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XPRESS Study: Heparin In ... Not Out

Drs. Agarwal and Nath raise the hypotheses that subcutaneous heparin may be efficacious in severe sepsis and that, in this setting, low molecular weight heparin is superior to unfractionated heparin, and intravenous administration of heparin is preferred to subcutaneous administration given concerns of bioavailability in critically ill patients. We acknowledged in our article (1) that small, uncontrolled, nonrandomized studies have suggested that heparin may be efficacious for patients with sepsis-induced coagulopathy. As Figure 2 in the article demonstrates, there was a trend for lower mortality in the heparin versus placebo group in a population or patients with severe sepsis who were receiving drotrecogin alfa (activated) per study protocol. On the other hand, the prospectively defined subgroup of over 1,000 heparin-naive patients (baseline heparin—no) demonstrated no difference in survival: 29.5 versus 28.9% 28-day mortality for heparin versus placebo, respectively. If heparin was truly efficacious in severe sepsis, one would expect a treatment signal in this important subgroup.

Regarding the suggestion that low molecular weight heparin may be superior to unfractionated heparin, Figure 3 clearly demonstrates no difference in these two survival curves. Finally, we chose to deliver unfractionated and low molecular weight heparin via the subcutaneous route, since this was a study examining whether prophylactic heparin interfered with the efficacy of drotrecogin alfa (activated) in patients with severe sepsis who were at a high risk of death. We followed standard ICU practice by administering prophylactic heparin subcutaneously.

We agree that in some patients (in particular those with high-dose vasopressor therapy) the bioavailability of subcutaneous heparin may be low (2), and we agree that it would be interesting to observe the effect of low-dose intravenous heparin in these patients. Despite the paucity of data demonstrating efficacy of heparin in sepsis animal models, we also agree with the authors that the results of the XPRESS study warrant further studies of heparin in sepsis.

Marcel Levi

University of Amsterdam
Amsterdam, The Netherlands

Mitchell M. Levy

Rhode Island Hospital
and
Brown University Medical School
Providence, Rhode Island

Mark D. Williams

Eli Lilly
Indianapolis, Indiana

FOOTNOTES

Conflict of Interest Statement: M.L. has participated in previous trials sponsored by Eli Lilly and has served as paid consultant for Eli Lilly. M.M.L. has received lecture fees from Eli Lilly and Edwards Lifesciences, as well as grants from Eli Lilly, Edwards Lifesciences, Philips Medical Systems, Novartis, and Biosite. M.D.W. is an employee of Eli Lilly.

REFERENCES

1. Levi M, Levy M, Williams MD, Douglas I, Artigas A, Antonelli M, Wyncoll D, Janes J, Booth FV, Wang D, et al.; Xigris and Prophylactic HepaRin Evaluation in Severe Sepsis (XPRESS) Study Group. Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated). Am J Respir Crit Care Med 2007;176:483–490.[Abstract/Free Full Text]
2. Dorffler-Melly J, de Jonge E, de Pont AC, Meijers JC, Vroom MB, Büller HR, Levi M. Bioavailability of subcutaneous low-molecular-weight heparin to patients on vasopressors. Lancet 2002;359:849–850.[CrossRef][Medline]

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