Intensive Care Medicine

, Volume 29, Issue 6, pp 894–903 | Cite as

Drotrecogin alfa (activated) in the treatment of severe sepsis patients with multiple-organ dysfunction: data from the PROWESS trial

  • Jean-François Dhainaut
  • Pierre-François Laterre
  • Jonathan M. Janes
  • Gordon R. Bernard
  • Antonio Artigas
  • Jan Bakker
  • Hanno Riess
  • Bruce R. Basson
  • Julien Charpentier
  • Barbara G. Utterback
  • Jean-Louis Vincent
  • Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) Study Group



Based on the results of the PROWESS trial the European Agency for the Evaluation of Medicinal Products has recently approved drotrecogin alfa (activated) for treatment of adult patients with severe sepsis and multiple-organ failure. We report study's data on efficacy and safety in patients with multiple-organ dysfunction.

Design and setting

Randomized, double-blind, placebo-controlled, multicenter trial in 164 medical centers.


1271 patients (75.2% of the intention-to-treat population, n=1690) with multiple-organ dysfunction at study entry.


Drotrecogin alfa (activated) n=634, 24 µg/kg per hour for 96 h or placebo (n=637).


Observed 28-day mortality was significantly lower with drug treatment than with placebo (26.5%vs. 33.9%), cardiovascular and respiratory organ dysfunction resolved more rapidly over the first 7 days, and serious bleeding events were more frequent (2.4% vs. 1.3%).


Treatment with drotrecogin alfa (activated) significantly reduced 28-day mortality and more quickly resolved cardiovascular and respiratory organ dysfunction. The difference in serious bleeding event rates may be clinically significant; however, the overall benefit-risk profile appears favorable.


Drotrecogin alfa (activated) Activated protein C Xigris Recombinant proteins Sepsis Septic shock 



The investigation would not have been possible without the effort of the product development team at Eli Lilly and Company. We are indebted to Samiha Sarwat for providing statistical analysis assistance. This study was sponsored by a grant from Eli Lilly and Company, Indianapolis, Ind., USA. J.-F. D had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.


