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1.
Design and conduct of the activated protein C and corticosteroids for human septic shock (APROCCHSS) trial
Annane D, Buisson CB, Cariou A, Martin C, Misset B, Renault A, Lehmann B, Millul V, Maxime V, Bellissant E
Annals of Intensive Care. 2016;6((1)):43.
Abstract
BACKGROUND We aimed at assessing the benefit-to-risk ratio of activated protein C (drotrecogin-alfa activated, DAA) and corticosteroids, given alone or in combination, in patients with septic shock. METHODS We implemented an investigator-led, publicly funded, multicenter, randomized according to a 2 x 2 factorial design, placebo-controlled, double-blind trial in four parallel groups in which adults with persistent septic shock and no contraindication to DAA were assigned to either DAA alone (24 mg/kg/h for 96 h), or hydrocortisone (50 mg intravenous bolus q6 for 7 days) and fludrocortisone (50 microg once daily through the nasogastric tube for 7 days) alone, or their respective combinations, or their respective placebos. Primary endpoint was 90-day mortality rate. Follow-up duration was 6 months. Statistical analysis was planned to be performed in intent-to-treat once after all participants completed 180-day follow-up and according to the 2 x 2 factorial design. RESULTS The first patient was recruited in September 2008. The trial was suspended on October 25, 2011, owing to the withdrawal from the market of DAA. At this time, 411 patients had been enrolled. On May 17, 2012, the continuation of the trial on two parallel groups was approved by all legal authorities with the aim of investigating the benefit-to-risk ratio of corticosteroids. On June 30, 2014, the trial was suspended again by the study sponsor upon request of the independent data and safety monitoring board. Recruitment restarted on October 7, 2014, after any safety concern was ruled out. Finally, the trial was completed on June 23, 2015, with the recruitment of 1241 patients. CONCLUSIONS This report details the design, statistical plan and conduct of a randomized controlled trial of hydrocortisone and fludrocortisone in septic shock. Trial registration The trial was registered at ClinicalTrials.gov under NCT00625209.
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2.
Activated protein C attenuates pulmonary coagulopathy in patients with acute respiratory distress syndrome
Cornet AD, Hofstra JJ, Vlaar AP, Tuinman PR, Levi M, Girbes AR, Schultz MJ, Groeneveld AB, Beishuizen A
Journal of Thrombosis and Haemostasis. 2013;11((5):):894-901.
Abstract
OBJECTIVE Acute respiratory distress syndrome (ARDS) frequently complicates critical illness. We hypothesized that an infusion of recombinant human activated protein C (rh-APC), a natural anticoagulant, would attenuate pulmonary coagulopathy and injury. METHODS In this sub study of a multicenter open-label randomized controlled trial of patients with ARDS, we compared an intravenous (i.v.) infusion of rh-APC (24 mcgkg(-1) h(-1) for 96h) with placebo. Patients with sepsis or septic shock were excluded. RESULTS In 27 patients serial non-directed bronchoalveolar lavage fluid (NBLF) samples were obtained: 16 patients were treated with rh-APC and 11 patients with placebo. The rh-APC infusion was associated with higher APC levels in plasma during the infusion period of 4days (P=0.001), as well as higher APC levels in NBLF up to day 5 after the start of the infusion (P=0.028). An infusion of rh-APC was associated with lower levels of thrombin-antithrombin complexes (P=0.009) and soluble tissue factor (P=0.011) in NBLF, compared with treatment with placebo. An infusion of rh-APC affected fibrinolysis, as plasminogen activator activity levels in NBLF were higher in the patients treated with rh-APC (P=0.01), presumably as a result of lower NBLF levels of plasminogen activator inhibitor 1, (P=0.01). The rh-APC infusion decreased the lung injury score (P=0.005) and simplified the acute physiology score (P=0.013) on day 5, when compared with baseline. The rh-APC infusion was not associated with bleeding complications. CONCLUSION An infusion of rh-APC in patients with ARDS attenuates pulmonary coagulopathy and injury. 2013 International Society on Thrombosis and Haemostasis.
