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Activated protein C in sepsis: down but not out, yet

We read with interest the recent commentary by Friedrich and coworkers [1], in which they consider whether the current evidence supports treatment for severe sepsis with drotrecogin alfa (activated). They conclude that the survival benefit is weak in patients with severe sepsis treated with activated protein C (APC) [1]. However, this conclusion has a number of limitations.

First, the authors have summated the individual studies by using a random effects model. Although the random effects model is generally used in the presence of significant heterogeneity, statistical tests erroneously detect heterogeneity when there are few studies [2]. Another problem with this model is that by adding a constant number to the weight of each study, the relative contributions of each trial become more equal. This can have a marked effect on the results, and only seldom does it afford an appropriate representation of the efficacy expected [3, 4]. In fact, if we use a fixed effects model then there is significant benefit with the use of APC in both of the classic indications, namely Acute Physiology and Chronic Health Evaluation II score above 25 (odds ratio 0.71, 95% confidence interval [CI] 0.56–0.91) and two or more organ dysfunctions (odds ratio 0.78, 95% CI 0.64–0.94), with the numbers needed to treat being 14 (95% CI 8–46) and 20 (95% CI 12–72), respectively.

The problem thus lies with the recognition of heterogeneity in a trial, which includes clinical heterogeneity (variability in the participants, interventions and outcomes), methodological heterogeneity (variability in trial design and quality) and statistical heterogeneity (variability in the treatment effects evaluated in different trials). Ideally, a meta-analysis should only be considered when a group of trials is sufficiently homogeneous. Such a situation is Utopian. Indeed, one could argue that because clinical and methodological diversity always occur in a meta-analysis, statistical heterogeneity is inevitable. Thus, the test for heterogeneity is irrelevant to the choice of analysis; heterogeneity will always exist, whether we are able to detect it using a statistical test or not [5].

Finally, the authors base their conclusions on an abstract patient data meta-analysis rather than individual patient data meta-analysis. Abstract patient data meta-analyses reflect the first step toward generating hypotheses, which need to be retested in a fully fledged individual patient data meta-analysis. Although methodologically difficult, the latter can evaluate randomization methods and correctness of data, re-analyze the original data, perform additional analyses and update patient outcomes that become 'frozen' in time, and can thus overcome the limitations of abstract patient data meta-analysis [6].

Is there a role for APC in severe sepsis? The PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation of Severe Sepsis) trial [7] demonstrated a 6.1% absolute reduction in mortality rate (P = 0.005). Therefore, the use of this drug should be continued in high-risk situations, as defined by the Surviving Sepsis Campaign guidelines, unless this recommendation is refuted in further trials.

References

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    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

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    Huedo-Medina TB, Sanchez-Meca J, Marin-Martinez F, Botella J: Assessing Heterogeneity in Meta-Analysis: Q Statistic or I2Index? Psychol Methods 2006, 11: 193-206. 10.1037/1082-989X.11.2.193

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    Ades AE, Lu G, Higgins JP: The interpretation of random-effects meta-analysis in decision models. Med Decis Making 2005, 25: 646-654. 10.1177/0272989X05282643

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    Moayyedi P: Meta-analysis: can we mix apples and oranges? Am J Gastroenterol 2004, 99: 2297-2301. 10.1111/j.1572-0241.2004.40948.x

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    Deeks JJ, Higgins JPT, Altman DG: Analysing and presenting results. In Cochrane Reviewers' Handbook 422 [updated March 2004]. Edited by: Alderson P, Green S, Higgins JPT. Chichester, UK: John Wiley & Sons Ltd; 2004:68-139.

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    Piedbois P, Buyse M: Meta-analyses based on abstracted data: a step in the right direction, but only a first step. J Clin Oncol 2004, 22: 3839-3841. 10.1200/JCO.2004.06.924

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    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: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001, 344: 699-709. 10.1056/NEJM200103083441001

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Correspondence to Ritesh Agarwal.

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The authors declare that they have no competing interests.

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Agarwal, R., Nath, A. Activated protein C in sepsis: down but not out, yet. Crit Care 10, 416 (2006). https://doi.org/10.1186/cc4988

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Keywords

  • Severe Sepsis
  • Organ Dysfunction
  • Random Effect Model
  • Significant Heterogeneity
  • Statistical Heterogeneity