  1. 1.
    American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference (1992) Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 20:864–874PubMedGoogle Scholar
  2. 2.
    Angus DC, Wax RS (2001) Epidemiology of sepsis: an update. Crit Care Med 29:S109–S116PubMedGoogle Scholar
  3. 3.
    Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR (2001) Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 29:1303–1310PubMedGoogle Scholar
  4. 4.
    Alberti C, Brun-Buisson C, Burchardi H, Martin C, Goodman S, Artigas A, Sicignano A, Palazzo M, Moreno R, Boulme R, et al (2002) Epidemiology of sepsis and infection in ICU patients from an international multicentre cohort study. Intensive Care Med 28:108–121PubMedGoogle Scholar
  5. 5.
    Vincent JL, Bihari DJ, Suter PM, Bruining HA, White J, Nicolas-Chanoin MH, Wolff M, Spencer RC, Hemmer M (1995) The prevalence of nosocomial infection in intensive care units in Europe. Results of the European Prevalence of Infection in Intensive Care (EPIC) Study. EPIC International Advisory Committee. JAMA 274:639–644PubMedGoogle Scholar
  6. 6.
    Brun-Buisson C, Doyon F, Carlet J, Dellamonica P, Gouin F, Letpoutre A, Mercier J, Offenstadt G, Regnier B (1995) Incidence, risk factors, and outcome of severe sepsis and septic shock in adults: a multicenter prospective study in intensive care units. JAMA 274:968–974PubMedGoogle Scholar
  7. 7.
    Davies, A, Green, C, Hutton, J, Chinn, C (2001) Severe sepsis: a European estimate of the burden of disease in ICU. Intensive Care Med 27:S284Google Scholar
  8. 8.
    Beutler B, Poltorak A (2001) Sepsis and evolution of the innate immune response. Crit Care Med 29:S2–S6PubMedGoogle Scholar
  9. 9.
    Ulevitch RJ (2001) New therapeutic targets revealed through investigations of innate immunity. Crit Care Med 29:S8–12PubMedGoogle Scholar
  10. 10.
    Aird WC (2001) Vascular bed-specific hemostasis: role of endothelium in sepsis pathogenesis. Crit Care Med 29:S28–S34PubMedGoogle Scholar
  11. 11.
    Hack CE, Zeerleder S (2001) The endothelium in sepsis: source of and a target for inflammation. Crit Care Med 29:S21–S27PubMedGoogle Scholar
  12. 12.
    Joyce DE, Gelbert L, Ciaccia A, DeHoff B, Grinnell BW (2001) Gene expression profile of antithrombotic protein c defines new mechanisms modulating inflammation and apoptosis. J Biol Chem 276:11199–111203CrossRefPubMedGoogle Scholar
  13. 13.
    Bauer PR (2002) Microvascular responses to sepsis: clinical significance. Pathophysiology 8:141–148CrossRefPubMedGoogle Scholar
  14. 14.
    Esmon CT (2000) The anticoagulant and anti-inflammatory roles of the protein C anticoagulant pathway. J Autoimmunol 15:113–116CrossRefGoogle Scholar
  15. 15.
    Bajzar L (2000) Thrombin activatable fibrinolysis inhibitor and an antifibrinolytic pathway. Arterioscler Thromb Vasc Biol 20:2511–2518Google Scholar
  16. 16.
    Grinnell BW, Joyce D (2001) Recombinant human activated protein C: a system modulator of vascular function for treatment of severe sepsis. Crit Care Med 29:S53–S60PubMedGoogle Scholar
  17. 17.
    Yoshikawa A, Kaido T, Seto S, Katsuura Y, Imamura M (2000) Activated protein C prevents multiple organ injury following extensive hepatectomy in cirrhotic rats. J Hepatol 33:953–960CrossRefPubMedGoogle Scholar
  18. 18.
    Murakami K, Okajima K, Uchiba M, Johno M, Nakagaki T, Okabe H, Takatsuki K (1997) Activated protein C prevents LPS-induced pulmonary vascular injury by inhibiting cytokine production. Am J Physiol 272:L197–L202PubMedGoogle Scholar
  19. 19.
    Taylor FB Jr, Chang A, Esmon CT, D'Angelo A, Vigano-D'Angelo S, Blick KE (1987) Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest 79:918–925PubMedGoogle Scholar
  20. 20.
    Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, et al (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699–709PubMedGoogle Scholar
  21. 21.
    Vincent JL, Angus DC, Artigas A, Kalil A, Basson BR, Jamal HH, Johnson G, Bernard GR (2003) Effects of drotrecogin alfa (activated) on organ dysfunction in the PROWESS trial. Crit Care Med 31:834–840Google Scholar
  22. 22.
    Ely EW, Bernard GR, Vincent JL (2002) Activated protein C for severe sepsis. N Engl J Med 347:1035–1036CrossRefPubMedGoogle Scholar
  23. 23.
    Siegel JP (2002) Assessing the use of activated protein C in the treatment of severe sepsis. N Engl J Med 347:1030–1034CrossRefPubMedGoogle Scholar
  24. 24.
    Warren HS, Suffredini AF, Eichacker PQ, Munford RS (2002) Risks and benefits of activated protein C treatment for severe sepsis. N Engl J Med 347:1027–1030CrossRefPubMedGoogle Scholar
  25. 25.
    Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG (1996) The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 22:707–710CrossRefPubMedGoogle Scholar
  26. 26.
