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Medwave 2016; 16(Suppl5):e6801 doi: 10.5867/medwave.2016.6801
¿Cuál es el rol de la proteína C activada en el tratamiento de la sepsis?
What is the role of recombinant activated protein C in the management of sepsis?
Juan Alvarado, Ricardo Castro
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Abstract

During an episode of sepsis, systemic inflammatory response phenomenon triggers a series of procoagulant mechanisms. It has been suggested that the use of activated protein C could play a role in the management of this pathology, but there is no consensus. Searching in Epistemonikos database, which is maintained by screening multiple databases, we identified seven systematic reviews covering 35 primary studies addressing the question of this article, including six randomized trials. We extracted data, combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded activated protein C in sepsis probably does not decrease the mortality rate and increases the rate of hemorrhagic events.


 
Problem

Sepsis continues leading the causes of morbidity and mortality in intensive care units. Its incidence has been increasing, with greater complications and with more resistant infectious agents. While there has been some tendency to decreased mortality through some interventions, effective therapeutic tools remain limited.

Human protein C is a vitamin K dependent glycoprotein, structurally similar to other proteins that affect blood clotting, such as prothrombin, Factor VII, Factor IX and Factor X. It is thought that it would play an important role by regulating the anticoagulation, inflammation, cell death and maintaining the permeability of the walls of blood vessels.

The pharmaceutical company that produced this drug withdrew it from the market in 2011.

Methods

We used Epistemonikos database, which is maintained by screening multiple databases, to identify systematic reviews and their included primary studies. With this information we generated a structured summary using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analysis of the total of studies, a summary of findings table following the GRADE approach and a table of other considerations for decision-making.

Key messages

  • The use of activated protein C in patients with sepsis probably does not decrease mortality.
  • The use of activated protein C in patients with sepsis increases the risk of severe bleeding.
  • Activated protein C is a high-cost therapy with clinically important adverse effects. For this reason it was withdrawn from the market.
About the body of evidence for this question

What is the evidence.
See evidence matrix  in Epistemonikos later

We found seven systematic reviews [1],[2],[3],[4],[5],[6],[7], including 35 primary studies [8],[9],[10],[11],
[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],
[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],
[34],[35],[36],[37],[38],[39],[40],[41],[42], six of which correspond to randomized controlled trials relevant to the question in this summary [8],[9],[10],[11],[12],[13].

This table and the summary in general are based on the latter.

What types of patients were included

Regarding the types of patients, it should be noted that the six trials were carried out after 1991, the year that the first consensus definition for sepsis and septic shock was performed, so that the definition and graduation of the severity of sepsis is homogenous between trials.

What types of interventions were included

In four of six trials, the type of activated protein C used was drotrecogin alpha-activated [8],[11],[12],[13] and in two was activated human C protein (rhAPC) [9],[10].

The route of administration was intravenous in all trials.

Regarding the dose, five used a standard dose of 24  μg/kg/hour for a total of 96 hours [8],[10],[11],[12],[13]. One trial used variable doses and different time than 96 hours [9].

All trials compared against placebo or standard treatment.

What types of outcomes
were measured

The different systematic reviews identified grouped the outcomes as follows:

  • Total mortality at 28 days of administration
  • 28-days mortality according to the age of the patients enrolled
  • 28-days mortality according to the duration of treatment
  • 28-days mortality according to protocol PROWESS (24 μg/kg/ hour of drotrecogin alpha for 96 hours)
  • 28-days mortality with treatment of more days than PROWESS
  • 28-days mortality according to APACHE II score
  • 28-days mortality according to levels of plasma protein C before infusion
  • 28-days mortality according to the number of organs affected
  • In-hospital overall mortality
  • Rate of massive bleeding during the first 28 days
  • Massive bleeding rate during administration of activated protein C
  • Overall hemorrhagic stroke rate during treatment


Both trials evaluated the use of tetrahydrocannabinol capsules administered orally. In one trial, the dose was 5 mg, 7.5 mg or 10 mg once [9], and in the other trials, the dose was not specified [8].

Both trials compared against placebo.
Summary of findings

The information on the effects of activated protein C on sepsis is based on six randomized trials including 6,781 patients. All trials measured the outcome mortality at 28 days and severe bleeding.

The summary of findings is as follows:

  • The use of activated protein C in patients with sepsis probably does not decrease the mortality rate. The certainty of the evidence is moderate.
  • The use of activated protein C in patients with sepsis increases the rate of severe bleeding during hospitalization. The certainty of the evidence is high.

