Skip to main content

Advertisement

SpringerLink
Log in

Why Activated Protein C Was Not Successful in Severe Sepsis and Septic Shock: Are We Still Tilting at Windmills?

  • Sepsis and ICU (J Russell, Section Editor)
  • Published:
Current Infectious Disease Reports Aims and scope Submit manuscript

Abstract

Drotrecogin alpha activated (DAA), trade name Xigris, is a recombinant human protein C that has been the subject of controversy since 2001, when it became the first biologic agent approved for the treatment of severe sepsis and septic shock. The PROWESS trial showed a 6.1 % absolute reduction in 28-day mortality, although these findings were not replicated in later trials, ultimately leading to the withdrawal of DAA in 2011. Observational trials, however, have consistently shown a mortality benefit with the use of DAA, leading to the following questions: Did DAA truly fail and, if so, why? While these questions may never be definitively answered on the basis of available evidence, several factors may explain the conflicting results. In clinical practice, DAA may have been preferentially given to subjects more likely to survive. Contemporary treatments, including early antibiotic administration and volume resuscitation, may have mitigated the inflammatory processes leading to disordered coagulation and microvascular thrombosis and, thus, reduced or abolished the therapeutic opportunity for DAA. Later randomized clinical trials of DAA focused on the clinical phenotype of refractory shock, largely due to a strong efficacy signal in this subset from PROWESS; however, this clinical phenotype may not be tightly linked, at least after contemporary early resuscitation strategies, to the mechanistic phenotype of dysregulated coagulation that may have been a better target for DAA. Future trials of biologic therapies in severe sepsis and septic shock should use a combination of clinical phenotype and biomarkers to identify responsive populations that may benefit from such therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

DAA:

Drotrecogin alpha activated

PAC:

Pulmonary artery catheter

rhAPC:

Recombinant human activated protein C

References

Papers of particular interest, published recently (2010 – 2013), have been high hlighted as: • Of importance •• Of major importance

  1. Jawad I, Luksic I, Rafnsson SB. Assessing available information on the burden of sepsis: global estimates of incidence, prevalence and mortality. J Glob Health. 2012;2(1):10404. PubMed PMID: 23198133. Pubmed Central PMCID: 3484761.

    Article  PubMed  Google Scholar 

  2. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29(7):1303–10. PubMed PMID: 11445675.

    Article  PubMed  CAS  Google Scholar 

  3. Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, et al. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med. 2006;34(2):344–53. PubMed PMID: 16424713. Epub 2006/01/21. eng.

    Article  PubMed  Google Scholar 

  4. Russell JA. Management of sepsis. N Engl J Med. 2006;355(16):1699–713. PubMed PMID: 17050894. Epub 2006/10/20. eng.

    Article  PubMed  CAS  Google Scholar 

  5. Ferrer R, Artigas A, Levy MM, Blanco J, Gonzalez-Diaz G, Garnacho-Montero J, et al. Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain. JAMA. 2008;299(19):2294–303. PubMed PMID: 18492971. Epub 2008/05/22. eng.

    Article  PubMed  CAS  Google Scholar 

  6. Levy MM, Dellinger RP, Townsend SR, Linde-Zwirble WT, Marshall JC, Bion J, et al. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Crit Care Med. 2010;38(2):367–74. PubMed PMID: 20035219.

    Article  PubMed  Google Scholar 

  7. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344(10):699–709. English.

    Article  PubMed  CAS  Google Scholar 

  8. Levi M, van der Poll T. Recombinant human activated protein C: current insights into its mechanism of action. Crit care. 2007;11 Suppl 5:S3. PubMed PMID: 18269690. Pubmed Central PMCID: 2230607.

    Article  PubMed  Google Scholar 

  9. Joyce DE, Grinnell BW. Recombinant human activated protein C attenuates the inflammatory response in endothelium and monocytes by modulating nuclear factor-kappaB. Crit Care Med. 2002;30(5 Suppl):S288–93. PubMed PMID: 12004250. Epub 2002/05/11. eng.

    Article  PubMed  CAS  Google Scholar 

  10. Schouten M. van 't Veer C, Roelofs JJ, Gerlitz B, Grinnell BW, Levi M, et al. Recombinant activated protein C attenuates coagulopathy and inflammation when administered early in murine pneumococcal pneumonia. Thromb Haemost. 2011;106(6):1189–96.

    Article  PubMed  CAS  Google Scholar 

  11. Food Drug Administration Center for Drugs Evaluation Research. FDA briefing document: drotrecogin alfa (activated)[recombinant human activated protein C (rhAPC)] Xigris, BLA# 125029/0. Anti-Infective Advisory Committee. Rockville, Md: FDA Maryland; 2001.

  12. Abraham E, Laterre P-F, Garg R, Levy H, Talwar D, Trzaskoma BL, et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. New Engl J Med. 2005;353(13):1332–41. English.

    Article  PubMed  CAS  Google Scholar 

  13. Nadel S, Goldstein B, Williams MD, Dalton H, Peters M, Macias WL, et al. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet. 2007;369(9564):836–43. English.

