Outpatient Unfractionated Heparin Equal To LMW Version?

By John R. Bell

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A new randomized, double-blind, noninferiority trial has found that not only does fixed-dose, weight-adjusted, subcutaneous unfractionated heparin appear to be as safe and effective as low-molecular-weight heparin in treating venous thromboembolism, but it also appears to be safe to give unfractionated heparin without the traditional monitoring that has so far limited it to inpatient use.

Dr. Clive Kearon of Hamilton (Ont.) Life Sciences and colleagues from the Fixed-Dose Heparin Investigators group enrolled 708 patients who had newly diagnosed deep vein thrombosis (DVT) in the legs (and who did not meet various exclusion criteria) from six centers in Canada and New Zealand over a 6-year period. Patients were randomly assigned either open-label unfractionated heparin (UH) or low-molecular-weight heparin (LMWH) (JAMA 2006;296;935-42).

UH was given subcutaneously with a beginning dose of 333 U/kg and a fixed dosage of 250 U/kg administered every 12 hours thereafter. LMWH was given subcutaneously every 12 hours at 100 U/kg. Patient weight was the only value used to adjust dosage; neither activated partial thromboplastin time (aPTT) nor heparin level was assessed by the clinical centers, although aPTT was assayed at a central laboratory by blinded technicians for end-of-study analysis.

Both regimens were administered with concomitant warfarin. Investigators assessed the patients at 3 days, 1 month, and 3 months after treatment initiation.

Of participants in the UH group, 72% were treated on an outpatient basis, versus 68% of those who were in the LMWH group.

For both the primary efficacy end point (venous thromboembolism [VTE] recurrence within 3 months) and the primary safety end point (incidence of major bleeding within 10 days of randomization), the results were not significantly different.

Of the 345 UH patients included in the efficacy analysis, 13 patients (3.8%) experienced recurrence of VTE within 3 months, versus 12 patients (3.4%) in the 352-patient LMWH group. Likewise, four (1.1%) of the 348 UH patients included in the safety analysis experienced major bleeding in the first 10 days of treatment, compared with five (1.4%) of the 352 included patients on LMWH.

In addition, there were 18 deaths (5.2%) in the first 3 months among patients on UH, and 22 patients (6.3%) in the LMWH group died in the same period.

Notably, the investigators also observed that low aPTT was not associated in the UH group with greater incidence of recurrent VTE, nor was high aPTT associated with severe bleeding--findings that "question the value of [aPTT] monitoring in patients who are treated with currently recommended doses of unfractionated heparin," they wrote.

The dosage of UH, unlike that of LMWH, is customarily adjusted according to the patient's ongoing aPTT.

Because LMWH does not require aPTT monitoring and can thus be given in the more economical outpatient setting, LMWH has in recent years been replacing unfractionated heparin as conventional therapy for DVT, despite the greater drug cost of LMWH. The authors noted that for the drug alone, an 80-kg patient would require $712 for a 6-day course of LMWH, versus only $37 for UH. If aPTT monitoring--and thus inpatient administration of UH--is no longer required, then the cost savings of using LMWH disappears.

Dr. Jeffrey Carson, of the department of medicine at Robert Wood Johnson Medical School in Piscataway, New Jersey, noted in an accompanying editorial that although the approach of UH without aPTT monitoring is "appealing ... results must be replicated using an adequately powered, double-blind trial design ... before this approach can be adopted widely in clinical practice." (JAMA 2006;296:991-3).

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