What is the Optimal Dosing for Unfractionated Heparin?

Abstract & Commentary

By Joseph E. Scherger, MD, MPH, Clinical Professor, University of California, San Diego. Dr. Scherger reports no financial relationship to this field of study.
This article originally appeared in the May 15, 2007 issue of Internal Medicine Alert. It was edited by Stephen Brunton, MD, and peer reviewed by Gerald Roberts, MD. Dr. Brunton is Clinical Professor, University of California, Irvine, and Dr. Roberts is Clinical Professor of Medicine, Albert Einstein College of Medicine. Dr. Brunton is a consultant for Sanofi-Aventis, Ortho-McNeil, McNeil, Abbott, Novo Nordisk, Eli Lilly, Endo, EXACT Sciences, and AstraZeneca, and serves on the speaker's bureau for McNeil, Sanofi-Aventis, and Ortho-McNeil. Dr. Roberts reports no financial relationships relevant to this field of study.

Synopsis: Unfractionated heparin (UH) is commonly used in acutely ill hospital patients at risk for venous thromboembolism (VTE). Dosage regimens of 5000 units twice daily and three times daily are used, and have never been directly compared in a randomized clinical trial. A meta-analysis looking at both regimens shows that three times daily therapy reduced the rate of proximal deep vein thrombosis (DVT) and pulmonary embolism (PE); however, there is a small increased risk of bleeding complications. Patients at high risk for VTE should be treated with three times daily UH, while patients at lower risk may be treated with twice daily therapy.

Source: King CS, et al. Twice vs three times daily heparin dosing for thromboembolism prophylaxis in the general medical population: A meta-analysis. Chest. 2007;131:507-516.

Clinical guidelines now recommend using prophylaxis against VTE in high risk hospitalized patients. Subcutaneous, unfractionated heparin (UH) has become the treatment of choice due to its safety and ease of monitoring and administration. Patients who are commonly treated include any acutely ill patient confined to bed, such as one with heart failure, respiratory disease, or postoperative care. Patients with a previous history of DVT or PE are at particularly high risk and should be treated.

Dosage regimens of 2 times daily and 3 times daily are used and have never been compared, according to King and colleagues, who did an extensive review of the literature from 1966 through 2004. Five thousand units subcutaneously is the usual dosage with both regimens. King et al from the Department of Medicine at Walter Reed Medical Center in Washington, DC, performed the meta-analysis, looking at 447 articles over 38 years. All but 12 of the articles were excluded, mainly because they studied surgical and postoperative patients. A total of 7978 patients were represented in these 12 studies, with 6314 receiving 2 times daily therapy and 1664 patients receiving 3e times daily therapy.

The patients receiving 3 times daily therapy had fewer episodes of VTE than those receiving twice daily therapy. Total VTE risk was not significantly different in the 2 groups (5.4 per 1000 patient days with twice daily compared with 3.5 in the 3 times daily patients, P = 0.87). The risk of PE was significantly lower in the 3 times daily group (0.5 per 1000 patient days compared with 1.5 in the twice daily group, P = .09). Also, the risk of proximal DVT and PE was significantly lower in the 3 times daily group (0.9 per 1000 patient days compared with 2.3 in the twice daily group, P = .05). This reduced VTE risk is offset some by a higher risk of bleeding complications in the 3 times daily group (0.96 per 1000 patient days compared with 0.35 in the twice daily group, P = .0001).


While a head-to-head study of these 2 dosage regimens is needed, this careful study indicated that 3 times daily dosing of UH is superior to twice daily dosing, with some increased risk of bleeding complications. Note that the risk of bleeding in the 3 times daily group is lower than the risk of VTE, DVT, or PE in the twice daily group.

So what should we do with this important study? A prudent recommendation would be to use 3 times daily therapy for all patients at high risk for VTE, such as patients with a past history of DVT or PE, and immobile patients in bed. In patients in which the risk of VTE is lower but prophylaxis is still warranted, twice daily therapy would be appropriate to reduce the risk of bleeding complications. We can all thank King et al for a painstaking analysis of 38 years of medical literature. I would hope that funding for a head-to-head study of these regiments is forthcoming since the differences here are small and a meta-analysis of studies in which none used both regimens is far from being definitive.