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3.
A dream deferred: the rise and fall of recombinant activated protein C
Holder AL, Huang DT
Critical Care. 2013;17((2):):309.
Abstract
BACKGROUND There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. METHODS RESULTS At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval (CI), 0.92 to 1.28; P = 0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P = 0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P = 0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P = 0.81). CONCLUSIONS DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock.
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4.
Effectiveness and safety of drotrecogin alfa (activated) for severe sepsis: a meta-analysis and metaregression
Kalil AC, Larosa SP
The Lancet Infectious Diseases. 2012;12((9):):678-86.
Abstract
BACKGROUND Drotrecogin alfa (activated) was approved for use in severe sepsis in 2001 on the basis of the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, but controversies about its effectiveness remain. We aimed to assess effectiveness and safety of use of this drug in the past 10 years and compare them with the original PROWESS results. METHODS We searched PubMed, Embase, Ovid, Cochrane Library, Evidence-Based Medicine, and the American College of Physicians Journal Club databases for experimental and analytical studies of drotrecogin alfa (activated) in adults with severe sepsis until Jan 31, 2012. We calculated adjusted risk ratios for effectiveness and safety outcomes with random-effects models. We did a metaregression to assess the effect of severity of illness on the risk of death and the risk of bleeding associated with drotrecogin alfa (activated). FINDINGS We included nine controlled trials (41[PUNCTUATION SPACE]401 patients) and 16 single-group studies (5822 patients) in effectiveness analyses and 20 studies (8245 patients) in safety analyses. Hospital mortality was reduced by 18% with drotrecogin alfa (activated) compared with controls (relative risk 0.822, 95% CI 0.779-0.867; p<0.0001; I(2)=40%). This mortality reduction was much the same as was noted in PROWESS (0.851, 0.740-0.979), but smaller than that of patients in PROWESS with high disease severity (0.708, 0.590-0.849). Propensity-adjusted studies also showed a significant mortality reduction with lower heterogeneity (0.844, 0.800-0.891; p<0.0001, I(2)=18%). These findings were not changed by the addition of PROWESS-SHOCK results. Metaregression showed greater benefits of drotrecogin alfa (activated) with increasing control mortality (p=0.01) and more severe disease (p=0.04). Hospital mortality for single-group studies of drotrecogin alfa (activated) was 41% (95% CI 35-48), and was higher than that noted in PROWESS at 31% (27-36; p<0.0001). The serious bleeding rate with drotrecogin alfa (activated) was 5.6% (4.5-6.9), which was higher than the 3.5% (2.5-5.0) noted in PROWESS (p=0.003), but similar to that reported in PROWESS high disease severity (p=0.073). INTERPRETATION Real-life use of drotrecrogin alfa (activated) was associated with significant reduction in hospital mortality and increased rates of bleeding in patients with severe sepsis. Our effectiveness findings were in line with the PROWESS trial but not with the PROWESS-SHOCK trial. FUNDING None. Copyright Copyright 2012 Elsevier Ltd. All rights reserved.
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5.
Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients
Marti-Carvajal AJ, Sola I, Gluud C, Lathyris D, Cardona AF
Cochrane Database of Systematic Reviews. 2012;12:CD004388.
