Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2005 Oct 14:5:7.
doi: 10.1186/1471-227X-5-7.

A meta-analysis of controlled trials of recombinant human activated protein C therapy in patients with sepsis

Christian J Wiedermann  1 , Nicole C Kaneider
Affiliations

A meta-analysis of controlled trials of recombinant human activated protein C therapy in patients with sepsis

Christian J Wiedermann et al. BMC Emerg Med. .

Abstract

Background: Meta-analysis of two randomised controlled trials in severe sepsis performed with recombinant human activated protein C may provide further insight as to the therapeutic utility of targeting the clotting cascade in this syndrome.

Methods: In search for relevant studies published, two randomized clinical trials were found eligible.

Results: The studies, PROWESS and ADDRESS, enrolled a total of 4329 patients with risk ratio (RR) and 95% confidence interval (CI) data for effect on 28-day mortality relative to control treatment of 0.92 (0.83-1.02) suggesting that recombinant human activated protein C is not beneficial in severe sepsis. In PROWESS, 873 of 1690 patients presented with low risk, and 2315 of 2639 patients in ADDRESS as defined by APACHE II score < 25. In this low-risk stratum, no effect of recombinant human activated protein C administration on 28-day mortality was observed. This observation appears to be consistent and homogenous. Heterogeneity between the two studies, however, was seen in patients with APACHE II score > or = 25 in whom recombinant activated protein C was effective in PROWESS (n = 817; RR 0.80, CI 0.68-0.94) whereas a tendency toward harm was present in ADDRESS (n = 324; RR 1.21, CI 0.85-1.74). Even though the overall treatment effect in this high-risk population was still in favour of treatment with recombinant activated protein C (n = 1141; RR 0.71, CI 0.59-0.85), the observed heterogeneity suggests that the efficacy of recombinant human activated protein C is not robust. Not unlikely, the adverse tendency observed could have become significant with higher statistical power would ADDRESS not have been terminated prematurely.

Conclusion: This meta-analysis, therefore, raises doubts about the clinical usefulness of recombinant activated protein C in patients with severe sepsis and an APACHE II score > or = 25 which can only be resolved by another properly designed clinical trial.

PubMed Disclaimer

References

    1. Freeman BD, Zehnbauer BA, Buchman TG. A meta-analysis of controlled trials of anticoagulant therapies in patients with sepsis. Shock. 2003;20:5–9. doi: 10.1097/01.shk.0000068327.26733.10. - DOI - PubMed
    1. Haley M, Cui X, Minneci PC, Deans KJ, Natanson C, Eichacker PQ. Activated protein C in sepsis: emerging insights regarding its mechanism of action and clinical effectiveness. Curr Opin Infect Dis. 2004;17:205–11. doi: 10.1097/00001432-200406000-00006. - DOI - PubMed
    1. Cohen J, Guyatt G, Bernard GR, Calandra T, Cook D, Elbourne D, Marshall J, Nunn A, Opal S, on behalf of a UK Medical Research Council International Working Party New strategies for clinical trials in patients with sepsis and septic shock. Crit Care Med. 2001;29:880–886. doi: 10.1097/00003246-200104000-00039. - DOI - PubMed
    1. Wiedermann CJ, Hoffmann JN, Ostermann H, Briegel J, Strauss R, Keinecke H, Jürs M, Kienast J. High-dose antithrombin III in the treatment of severe sepsis with a high risk of death. Intensive Care Med. 2004;30:S90. - PubMed
    1. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ, Jr, Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344:699–709. doi: 10.1056/NEJM200103083441001. - DOI - PubMed

LinkOut - more resources