Under what circumstances is outpatient therapy possible? Using low molecular weight heparins to treat venous thromboembolism key words: Deep venous thrombosis, Pulmonary embolism, Heparin, Anticoagulant therapy

Physicians have relied on unfractionated heparin to treat acute venous thromboembolism (VTE) for more than 45 years.¹ Symptomatic recurrences of VTE are uncommon when the patient receives adequate initial doses of unfractionated heparin that result in therapeutic prolongation of the activated partial thromboplastin time (aPTT). In fact, most clinical trials report that fewer than 10% of patients have such recurrences during the first 3 months of treatment with unfractionated heparin followed by warfarin.^2-9 Failure to achieve a therapeutic anticoagulant effect with unfractionated heparin substantially increases the risk of recurrence of VTE.^10-12

To ensure therapeutic levels of heparin, the patient's aPTT must be checked often during the initiation of therapy and the dose adjusted promptly when the aPTT remains below the therapeutic threshold. Intuitive heparin dosing often leads to inadequate initial treatment, whereas standard protocols are highly effective.^5,13

Low molecular weight heparins (LMWHs) offer an alternative to unfractionated heparin, and they do not require frequent measurement of aPTT. But how do these agents compare with unfractionated heparin in efficacy and safety?

In this article, we will review the role of LMWHs in the management of deep venous thrombosis and pulmonary embolism. We will also briefly discuss heparin-induced thrombocytopenia.

What are LMWHs?

Produced by enzymatic or chemical depolymerization, LMWHs are fragments of unfractionated heparin. Unlike unfractionated heparin, LMWHs do not bind to circulating proteins, endothelial cells, or macrophages (Table 1).

Consequently, the dose of a LMWH is predictable based on the patient's body weight. Because LMWH dosing is predictable, monitoring the anticoagulant effect is unnecessary. This represents a distinct advantage over using conventional therapy with unfractionated heparin.

Heparin, both unfractionated and low molecular weight, inhibits thrombus formation. The anticoagulant properties of unfractionated heparin and LMWHs increase the risk of bleeding. Therefore, active bleeding is a contraindication to their use. Physicians must exercise judgment when using LMWHs to treat patients who are at increased risk for major bleeding complications (Table 2).

Several LMWHs have been developed (Table 3). Although these preparations are pharmacologically similar, they are not interchangeable; their therapeutic use is based on clinical data for each agent.

Deep venous thrombosis

•Inpatient treatment: LMWHs are important additions to the therapeutic armamentarium because deep venous thrombosis can be managed with once- or twice-daily subcutaneous doses based on the patient's weight and because no dose adjustment is required. In well-designed clinical trials, LMWHs have proved to be modestly superior to conventional treatment with unfractionated heparin.^4,14

The patient must receive at least 5 days of treatment with LMWHs in conjunction with the initiation of warfarin therapy. Physicians generally start administering warfarin during the first or second day of treatment. LMWHs should not be discontinued until the prothrombin time is therapeutic: the international normalized ratio (INR) is 2.0 to 3.0 for 2 consecutive days.

Table 4 lists the dosages of sev-eral LMWHs for treating VTE. Be careful to avoid the error of prescribing the lower doses of LMWHs that are indicated to prevent deep venous thrombosis.

The optimal doses of LMWHs for some patients (such as those who are morbidly obese or have severely impaired renal function) remain uncertain. Physicians may prefer to use unfractionated heparin in patients who weigh more than 150 kg (330 lb) or who have renal failure or unstable renal function. However, limited data suggest that body mass (up to 190 kg [418 lb]) does not alter the response to LMWH.^15,16

Conversely, caution and dose adjustments are necessary when LMWHs are used in the setting of renal insufficiency.^17-19 The FDA has approved dose adjustments for enoxaparin for patients with a creatinine clearance less than 30 mL/min (Table 5). However, there is no approved dosing regimen for patients receiving dialysis. Unfractionated heparin and LMWH remain the treatments of choice for pregnant or nursing women.¹⁴

•Outpatient treatment: Therapy with LMWHs allows select patients to avoid hospital admission or to have a shortened length of stay.^7,8,20 Inpatient treatment remains necessary for persons with risk factors for major bleeding complications, for those with symptomatic pulmonary embolism, or when noncompliance with treatment is likely.

