Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients
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.
Available from: Vaibhav Wadhwa
- "The meta-analysis, however, also included retrospective studies along with the randomized controlled trials and therefore might have lead to the results being biased. A meta-analysis including only RCTs was published in 2007 and was recently updated after addition of another RCT . The update, in line with the original results, failed to show any benefit of rhAPC in patients with severe sepsis and it concluded that rhAPC was associated with a higher risk of bleeding. "
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ABSTRACT: Disseminated Intravascular Coagulation (DIC) is a life threatening complication that occurs in a wide variety of clinical conditions. DIC predisposes the patients for bleeding, organ failure, shock & thromboembolism and hence has a higher morbidity and mortality. Therefore prevention, early detection and prompt treatment of DIC can increase the chances of patient survival by manifolds. There is a lot of confusion and apprehension that surrounds the management of DIC. The saying 'one size doesn't fit all' stands true in case of DIC. The unpredictable course of the disease process makes it important for the physician to understand that following standard protocol may not give the desired results in all cases. The clinical picture of the patient usually gets
Available from: Zhongheng Zhang
- "Interventions RCTs or meta-analysis No. of component studies No. of patients Sequence generation Allocation concealment Blindness ITT APC Marti-Carvajal et al (2012)  "
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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.
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.
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.
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.
Available from: jid.oxfordjournals.org
- "There is a common perception, not only in EHF but also in routine sepsis, that correction of coagulopathy will improve survival outcomes. However, therapeutic interventions that have focused on targeting coagulopathy in nonhuman primate models of EBOV only moderately increased survival [27, 28], and use of activated protein C in septic patients in the intensive care unit has been similarly disappointing . A large focus has been placed on understanding the role of TF in EHF, given the marked increases in TF expression seen in monocytes in nonhuman primates infected with EBOV . "
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Ebola hemorrhagic fever (EHF) outbreaks occur sporadically in Africa and result in high rates of death. The 2000-2001 outbreak of Sudan virus-associated EHF in the Gulu district of Uganda led to 425 cases, of which 216 were laboratory confirmed, making it the largest EHF outbreak on record. Serum specimens from this outbreak had been preserved in liquid nitrogen from the time of collection and were available for analysis.
Available samples were tested using a series of multiplex assays to measure the concentrations of 55 biomarkers. The data were analyzed to identify statistically significant associations between the tested biomarkers and hemorrhagic manifestations, viremia, and/or death.
Death, hemorrhage, and viremia were independently associated with elevated levels of several chemokines and cytokines. Death and hemorrhage were associated with elevated thrombomodulin and ferritin levels. Hemorrhage was also associated with elevated levels of soluble intracellular adhesion molecule. Viremia was independently associated with elevated levels of tissue factor and tissue plasminogen activator. Finally, samples from nonfatal cases had higher levels of sCD40L.
These novel associations provide a better understanding of EHF pathophysiology and a starting point for researching new potential targets for therapeutic interventions.
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