Frequently Asked Questions

Low Molecular Weight Heparins (LMWHs)

What low molecular weight heparins are indicated to treat deep vein thrombosis (DVT)?

The only LMWH that is indicated to treat DVT is Lovenox®(enoxaparin sodium, Rhône Poulenc-Rorer).

How do LMWHs work?

The exact mechanism of action is unknown. However, it is thought that LMWHs bind to antithrombin III causing a conformational change in that molecule. This change allows antithrombin III to bind Factor Xa to a much greater extent than factor IIa. With Factor Xa tightly bound to antithrombin III, it can not interact with prothrombin. This inhibits the conversion of prothrombin to thrombin and inhibits clot formation.

Inpatient vs. Outpatient Treatment

How can I be sure that Lovenox is safe and effective for outpatient treatment?

The safety and efficacy of Lovenox used in the outpatient treatment of DVT has been evaluated by clinical trials. A study by Levine and colleagues found that Lovenox provides efficacy and safety comparable to heparin in the hospital. In this randomized study, Lovenox administered twice a day at home was compared to heparin administered in the hospital. The incidence of recurrent thromboembolism within 90 days after the start of therapy was 5.3% in the Lovenox group compared to 6.7% in the heparin group.

Clinical Administration

Are there any special precautions that I should take when administering Lovenox?

You may notice a gas bubble in the prefilled Lovenox syringe. This gas bubble should not be expelled. The full length of the needle should be introduced vertically. Finally, the injected area should not be rubbed.

How long should I continue treatment with Lovenox?

Treatment of DVT with or without PE with Lovenox should continue for a minimum of 5 days and until a therapeutic anticoagulant effect from warfarin has been achieved (International Normalization Ratio [INR] 2.0 to 3.0). The average duration of administration is 7 days, although up to 17 days of Lovenox therapy has been well tolerated in clinical trials.

Safety

What safety precautions are necessary with Lovenox treatment?

Can I use Lovenox for pregnant or nursing women?

Lovenox is in pregnancy category B meaning that studies in animals showed no evidence of teratogenicity or fetotoxicity. Lactating mothers should be cautioned when receiving Lovenox. Several small studies have shown that the use of LMWH in pregnant women was safe. However, there are no adequate and well controlled studies in this patient population.

Will I need to adjust the dose for elderly patients?

Because elderly patients may have decreased renal function, Lovenox elimination could be delayed. For this reason, Lovenox should be used with care in these patients. In addition, adjustment of Lovenox dosage may be considered for patients of low weight (< 45 kg) and/or for patients with severe renal impairment (creatinine clearance < 30 mL/min) (Lovenox Full Prescribing Information). There are two studies that looked at outpatient treatment of DVT. The average age of the patients in each study was 57 and 59 years. Both studies concluded that Lovenox was as safe as heparin.

Do I have to worry about my patients developing thrombocytopenia in patients on Lovenox?

Lovenox is associated with a lower risk of immune sensitization and thrombocytopenia than heparin. However, it is possible for Lovenox to produce a positive in-vitro test for heparin induced thrombocytopenia (HIT) in patients with a history of HIT. Thrombocytopenia may occur in these patients. Warkentin et. al. conducted a large randomized clinical trial comparing the occurrence rate of thrombocytopenia between unfractionated heparin and Lovenox. His group found that HIT occurred in 2.7% of patients treated with UFH and 0.0% of patients treated with Lovenox.

Are all LMWHs the same?

No, they are not the same. They differ in their manufacturing process, molecular weight distribution, anti-Xa and anti-IIa activities, units and dosage. They can not be used interchangeably.

Complications During Treatment

How should a hemorrhagic manifestation be managed during treatment?

It is important to rule out other causes of bleeding. For example:

Major bleeding defined as a decrease in the hemoglobin level of at least 2.0 g/dL or a need for the transfusion of 2 or more units of blood, requires withdrawal of the drug. The patient's condition will determine other support measures. Less severe cases simply may require temporary withdrawal of Lovenox and close observation of the patient's progress.

What if a patient suffers a thromboembolic event during Lovenox treatment?

If this occurs, Lovenox should be discontinued. The patient's condition needs to be reassessed in order to determine appropriate therapy.

Laboratory Tests

How can/should treatment with Lovenox be monitored?

Lovenox does not require coagulation tests when recommended treatment doses are used. It has little effect on aPTT or PT. Only tests evaluating anti-Xa activity can be used (e.g., anti-Xa mucolytic assay or a chronometric test such as the Heptest). Periodic complete blood counts, including platelet count and stool occult blood tests, are recommended during the course of treatment with Lovenox.

Why don't I have to monitor a patient's aPTT while they are on Lovenox?

At the recommended doses, single injections of enoxaparin do not significantly influence platelet aggregation or affect global clotting tests (i.e., prothrombin time [PT] or activated partial thromboplastin time [aPTT]). Therefore, these tests, are not useful in monitoring therapy with Lovenox.

The major anticoagulant effect of the LMWHs is the accelerated inactivation of coagulation Factor Xa. While there are laboratory methods for determining anti-Xa activity of LMWH in plasma, the antithrombotic action of LMWH may not be directly related alone to the anti-Xa effect measured in plasma Other factors, such as platelet effects, may be involved as well.

