Remember that Activated Protein C is not as Useful for Sepsis as Once Hoped



Remember that Activated Protein C is not as Useful for Sepsis as Once Hoped


Ronald W. Pauldine MD



Activated protein C (APC) exerts a number of biological effects including anti-inflammatory, antithrombotic, and profibrinolytic properties. Profibrinolytic effects include inactivation of plasminogen activator inhibitor. Antithrombotic effects include inactivation of factor Va and VIIIa. These effects are thought to aid in restoration and maintenance of microcirculatory blood flow, re-establishment of coagulation homeostasis, and preservation of the microcirculation. Tissue injury and organ dysfunction is thought to be attenuated by anti-inflammatory properties including decreasing thrombin-related inflammation, inhibiting tumor necrosis factor (TNF) and macrophage migration inhibitory factor production, blocking adhesion of leukocytes to selectins, and decreasing nuclear factor–Kβ activation.

The initial optimism associated with recombinant human activated protein C (rhAPC), (drotrecogin alfa [activated]) has been tempered by subsequent clinical trials. Data from the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESSS) trial demonstrated an absolute reduction of death from all causes at 28 days of 6.1%. The trial observed an increase in serious bleeding from 2.0% in the placebo group to 3.5% in the APC group. However, this effect was not statistically significant (it must be noted that this study was not powered to detect significance). Subgroup analysis revealed that the greatest risk reduction occurred in patients with the greatest severity of disease as assessed by APACHE II scores. Subsequently the drug was approved by the Food and Drug Administration (FDA) for use in patients with APACHE II scores >25. The recommendation to limit therapy to the sicker group of patients was confirmed in a trial of APC in patients with APACHE II scores < 25 or with single organ failure. This trial, the Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS), was discontinued after enrolling 2,640 patients because of an inability to demonstrate reduced mortality in this less severely ill group withAPC. Adding further to the argument against using APC is that the risk of serious bleeding with APC may be greater than originally reported in PROWESS. An uncontrolled open label trial (ENHANCE) reported
incidence of serious bleeding at 6.5%. Other open-label trials have also demonstrated lack of benefit in pediatric patients.

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Jul 1, 2016 | Posted by in ANESTHESIA | Comments Off on Remember that Activated Protein C is not as Useful for Sepsis as Once Hoped
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