade JF, Buchanan MR, Boneu B, et al. A comparison of the antithrombotic and haemorrhagic effects of low-molecular-weight heparin fractions: The influence of the method of preparation. Thromb Res. 1984; 35:613-625.

4. Turpie AGG. Thromboprophylaxis in orthopaedic surgery. Orthopaedics International. 1993; 1:396-402.

5. Collins R, Scrimgeour A, Yusuf S, et al. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. Overview of results of randomized trials in general, orthopedic and urologie surgery. N Engl J Med. 1988;318:1162-1173.

6. Nurmohamed MT, Rosendaal FR, Buller HR, et al. Low molecular weight heparin versus standard heparin in general and orthopaedic surgery. A meta-analysis. Lancet. 1992;340:152-156.

7. Mohr DN, Silverstein MD, Murtaugh PA, et al. Prophylactic agents for venous thrombosis in elective hip surgery. Meta-analysis of studies using venographic assessment. Arch Intern Med. 1993; 153:2221-2228.

8. Clagett GP, Anderson FA Jr, Heit J, Levine M. Prevention of venous thromboembolism. Chest. 1995; 108:312S-334S.

9. Hyers TM. Hull RD, Weg JG. Antithrombotic therapy for venous thromboembolic disease. Chest. 1995; 108:335S-351S.

10. Lensing AWA, Prins MH, Davidson BL, Hirsh J. Treatment of deep venous thrombosis with low molecular weight heparins. A metaanalysis. Arch Intern Med. 1995; 155:601-607.

11. Levine M, Gent M, Hirsh J, et al. A comparison of low-molecular weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep vein thrombosis. N Engl J Med. 1996;334:677-681.

12. Koopman MMW, Prandoni P, Piovella F, et al (for the Tasman Study Group). Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular weight heparin administered at home. N Engl J Med. 1996; 334:682-687.

TABLE 1

Different types of LMWH

TABLE 2

Comparison of LMWH and heparin as DVT prophylaxis in general surgery: results of a meta-analysis

TABLE 3

DVT prophylaxis in elective hip surgery: results of a meta-analysis

TABLE 4

Comparison of LMWH and standard heparin prophylaxis for DVT in orthopedic patients: results of a meta-analysis

TABLE 5

ACCP consensus conference on antithrombotic therapy

TABLE 6

Comparison of LMVVH and standard heparin In the treatment of DVT: a meta-analysis

TABLE 7

Comparison of LMVVH and standard heparin in the treatment of venous thrombosis

10.3928/0147-7447-19970202-06

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