Patients who have symptomatic proximal deep venous thrombosis frequently have asymptomatic pulmonary embolism. These patients may receive outpatient LMWH therapy if there are no other contraindications. An example of VTE (iliac vein thrombosis) can be seen in the Figure.

Outpatient management requires a system for monitoring patients and their response to treatment. Many physicians arrange daily telephone follow-up, prothrombin time tests (reported as the INR), and warfarin dose adjustments, while others arrange for home visits by a nurse or for office visits by the patient.

Clearly, the cost of treatment is reduced by outpatient therapy; in one analysis, costs were reduced by more than $400 per patient.²¹

Acute pulmonary embolism

Available data suggest that LMWHs are as effective as unfractionated heparin for the initial treatment of acute pulmonary embolism.^2,3,14 The largest clinical trial of patients with acute pulmonary embolism excluded those with massive pulmonary emboli,² and no trial has carefully evaluated outpatient treatment of symptomatic pulmonary embolism. Thus, at present, the option of treating pulmonary embolism with LMWHs remains limited to inpatients with less severe disease.

Heparin-induced thrombocytopenia

LMWHs can cause thrombocytopenia. However, this complication appears to occur less frequently with LMWHs than with unfractionated heparin.²²

Because heparin-induced thrombocytopenia can complicate treatment with LMWHs, the patient's platelet count must be monitored periodically during therapy. If the patient's platelet count falls be- low 100,000/µL, discontinue the LMWH. Do not use LMWHs if the patient has a history of heparin- induced thrombocytopenia. If there is a history of well-documented heparin-induced thrombocytopenia or if heparin-induced thrombocytopenia develops, you may use danap- aroid, recombinant hirudin, or argatroban, depending on the availability of these agents.²³

References:

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2. Simonneau G, Sors H, Charbonnier B, et al, for the THESEE Study Group. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. Tinzaparine ou Heparine Standard: Evaluations dans l'Embolie Pulmonaire. N Engl J Med. 1997;337:663-669.

3.The Columbus Investigators. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med. 1997;337: 657-662.

4. Hull RD, Raskob GE, Pineo GF, et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med. 1992;326:975-982.

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10. Hull RD, Raskob GE, Brant RF, et al. Relation between the time to achieve the lower limit of the APTT therapeutic range and recurrent venous thromboembolism during heparin treatment for deep vein thrombosis. Arch Intern Med. 1997; 157:2562-2568.

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16. Bazinet A, Almanric K, Brunet C, et al. Dosage of enoxaparin among obese and renal impairment patients. Thromb Res. 2005;116:41-50.

17. Hulot JS, Montalescot G, Lechat P, et al. Dosing strategy in patients with renal failure receiving enoxaparin for the treatment of non-ST-segment elevation acute coronary syndrome. Clin Pharmacol Ther. 2005;77:542-552.

18. Kruse MW, Lee JJ. Retrospective evaluation of a pharmacokinetic program for adjusting enoxaparin in renal impairment. Am Heart J. 2004;148: 582-589.

19. Lim W, Dentali F, Eikelboom JW, Crowther MA. Meta-analysis: low-molecular-weight heparin and bleeding in patients with severe renal insufficiency. Ann Intern Med. 2006;144:673-684.

20. Goldhaber SZ, Morrison RB, Diran LL, et al. Abbreviated hospitalization for deep vein thrombosis with the use of ardeparin. Arch Intern Med. 1998;158:2325-2328.

21. Hull RD, Raskob GE, Rosenbloom D, et al. Treatment of proximal vein thrombosis with subcutaneous low-molecular-weight heparin vs intravenous heparin. An economic perspective. Arch Intern Med. 1997;157:289-294.

22. Warkentin TE, Kelton JG. Heparin-induced thrombocytopenia. Prog Hemost Thromb. 1991; 10:1-34.

23. Hirsh J, Raschke R. Heparin and low-molecular-weight heparin: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(suppl 3):188S-203S.