    Taylor FB Jr, Toh CH, Hoots WK, Wada H, Levi M (2001) Scientific and standardization committee communications: towards a definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Available online at: Accessed January 15:2002Google Scholar
  27. 27.
    Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985) APACHE II: a severity of disease classification system. Crit Care Med 13:818–829PubMedGoogle Scholar
  28. 28.
    Breslow NE, Day NE (1980) Statistical methods in cancer research, vol I. IARC, Lyon, pp 5–338Google Scholar
  29. 29.
    Fourrier F, Chopin C, Goudemand J, Hendrycx S, Caron C, Rime A, Marey A, Lestavel P (1992) Septic shock, multiple organ failure, and disseminated intravascular coagulation. Compared patterns of antithrombin III, protein C, and protein S deficiencies. Chest 101:816–823PubMedGoogle Scholar
  30. 30.
    Kidokoro A, Iba T, Fukunaga M, Yagi Y (1996) Alterations in coagulation and fibrinolysis during sepsis. Shock 5:223–228PubMedGoogle Scholar
  31. 31.
    Gando S, Nanzaki S, Sasaki S, Aoi K, Kemmotsu O (1998) Activation of the extrinsic coagulation pathway in patients with severe sepsis and septic shock. Crit Care Med 26:2005–2009Google Scholar
  32. 32.
    Asakura H, Ontachi Y, Mizutani T, Kato M, Saito M, Kumabashiri I, Morishita E, Yamazaki M, Aoshima K, Nakao S (2001) An enhanced fibrinolysis prevents the development of multiple organ failure in disseminated intravascular coagulation in spite of much activation of blood coagulation. Crit Care Med 29:1164–1168PubMedGoogle Scholar
  33. 33.
    Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985) Prognosis in acute organ-system failure. Ann Surg 202:685–693PubMedGoogle Scholar
  34. 34.
    Knaus WA, Wagner DP (1989) Multiple systems organ failure: epidemiology and prognosis. Crit Care Clin 5:221–232PubMedGoogle Scholar
  35. 35.
    Suzuki K, Nishioka J, Kusumoto H, Hashimoto S (1984) Mechanism of inhibition of activated protein C by protein C inhibitor. J Biochem (Tokyo) 95:187–195Google Scholar
  36. 36.
    Macias WL, Dhainaut JF, Yan SC, Helterbrand JD, Seger M, Johnson G III, Small DS (2002) Pharmacokinetic-pharmacodynamic analysis of drotrecogin alfa (activated) in patients with severe sepsis. Clin Pharmacol Ther 72:391–402CrossRefPubMedGoogle Scholar
  37. 37.
    Roback MG, Stack AM, Thompson C, Brugnara C, Schwarz HP, Saladino RA (1998) Activated protein C concentrate for the treatment of meningococcal endotoxin shock in rabbits. Shock 9:138–142PubMedGoogle Scholar
  38. 38.
    Sakata Y, Loskutoff DJ, Gladson CL, Hekman CM, Griffin JH (1986) Mechanism of protein C-dependent clot lysis: role of plasminogen activator inhibitor. Blood 68:1218–1223PubMedGoogle Scholar
  39. 39.
    Begg C, Cho M, Eastwood S, Horton R, Moher D, Olkin I, Pitkin R, Rennie D, Schulz KF, Simel D, et al (1996) Improving the quality of reporting of randomized controlled trials. The CONSORT statement. JAMA 276:637–639PubMedGoogle Scholar
  40. 40.
    Collins R, MacMahon S (2001) Reliable assessment of the effects of treatment on mortality and major morbidity. I. clinical trials. Lancet 357:373–380CrossRefPubMedGoogle Scholar
  41. 41.
    Altman DG, Schulz KF, Moher D, Egger M, Davidoff F, Elbourne D, Gotzsche PC, Lang T (2001) The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Intern Med 134:663–694PubMedGoogle Scholar
  42. 42.
    Sleight P (2000) Debate: subgroup analyses in clinical trials: fun to look at-but don't believe them! Curr Control Trials Cardiovasc Med 1:25–271CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Jean-François Dhainaut
    • 1
  • Pierre-François Laterre
    • 2
  • Jonathan M. Janes
    • 3
  • Gordon R. Bernard
    • 4
  • Antonio Artigas
    • 5
  • Jan Bakker
    • 6
  • Hanno Riess
    • 7
  • Bruce R. Basson
    • 8
  • Julien Charpentier
    • 1
  • Barbara G. Utterback
    • 8
  • Jean-Louis Vincent
    • 9
  • Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) Study Group
  1. 1.Department of Intensive Care, Cochin Hospital AP-HP, Cochin Institute, Cochin Port-Royal Medical SchoolParis V UniversityParis cedex 14France
  2. 2.Department of Critical Care and Emergency MedicineCliniques Universitaires St. LucBrusselsBelgium
  3. 3.Lilly Research CentreEli Lilly & Co. Ltd.Erl Wood Manor, SurreyUK
  4. 4.Divisions of Allergy, Pulmonary and Critical Care MedicineVanderbilt University School of MedicineNashvilleUSA
  5. 5.Critical Care Center, Sabadell Hospital, University Institute parc TauliAutonomous University of BarcelonaSabadellSpain
  6. 6.Isala KliniekenZwolleThe Netherlands
  7. 7.Universitätsklinikum Charité,Medizinische Klinik für Haematologie und OnkologieHumbolt UniversitätBerlinGermany
  8. 8.Lilly Research LaboratoriesEli Lilly and CompanyIndianapolisUSA
  9. 9.Department of Intensive Care, Erasme University HospitalFree University of BrusselsBrusselsBelgium

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