Other considerations for decision-making

To whom this evidence does and does not apply
  • The first consensus on the definition of sepsis was developed in 1991 where a definition of sepsis was made and the terms severe sepsis and septic shock were proposed. In the year 2016, the third consensus gave rise to the new definition of sepsis involving organic dysfunction, eliminating the concept of severe sepsis. All patients would fall into the last definition involving the concepts of sepsis and septic shock. So the evidence summarized in this article can be applied to patients with any type of sepsis and septic shock.
About the outcomes included in this summary
  • This summary includes the two most important outcomes in deciding whether or not to use activated protein C, according to the opinion of the authors of this summary. These two outcomes are also those in which systematic reviews place greater emphasis. In addition, it would increase other adverse events not disaggregated in this article.
Balance between benefits and risks, and certainty of the evidence
  • Activated protein C in patients with sepsis probably does not decrease the rate of 28-days mortality and, according to the analyses, produces an increase in the rate of massive hemorrhage within treated patients. The benefit/risk balance is unfavorable to the use of activated protein C.
What would patients and their doctors think about this intervention
  • While Eli Lilly's drotrecogin alfa product generated high expectations for its promising results, in the light of all the existing evidence, all clinicians should give up their use.
Resource considerations
  • It is an intervention that does not produce benefit and is associated to adverse effects, and that also carries a high cost.

Differences between this summary and other sources
  • Our summary is consistent with the conclusions of most identified systematic reviews. However, in three systematic reviews [1],[2],[6] the findings are different and support the use of activated C protein either in patients with septic shock [1],[2] or in any type of patient [6].
  • Following the results found in one of the systematic reviews the drug was withdrawn from the market in several countries and the main guideline recommends against its use [43].
Could this evidence change in the future?
  • The probability that the presented evidence changes in the future is very low due to the certainty of the existing evidence and the withdrawal of the drug from the market.
How we conducted this summary

Using automated and collaborative means, we compiled all the relevant evidence for the question of interest and we present it as a matrix of evidence.

Follow the link to access the interactive version: Recombinant activated protein C for the treatment of sepsis

Notes

The upper portion of the matrix of evidence will display a warning of “new evidence” if new systematic reviews are published after the publication of this summary. Even though the project considers the periodical update of these summaries, users are invited to comment in Medwave or to contact the authors through email if they find new evidence and the summary should be updated earlier. After creating an account in Epistemonikos, users will be able to save the matrixes and to receive automated notifications any time new evidence potentially relevant for the question appears.

The details about the methods used to produce these summaries are described here http://dx.doi.org/10.5867/medwave.2014.06.5997.

Epistemonikos foundation is a non-for-profit organization aiming to bring information closer to health decision-makers with technology. Its main development is Epistemonikos database (www.epistemonikos.org).

These summaries follow a rigorous process of internal peer review.

Conflicts of interest
The authors do not have relevant interests to declare.

Licencia Creative Commons Esta obra de Medwave está bajo una licencia Creative Commons Atribución-NoComercial 3.0 Unported. Esta licencia permite el uso, distribución y reproducción del artículo en cualquier medio, siempre y cuando se otorgue el crédito correspondiente al autor del artículo y al medio en que se publica, en este caso, Medwave.

 

During an episode of sepsis, systemic inflammatory response phenomenon triggers a series of procoagulant mechanisms. It has been suggested that the use of activated protein C could play a role in the management of this pathology, but there is no consensus. Searching in Epistemonikos database, which is maintained by screening multiple databases, we identified seven systematic reviews covering 35 primary studies addressing the question of this article, including six randomized trials. We extracted data, combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded activated protein C in sepsis probably does not decrease the mortality rate and increases the rate of hemorrhagic events.

Autores: Juan Alvarado[1,2], Ricardo Castro[2,3]

Filiación:
[1] Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
[2] Proyecto Epistemonikos, Santiago, Chile
[3] Departamento de Medicina Intensiva, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile

E-mail: rcastro@med.puc.cl

Correspondencia a:
[1] Facultad de Medicina
Pontificia Universidad Católica de Chile
Lira 63
Santiago Centro
Chile

Citación: Alvarado J, Castro R. What is the role of recombinant activated protein C in the management of sepsis?. Medwave 2016; 16(Suppl5):e6801 doi: 10.5867/medwave.2016.6801

Fecha de publicación: 20/12/2016

Ficha PubMed

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Costa V, Brophy JM. Drotrecogin alfa (activated) in severe sepsis: a systematic review and new cost-effectiveness analysis. BMC Anesthesiol. 2007 Jun 25;7:5 | PubMed |

Green C, Dinnes J, Takeda A, Shepherd J, Hartwell D, Cave C, Payne E, Cuthbertson BH. 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 Mar;9(11):1-126, iii-iv | PubMed |

