Human Recombinant Activated Protein C for Severe Sepsis: A Meta-Analysis_Chinese Journal of Evidence-Based Medicine

Authors：

WANG Qian ¹ , ZHAO Yang ² ,  ZHU Jie ¹

1. Department of Emergency, The Fourth Hospital Affiliated to China Medical University, Shenyang 110032, China;2. Department of Intensive Care Unit, Shengjing Hospital Affiliated to China Medical University, Shengyang 110004, China;

Corresponding author：

ZHU Jie, Email: cmu4h-zhujie@126.com

Keywords：

Human recombinant activated protein C; Severe sepsis; Systematic review; Meta-analysis; Randomized controlled trial

DOI：

10.7507/1672-2531.20130229

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Objective 　To systemically review the effectiveness and safety of human recombinant activated protein C (rhAPC) for severe sepsis.
Methods 　Such databases as MEDLINE, EMbase, The Cochrane Library, VIP, CNKI and CBM were electronically searched for comprehensively collecting randomized controlled trials (RCTs) on the effectiveness and safety of human recombinant activated protein C (rhAPC) for severe sepsis from inception to July 2012. References of included studies were also retrieved. Two reviewers independently screened literature according to the inclusion and exclusion criteria, extracted data, and assessed the methodological quality of included studies. Then, meta-analysis was performed using RevMan 5.0 software.
Results 　Totally, five RCTs involving 6 307 patients were included. The results of meta-analysis showed that, no significant difference was found in 28-day mortality (RR=1.00, 95%CI 0.84 to 1.19, P=1.00) and 90-day mortality (RR=1.00, 95%CI 0.87 to 1.14, P=0.96) between the rhAPC group and the placebo group. The results of subgroup analysis showed that, the two groups were similar in the 28-day mortality of patients with different Acute Physiology and Chronic Health Evaluation II (APACHE II) scores (APACHE II score lt;25: RR=1.06, 95%CI 0.93 to 1.21, P=0.37; APACHE II score≥25: RR=0.93, 95%CI 0.69 to 1.24, P=0.60), and in the 28-day mortality by protein C deficiency class (APC deficiency lt;80%: RR=0.96, 95%CI 0.56 to 1.65, P=0.89; APC deficiency gt;80%: RR=0.61, 95%CI 0.34 to 1.08, P=0.09). Besides, bleeding risk in the rhAPC group was 1.62 fold more than that in the placebo group (RR=1.62, 95%CI 1.17 to 2.23, P=0.004). No significant difference was found in the incidence of adverse reaction (RR=1.04, 95%CI 0.92 to 1.18, P=0.53).
Conclusion 　Current evidence suggests that, rhAPC could not improve the prognosis of patients with severe sepsis, but it significantly increases bleeding risk.

Citation： WANG Qian,ZHAO Yang,ZHU Jie. Human Recombinant Activated Protein C for Severe Sepsis: A Meta-Analysis. Chinese Journal of Evidence-Based Medicine, 2013, 13(11): 1333-1339. doi: 10.7507/1672-2531.20130229 Copy

