Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients

Facultad de Ciencias de la Salud Eugenio Espejo, Universidad Tecnológica Equinoccial, Quito, Ecuador.
Cochrane database of systematic reviews (Online) (Impact Factor: 5.94). 01/2012; 12(12):CD004388. DOI: 10.1002/14651858.CD004388.pub6
Source: PubMed

ABSTRACT Sepsis is a common and frequently fatal condition. Human recombinant activated protein C (APC) has been introduced to reduce the high risk of death associated with severe sepsis or septic shock. This systematic review is an update of a Cochrane review originally published in 2007.
We assessed the benefits and harms of APC for patients with severe sepsis or septic shock.
We searched CENTRAL (The Cochrane Library 2012, Issue 6); MEDLINE (2010 to June 2012); EMBASE (2010 to June 2012); BIOSIS (1965 to June 2012); CINAHL (1982 to June 2012) and LILACS (1982 to June 2012). There was no language restriction.
We included randomized clinical trials assessing the effects of APC for severe sepsis or septic shock in adults and children. We excluded studies on neonates. We considered all-cause mortality at day 28 and at the end of study follow up, and hospital mortality as the primary outcomes.
We independently performed trial selection, risk of bias assessment, and data extraction in duplicate. We estimated relative risks (RR) for dichotomous outcomes. We measured statistical heterogeneity using the I(2) statistic. We used a random-effects model.
We identified one new randomized clinical trial in this update which includes six randomized clinical trials involving 6781 participants in total, five randomized clinical trials in adult (N = 6307) and one randomized clinical trial in paediatric (N = 474) participants. All trials had high risk of bias and were sponsored by the pharmaceutical industry. APC compared with placebo did not significantly affect all-cause mortality at day 28 compared with placebo (780/3435 (22.7%) versus 767/3346 (22.9%); RR 1.00, 95% confidence interval (CI) 0.86 to 1.16; I(2) = 56%). APC did not significantly affect in-hospital mortality (393/1767 (22.2%) versus 379/1710 (22.1%); RR 1.01, 95% CI 0.87 to 1.16; I(2) = 20%). APC was associated with an increased risk of serious bleeding (113/3424 (3.3%) versus 74/3343 (2.2%); RR 1.45, 95% CI 1.08 to 1.94; I(2) = 0%). APC did not significantly affect serious adverse events (463/3334 (13.9%) versus 439/3302 (13.2%); RR 1.04, 95% CI 0.92 to 1.18; I(2) = 0%). Trial sequential analyses showed that more trials do not seem to be needed for reliable conclusions regarding these outcomes.
This updated review found no evidence suggesting that APC should be used for treating patients with severe sepsis or septic shock. APC seems to be associated with a higher risk of bleeding. The drug company behind APC, Eli Lilly, has announced the discontinuation of all ongoing clinical trials using this drug for treating patients with severe sepsis or septic shock. APC should not be used for sepsis or septic shock outside randomized clinical trials.

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    • "Interventions RCTs or meta-analysis No. of component studies No. of patients Sequence generation Allocation concealment Blindness ITT APC Marti-Carvajal et al (2012) [28] "
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    ABSTRACT: Background and objectives sepsis is a leading cause of mortality and morbidity in intensive care unit and many studies have been conducted aiming to improve its outcome. Randomized controlled trials (RCT) and observational studies using propensity score (PS) method are commonly employed for this purpose. However, the agreement between these two major methodological designs has never been investigated in this specific area. The present study aimed to compare the effect sizes between RCTs and PS-based studies. Methods Electronic databases including Pubmed, SCOPUS and EBSCO were searched to obtain PS-based studies in the area of sepsis. The studies were matched to RCTs or systematic reviews and meta-analysis in terms of population, intervention, control and outcome. When there were multiple PS-based studies or RCTs in one area, the effect sizes were pooled by using random-effects model and inverse variance method. The comparisons were performed by using differences in the effect size. Results A total of 8 topics were identified fulfilling the criterion that at least one pair of RCT and PS-based study could be matched. The interventions included activated protein C, low dose steroid, antithrombin III, combination antibiotic therapy, fish oil supplementation, statin, etomidate for intubation, recombinant human soluble thrombomodulin. The effect sizes were statistically different between RCTs and PS-based studies in most circumstances (6/8). The pooled mean difference in effect sizes was -0.16 (95% CI: -0.33-0.01), indicating a trend towards larger treatment effect in PS studies than that in RCTs. The result remains unaltered by restricting to RCTs and PS studies with the largest sample sizes. Conclusion Our study shows that PS studies tend to report larger treatment effect than RCTs in the field of sepsis, indicating the difference between efficacy trials and effectiveness studies.
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