    Article  PubMed  CAS  Google Scholar 

  14. Dhainaut JF, Antonelli M, Wright P, Desachy A, Reignier J, Lavoue S, et al. Extended drotrecogin alfa (activated) treatment in patients with prolonged septic shock. Intensive Care Med. 2009;35(7):1187–95. English.

    Article  PubMed  CAS  Google Scholar 

  15. •• Ranieri VM, Thompson BT, Barie PS, Dhainaut J-F, Douglas IS, Finfer S, et al. Drotrecogin alfa (activated) in adults with septic shock. New Engl J Med. 2012;366(21):1–10. Randomized controlled clinical trial of DAA vs. placebo in adults with refractory septic shock after early goal directed therapy which did not demonstrate efficacy of DAA over placebo, leading to the withdrawal of DAA from the market.

    Google Scholar 

  16. Lilly Announces Withdrawal of Xigris® Following Recent Clinical Trial http://newsroomlillycom/releasedetailcfm?ReleaseID=617602. Accessed May 9, 2012.

  17. Annane D, Timsit JF, Megarbane B, Martin C, Misset B, Mourvillier B, et al. Recombinant human activated protein C for adults with septic shock: a randomized controlled trial. Am J Respir Crit Care Med. 2013;187(10):1091–7. PMID: 23525934.

    Google Scholar 

  18. Kubler A, Mayzner-Zawadzka E, Durek G, Gaszynski W, Karpel E, Mikaszewska-Sokolewicz M, et al. Results of severe sepsis treatment program using recombinant human activated protein C in Poland. Med Sci Monit Int Med J Exp Clin Res. 2006;12(3):CR107–12. PubMed PMID: 16501420. Epub 2006/02/28. eng.

    CAS  Google Scholar 

  19. Bertolini G, Rossi C, Anghileri A, Livigni S, Addis A, Poole D. Use of Drotrecogin alfa (activated) in Italian intensive care units: the results of a nationwide survey. Intensive Care Med. 2007;33(3):426–34. PubMed PMID: 17325836.

    Article  PubMed  CAS  Google Scholar 

  20. Rowan KM, Welch CA, North E, Harrison DA. Drotrecogin alfa (activated): real-life use and outcomes for the UK. Crit Care. 2008;12(2):R58. PubMed PMID: 18430215. Pubmed Central PMCID: PMC2447613. Epub 2008/04/24. eng.

    Article  PubMed  Google Scholar 

  21. Vincent JL, Laterre PF, Decruyenaere J, Spapen H, Raemaekers J, Damas F, et al. A registry of patients treated with drotrecogin alfa (activated) in Belgian intensive care units–an observational study. Acta Clin Belg. 2008;63(1):25–30. PubMed PMID: 18386762. Epub 2008/04/05. eng.

    PubMed  CAS  Google Scholar 

  22. Martin G, Brunkhorst FM, Janes JM, Reinhart K, Sundin DP, Garnett K, et al. The international PROGRESS registry of patients with severe sepsis: drotrecogin alfa (activated) use and patient outcomes. Crit Care. 2009;13(3):R103. PubMed PMID: 19566927. Pubmed Central PMCID: 2717475.

    Article  PubMed  Google Scholar 

  23. Ferrer R, Artigas A, Suarez D, Palencia E, Levy MM, Arenzana A, et al. Effectiveness of treatments for severe sepsis: a prospective, multicenter, observational study. Am J Respir Crit Care Med. 2009;180(9):861–6. PubMed PMID: 19696442. Epub 2009/08/22. eng.

    Article  PubMed  CAS  Google Scholar 

  24. Lindenauer PK, Rothberg MB, Nathanson BH, Pekow PS, Steingrub JS. Activated protein C and hospital mortality in septic shock: a propensity-matched analysis. Crit Care Med. 2010;38(4):1101–7. PubMed PMID: 20154607. Epub 2010/02/16. eng.

    Article  PubMed  Google Scholar 

  25. Sadaka F, O'Brien J, Migneron M, Stortz J, Vanston A, Taylor RW. Activated protein C in septic shock: a propensity-matched analysis. Crit Care. 2011;15(2):R89. PubMed PMID: 21385410. Pubmed Central PMCID: PMC3219349. Epub 2011/03/10. eng.

    Article  PubMed  Google Scholar 

  26. Rimmer E, Kumar A, Doucette S, Marshall J, Dial S, Gurka D, et al. Activated protein C and septic shock: a propensity-matched cohort study*. Crit Care Med. 2012;40(11):2974–81. PubMed PMID: 22932397. Epub 2012/08/31. eng.

    Article  PubMed  CAS  Google Scholar 

  27. • Kalil AC, LaRosa SP. Effectiveness and safety of drotrecogin alfa (activated) for severe sepsis: a meta-analysis and metaregression. Lancet Infect Dis. 2012;12(9):678–86. PubMed PMID: 22809883. A meta-analysis focused on observational studies suggesting that in clinical practice DAA provides a mortality benefit to patients with septic shock. However this study should be interpreted with caution as observational studies, even after adjustment for measured confounders, may not fully adjust for indication bias.

