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Growing insights into the potential benefits and risks of activated protein C administration in sepsis: a review of preclinical and clinical studies.

Altaweel L, Sweeney D, Cui X, Barochia A, Natanson C, Eichacker PQ - Biologics (2009)

Bottom Line: Recombinant human activated protein C (rhAPC) was developed to reduce excessive coagulant and inflammatory activity during sepsis.Basic and clinical research has suggested these pathways contribute to the pathogenesis of this lethal syndrome and are inhibited by rhAPC.Since 2001, continuing basic and clinical research has further elucidated the complex role activated protein C may have in both adaptive and maladaptive responses during sepsis.

View Article: PubMed Central - PubMed

Affiliation: Critical Care Medicine Department, Clinical Center, National institutes of Health, Bethesda, MD, USA. altaweellr@cc.nih.gov

ABSTRACT
Recombinant human activated protein C (rhAPC) was developed to reduce excessive coagulant and inflammatory activity during sepsis. Basic and clinical research has suggested these pathways contribute to the pathogenesis of this lethal syndrome and are inhibited by rhAPC. Based in large part on the results of a single multicenter randomized controlled trial, rhAPC was first approved in 2001 by the US Food and Drug Administration (FDA) as adjunctive therapy in septic patients with a high risk of death. This was followed closely by approval in Europe, Australia, and New Zealand. At the original FDA review of rhAPC, concerns were raised as to whether a confirmatory trial should be done before final regulatory approval because of concerns that rhAPCs bleeding risk might outweigh its potential benefit during clinical use. Since 2001, continuing basic and clinical research has further elucidated the complex role activated protein C may have in both adaptive and maladaptive responses during sepsis. Moreover, subsequent controlled trials in other types of septic patients and observational studies appear to support earlier concerns that the benefit-to-risk ratio of rhAPC may not support its clinical use. This experience has prompted additional trials presently underway, to define whether treatment with rhAPC as it was originally indicated in septic patients with persistent shock, is safe and effective. Until such trials are complete, physicians employing this agent must carefully consider which patients may be appropriate candidates for rhAPC administration.

No MeSH data available.


Related in: MedlinePlus

Comparison of the incidence of serious bleeding events (upper panel) and intracerebral hemorrhage (lower panel) during drug infusion or up until intensive care unit or hospital discharge in patients receiving rhAPC in PROWESS to those in subsequent uncontrolled trials. in almost all uncontrolled studies, these incidences were greater than in the PROWESS trial.Notes: aICU stay; bHospital stay. Abbreviation: ICU, intensive care unit; rhAPC, recombinant human activated protein C.
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f5-btt-3-391: Comparison of the incidence of serious bleeding events (upper panel) and intracerebral hemorrhage (lower panel) during drug infusion or up until intensive care unit or hospital discharge in patients receiving rhAPC in PROWESS to those in subsequent uncontrolled trials. in almost all uncontrolled studies, these incidences were greater than in the PROWESS trial.Notes: aICU stay; bHospital stay. Abbreviation: ICU, intensive care unit; rhAPC, recombinant human activated protein C.

Mentions: The ENHANCE trial employed exclusion criteria similar to PROWESS.73 It was therefore concerning that the incidence of serious bleeding and ICH during rhAPC infusion (3.6% and 0.6%, respectively) and over the 28-day study period (6.5% and 1.4%, respectively) in ENHANCE was substantially higher than in PROWESS (Table 3) (Figure 5).


Growing insights into the potential benefits and risks of activated protein C administration in sepsis: a review of preclinical and clinical studies.

Altaweel L, Sweeney D, Cui X, Barochia A, Natanson C, Eichacker PQ - Biologics (2009)

Comparison of the incidence of serious bleeding events (upper panel) and intracerebral hemorrhage (lower panel) during drug infusion or up until intensive care unit or hospital discharge in patients receiving rhAPC in PROWESS to those in subsequent uncontrolled trials. in almost all uncontrolled studies, these incidences were greater than in the PROWESS trial.Notes: aICU stay; bHospital stay. Abbreviation: ICU, intensive care unit; rhAPC, recombinant human activated protein C.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2747338&req=5

f5-btt-3-391: Comparison of the incidence of serious bleeding events (upper panel) and intracerebral hemorrhage (lower panel) during drug infusion or up until intensive care unit or hospital discharge in patients receiving rhAPC in PROWESS to those in subsequent uncontrolled trials. in almost all uncontrolled studies, these incidences were greater than in the PROWESS trial.Notes: aICU stay; bHospital stay. Abbreviation: ICU, intensive care unit; rhAPC, recombinant human activated protein C.
Mentions: The ENHANCE trial employed exclusion criteria similar to PROWESS.73 It was therefore concerning that the incidence of serious bleeding and ICH during rhAPC infusion (3.6% and 0.6%, respectively) and over the 28-day study period (6.5% and 1.4%, respectively) in ENHANCE was substantially higher than in PROWESS (Table 3) (Figure 5).

Bottom Line: Recombinant human activated protein C (rhAPC) was developed to reduce excessive coagulant and inflammatory activity during sepsis.Basic and clinical research has suggested these pathways contribute to the pathogenesis of this lethal syndrome and are inhibited by rhAPC.Since 2001, continuing basic and clinical research has further elucidated the complex role activated protein C may have in both adaptive and maladaptive responses during sepsis.

View Article: PubMed Central - PubMed

Affiliation: Critical Care Medicine Department, Clinical Center, National institutes of Health, Bethesda, MD, USA. altaweellr@cc.nih.gov

ABSTRACT
Recombinant human activated protein C (rhAPC) was developed to reduce excessive coagulant and inflammatory activity during sepsis. Basic and clinical research has suggested these pathways contribute to the pathogenesis of this lethal syndrome and are inhibited by rhAPC. Based in large part on the results of a single multicenter randomized controlled trial, rhAPC was first approved in 2001 by the US Food and Drug Administration (FDA) as adjunctive therapy in septic patients with a high risk of death. This was followed closely by approval in Europe, Australia, and New Zealand. At the original FDA review of rhAPC, concerns were raised as to whether a confirmatory trial should be done before final regulatory approval because of concerns that rhAPCs bleeding risk might outweigh its potential benefit during clinical use. Since 2001, continuing basic and clinical research has further elucidated the complex role activated protein C may have in both adaptive and maladaptive responses during sepsis. Moreover, subsequent controlled trials in other types of septic patients and observational studies appear to support earlier concerns that the benefit-to-risk ratio of rhAPC may not support its clinical use. This experience has prompted additional trials presently underway, to define whether treatment with rhAPC as it was originally indicated in septic patients with persistent shock, is safe and effective. Until such trials are complete, physicians employing this agent must carefully consider which patients may be appropriate candidates for rhAPC administration.

No MeSH data available.


Related in: MedlinePlus