Correspondence

Correction

Low-Dose Heparin for Severe Sepsis

N Engl J Med 2003; 348:1185-1186March 20, 2003

Article

To the Editor:

We read with concern the analysis by Davidson et al. (Sept. 26 issue).1 They use the pooled placebo groups from two sepsis trials, divided into two groups — patients who either were receiving heparin at the time they entered the trial or began heparin therapy during the trial and those who never received heparin.2,3 Patients who began receiving heparin treatment during the trials were moved from the nonheparin group to the heparin group. Not only was the intention-to-treat population therefore unknown at trial entry, but also patients who survived longer had a greater chance of receiving heparin. This uncontrolled, unidirectional movement of patients receiving new heparin treatment during the trial preferentially selects for those who survive until treatment begins, creating a fundamental flaw in the analysis. The observed benefit associated with the use of heparin may be entirely due to the movement of patients from the nonheparin group to the heparin group. Thus, the analysis by Davidson et al. does not provide evidence of a benefit from heparin in severe sepsis.

Ross Freebairn, M.B., Ch.B.
Hawke's Bay Hospital, Hastings 4201, New Zealand

Sarah Ramsay, M.B., B.S.
Charles Gomersall, M.B., B.S.
Chinese University of Hong Kong, Hong Kong, China

3 References

1. 1

   Davidson BL, Geerts WH, Lensing AWA. Low-dose heparin for severe sepsis. N Engl J Med 2002;347:1036-1037
   Full Text | Web of Science | Medline

2. 2

   Bernard GR, Vincent J-L, Laterre P-F, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699-709
   Full Text | Web of Science | Medline

3. 3

   Warren BL, Eid A, Singer P, et al. Caring for the critically ill patient: high-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001;286:1869-1878[Erratum, JAMA 2002;287:192.]
   CrossRef | Web of Science | Medline

Author/Editor Response

We disagree with the explanation proposed by Freebairn et al. to account for our findings. We wish to clarify that the report on the antithrombin III study1 and the analysis by the Food and Drug Administration of the trial of activated protein C,2 the sources of our data, explicitly define heparin recipients as those receiving heparin from day 1 to day 4 — the same period during which the study drugs were administered. Therefore, longer survival is not required to “enter” the heparin group, and such a bias could not reasonably explain our results.

We reiterate that our findings are hypothesis-generating. Given the strong suggestion of the efficacy as well as the safety and low expense of heparin, a prospective trial is warranted to compare low-dose heparin, low-molecular-weight heparin, or both with placebo and activated protein C in order to assess the relative contributions of these agents to the survival of patients with sepsis.

We apologize for the oversight but wish to disclose that Drs. Davidson and Geerts have served as clinical investigators, consultants, or both for one or more of the following manufacturers of low-molecular-weight heparin: Aventis, Sanofi, and Pharmacia.

Bruce L. Davidson, M.D., M.P.H.
Swedish Medical Center, Seattle, WA 98122
brucedavidson@pobox.com

William H. Geerts, M.D.
Sunnybrook and Women's College Health Sciences Centre, Toronto, ON M5S 1B2, Canada

Anthonie W.A. Lensing, M.D., Ph.D.
Academic Medical Center, 1105 AZ Amsterdam, the Netherlands

2 References

1. 1

   Warren BL, Eid A, Singer P, et al. Caring for the critically ill patient: high-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001;286:1869-1878[Erratum, JAMA 2002;287:192.]
   CrossRef | Web of Science | Medline

2. 2

   Anti-Infective Advisory Committee. FDA briefing document: drotrecogin alfa (activated) [recombinant human activated protein C (rhAPC)]: Xigris. BLA no. 125029/0. Rockville, Md.: Food and Drug Administration, September 2001. (Accessed February 12, 2003, at http://www.fda.gov/ohrms/dockets/ac/01/briefing/3797b1_02_FDAbriefing.pdf.)
   

Citing Articles (1)

Citing Articles

1. 1

   Toshiaki Iba, Akio Kidokoro. (2004) WHAT CAN WE LEARN FROM THE THREE MEGATRIALS USING ANTICOAGULANTS IN SEVERE SEPSIS?. Shock 22:6, 508-512
   CrossRef