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Drotrecogin alfa (activated) in patients with severe sepsis and a high risk of death
Critical Care volume 10, Article number: 427 (2006)
We are pleased that Williams and coworkers  confirmed our random effects analysis , which relied on publicly available data. This analysis pooled the results from patients with Acute Physiology and Chronic Health Evaluation (APACHE) II scores of 25 or greater from the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation of Severe Sepsis)  and ADDRESS (Administration of Drotrecogin Alfa [Activated] in Early Stage Severe Sepsis)  trials. As we discussed previously , this analysis demonstrates a surprising degree of statistical heterogeneity, which remains despite minimal methodologic differences between the two trials and further minimization of clinical heterogeneity by selecting a more uniform subgroup of patients with severe sepsis and a high risk for death. This heterogeneity is illustrated in Figure 1 presented by Williams and coworkers , in which I2 (the percentage of total variation in results across studies that is due to heterogeneity rather than chance ), is more than 80% for each of the methods presented. Given this degree of unexplained heterogeneity, the use of a fixed effects model, as suggested by Williams and coworkers , would be highly unconventional .
We also support the pooling of individual patient data from these trials to generate hypotheses regarding appropriate patient selection for drotrecogin alfa (activated) that could be tested in subsequent trials . Furthermore, we encourage public release of these data for the purposes of a meta-analysis of individual patient data to be undertaken by an independent group, using appropriate statistical methods that incorporate random effects, and that is subject to peer review.
Williams MD, Janes JM, Nelson DR: Drotrecogin alfa (activated): current evidence supports treatment for severe sepsis patients with a high risk of death. Crit Care 2006, 10: 424. 10.1186/cc5062
Friedrich JO, Adhikari NK, Meade MO: Drotrecogin alfa (activated): does current evidence support treatment for any patients with severe sepsis? Crit Care 2006, 10: 145. 10.1186/cc4947
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 Activated 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
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
Friedrich JO, Adhikari NKJ, Meade MO: Drotrecogin alfa (activated): down and not out, but not really in either. Crit Care 2006, 10: 420. 10.1186/cc5022
Higgins JP, Thompson SG, Deeks JJ, Altman DG: Measuring inconsistency in meta-analyses. BMJ 2003, 327: 557-560. 10.1136/bmj.327.7414.557
Egger M, Davey Smith G, Altman DG, (editors): Systematic Reviews in Healthcare: Meta-Analysis in Context. London, UK: BMJ Books; 2001.
The authors declare that they have no competing interests.
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Friedrich, J.O., Adhikari, N.K. & Meade, M.O. Drotrecogin alfa (activated) in patients with severe sepsis and a high risk of death. Crit Care 10, 427 (2006). https://doi.org/10.1186/cc5117
- Random Effect
- Severe Sepsis
- Health Evaluation
- Fixed Effect Model
- Methodologic Difference