Meta-analysis of Anti-TNF Therapies in Clinical Sepsis Trials

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Abstract

Despite conventional therapy, infection causing sepsis and septic shock is associated with a high mortality rate. The incidence of sepsis is also rising related to several factors. Despite a disappointing clinical experience with mediator-selective anti-inflammatory agents as adjunctive treatments for sepsis during the 1990s, excessive host inflammation is still considered an important pathogenic mechanism underlying sepsis. This point is highlighted by ongoing and proposed clinical sepsis trials of therapies targeting components in this response (e.g. corticosteroids, Eritoran tetrasodium, recombinant human activated protein C5). One of these agents is AZD9773 (AstraZeneca), a polyclonal antibody directed against human tumor necrosis factor- (TNF) (ClinicalTrials.gov identifier: NCT01145560 and NCT01144624). Continued industry interest in selective TNF inhibitors for sepsis might be unexpected. During the 1990s when there was high industry enthusiasm for the development of mediator-selective anti-inflammatory therapies for sepsis, anti-TNF agents were the most studied. Despite promising preclinical findings however, selective TNF inhibitors showed little benefit in more than 10 randomized controlled trials (RCT). However, when examined overall, there does appear to be potential benefit with this approach. At this time however, a systematic analysis of this entire experience, which now includes 15 trials, has not been undertaken. In light of continued interest in the application of anti-inflammatory agents for sepsis and with the ongoing studies of AZD9773, which is directed specifically at TNF, it is relevant to systematically review the prior experience with anti-TNF agents in sepsis in its entirety. The purpose of the present project has been to do such an analysis, examining not only the overall effect of this type of agent on survival, but on other outcomes such as reversal of shock, prevention of organ injury and potential adverse effects. In addition, systematic analysis has been performed to determine whether there are identifiable patient subgroups which are more amenable to the potential beneficial effects of this type of therapy. This analysis shows that overall anti-TNF agents showed highly consistent and significant benefit across the trials examined. However, while anti-TNF therapies did result in reductions in TNF levels in most studies in which this was examined, other changes such as reversal of shock or organ injury, could not be detected to provide a basis for this beneficial effect on survival. Findings from this study were presented at the 2012 ATS International Conference and a manuscript describing the work has been submitted and is under consideration of publication.