Background: The search for a life-preserving drug to treat sepsis has increased understanding of the pathogenesis of the process but produced little in the way of successful treatments. The prospective, randomized, double-blind, placebo-controlled, Phase III, multicenter Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial suggested that drotrecogin alfa--recombinant human activated protein C--significantly improved 28-day mortality rates in acute sepsis (P = 0.005).
Objectives: The goals of this drug review were to summarize the recent findings regarding the pathogenesis of sepsis and septic shock, as well as the results of select immunomodulator drug trials, and to offer a comprehensive review of the mechanism of action, pharmacokinetic profile, efficacy and safety profile, and pharmacoeconomics of drotrecogin alfa.
Methods: The English-language literature was searched using the EMBASE and MEDLINE databases. In EMBASE, the subject headings drotrecogin, activated protein C, and sepsis were used to search publications from 1980 through September 2002. In MEDLINE, the MeSH heading protein C and subject heading sepsis were used to search publications from 1966 through September 2002. Published abstracts of recent meetings and proceedings of the US Food and Drug Administration were also reviewed.
Results: Drotrecogin alfa mimics the endogenous protein depleted during acute sepsis. Its activity as an antithrombotic, anti-inflammatory, and profibrinolytic agent appears to diminish the negative outcomes of acute sepsis, notably mortality at 28 days. The results of the PROWESS trial support this finding. A bleeding risk was noted during Phase II and III trials despite efforts to exclude those patients at high risk of bleeding.
Conclusions: Drotrecogin alfa is the first adjunctive agent for the treatment of sepsis to display clinically and statistically significant effects on mortality rates at 28 days. Many questions remain regarding which patients are ideal candidates for treatment. New research and treatment guidelines are necessary to address these questions.
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