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Critical Care
Published in: Critical Care 3/2006

01-06-2006 | Commentary

Drotrecogin alfa (activated): does current evidence support treatment for any patients with severe sepsis?

Authors: Jan O Friedrich, Neill KJ Adhikari, Maureen O Meade

Published in: Critical Care | Issue 3/2006

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Abstract

Two international multicentre randomised controlled trials of drotrecogin alfa (activated) (DrotAA), the Recombinant Human Activated Protein C Worldwide Evaluation of Severe Sepsis (PROWESS) and Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) trials, have produced inconsistent results. When 28-day mortality data from these trials for patients with severe sepsis and at high risk of death are pooled using a standard random-effects meta-analysis technique, there is no statistically significant survival benefit (for patients with Acute Physiology and Chronic Health Evaluation (APACHE II) scores of 25 or more), or a borderline significant benefit (for patients with multi-organ failure). We argue that two important methodological issues might explain the disparate results between the two trials. These issues centre on early trial stopping, which exaggerates treatment effects, and reliance on subgroup analyses, which for DrotAA yields inconsistent results across different definitions of high risk. These concerns call into question the effectiveness of DrotAA in any patients with severe sepsis. Consequently, further randomised trials of this agent in prospectively defined high-risk patients are required to clarify its role in the management of severe sepsis.
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Literature
1.
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: 1303-1310. 10.1097/00003246-200107000-00002.CrossRefPubMed
2.
Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand D, Ely EW, for the Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group, et al: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001, 344: 699-709. 10.1056/NEJM200103083441001.CrossRefPubMed
3.
Warren HS, Suffredini AF, Eichacker PQ, Munford RS: Risks and benefits of activated protein C treatment for severe sepsis. N Engl J Med. 2002, 347: 1027-1030. 10.1056/NEJMsb020574.CrossRefPubMed
4.
Siegel JP: Assessing the use of activated protein C in the treatment of severe sepsis. N Engl J Med. 2002, 347: 1030-1034. 10.1056/NEJMsb021512.CrossRefPubMed
5.
Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL, Francois B, Guy JS, Bruckmann M, Rea-Neto A, for the Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) Study Group, et al: Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med. 2005, 353: 1332-1341. 10.1056/NEJMoa050935.CrossRefPubMed
6.
Friedrich JO: Drotrecogin alfa (activated) in severe sepsis. N Engl J Med. 2006, 354: 94-95. 10.1056/NEJMc052759.CrossRefPubMed
7.
Bernard GR, Ely EW, Wright TJ, Fraiz J, Stasek JE, Russell JA, Mayers I, Rosenfeld BA, Morris PE, Yan SB: Safety and dose relationship of recombinant human activated protein C for coagulopathy in severe sepsis. Crit Care Med. 2001, 29: 2051-2059. 10.1097/00003246-200111000-00003.CrossRefPubMed
8.
9.
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, 9: 1-126. iii–ivCrossRefPubMed
10.
Knaus WA, Draper EA, Wagner DP, Zimmerman JE: APACHE II: a severity of disease classification system. Crit Care Med. 1985, 13: 818-829. 10.1097/00003246-198510000-00009.CrossRefPubMed
11.
Ely EW, Laterre PF, Angus DC, Helterbrand JD, Levy H, Dhainaut JF, Vincent JL, Macias WL, Bernard GR, PROWESS Investigators: Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis. Crit Care Med. 2003, 31: 12-19. 10.1097/00003246-200301000-00002.CrossRefPubMed
12.
Abraham E, Laterre P-F: Drotrecogin alfa (activated) in severe sepsis. N Engl J Med. 2006, 354: 95-96.
13.
14.
Booth FV, Short M, Shorr AF, Arkins N, Bates B, Qualy RL, Levy H: Application of a population-based severity scoring system to individual patients results in frequent misclassification. Crit Care. 2005, 9: R522-R529. 10.1186/cc3790.PubMedCentralCrossRefPubMed
15.