Since more extensive studies are needed to determine the clinical relevance of such laboratory results in treating patients with Lovenox, this laboratory test is only recommended in extreme situations, such as when there is evidence or suspicion of bleeding.

Clinical Trials of Lovenox

What support do you have for the use of Lovenox in the treatment of DVT?

Clinical studies of Lovenox support its safety and efficacy in the treatment of DVT with or without PE. In a multi-center, parallel group study, 900 patients with acute DVT were randomized to either inpatient treatment with Lovenox administered 1.5 mg/kg once a day SC, Lovenox administered 1.0 mg/kg every 12 hours SC, or heparin IV bolus (5,000 IU) followed by a continuous infusion. All patients in the study received treatment with warfarin sodium within 72 hours of the initiation of Lovenox or heparin therapy. The results of this study revealed that both Lovenox injections were equivalent to standard heparin therapy in the prevention of recurrent venous thromboembolism.

A clinical study by Levine and colleagues evaluated 501 patients with acute DVT. These patients were randomized to either outpatient treatment with Lovenox or inpatient treatment with heparin. It is important to mention that patients who were not eligible for outpatient treatment were excluded from the study and only those patients randomized to the Lovenox group were allowed to go home. Patients received either Lovenox injection 1.0 mg/kg every 12 hours SC or heparin IV bolus, 5000 IU followed by a continuous infusion.

Both Lovenox and heparin were administered for a minimum of 5 days, and all patients received treatment with warfarin sodium as well. The results of this study show that Lovenox injection is equivalent to standard heparin therapy in the prevention of recurrent thromboembolism.

Lovenox Compared to Heparin

Why should I try Lovenox?

Lovenox has been proven to be as safe and effective as heparin in clinical trials. Lovenox has several advantages over heparin, including the fact that it has an indication for outpatient therapy and it does not require routine monitoring. Also, unlike heparin, Lovenox has excellent bioavailability, resulting in a predictable dose response. Finally, therapy with Lovenox is potentially less expensive than heparin therapy when all costs of monitoring and staff time are considered.

Concurrent Therapy

Can other drugs that require intramuscular injection be administered while patients are receiving Lovenox therapy?

Intramuscular injections are not recommended in patients receiving Lovenox.

Are NSAIDs contraindicated with concurrent use of Lovenox?

NSAIDs are not specifically contraindicated, but the Lovenox labeling includes a warning about the use of concomitant treatment with platelet inhibitors, such as aspirin. All NSAIDs inhibit platelet function and, as a result, may affect primary hemostasis. Aspirin is a particularly important NSAID in this regard since it irreversibly inhibits platelet function. The lifetime of a platelet is approximately 7 days, thus primary hemostasis will be affected for this period following treatment with ASA. Other NSAIDs have reversible platelet inhibiting effects but nevertheless may interfere with primary hemostasis. However, this inhibition is more transient, lasting 24 to 48 hours after cessation of use.

In any event, the concomitant use of these agents with any antithrombotic agent, including Lovenox, may increase the possibility of bleeding, since both primary hemostasis and coagulation will be affected simultaneously. Lovenox should be used with care in patients receiving any platelet inhibitors, including NSAIDs.

References

Important Studies That Evaluate Safety and Effectiveness of Low-Molecular-Weight Heparins in Treatment of DVT

Enoxaparin
Venous Thromboembolic Disease Treatment Study 529: Data on file Rhône Poulenc-Rorer		 Multicenter randomized partially-blind parallel-group study of 900 patients
  • DVT confirmed by venography
  • Warfarin begun within 72 hours
  • Primary outcomes: anatomic outcome at 6 to 10 days, clinical outcome over 3 months
    		•  Subcutaneous enoxaparin once or twice daily is as safe as unfractionated heparin (UFH). No significant difference between enoxaparin and UFH groups.
    Subcutaneous enoxaparin once or twice daily is equivalent to intravenous UFH.
    Simonneau et al., Arch Intern Med 1993;153:1541-1546 Multicenter, randomized study of 134 patients
  • Bilateral ascending venography in all patients at baseline and day 10; repeat bilateral venography in patients with clinically suspected DVT; outcome measures clot size evolution
  • Lung perfusion scan within first 48 hours; repeat scan on day 10 or sooner if symptomatic
  • 3-month follow-up
    		•  Enoxaparin is at least as effective and safe as UFH, more comfortable for patients, and less time consuming for nurses and laboratories.
    Levine et al., N Engl J Med 1996;334:677-681 Randomized study of 500 patients. Exclusion criteria included patients with 2 or more previous venous thromboembolisms,PE, currently active bleeding, active PUD, bleeding disorder, or pregnancy
  • DVT confirmed by venography or duplex ultrasonography
  • Clinical outcomes: symptomatic DVT/PE, death, major bleeding
  • Warfarin begun on day 2, usually at 10mg
  • PT measured daily in outpatients
  • Each outpatient contacted by study nurse daily and warfarin dose adjusted
    		•  No significant difference between groups LMWH (enoxaparin) and UFH in recurrence of thromboembolism or major bleeding; LMWH patients spent (mean) 1.1 days hospitalized, UFH patients spent 6.5 days; 120/247 LMWH patients never hospitalized

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