Abstract
BACKGROUND Sepsis is a common and frequently fatal condition. Human recombinant activated protein C (APC) has been introduced to reduce the high risk of death associated with severe sepsis or septic shock. This systematic review is an update of a Cochrane review originally published in 2007. OBJECTIVES We assessed the benefits and harms of APC for patients with severe sepsis or septic shock. SEARCH METHODS We searched CENTRAL (The Cochrane Library 2012, Issue 6); MEDLINE (2010 to June 2012); EMBASE (2010 to June 2012); BIOSIS (1965 to June 2012); CINAHL (1982 to June 2012) and LILACS (1982 to June 2012). There was no language restriction. SELECTION CRITERIA We included randomized clinical trials assessing the effects of APC for severe sepsis or septic shock in adults and children. We excluded studies on neonates. We considered all-cause mortality at day 28 and at the end of study follow up, and hospital mortality as the primary outcomes. DATA COLLECTION AND ANALYSIS We independently performed trial selection, risk of bias assessment, and data extraction in duplicate. We estimated relative risks (RR) for dichotomous outcomes. We measured statistical heterogeneity using the I(2) statistic. We used a random-effects model. MAIN RESULTS We identified one new randomized clinical trial in this update which includes six randomized clinical trials involving 6781 participants in total, five randomized clinical trials in adult (N = 6307) and one randomized clinical trial in paediatric (N = 474) participants. All trials had high risk of bias and were sponsored by the pharmaceutical industry. APC compared with placebo did not significantly affect all-cause mortality at day 28 compared with placebo (780/3435 (22.7%) versus 767/3346 (22.9%); RR 1.00, 95% confidence interval (CI) 0.86 to 1.16; I(2) = 56%). APC did not significantly affect in-hospital mortality (393/1767 (22.2%) versus 379/1710 (22.1%); RR 1.01, 95% CI 0.87 to 1.16; I(2) = 20%). APC was associated with an increased risk of serious bleeding (113/3424 (3.3%) versus 74/3343 (2.2%); RR 1.45, 95% CI 1.08 to 1.94; I(2) = 0%). APC did not significantly affect serious adverse events (463/3334 (13.9%) versus 439/3302 (13.2%); RR 1.04, 95% CI 0.92 to 1.18; I(2) = 0%). Trial sequential analyses showed that more trials do not seem to be needed for reliable conclusions regarding these outcomes. AUTHORS' CONCLUSIONS This updated review found no evidence suggesting that APC should be used for treating patients with severe sepsis or septic shock. APC seems to be associated with a higher risk of bleeding. The drug company behind APC, Eli Lilly, has announced the discontinuation of all ongoing clinical trials using this drug for treating patients with severe sepsis or septic shock. APC should not be used for sepsis or septic shock outside randomized clinical trials.
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6.
Recombinant human activated protein C for severe sepsis in neonates
Kylat RI, Ohlsson A
Cochrane Database of Systematic Reviews.. 2012;:CD005385.
Abstract
BACKGROUND Sepsis is a common problem in preterm and term infants. The incidence of neonatal sepsis has declined, but mortality remains high. Recombinant human activated protein C (rhAPC) possess a broad spectrum of activity modulating coagulation and inflammation. In septic adults it may reduce mortality, but no significant benefit has been reported in children with severe sepsis. OBJECTIVES To determine whether treatment with rhAPC reduces mortality and/or morbidity in neonatal sepsis. SEARCH METHODS For this update searches were carried out in May 2011 of the Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE, EMBASE, CINAHL, and abstracts of annual meetings of the Pediatric Academic Societies. Doctoral dissertations, theses and the Science Citation Index for articles on activated protein C were searched. No language restriction was applied. SELECTION CRITERIA Randomized or quasi-randomized trials, assessing the efficacy of rhAPC compared to placebo or no intervention as an adjunct to antibiotic therapy of suspected or confirmed severe sepsis in term and preterm infants less than 28 days old. Eligible trials should report at least one of the following outcomes: mortality during initial hospital stay, neurodevelopmental assessment at two years of age or later, length of hospital stay, duration of ventilation, chronic lung disease, periventricular leukomalacia, intraventricular haemorrhage, necrotizing enterocolitis, bleeding, and any other adverse events. DATA COLLECTION AND ANALYSIS Review authors were to independently evaluate the articles for inclusion criteria and quality, and abstract information for the outcomes of interest. Differences were to be resolved by consensus. The statistical methods were to include relative risk, risk difference, number needed to treat to benefit or number needed to treat to harm for dichotomous and weighed mean difference for continuous outcomes reported with 95% confidence intervals. A fixed effect model was to be used for meta-analysis. Heterogeneity tests, including the I(2) statistic, were to be performed to assess the appropriateness of pooling the data. MAIN RESULTS No eligible trials were identified. In October 2011 rhAPC (Xigris[REGISTERED]) was withdrawn from the market by Eli Lilly due to a higher mortality in a trial among adults. Xigris[REGISTERED] (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 insufficient data to use rhAPC for the management of severe sepsis in newborn infants. Due to the results among adults with lack of efficacy, 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.
