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LETTER TO EDITOR
Year : 2012  |  Volume : 56  |  Issue : 6  |  Page : 597-598  

Updates on role of human recombinant activated protein C in patients with sepsis and severe sepsis: Changed scenario after PROWESS SHOCK trial


Integral Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Date of Web Publication14-Dec-2012

Correspondence Address:
Aparna Shukla
Integral Institute of Medical Sciences, Lucknow, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-5049.104597

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How to cite this article:
Shukla A. Updates on role of human recombinant activated protein C in patients with sepsis and severe sepsis: Changed scenario after PROWESS SHOCK trial. Indian J Anaesth 2012;56:597-8

How to cite this URL:
Shukla A. Updates on role of human recombinant activated protein C in patients with sepsis and severe sepsis: Changed scenario after PROWESS SHOCK trial. Indian J Anaesth [serial online] 2012 [cited 2019 Dec 10];56:597-8. Available from: http://www.ijaweb.org/text.asp?2012/56/6/597/104597

Sir,

In the previous publication in Indian Journal of Anesthesia, the role of human recombinant activated protein C in sepsis and severe sepsis has been discussed. [1]

Initially, there was great confusion regarding the use of activated protein C (APC) in sepsis. PROWESS (recombinant human activated protein C world wide evaluation in severe sepsis) trial [2] conducted in July 1998 was a multi-center, randomized, double blind, placebo-controlled trial of 1690 patients with severe sepsis. Results of the trial clearly indicated that one in every five patients who would have died was saved with Drotrecogin alfa treatment, added to best treatment of care. Then use of this drug started judiciously in patients with septic shock worldwide till results of other trials were declared.

Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) trial completed in 2005 found no significant difference in 28-day mortality (17% placebo versus 18.5% APC, ρ=0.34) with the use of APC. On the contrary, risk of serious bleeding was increased (2.4% with APC and 1.2% with placebo during infusion period). [3]

Researching Severe Sepsis and Organ Dysfunction in Children (RESOLVE) trial with 240 children getting APC and 237 children getting placebo submitted its report in 2007. In this trial too, 28-day mortality rate was not improved significantly (placebo 17.5% versus APC 17.7%, ρ=0.39). Unlike previous studies, risk of bleeding was equal for placebo and APC (6.8% placebo and 6.7% APC, ρ=0.97). [4]

Cochrane Database, which submitted its review in 2008, did not found any significant reduction in 28-day mortality in adults who were given APC. However, risk of bleeding was increased. [5]

So, Food and drug association (FDA) recommended another multi center, placebo controlled, trial to determine the efficacy of APC, named PROWESS-SHOCK trial. [6] PROWESS-SHOCK was started in 2008 and submitted its report in March 2011. Its results have been published recently in 2011. PROWESS-SHOCK trial included 1,696 patients with severe sepsis and septic shock. The inclusion criteria were the following: (1) At least two of the four systemic inflammatory response syndrome criteria (2) Clear evidence of infection (3) Received IV resuscitation of ≥30 mL/kg administered 4 h before or after initiation of vasopressor therapy (4) Continuous requirement of at least one of four vasopressors for at least 4 h (5) Hypoperfusion (renal, acidosis, hepatic) (6) Drotrecogin initiated within 24 h of shock onset. The 28-day mortality was greater in patients receiving drotrecogin alfa (n=846, 26.4%) as compared with the placebo arm (n=834, 24.2%). The difference was not significant statistically (P=0.31). Mortality was not improved even in patients with severe protein C deficiency. During infusion, serious bleeding was not identified. [7]

After results of PROWESS-SHOCK trial, the scenario has been changed completely. APC was withdrawn from the market on Oct 25, 2011. In response to the removal of Drotrecogin alfa (activated), also referred to as rhAPC, in all markets following results of the PROWESS-SHOCK study, the Surviving Sepsis Campaign withdraws its suggestions for use of rhAPC as stated in "Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock. [8],[9]

We can take a lesson from the failed PROWESS trial that single study is not sufficient in confirming the treatment benefits especially in complex disease like sepsis. And the search continues for an ideal agent in the management of sepsis.

 
   References Top

1.Shukla A, Awasthi S. Role of human recombinant activated protein C and low dose corticosteroid therapy in sepsis. Indian J Anaesth 2010;54:496-503.  Back to cited text no. 1
[PUBMED]  Medknow Journal  
2.Bernard GR, Vincet JL et al., 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;344:699-709.  Back to cited text no. 2
    
3.Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL, et al. Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) Study Group. Drotrecogin Alfa (Activated) for adult with severe sepsis and low risk of death. N Engl J Med 2005;353:1332-41.  Back to cited text no. 3
[PUBMED]    
4.Nadel S, Goldstein B, Williams MD, Dalton H, Peters M, Macias WL, et al. Researching severe Sepsis and Organ dysfunction in children: A gLobal perspective (RESOLVE) study group. Drotrecogin Alfa (Activated) in children with severe sepsis: A multicenter phase III randomised controlled trial. Lancet 2007;369:836-43.  Back to cited text no. 4
[PUBMED]    
5.Marti-Carvajal A, Salanti G, Cardona AF. Human recombinant activated protein C for severe sepsis. Cochrane Database Syst Rev 2008 Jan 23;(1):CD004388. [Last accessed on 2012 May 22].  Back to cited text no. 5
    
6.Finfer S, Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, et al. Design, conduct, analysis and reporting of a multi-national placebo-controlled trial of activated protein C for septic shock. Intensive Care Med 2008;34:1935-47.  Back to cited text no. 6
[PUBMED]    
7.Kate O'Rourke. Gloom and Doom Swirls Around Sepsis Research. Infectious disease special edition. ISSUE: MARCH 2012 | VOLUME: 1. Available from: http://www.www.idse.net/ViewArticle.aspx. [Last accessed on 2012 May 22].  Back to cited text no. 7
    
8.Poole D, Bertolini G, Garattini S. Withdrawal of 'Xigris' from the market: Old and new lessons. J Epidemiol Community Health 2012;66:571-2.  Back to cited text no. 8
[PUBMED]    
9.Update regarding rhAPC Recommendation in Surviving Sepsis Campaign Guidelines . Available from: http://www.survivingsepsis.org/guidelines.[Last accessed on 2012 May 22].  Back to cited text no. 9
    



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