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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 mortality rates and the average APACHE II score in the subgroup of patients receiving rhAPC with APACHE II scores ≥ 25 from the PROWESS trial to mortality rates and average APACHE II scores in patients receiving rhAPC in subsequent uncontrolled trials. Mortality rates at 28 days are shown in the upper panel A) and at hospital or intensive care unit discharge or 90 days in the lower panel B). results from the subgroup of patients shown from the PROWESS trial provided the basis for approval of rhAPC. in almost all uncontrolled studies, mortality rates have been higher and average APACHE II scores lower than in the subgroup in PROWESS with APACHE II ≥ 25.Notes: aNA, Not available; bICU mortality; cInterquartile range; d90-day mortality.
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f2-btt-3-391: Comparison of mortality rates and the average APACHE II score in the subgroup of patients receiving rhAPC with APACHE II scores ≥ 25 from the PROWESS trial to mortality rates and average APACHE II scores in patients receiving rhAPC in subsequent uncontrolled trials. Mortality rates at 28 days are shown in the upper panel A) and at hospital or intensive care unit discharge or 90 days in the lower panel B). results from the subgroup of patients shown from the PROWESS trial provided the basis for approval of rhAPC. in almost all uncontrolled studies, mortality rates have been higher and average APACHE II scores lower than in the subgroup in PROWESS with APACHE II ≥ 25.Notes: aNA, Not available; bICU mortality; cInterquartile range; d90-day mortality.

Mentions: The extended evaluation of rhAPC in the treatment of severe sepsis (ENHANCE) trial was a single arm, multinational study designed to further examine the safety and efficacy of rhAPC in adult patients with sepsis73 (Table 2). Although an open label study, inclusion and exclusion criteria and time to treatment (within 48 hours of organ dysfunction) were the same as in PROWESS. It was considered a phase IIIB trial because it was initiated before final regulatory approval of rhAPC. A total of 2,378 patients were treated with rhAPC and the overall 28-day mortality rate (25.3%) was not different than in PROWESS (24.7%). However, in ENHANCE patients with APACHE II ≥ 25, mortality was higher than in similar patients in PROWESS (36.7% vs 30.9%) (Figure 2). Despite this difference, the mortality rate in this subgroup from ENHANCE was still lower than in control patients from PROWESS (43.7%). Also, when stratified by number of organs injured, the mortality rates in PROWESS and ENHANCE were similar (Figure 3). Based on these latter points, some would argue that the efficacy of rhAPC in PROWESS was reproduced in ENHANCE.


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 mortality rates and the average APACHE II score in the subgroup of patients receiving rhAPC with APACHE II scores ≥ 25 from the PROWESS trial to mortality rates and average APACHE II scores in patients receiving rhAPC in subsequent uncontrolled trials. Mortality rates at 28 days are shown in the upper panel A) and at hospital or intensive care unit discharge or 90 days in the lower panel B). results from the subgroup of patients shown from the PROWESS trial provided the basis for approval of rhAPC. in almost all uncontrolled studies, mortality rates have been higher and average APACHE II scores lower than in the subgroup in PROWESS with APACHE II ≥ 25.Notes: aNA, Not available; bICU mortality; cInterquartile range; d90-day mortality.
© Copyright Policy
Related In: Results  -  Collection

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

f2-btt-3-391: Comparison of mortality rates and the average APACHE II score in the subgroup of patients receiving rhAPC with APACHE II scores ≥ 25 from the PROWESS trial to mortality rates and average APACHE II scores in patients receiving rhAPC in subsequent uncontrolled trials. Mortality rates at 28 days are shown in the upper panel A) and at hospital or intensive care unit discharge or 90 days in the lower panel B). results from the subgroup of patients shown from the PROWESS trial provided the basis for approval of rhAPC. in almost all uncontrolled studies, mortality rates have been higher and average APACHE II scores lower than in the subgroup in PROWESS with APACHE II ≥ 25.Notes: aNA, Not available; bICU mortality; cInterquartile range; d90-day mortality.
Mentions: The extended evaluation of rhAPC in the treatment of severe sepsis (ENHANCE) trial was a single arm, multinational study designed to further examine the safety and efficacy of rhAPC in adult patients with sepsis73 (Table 2). Although an open label study, inclusion and exclusion criteria and time to treatment (within 48 hours of organ dysfunction) were the same as in PROWESS. It was considered a phase IIIB trial because it was initiated before final regulatory approval of rhAPC. A total of 2,378 patients were treated with rhAPC and the overall 28-day mortality rate (25.3%) was not different than in PROWESS (24.7%). However, in ENHANCE patients with APACHE II ≥ 25, mortality was higher than in similar patients in PROWESS (36.7% vs 30.9%) (Figure 2). Despite this difference, the mortality rate in this subgroup from ENHANCE was still lower than in control patients from PROWESS (43.7%). Also, when stratified by number of organs injured, the mortality rates in PROWESS and ENHANCE were similar (Figure 3). Based on these latter points, some would argue that the efficacy of rhAPC in PROWESS was reproduced in ENHANCE.

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