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7.
Drotrecogin alfa (activated) in adults with septic shock
Ranieri VM, Thompson BT, Barie PS, Dhainaut JF, Douglas IS, Finfer S, Gårdlund B, Marshall JC, Rhodes A, Artigas A, et al
The New England Journal of Medicine. 2012;366((22):):2055-64.
Abstract
BACKGROUND There have been conflicting reports on the efficacy of recombinant human activated protein C, or drotrecogin alfa (activated) (DrotAA), for the treatment of patients with septic shock. METHODS In this randomized, double-blind, placebo-controlled, multicenter trial, we assigned 1697 patients with infection, systemic inflammation, and shock who were receiving fluids and vasopressors above a threshold dose for 4 hours to receive either DrotAA (at a dose of 24 ?g per kilogram of body weight per hour) or placebo for 96 hours. The primary outcome was death from any cause 28 days after randomization. RESULTS At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P=0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P=0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P=0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P=0.81). CONCLUSIONS DrotAA did not significantly reduce mortality at 28 or 90 days, as compared with placebo, in patients with septic shock. (Funded by Eli Lilly; PROWESS-SHOCK ClinicalTrials.gov number, NCT00604214.).
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8.
Endogenous plasma activated protein C levels and the effect of enoxaparin and drotrecogin alfa (activated) on markers of coagulation activation and fibrinolysis in pulmonary embolism
Dempfle CE, Elmas E, Link A, Suvajac N, Liebe V, Janes J, Borggrefe M
Critical Care (London, England). 2011;15((1):):R23.
Abstract
INTRODUCTION There are no published data on the status of endogenous activated protein C (APC) in pulmonary embolism (PE), and no data on the effect of drotrecogin alfa (activated) (DAA) given in addition to therapeutic dose enoxaparin. METHODS In this double-blind clinical trial, 47 patients with computed tomography (CT)-confirmed acute submassive PE treated with 1 mg/kg body weight of enoxaparin twice daily were randomized to groups receiving a 12-hour intravenous infusion of 6, 12, 18, or 24 μg/kg/hour of DAA or a placebo. Blood samples were drawn before starting DAA infusion, after 4, 8 and 12 hours (at the end of the infusion period), and on treatment days 2, 3, 4, 5 and 6. RESULTS Initial endogenous plasma activated protein C (APC) levels were 0.36 ± 0.48 ng/ml (<0.10 to 1.72 ng/ml) and remained in the same range in the placebo group. APC levels in patients treated with DAA were 13.67 ± 3.57 ng/ml, 32.71 ± 8.76 ng/ml, 36.13 ± 7.60 ng/ml, and 51.79 ± 15.84 ng/ml in patients treated with 6, 12, 18, and 24 μg/kg/hour DAA, respectively. In patients with a D-dimer level >4 mg/L indicating a high level of acute fibrin formation and dissolution, DAA infusion resulted in a more rapid drop in soluble fibrin, D-dimer, and fibrinogen/fibrin degradation products (FDP) levels, compared to enoxaparin alone. There was a parallel decline of soluble fibrin, D-dimer, FDP, and plasmin-plasmin inhibitor complex (PPIC) in response to treatment with enoxaparin ± DAA, with no evidence of a systemic profibrinolytic effect of the treatment. CONCLUSIONS In patients with acute submassive PE endogenous APC levels are low. DAA infusion enhances the inhibition of fibrin formation. TRIAL REGISTRATION ClinicalTrials.gov: NCT00191724.
