Recombinant human activated protein C for severe sepsis in neonates

Abstract

Cochrane Database of Systematic Reviews Main results No eligible trials were identified. In October 2011 rhAPC (Xigris®) was withdrawn from the market by Eli Lilly due to a higher mortality in a trial among adults. Xigris® (DrotAA)(rhAPC) should no longer be used in any age category and the product should be returned to the distributor. Authors' conclusions Despite the scientific rationale for its use, there is insu icient data to use rhAPC for the management of severe sepsis in newborn infants. Due to the results among adults with lack of e icacy, an increase in bleeding and resulting withdrawal of rhAPC from the market, neonates should not be treated with rhAPC and further trials should not be conducted.

Activated Protein C in Cutaneous Wound Healing: From Bench to Bedside

“…This resulted in Eli Lilly, a global pharmaceutical company that produced rhAPC, to voluntarily withdraw their drug from public use worldwide in 2011. A series of Cochrane reviews in 2011 and 2012 concluded that despite the scientific rationale, there is insufficient data for APC’s use in septic neonates, children or adults, and advised against its further promotion [91,92,93]. However, further developments in mutant APC, without its anticoagulant properties, have reinvigorated research into its potential benefits.…”

A Systematic Summary of Systematic Reviews on Anticoagulant Therapy in Sepsis

“…Study characteristics are summarized in Table 1. The target agent of 19 systematic reviews is as follows: antithrombin ( n = 4) [10,11,12,13], rTM ( n = 3) [9,14,15], heparin and low-molecular-weight heparin (LMWH) ( n = 3) [16,17,18], recombinant human activated protein C ( n = 8) [19,20,21,22,23,24,25,26], and all anticoagulants ( n = 1), which included all anticoagulant agents and evaluated separate meta-analyses in different populations [27].…”

“…Our umbrella review examined the current evidence from systematic reviews of randomized controlled trials evaluating anticoagulant therapy for sepsis. We identified adequate systematic reviews targeted to overall sepsis patients, most of which did not show improved mortality, except for the prophylactic use of heparin [10,16,17,18,19,20,21,22,23,24,25,26,28]. In these systematic reviews of antithrombin and rAPC on overall populations with sepsis, large-scale, multinational, multicenter, randomized controlled trials were included, but they failed to show an improvement in mortality in patients with sepsis or septic shock [4,6,32,33].…”

“…We found nine systematic reviews of rAPC, and seven meta-analyses were available [18,19,20,21,22,23,24,25]. All meta-analyses reported the consistent conclusion that rAPC did not show a beneficial effect in sepsis patients, but it increased the risk of bleeding.…”

New insights for C5a and C5a receptors in sepsis

“…Injection of exogenous protein C inhibited initiation of coagulation pathway, reduced organ dysfunction, and improved survival rate in a sepsis model performed in baboon, while in vivo blockade of protein C activation by using anti-protein C antibody worsened E. coli -induced septic shock (Taylor et al, 1987). However, due to risk of serious bleeding in 35% patients receiving rhAPC (recombinant human activated protein C), the FDA and European Medicines Agency (EMEA) have recently withdrawn their support and recommends not using the product, and the manufacturer has withdrawn the product from the market (Kylat and Ohlsson, 2012). …”