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Decreasing mortality with drotrecogin alfa in high risk septic patients A meta-analysis of randomized trials in adult patients with multiple organ failure and mortality >40%

  • MASSIMILIANO GRECO1
  • GIOVANNI LANDONI1
  • LEDA NOBILE1
  • GIACOMO MONTI1
  • LAURA PASIN1
  • CAETANO NIGRO2
  • LUCA CABRINI1
  • ALBERTO ZANGRILLO1

1,Department of Anesthesia and Intensive Care IRCCS San Raffaele Scientific Institute

2,Dante Pazzanese Institute of Cardiology

DOI: 10.22514/SV91.042014.2 Vol.9,Issue 1,April 2014 pp.16-21

Published: 30 April 2014

*Corresponding Author(s): GIOVANNI LANDONI E-mail: landoni.giovanni@hsr.it

Abstract

Objective. Sepsis is a complex inflammatory disease, rising in response to infection. Drotrecogin alfa, approved in 2001 for severe sepsis, has been withdrawn from the market. The aim of this study was to assess if drotrecogin alfa-activated can reduce mortality in the more severe septic patients.

Methods. We searched PubMed, Embase, Scopus, BioMedCentral, and in Clinicaltrials. gov databases to identify every randomized study performed on drotrecogin alfa-activated in any clinical setting in humans, without restrictions on dose or time of administration. Our primary end-point was mortality rate in high risk patients. Secondary endpoints were mortality in all patients, in patients with an Acute Physiology and Chronic Health Evaluation (APACHE) 2 score ≥ 25 and in those with an APACHE 2 score ≤25.

Results. Five trials were identified and included in the analysis. They randomized 3196 patients to drotrecogin alfa and 3111 to the control group. Drotrecogin alfa was associated with a reduction in mortality (99/263 [37.6%] vs 115/244 [47.1%], risk ratios (RR) = 0.80[0.65; 0.98], p = 0.03) in patients with multiple organ failure and a mortality risk in the control group of 40%, but not in the overall population or in lower risk populations.

Conclusions. In high risk populations of patients with multiple organ failure and a mortality of >40% in the control group, Drotrecogin alfa may still have a role as a lifesaving treatment. No beneficial effect in low risk patients was found. An indivi-dual patient meta-analysis including all randomized controlled trial on sepsis is warranted, along with new studies on similar drugs such as protein C zymogen.

Keywords

sepsis, shock, intensive care, critically ill, mortality, drotreco-gin alfa, recombinant human activa-ted protein C

Cite and Share

MASSIMILIANO GRECO,GIOVANNI LANDONI,LEDA NOBILE,GIACOMO MONTI,LAURA PASIN,CAETANO NIGRO,LUCA CABRINI,ALBERTO ZANGRILLO. Decreasing mortality with drotrecogin alfa in high risk septic patients A meta-analysis of randomized trials in adult patients with multiple organ failure and mortality >40%. Signa Vitae. 2014. 9(1);16-21.

References

1. Slade E, Tamber PS, Vincent J-L. The Surviving Sepsis Campaign: raising awareness to reduce mortality. Crit Care 2003;7:1–2.

2. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. New Engl J Med 2003;348:138–50.

3. Trzeciak S, Cinel I, Dellinger RP, Shapiro NI, Arnold RC, Parrillo JE, et al. Resuscitating the Microcirculation in Sepsis: The Central Role of Nitric Oxide, Emerging Concepts for Novel Therapies, and Challenges for Clinical Trials. Acad Emerg Med 2008;15:399–413.

4. Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, et al. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med 31 2012;366(22):2055–64.

5. Rosenberg RD, Aird WC. Vascular-bed-specific hemostasis and hypercoagulable states. N Engl J Med 1999;340:1555–64.

6. Murakami K, Okajima K, Uchiba M, Johno M, Nakagaki T, Okabe H, et al. Activated protein C attenuates endotoxin-induced pulmonary vascular injury by inhibiting activated leukocytes in rats. Blood 1996;87:642–7.

7. Esmon CT. The endothelial cell protein C receptor. Thromb Haemost 2000;83:639–43.

8. Bernard GR, Ely E, Wright TJ, Fraiz J, Stasek JE Jr, Russell JA, et al. Safety and dose relationship of recombinant human activated protein C for coagulopathy in severe sepsis. Crit care med 2001;29:2051.

9. Biondi-Zoccai GGL, Agostoni P, Abbate A, Testa L, Burzotta F. A simple hint to improve Robinson and Dickersin’s highly sensitive PubMed search strategy for controlled clinical trials. Int J Epidemiol 2005;34:224–5.

10. Cochrane Handbook for Systematic Reviews of Interventions (v 5.0.2). Available on-line at: http://www.cochrane-handbook.org. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.

11. Review Manager (RevMan) [Computer program] Version 5.0. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008. Available from http://ims.cochrane.org/revman.

12. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009;339:b2700.

13. De Pont AC, Bakhtiari K, Hutten B, de Jonge E, Vroom MB, Meijers JC, et al. Recombinant human activated protein C resets thrombin generation in patients with severe sepsis–a case control study. Critical Care 2005;9:R490–7.

14. 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;33:426–34.

15. Benefield RJ, Drevets DA, Huycke MM, Gentry CA. A multicenter evaluation of the safety of drotrecogin alfa (activated) in patients with baseline bleeding precautions. Curr Drug Saf 2012;7:3–7.

16. Spapen H, Nguyen DN, Troubleyn J, Huyghens L, Schiettecatte J. Drotrecogin alfa (activated) may attenuate severe sepsis-associated encephalopathy in clinical septic shock. Crit Care 2010;14:R54.

