Hostname: page-component-586b7cd67f-t7fkt Total loading time: 0 Render date: 2024-11-22T19:41:57.734Z Has data issue: false hasContentIssue false
  • English
  • Français

Drotrecogin alfa (activated): diffusion from clinical trials to clinical practice

Published online by Cambridge University Press:  01 October 2008

A. F. Mackenzie
A. F. Mackenzie*
Affiliation:
Department of Anaesthetics, Queen Margeret HospitalDunfermline, Scotland, UK
*
Correspondence to: Alasdair F. Mackenzie, Department of Anaesthetics, Queen Margeret Hospital, Whitefield Road, Dunfermline, Scotland, KY12 0SU, UK. E-mail: [email protected]; Tel: +1383 623623; Fax: +1383 627042

Abstract

An abstract is not available for this content. As you have access to this content, full HTML content is provided on this page. A PDF of this content is also available in through the ‘Save PDF’ action button.
Type
Correspondence
Information
European Journal of Anaesthesiology , Volume 25 , Issue 10 , October 2008 , pp. 861 - 862
Copyright
Copyright © European Society of Anaesthesiology 2008

EDITOR:

Ridley and colleagues present retrospective data on the use of activated protein C (APC) in five UK hospitals in 2002–2005 [Reference Ridley, Lwin and Wyncoll1]. To identify patient groups that might benefit from APC the authors considered it more rational to use their cited approach rather than have further formal appraisal of the drug. The authors discuss the European Medicine Agency (EMEA) 2002 approval but, surprisingly, their crucial decision in early 2007 is not mentioned: the EMEA demanded a new randomized, placebo controlled trial of APC in severe sepsis to clarify the risk/benefit balance of APC [2] in the currently indicated high-risk population [3].

This EMEA opinion, on the most rational way to proceed, reflects results of the trials requested by the FDA. The PROWESS follow-up trial showed no significant difference in the number of patients discharged home between APC and placebo groups [Reference Laterre, Levy and Clermont4]. The authors suggest that ENHANCE confirmed drug efficacy and safety. However, this has been seriously questioned: as a non-randomized, uncontrolled trial it was not designed to assess efficacy; compared with PROWESS the serious bleeding rates were greatly increased in ENHANCE (a NNT of 16 for a serious bleed) [Reference Farmer5]. As the authors indicate, ADDRESS did not help APC and the drug’s failure to demonstrate efficacy and safety in paediatric sepsis [Reference Nadel, Goldstein and Williams6] raised further doubts around APC having any beneficial effect, even in adults [Reference Opal7].

It may be a particular concern that the authors’ data included a relatively high proportion of surgical patients (50%) vs. PROWESS (455/1690: 27%). Original Phase II and PROWESS trial data showed a higher mortality in the surgical patients randomized to APC [8]. A later retrospective reclassification of PROWESS patients may be difficult to interpret [Reference Barie, Williams and McCollam9]. With treated surgical patients in ADDRESS also having a higher mortality, there is a consistent trend towards poorer outcome, with APC administration, in almost 1500 surgical patients enrolled to all three placebo controlled trials in adults. It may be hazardous to imply that APC has an acceptable benefit/risk profile in this group of patients.

Finally, data from a small number of hospitals in 2002–2005 may not reflect current UK practice. Following recent trial results use may now be very low as in other countries: recent French data (2006) showed that APC was not used in 14 of the 15 ICUs surveyed [Reference Muller, Jaber, Raillard and Lefrant10]. Low usage will probably persist unless new trials demonstrate clear benefit in easily identifiable patient groups.

References

1.Ridley, S, Lwin, A, Wyncoll, D et al. Drotrecogin alfa (activated): diffusion from clinical trials to clinical practice. Eur J Anaesthesiol 2008; 25: 211–216.Google Scholar
2.www.emea.europa.eu/humandocs/PDFs/EPAR/xigris/Xigris-H-C-396-S-21.pdf (accessed 23 March 2008).Google Scholar
3.www.medicalnewstoday.com/articles/63959.php (accessed 23 March 2008).Google Scholar
4.Laterre, PF, Levy, H, Clermont, G et al. Hospital mortality and resource use in subgroups of the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial. Crit Care Med 2004; 32: 2207–2218.CrossRefGoogle ScholarPubMed
5.Farmer, JC. Drotrecogin alfa (activated) treatment in severe sepsis: A “journal club” review of the global ENHANCE trial. Crit Care Med 2005; 33: 2428–2431.CrossRefGoogle ScholarPubMed
6.Nadel, S, Goldstein, B, Williams, MD et al. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet 2007; 369: 836–843.Google Scholar
7.Opal, SM. Can we RESOLVE the treatment of sepsis. Lancet 2007; 369: 803–804.Google Scholar
8.www.fda.gov/cder/biologics/review/droteli112101r1.htmFDA Clinical Review Drotrecogin Alfa (activated) (Table 97 – accessed 23 March 2008).Google Scholar
9.Barie, PS, Williams, MD, McCollam, JS et al. Benefit/risk profile of drotrecogin alfa (activated) in surgical patients with severe sepsis. Am J Surg 2004; 188: 212–220.Google Scholar
10.Muller, L, Jaber, S, Raillard, A, Lefrant, JY. Use of recombinant human activated protein C in patients with severe sepsis: a French retrospective multicentre study. Intensive Care Med 2008; 34 (5): 977–979.Google Scholar