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9.
Prevalence of serious bleeding events and intracranial hemorrhage in patients receiving activated protein C: a systematic review and meta-analysis
Khan A, Agarwal R, Aggarwal AN, Gupta D
Respiratory Care. 2010;55((7):):901-10.
Abstract
BACKGROUND Activated protein C reduces 28-day mortality in patients with severe sepsis, but its anticoagulant properties entail a risk of bleeding. OBJECTIVE The aim of this systematic review was to evaluate the prevalence of serious bleeding events in patients receiving activated protein C. METHODS We searched the MEDLINE and EMBASE databases for studies that described the prevalence of serious bleeding events and intracranial hemorrhage in patients receiving activated protein C. We calculated the bleeding rates by calculating proportions and 95% CIs for each study, and then pooled the data to derive a pooled proportion and 95% CI. RESULTS Our search yielded 17 studies, which included 10,679 patients. The occurrence of serious bleeding events in patients receiving activated protein C ranged from 0.5% to 9.6%, and the pooled prevalence was 3.3% (95% CI 2.4-4.4%) by the random effects model. The occurrence of intracranial hemorrhage ranged from 0% to 1.4%, and the pooled prevalence was 0.44% (95% CI 0.31-0.6%). Sensitivity analysis showed a higher prevalence of bleeding in the observational studies than in the randomized controlled trials. There was substantial clinical and statistical heterogeneity, but no evidence of publication bias. CONCLUSIONS Activated protein C is associated with significant risk of bleeding, so strict inclusion and exclusion criteria should be set prior to administering activated protein C.
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10.
Effects of recombinant human activated protein C on the fibrinolytic system of patients undergoing conventional or tight glycemic control
Polli F, Savioli M, Cugno M, Taccone P, Bellani G, Spanu P, Pesenti A, Iapichino G, Gattinoni L
Minerva Anestesiologica. 2009;75((7-8):):417-26.
Abstract
AIM: Recombinant human activated protein C (rh-APC) and tight glycemic control (TGC) have been shown to reduce mortality in septic patients. Both interventions can reduce the plasma concentration and/or activity of the most powerful suppressor of fibrinolysis, plasminogen activator inhibitor-1 (PAI-1). Our aim was to evaluate the effects on the fibrinolytic system after the administration of rh-APC in septic patients undergoing conventional or TGC. METHODS Posthoc analysis of data was collected from 90 patients with severe sepsis/septic shock, randomized to either conventional or TGC groups. Independent of these treatments, patients with at least two organ dysfunctions simultaneously received rh-APC. Plasma levels of multiple biochemical markers for fibrinolysis, coagulation, and inflammation were determined every day for the 1st week and then on study days 9, 11, 13, 18, 23, and 28. Clinical data and sepsis-related organ failure assessment (SOFA) scores were also recorded. RESULTS Patients who had received rh-APC exhibited significantly more impairments in fibrinolysis at baseline (PAI-1 activity 49. 76 [24. 61-71. 82] vs 21. 92 [6. 47-55-83] IU/mL, P=0. 03). The reductions in plasma PAI-1 activity over time associated with rh-APC treatment were different according to whether the treatment was administered to patients undergoing conventional or TGC (P=0. 01). However, the most prominent reductions were in patients undergoing conventional glycemic control. Significant interactions between the two study interventions were also found for PAI-1 concentration (P<0. 001), C-reactive protein (P=0. 02), and interleukin-6 levels (P<0. 001). CONCLUSIONS Both rh-APC and TGC appear to improve fibrinolysis in septic patients. The reduction in the impairment of fibrinolysis associated with rh-APC treatment seems greater in patients undergoing conventional glycemic control than in those undergoing TGC.