17. Kanji S, Perreault MM, Chant C, Williamson D, Burry L. Evaluating the use of Drotrecogin alfa (activated) in adult severe sepsis: a Canadian multicenter observational study. Intensive Care Med 2007;33:517–23.

18. 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.

19. Barton P, Kalil AC, Nadel S, Goldstein B, Okhuysen-Cawley R, Brilli RJ, et al. Safety, pharmacokinetics, and pharmacodynamics of drotre-cogin alfa (activated) in children with severe sepsis. Pediatrics 2004;113:7–17.

20. Dempfle CEH, Elmas E, Link A, Suvajac N, Liebe V, Janes J, et al. Endogenous plasma activated protein C levels and the effect of enoxapa-rin and drotrecogin alfa (activated) on markers of coagulation activation and fibrinolysis in pulmonary embolism. Crit Care 2011;15:R23.

21. Kyhälä L, Mentula P, Kylänpää L, Moilanen E, Puolakkainen P, Pettilä V, et al. Activated Protein C Does Not Alleviate the Course of Systemic Inflammation in the APCAP Trial Int J Inflam 2012;2012:1–8.

22. Shorr AF, Janes JM, Artigas A, Tenhunen J, Wyncoll DL, Mercier E, et al. Randomized trial evaluating serial protein C levels in severe sepsis patients treated with variable doses of drotrecogin alfa (activated). Crit Care 2010;14:R229.

23. 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;344:699–709.

24. 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. N Engl J Med 2005;353:1332–41.

25. Dhainaut J-F, 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;35:1187–95.

26. Costa V, Brophy JM. Drotrecogin alfa (activated) in severe sepsis: a systematic review and new cost-effectiveness analysis. BMC Anes-thesiol 2007;7:5.

27. Martí-Carvajal AJ, Solà I, Gluud C, Lathyris D, Cardona AF. Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients. Cochrane Database Syst Rev. 2012;12:CD00438829.

28. Ely E, Laterre PF, Angus DC, Helterbrand JD, Levy H, Dhainaut JF, et al. Drotrecogin alfa (activated) administration across clinically impor-tant subgroups of patients with severe sepsis. Critical care med 2003;31:12.

29. Vincent J-L, Angus DC, Artigas A, Kalil A, Basson BR, Jamal HH, et al. Effects of drotrecogin alfa (activated) on organ dysfunction in the PROWESS trial. Crit Care Med 2003;31:834–40.

30. Laterre P-F, Abraham E, Janes JM, Trzaskoma BL, Correll NL, Booth FV. ADDRESS (ADministration of DRotrecogin alfa [activated] in Early stage Severe Sepsis) long-term follow-up: One-year safety and efficacy evaluation. Crit Care Med 2007;35:1457–63.

31. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Surviving sepsis campaign: International guidelines for manage-ment of severe sepsis and septic shock: 2008. Crit Care Med 2008;36:296–327.

32. 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;345:1368–77.

33. Sevransky JE, Levy MM, Marini JJ. Mechanical ventilation in sepsis-induced acute lung injury/acute respiratory distress syndrome: an evidence-based review. Crit Care Med 2004;32:S548–53.

34. Van Den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive insulin therapy in critically ill patients. New Engl J Med 2001;345:1359–67.

35. Annane D. Corticosteroids for severe sepsis: An evidence-based guide for physicians. Ann Intensive Care 2011;1:1–7.

36. Castellanos-Ortega A, Suberviola B, García-Astudillo LA, Holanda MS, Ortiz F, Llorca J, et al. Impact of the Surviving Sepsis Campaign protocols on hospital length of stay and mortality in septic shock patients: results of a three-year follow-up quasi-experimental study. Crit Care Med 2010;38:1036–43.

37. Girardis M, Rinaldi L, Donno L, Marietta M, Codeluppi M, Marchegiano P, et al. Effects on management and outcome of severe sepsis and septic shock patients admitted to the intensive care unit after implementation of a sepsis program: a pilot study. Crit Care 2009;13:R143.

38. Rice TW, Wheeler AP, Bernard GR, Vincent JL, Angus DC, Aikawa N, et al. A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis. Crit Care Med 2010;38:1685–94.

39. ARISE; ANZICS APD Management Committee. The outcome of patients with sepsis and septic shock presenting to emergency depart-ments in Australia and New Zealand. Crit Care Resusc 2007;9:8–18.

40. Levy MM, Dellinger RP, Townsend SR, Linde-Zwirble WT, Marshall JC, Bion J, et al. The Surviving Sepsis Campaign: results of an interna-tional guideline-based performance improvement program targeting severe sepsis. Intensive Care Med 2010;36:222–31.

41. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: A severity of disease classification system. Crit Care Med 1985;13:818–29.

42. Kalil AC, Larosa SP. Effectiveness and safety of drotrecogin alfa (activated) for severe sepsis: a meta-analysis and metaregression. Lancet Infect Dis 2012;12:678–86.

43. Silvetti S, Crivellari M, Mucchetti M, Taddeo D, Franco A, Landoni G, Zangrillo A. Administration of protein C concentrates in patients without congenital deficit: a systematic review of the literature. SIGNA VITAE 2013;8:15-9.

44. Crivellari M, Della Valle P, Landoni G, Pappalardo F, Gerli C, Bignami E, et al. Human protein C zymogen concentrate in patients with severe sepsis and multiple organ failure after adult cardiac surgery. Intensive Care Med 2009;35:1959-63.

45. Crivellari M, Silvetti S, Gerli C, Landoni G, Franco A, Bove T, et al. Protein C zymogen in adults with severe sepsis or septic shock. Med Intensiva 2013 doi: 10.1016/j.medin.2013.04.005. [Epub ahead of print]

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