Kalil AC, LaRosa SP. Effectiveness and safety of drotrecogin alfa (activated) for severe sepsis: a meta-analysis and metaregression. Lancet Infect Dis. 2012 Sep;12(9):678-86 | CrossRef | PubMed |

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 Jan;79(1):33-43. | PubMed |

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 Dec 12;12:CD004388 | CrossRef | PubMed |

Sashegyi A, Trzaskoma BL, Nelson DR, Williams MD, Macias W. International INtegrated Database for the Evaluation of severe sePsis and drotrecogin alfa (activated) THerapy: component trials and statistical methods for INDEPTH. Curr Med Res Opin. 2006 May;22(5):1001-12 | PubMed |

Wiedermann CJ, Kaneider NC. A meta-analysis of controlled trials of recombinant human activated protein C therapy in patients with sepsis. BMC Emerg Med. 2005 Oct 14;5:7 | PubMed |

Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL, François B, Guy JS, Brückmann M, Rea-Neto A, Rossaint R, Perrotin D, Sablotzki A, Arkins N, Utterback BG, Macias WL; 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 Sep 29;353(13):1332-41 | PubMed |

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 Mar 8;344(10):699-709 | PubMed |

Bernard GR, Ely EW, Wright TJ, Fraiz J, Stasek JE Jr, Russell JA, Mayers I, Rosenfeld BA, Morris PE, Yan SB, Helterbrand JD. Safety and dose relationship of recombinant human activated protein C for coagulopathy in severe sepsis. Crit Care Med. 2001 Nov;29(11):2051-9 | PubMed |

Dhainaut JF, Antonelli M, Wright P, Desachy A, Reignier J, Lavoue S, Charpentier J, Belger M, Cobas-Meyer M, Maier C, Mignini MA, Janes J. Extended drotrecogin alfa (activated) treatment in patients with prolonged septic shock. Intensive Care Med. 2009 Jul;35(7):1187-95 | CrossRef | PubMed |

Nadel S, Goldstein B, Williams MD, Dalton H, Peters M, Macias WL, Abd-Allah SA, Levy H, Angle R, Wang D, Sundin DP, Giroir B; 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 Mar 10;369(9564):836-43 | PubMed |

ROWESS SHOCK Steering Committee., Thompson BT, Ranieri VM, Finfer S, Barie PS, Dhainaut JF, Douglas IS, Gårdlund B, Marshall JC, Rhodes A. Statistical analysis plan of PROWESS SHOCK study. Intensive Care Med. 2010 Nov;36(11):1972-3. | CrossRef | PubMed |

Martin G, Brunkhorst FM, Janes JM, Reinhart K, Sundin DP, Garnett K, Beale R. The international PROGRESS registry of patients with severe sepsis: drotrecogin alfa (activated) use and patient outcomes. Crit Care. 2009;13(3):R103 | CrossRef | PubMed |

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 Apr;38(4):1101-7 | CrossRef | PubMed |

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 Mar;33(3):517-23 | PubMed |

Decruyenaere J, De Backer D, Spapen H, Laterre PF, Raemaekers J, Rogiers P, Trine H, Sartral M, Haentjens T, Wagner T. 90-day follow-up of patients treated with Drotrecogin Alfa (activated) for severe sepsis: a Belgian open label study. Acta Clin Belg. 2009 Jan-Feb;64(1):16-22 | PubMed |

Hecksher CA, Lacerda HR, Maciel MA. Characteristics and outcomes of patients treated with drotrecogin alpha and other interventions of the "Surviving Sepsis" campaign in clinical practice. Rev Bras Ter Intensiva. 2008 Jun;20(2):135-43. | PubMed |

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 Jan;37(1):19-25 | CrossRef | PubMed |

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 Mar;33(3):426-34 | PubMed |

Anger KE, Degrado JR, Greenwood BC, Cohen SA, Szumita PM. Evaluation of recombinant activated protein C for severe sepsis at a tertiary academic medical center. Therapeutics and clinical risk management. 2013;9:277-84. | Link |

Bollinger J, Coley K, Rea R, Saul M. Outcomes in patients with recombinant human activated protein c at an academic medical center versus the ENHANCE US trial. Crit Care Med 2006; 34: A111. | Link |

Wheeler A, Steingrub J, Schmidt GA, Sanchez P, Jacobi J, Linde-Zwirble W, Bates B, Qualy RL, Woodward B, Zeckel M. A retrospective observational study of drotrecogin alfa (activated) in adults with severe sepsis: comparison with a controlled clinical trial. Crit Care Med. 2008 Jan;36(1):14-23 | PubMed |

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Edición Julio 2022
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