HAMILTON, Ontario -- For treatment of acute thromboembolism, fixed-dose weight-adjusted unfractionated heparin delivered subcutaneously may be as effective and safe as low molecular weight heparin, but at a fraction of the cost.
HAMILTON, Ontario, Aug. 22 -- For treatment of acute thromboembolism, fixed-dose weight-adjusted unfractionated heparin delivered subcutaneously may be as effective and safe as low molecular weight heparin, but at a fraction of the cost.
In an open-label, non-inferiority trial that compared the two treatments in 697 adults with acute venous thromboembolism, there was no significant difference in recurrent thromboembolism at three months or in major bleeding within 10 days of randomization, wrote Clive Kearon, M.B., Ph.D., and his fellow FIDO (Fixed-Dose Heparin) investigators.
Moreover, drug costs for a six-day course of treatment for a patient weighing 176 pounds would be for low molecular weight heparin Lovenox (enoxaparin) or Fragmin (dalteparin) versus for unfractionated heparin, they reported in the Aug. 23 issue of the Journal of the American Medical Association.
The patients received either a loading dose of 333 U/kg of unfractionated heparin, followed by a fixed dose of 250 U/kg every 12 hours or 100 IU/kg of Lovenox or Fragmin every 12 hours.
The cost-effectiveness of the study was further enhanced by its design. Contrary to current clinical practice, which requires ongoing activated partial thromboplastin time (aPTT) monitoring, measurement of activated partial thromboplastin time or heparin levels was prohibited.
Instead, activated partial thromboplastin time was measured midway between injections in just 197 of the 345 patients randomized to unfractionated heparin. These values were shorter than 60 seconds in 39 patients, 60 to 85 seconds in 37 patients, and longer than 85 seconds in 121 patients.
There was no recurrent thromboembolism at three months in patients with an activated partial thromboplastin time of less than 60 seconds and no major bleeding at 10 days in patients who had such measurements, which led the authors to conclude that it is time to "question the value of activated partial thromboplastin time monitoring in patients who are treated with currently recommended doses of unfractionated heparin."
The mean age of patients was 60, and in 81% of the qualifying thrombotic event was isolated deep vein thrombosis.
Recurrent thrombosis occurred in 13 patients treated with unfractionated heparin and in 12 patients treated with Lovenox or Fragmin. Major bleeding during the first 10 days of treatment occurred in four patients treated with unfractionated heparin and four patients in the comparison arm.
Seventy-two percent of the unfractionated heparin patients and 68% of the Lovenox and Fragmin patients were treated as outpatients.
The authors said the study was limited by its open-label design, which could have led to a biased assessment of outcome, a limitation they said was overcome by blinded, central adjudication.
It was also limited by its small size, and by more post randomization exclusions in the unfractionated heparin arm than in the Lovenox/Fragmin group (ten patients versus one patient).
Steven Deitelzweig, M.D., chairman of hospital medicine at the Ochsner Health System in New Orleans, said it will take more than this study to convince him that unfractionated heparin is a as good as Lovenox.
He said that although the difference in price is impressive, "we would need a very robust finding from a large well, designed clinical trial to change clinical practice-and that is true worldwide, not just here in the U.S."
Dr. Deitelzweig said that "low molecular weight heparin receives a class I recommendation from the American College of Chest Physicians, so it would take a preponderance of evidence-not one 700-patient study-to change that."
In an accompanying editorial, Jeffrey L. Carson, M.D., of the UMDNJ-Robert Wood Johnson Medical School in New Brunswick, N.J., said it is clear that the biggest argument in favor of unfractionated heparin over Lovenox or Fragmin is cost, and by itself that "may be an important advance in the treatment of thromboembolism."
But the question for physicians is whether the evidence presented by Dr. Kearon and colleagues is persuasive enough to change clinical practice, said Dr. Carson, and he concluded that as appealing as this evidence may be-especially since it demonstrated that monitoring of activated partial thromboplastin time is not required--it is not enough.
He concluded that "more than one study that demonstrates the efficacy of this new treatment regimen is necessary before changing the management strategy for this potentially lethal disease."