Hamilton, ON - Fixed-dose subcutaneous unfractionated heparin, without monitoring of activated partial thromboplastin time (APTT), is as effective as fixed-dose low-molecular-weight heparin in patients with acute venous thromboembolism, according to the results of a new study [1]. In addition, the administration of unfractionated heparin was safe, with no increased bleeding risks, and could be considered an alternative for outpatient use, say investigators.

"We're pleased with the results, and we feel the findings are consistent with our expectations, that there would not be a difference between outcomes when you use unfractionated heparin and low-molecular-weight heparin in the same way," lead investigator Dr Clive Kearon (McMaster University, Hamilton, ON) told heartwire. "I think the data will be of interest to the medical community because it departs from what has been usual practice with a drug that has been in use clinically now for over 50 years."

The results of the study are published in the August 23, 2006 issue of the Journal of the American Medical Association.

Speaking with heartwire, Kearon noted there was indirect evidence suggesting that APTT monitoring didn't help improve the efficacy or safety of using unfractionated heparin if the patient had been started on an appropriate dose, leading the Fixed-Dose Heparin (FIDO) investigators to believe treatment adjustments in response to the APTT, which greatly complicates the use of heparin therapy, were unnecessary. Also, there was some evidence suggesting that heparin was at least as effective and as safe when given subcutaneously.

To test this hypothesis, 345 patients were randomized to initial treatment with open-label unfractionated heparin and 352 to low-molecular-weight heparin, each administered subcutaneously, twice daily, in doses determined by patient weight and without subsequent use of anticoagulation tests to modify the doses. Unfractionated heparin was administered as a first dose of 333 U/kg and followed by subsequent doses of 250 U/kg. Low-molecular-weight heparin, either dalteparin or enoxaparin, was administered at 100 IU/kg for all doses. Warfarin was typically started the same day as heparin and continued for a minimum of three months.

Patients were assessed at three days, one month, and three months after the initiation of drug treatment. Designed to test whether fixed-dose subcutaneous unfractionated heparin was as effective (noninferior) as low-molecular-weight heparin, the primary efficacy end point was the absolute difference in the proportion of patients who had recurrent venous thromboembolism at three months. The safety-analysis end point was the absolute difference in the episodes of major bleeding at 10 days between the two treatment arms.

Recurrent venous thromboembolism occurred in 3.8% of patients in the unfractionated-heparin-treatment arm and 3.4% of patients treated with low-molecular-weight heparin. The recurrent episode of venous thromboembolism was pulmonary embolism in two patients in the unfractionated heparin arm and four patients in the low-molecular-weight heparin arm. All remaining episodes were deep vein thrombosis. In terms of safety, major bleeding episodes at 10 days were equivalent in both treatment arms. Of those treated, 72% of unfractionated heparin patients and 68% of low-molecular-weight heparin patients were treated as outpatients.

The FIDO investigators obtained blood samples from patients six hours after the injection of unfractionated heparin on the third day for the measurement of the APTT. Although these results were not available to the clinical centers, the data showed a lack of association between low APTT results and recurrent venous thromboembolism or between high APTT results and bleeding, providing evidence that monitoring is not required with the dosing regimen.

Kearon said the immediate benefit of the simplified approach is the reduction in cost with the use of unfractionated heparin. For example, based on an average US wholesale price of $7.42 per 1000 IU of enoxaparin and $0.15 per 1000 U of unfractionated heparin, the drug costs for a six-day course of treatment for a patient weighing 80 kg would be $712 for low-molecular-weight heparin and $37 for unfractionated heparin (assuming both drugs were administered twice daily).

In an editorial accompanying the published study, Dr Jeffrey Carson (University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick) notes that low-molecular-weight heparin had proven advantageous in the past because it could be administered subcutaneously to ambulatory outpatients who were clinically stable, all without the need for APTT monitoring [2]. However, these new data are an important advance specifically because of the potential cost savings with unfractionated heparin.

"The question that physicians must now answer is whether this evidence is strong enough to change practice," writes Carson. "Specifically, should patients with venous thromboembolism be treated with fixed-dose weight-based subcutaneous unfractionated heparin instead of low-molecular-weight heparin to save money?"

Carson, echoing Kearon, calls for further study before practice is altered but writes that if the "patient can be observed very closely, this treatment regimen might be used very cautiously in carefully selected patients who prefer outpatient treatment of venous thromboembolism and cannot afford the expense of low-molecular-weight heparin."