  28. Lai PS, Matteau A, Iddriss A, Hawes JC, Ranieri V, Thompson BT. An updated meta-analysis to understand the variable efficacy of drotrecogin alfa (activated) in severe sepsis and septic shock. Minerva Anestesiol. 2013;79(1):33–43. PubMed PMID: 23174922.

    PubMed  CAS  Google Scholar 

  29. Connors Jr AF, Speroff T, Dawson NV, Thomas C, Harrell Jr FE, Wagner D, et al. The effectiveness of right heart catheterization in the initial care of critically ill patients. SUPPORT Investigators. JAMA. 1996;276(11):889–97. PubMed PMID: 8782638.

    Article  PubMed  Google Scholar 

  30. National Heart L, Blood Institute Acute Respiratory Distress Syndrome Clinical Trials N, Wheeler AP, Bernard GR, Thompson BT, Schoenfeld D, et al. Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. New Engl J Med. 2006;354(21):2213–24. PubMed PMID: 16714768.

    Article  PubMed  Google Scholar 

  31. Richard C, Warszawski J, Anguel N, Deye N, Combes A, Barnoud D, et al. Early use of the pulmonary artery catheter and outcomes in patients with shock and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2003;290(20):2713–20. PubMed PMID: 14645314.

    Article  PubMed  CAS  Google Scholar 

  32. Harvey S, Harrison DA, Singer M, Ashcroft J, Jones CM, Elbourne D, et al. Assessment of the clinical effectiveness of pulmonary artery catheters in management of patients in intensive care (PAC-Man): a randomised controlled trial. Lancet. 2005;366(9484):472–7. PubMed PMID: 16084255.

    Article  PubMed  Google Scholar 

  33. Binanay C, Califf RM, Hasselblad V, O'Connor CM, Shah MR, Sopko G, et al. Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial. JAMA. 2005;294(13):1625–33. PubMed PMID: 16204662.

    Article  PubMed  Google Scholar 

  34. Sandham JD, Hull RD, Brant RF, Knox L, Pineo GF, Doig CJ, et al. A randomized, controlled trial of the use of pulmonary-artery catheters in high-risk surgical patients. N Engl J Med. 2003;348(1):5–14. PubMed PMID: 12510037.

    Article  PubMed  Google Scholar 

  35. Estenssoro E, Rios FG, Apezteguia C, Reina R, Neira J, Ceraso DH, et al. Pandemic 2009 influenza A in Argentina: a study of 337 patients on mechanical ventilation. Am J Respir Crit Care Med. 2010;182(1):41–8. PubMed PMID: 20203241.

    Article  PubMed  Google Scholar 

  36. Green C, Dinnes J, Takeda A, Shepherd J, Hartwell D, Cave C, et al. Clinical effectiveness and cost-effectiveness of drotrecogin alfa (activated) (Xigris) for the treatment of severe sepsis in adults: a systematic review and economic evaluation. Health Technol Assess. 2005;9(11):1–126. iii-iv. PubMed PMID: 15774234.

    PubMed  CAS  Google Scholar 

  37. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. New Engl J Med. 2001;345(19):1368–77. English.

    Article  PubMed  CAS  Google Scholar 

  38. Gentry CA, Gross KB, Sud B, Drevets DA. Adverse outcomes associated with the use of drotrecogin alfa (activated) in patients with severe sepsis and baseline bleeding precautions. Crit Care Med. 2009;37(1):19–25. PubMed PMID: 19050637.

    Article  PubMed  CAS  Google Scholar 

  39. Shorr AF, Bernard GR, Dhainaut JF, Russell JR, Macias WL, Nelson DR, et al. Protein C concentrations in severe sepsis: an early directional change in plasma levels predicts outcome. Crit Care. 2006;10(3):R92. English.

    Article  PubMed  Google Scholar 

  40. De Backer D, Donadello K, Sakr Y, Ospina-Tascon G, Salgado D, Scolletta S, et al. Microcirculatory alterations in patients with severe sepsis: impact of time of assessment and relationship with outcome. Crit Care Med. 2013;41(3):791–9. PubMed PMID: 23318492.

    Article  PubMed  Google Scholar 

  41. Bone RC. Sepsis clinical trials. Don Quixote revisited. Chest. 1995;107(2):298–9. PubMed PMID: 7842747.

    Article  PubMed  CAS  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Peggy S. Lai declares no conflict of interest.

Taylor Thompson has been a board member for Astra Zeneca; has been a consultant for Sirius Genetics, Immunetrics, and Lilly; and has received grant funding from NHLBI.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Bulfinch Suite 148, 55 Fruit Street, Boston, MA, 02114, USA

    Peggy S. Lai & B. Taylor Thompson

Authors
  1. Peggy S. Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B. Taylor Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B. Taylor Thompson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lai, P.S., Thompson, B.T. Why Activated Protein C Was Not Successful in Severe Sepsis and Septic Shock: Are We Still Tilting at Windmills?. Curr Infect Dis Rep 15, 407–412 (2013). https://doi.org/10.1007/s11908-013-0358-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11908-013-0358-9

Keywords

Search

Navigation