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2.	Hall MJ, Williams SN, DeFrances CJ, et al. Inpatient care for septicemia or sepsis: a challenge for patients and hospitals. NCHS Data Brief, 2011, (62): 1-8.
3.	Brun-Buisson C. Epidemiology of severe sepsis. Presse Médicale, 2006, 35(3 Pt 2): 513-520.
4.	Danai PA, Sinha S, Moss M, et al. Seasonal variation in the epidemiology of sepsis. Critical Care Medicine, 2007, 35(2): 410-415.
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9.	Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit Care Med, 2001, 29(7): 1303-1313.
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13.	Grey ST, Hancock WW. Inhibition of LPS-induced activation of human monocytes by activated protein C (APC) occurs through a novel mechanism. J Leukoc Biol, 1993, 114(6): A487.
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25.	Mosnier LO, Zlokovic BV, Griffin JH. The cytoprotective protein C pathway. Blood, 2007, 109(8): 3161-3172.
26.	Shorr AF, Bernard GR, Dhainaut JF, et al. Protein C concentrations in severe sepsis: An early directional change in plasma levels predicts outcome. Crit Care, 2006, 10(6): R92.
27.	MammenE. Thehaematological manifestations of sepsis. J Antimicrob Chemother, 1998, 41(Suppl A): S17-S24.
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29.	Casserly B, Gerlach H, Phillips GS, et al. Evaluating the use of recombinant human activated protein C in adult severe sepsis: results of the Surviving Sepsis Campaign. Crit Care Med, 2012, 40(5): 1417-1426.
30.	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): 678-686.
31.	Rimmer E, Kumar A, Doucette S, et al, and Cooperative Antimicrobial Therapy of Septic Shock Database Research Group. Activated protein C and septic shock: A propensity-matched cohort study. Crit Care Med, 2012, 40(11): 2974-2981.
32.	Martí-Carvajal AJ, Solà I, Lathyris D, et al. Human recombinant activated protein C for severe sepsis. Cochrane Database Syst Rev, 2012, 3: CD004388.
33.	Nadel S, Goldstein B, Williams MD, et al, and Researching severe Sepsis and Organ dysfunction in children: a global perspective (RESOLVE) study group. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet, 2007, 369(9564): 836-843.
34.	University of Versailles: Activated protein C and corticosteroids for human septic shock (APROCCHS). Available from: http://clinicaltrials.gov/ct2/show/NCT00625209. Accessed Oct 3, 2012.
35.	University of Versailles: Pharmacogenomic Biomarker Study for Recombinant Human Activated Protein C Treatment in Severe Sepsis. Available from: http://clinicaltrials.gov/ct2/show/NCT01486524. Accessed Oct 3, 2012.
36.	Guyatt G, Oxman A, Montori V, et al. GRADE指南: Ⅴ.证据质量评价—发表偏倚. 中国循证医学杂志, 2011, 11(12): 1430-1434.

1. Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med, 2003, 348(12): 1546-1554.
2. Hall MJ, Williams SN, DeFrances CJ, et al. Inpatient care for septicemia or sepsis: a challenge for patients and hospitals. NCHS Data Brief, 2011, (62): 1-8.
3. Brun-Buisson C. Epidemiology of severe sepsis. Presse Médicale, 2006, 35(3 Pt 2): 513-520.
4. Danai PA, Sinha S, Moss M, et al. Seasonal variation in the epidemiology of sepsis. Critical Care Medicine, 2007, 35(2): 410-415.
5. Das UN. Critical advances in septicemia and septic shock. Criti Care, 2000, 4(5): 290-296.
6. Khwannimit B, Bhurayanontachai R. The epidemiology of, and risk factors for, mortality from severe sepsis and septic shock in a tertiary-care university hospital setting. Epidemiology and Infection, 2009, 137(9): 1-9.
7. Linde-Zwirble WT, Angus DC. Severe sepsis epidemiology: sampling, selection, and society. Crit Care, 2004, 8(4): 222-226.?.
8. Brun-Buisson C, Meshaka P, Pinton P, et al. EPISEPSIS: a reappraisal of the epidemiology and out- come of severe sepsis in French intensive care units. Intensive Care Med, 2004, 30(4): 580-588.
9. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care. Crit Care Med, 2001, 29(7): 1303-1313.
10. Cheng B, Xie G, Yao S, et al. Epidemiology of severe sepsis in critically ill surgical patients in ten university hospitals in China. Critical Care Medicine, 2007, 35(11): 2538-2546.
11. Paul M. Is there a treatment for sepsis other than antibiotics? Clinical Microbiology and Infection, 2009, 15(4): 297.
12. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med, 2003, 348(2): 138-150.
13. Grey ST, Hancock WW. Inhibition of LPS-induced activation of human monocytes by activated protein C (APC) occurs through a novel mechanism. J Leukoc Biol, 1993, 114(6): A487.
14. Bernard GR, Vincent JL, Laterre PF, et al, and the Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. E?cacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med, 2001, 344(5): 699-709.
15. 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.
16. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med, 2002, 21(11): 1539-1558.
17. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ, 2003, 327()7414: 557-560.
18. Egger M, Altman DG, Smith GD. Systematic reviews in health-care: meta-analysis in context. 2nd Ed. BMJ Books, Wiley: London, 2001.
19. . Bernard GR, Ely EW, Wright TJ, et al. Safety and dose relationship of recombinant human activated protein C for coagulopathy in severe sepsis. Crit Care Med, 2001, 29(11): 2051-2059.
20. Angus DC, Laterre PF, Helterbrand J, et al, and PROWESS Investigators. The effect of drotrecogin alfa (activated) on long-term survival after severe sepsis. Crit Care Med, 2004, 32(11): 2199-2206.
21. Abraham E, Laterre PF, Garg R, et al, and Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) Study Group. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med, 2005, 353(13): 1332-1341.
22. Dhainaut JF, Antonelli M, Wright P, et al. Extended drotrecogin alfa (activated) treatment in patients with prolonged septic shock. Intensive Care Med, 2009, 35(7): 1187-1195.
23. Ranieri VM, Thompson BT, Barie PS, et al, and PROWESS-SHOCK Study Group. Drotrecogin alfa (activated) in adults with septic shock. N Engl J Med, 2012, 366(22): 2055-2064.
24. Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet, 2005, 365(9453): 63-78.
25. Mosnier LO, Zlokovic BV, Griffin JH. The cytoprotective protein C pathway. Blood, 2007, 109(8): 3161-3172.
26. Shorr AF, Bernard GR, Dhainaut JF, et al. Protein C concentrations in severe sepsis: An early directional change in plasma levels predicts outcome. Crit Care, 2006, 10(6): R92.
27. MammenE. Thehaematological manifestations of sepsis. J Antimicrob Chemother, 1998, 41(Suppl A): S17-S24.
28. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med, 2008, 36(12): 296-327.
29. Casserly B, Gerlach H, Phillips GS, et al. Evaluating the use of recombinant human activated protein C in adult severe sepsis: results of the Surviving Sepsis Campaign. Crit Care Med, 2012, 40(5): 1417-1426.
30. 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): 678-686.
31. Rimmer E, Kumar A, Doucette S, et al, and Cooperative Antimicrobial Therapy of Septic Shock Database Research Group. Activated protein C and septic shock: A propensity-matched cohort study. Crit Care Med, 2012, 40(11): 2974-2981.
32. Martí-Carvajal AJ, Solà I, Lathyris D, et al. Human recombinant activated protein C for severe sepsis. Cochrane Database Syst Rev, 2012, 3: CD004388.
33. Nadel S, Goldstein B, Williams MD, et al, and Researching severe Sepsis and Organ dysfunction in children: a global perspective (RESOLVE) study group. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet, 2007, 369(9564): 836-843.
34. University of Versailles: Activated protein C and corticosteroids for human septic shock (APROCCHS). Available from: http://clinicaltrials.gov/ct2/show/NCT00625209. Accessed Oct 3, 2012.
35. University of Versailles: Pharmacogenomic Biomarker Study for Recombinant Human Activated Protein C Treatment in Severe Sepsis. Available from: http://clinicaltrials.gov/ct2/show/NCT01486524. Accessed Oct 3, 2012.
36. Guyatt G, Oxman A, Montori V, et al. GRADE指南: Ⅴ.证据质量评价—发表偏倚. 中国循证医学杂志, 2011, 11(12): 1430-1434.

Chinese Journal of Evidence-Based Medicine

Human Recombinant Activated Protein C for Severe Sepsis: A Meta-Analysis

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