Carlet J: Prescribing indications based on successful clinical trials in sepsis: a difficult exercise. Crit Care Med. 2006, 34: 525-529. 10.1097/01.CCM.0000198329.85851.8E.CrossRefPubMed
16.
Montori VM, Devereaux PJ, Adhikari NKJ, Burns KEA, Eggert CH, Briel M, Lacchetti C, Leung TW, Darling E, Bryant DM, et al: Randomized trials stopped early for benefit: a systematic review. JAMA. 2005, 294: 2203-2209. 10.1001/jama.294.17.2203.CrossRefPubMed
17.
Pocock SJ, Hughes MD: Practical problems in interim analyses, with particular regard to estimation. Control Clin Trials. 1989, 10 (Suppl): 209S-221S. 10.1016/0197-2456(89)90059-7.CrossRefPubMed
18.
Abraham E, Reinhart K, Opal S, Demeyer I, Doig C, Rodriguez AL, Beale R, Svoboda P, Laterre PF, Simon S, et al: Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis. A randomized controlled trial. JAMA. 2003, 290: 238-247. 10.1001/jama.290.2.238.CrossRefPubMed
19.
Wheatley K, Clayton D: Be skeptical about unexpected large apparent treatment effects: the case of an MRC AML12 randomization. Control Clin Trials. 2003, 24: 66-70. 10.1016/S0197-2456(02)00273-8.CrossRefPubMed
20.
Parmar MK, Griffiths GO, Spiegelhalter DJ, Souhami RL, Altman DG, van der Scheuren E, CHART steering committee: Monitoring of large randomised clinical trials: a new approach with Bayesian methods. Lancet. 2001, 358: 375-381. 10.1016/S0140-6736(01)05558-1.CrossRefPubMed
21.
Peto R: Clinical trials. Treatment of Cancer. Edited by: Sikora K, Halnan KE. 1990, London: Chapman & Hall, 873-877. 2
22.
23.
Assmann SF, Pocock SJ, Enos LE, Kasten LE: Subgroup analysis and other (mis)uses of baseline data in clinical trials. Lancet. 2000, 355: 1064-1069. 10.1016/S0140-6736(00)02039-0.CrossRefPubMed
24.
van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R: Intensive insulin therapy in critically ill patients. N Engl J Med. 2001, 345: 1359-1367. 10.1056/NEJMoa011300.CrossRefPubMed
25.
Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troche G, et al: Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002, 288: 862-871. 10.1001/jama.288.7.862.CrossRefPubMed
26.
Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker MM, et al: Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004, 32: 858-873. 10.1097/01.CCM.0000117317.18092.E4.CrossRefPubMed
27.
Van den Berghe GH, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, Van Wijngaerden E, Bobbaers H, Bouillon R: Intensive insulin therapy in the medical ICU. N Engl J Med. 2006, 354: 449-461. 10.1056/NEJMoa052521.CrossRefPubMed
28.
29.
Brunkhorst FM, Kuhnt E, Engel C, Meier-Hellmann A, Ragaller M, Quintel M, Weiler N, Grundling M, Oppert M, Deufel T, et al: Intensive insulin therapy in patients with severe sepsis and septic shock is associated with an increased rate of hypoglycemia – results from a randomized controlled study (VISEP) [abstract]. Infection. 2005, 33 (Suppl 1): 19-20.
30.
31.
32.
Vincent JL, Bernard GR, Beale R, Doig C, Putensen C, Dhainaut JF, Artigas A, Fumagalli R, Macias W, Wright T, et al: Drotrecogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE: further evidence for survival and safety and implications for early treatment. Crit Care Med. 2005, 33: 2266-2277. 10.1097/01.CCM.0000181729.46010.83.CrossRefPubMed
33.
Eichacker PQ, Danner RL, Suffrendini AF, Cui X, Natanson C: Reassessing recombinant human activated protein C for sepsis: time for a new randomized controlled trial. Crit Care Med. 2005, 33: 2426-2428. 10.1097/01.CCM.0000183002.26587.FF.CrossRefPubMed
34.
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, 5: 7-10.1186/1471-227X-5-7.PubMedCentralCrossRefPubMed
35.
Mackenzie AF: Activated protein C: do more survive?. Intensive Care Med. 2005, 31: 1624-1626. 10.1007/s00134-005-2829-4.CrossRefPubMed
36.
LaRosa SP: Drotrecogin alfa (activated) in severe sepsis. N Engl J Med. 2006, 354: 95-
37.
Metadata
Title
Drotrecogin alfa (activated): does current evidence support treatment for any patients with severe sepsis?
Authors
Jan O Friedrich
Neill KJ Adhikari
Maureen O Meade
Publication date
01-06-2006
Publisher
BioMed Central
Published in
Critical Care / Issue 3/2006
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/cc4947

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