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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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Recombinant human activated protein C in the treatment of acute respiratory distress syndrome: a randomized clinical trial
Cornet AD, Groeneveld AB, Hofstra JJ, Vlaar AP, Tuinman PR, van Lingen A, Levi M, Girbes AR, Schultz MJ, Beishuizen A
PLoS ONE. 2014;9((3):):e90983.
Abstract
RATIONALE Pulmonary coagulopathy may play a pathogenetic role in acute respiratory distress syndrome (ARDS), by contributing to alveolocapillary inflammation and increased permeability. Recombinant human activated protein C (rh-APC) may inhibit this process and thereby improve patient outcome. METHODS A prospective randomized, saline-controlled, single-blinded clinical trial was performed in the intensive care units of two university hospitals, and patients with ARDS were included within 24 h after meeting inclusion criteria. INTERVENTION A 4-day course of intravenous rh-APC (24 mcg/kg/h) (n = 33) versus saline (n = 38). OUTCOMES The primary outcome parameter was the pulmonary leak index (PLI) of 67Gallium-transferrin as a measure of alveolocapillary permeability and secondary outcomes were disease severity scores and ventilator-free days, among others. RESULTS Baseline characteristics were similar; in 87% of patients the PLI was above normal and in 90% mechanical or non-invasive ventilation was instituted at a median lung injury score of 2.5. There was no evidence that Rh-APC treatment affected the PLI or attenuated lung injury and sequential organ failure assessment scores. Mean ventilator-free days amounted to 14 (rh-APC) and 12 days (saline, P = 0.35). 28-day mortality was 6% in rh-APC- and 18% in saline-treated patients (P = 0.12). There was no difference in bleeding events. The study was prematurely discontinued because rh-APC was withdrawn from the market. CONCLUSION There is no evidence that treatment with intravenous rh-APC during 4 days for infectious or inflammatory ARDS ameliorates increased alveolocapillary permeability or the clinical course of ARDS patients. We cannot exclude underpowering. TRIAL REGISTRATION Nederlands Trial Register ISRCTN 52566874.
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3.
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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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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Activated protein C does not alleviate the course of systemic inflammation in the APCAP Trial
Kyhala L, Mentula P, Kylanpaa L, Moilanen E, Puolakkainen P, Pettila V, Repo H
International Journal of Inflammation. 2012;2012:712739.
Abstract
The study aimed to determine the effect of the activated protein C on the course of systemic inflammation in the APCAP (activated protein C in acute pancreatitis) trial where we randomized 32 patients with severe acute pancreatitis to receive either recombinant activated protein C (drotrecogin alfa activated) (n = 16) or placebo (n = 16) for 96 hours. In the present study, we present the time course of the patients' plasma or serum levels of soluble markers (IL-8, IL-6, IL-10, IL-1ra, sE-selectin, PCT) and monocyte and neutrophil cell surface (CD11b, CD14, CD62L, HLA-DR) markers of systemic inflammatory response during the first 14 days after the randomization. The results of the intervention and placebo groups were comparable showing that recombinant APC treatment did not alter the course of systemic inflammation in severe acute pancreatitis. Our finding is in accordance with the clinical findings in the APCAP trial indicating that the intervention did not affect evolution of multiple organ dysfunctions.
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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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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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APCAP--activated protein C in acute pancreatitis: a double-blind randomized human pilot trial
Pettilä V, Kyhälä L, Kylänpää ML, Leppäniemi A, Tallgren M, Markkola A, Puolakkainen P, Repo H, Kemppainen E
Critical Care (London, England). 2010;14((4):):R139.
Abstract
INTRODUCTION Previous human studies have shown low activity of protein C (APC) in severe acute pancreatitis (SAP). This, together with the findings in animal models, suggests that activated protein C (APC) may protect against pancreatic injury and ameliorate the disease. We, therefore, evaluated its effect on multiple organ dysfunction (MOD) measured by the SOFA (Sequential Organ Failure Assessment) and on organ-failure-free days, and the safety of APC in SAP. METHODS A prospective double blind randomized pilot study was use. The study occurred in one university hospital tertiary intensive care unit (ICU) with eight beds. The patients were chosen according to the following inclusion criteria: 1) Those admitted to the hospital < 96 h from the onset of pain, 2) Those who had a three-fold increase in serum amylase over normal upper range or/and in whom computed tomography (CT) verification of SAP was noted, 3) Those who had one or more organ dysfunction (OD), and 4) Those in whom less than 48 hours had passed since their first OD. Of a total of 215 adult patients with SAP screened between June 2003 and August 2007, 158 fulfilled the study inclusion criteria. After exclusions 32 patients were randomized to the study. The intervention consisted of APC (N = 16) administered intravenously for 96 hours with a dose of 24 μg/kg/hour or placebo (N = 16) with a similar infusion rate. The sample size for the study was calculated according to the primary end-point: the change in SOFA during study drug infusion (Days 0 and 5). Comparisons between the study groups were performed using patient-related changes and calculation of difference in means (DIM, 95% CIs) and regarding categorical variables with Fisher's exact test. For all comparisons P < 0. 05 was considered significant. RESULTS No serious bleeding was detected clinically or by CT scans in either group. No significant difference in SOFA score change between the APC and placebo groups was found (difference in means (DIM) +2. 3, 95% CI -0. 7 to +5. 3). Treatment with APC was associated with an increase in serum levels of both total and conjugated bilirubin. No differences in ventilator-free days, in renal replacement therapy-free days, in vasopressor-free days, or in days alive outside the hospital were detected. CONCLUSIONS No serious bleeding or differences in the evolution of MOD were detected between APC and the placebo. Instead we found an increase in serum bilirubin in the APC group compared to the placebo group in patients with SAP. TRIAL REGISTRATION ClinicalTrials. gov NCT01017107.
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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.
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Randomized clinical trial of activated protein C for the treatment of acute lung injury
Liu KD, Levitt J, Zhuo H, Kallet RH, Brady S, Steingrub J, Tidswell M, Siegel MD, Soto G, Peterson MW, et al
American Journal of Respiratory and Critical Care Medicine. 2008;178((6):):618-23.
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Abstract
RATIONALE Microvascular injury, inflammation, and coagulation play critical roles in the pathogenesis of acute lung injury (ALI). Plasma protein C levels are decreased in patients with acute lung injury and are associated with higher mortality and fewer ventilator-free days. OBJECTIVES To test the efficacy of activated protein C (APC) as a therapy for patients with ALI. METHODS Eligible subjects were critically ill patients who met the American/European consensus criteria for ALI. Patients with severe sepsis and an APACHE II score of 25 or more were excluded. Participants were randomized to receive APC (24 microg/kg/h for 96 h) or placebo in a double-blind fashion within 72 hours of the onset of ALI. The primary endpoint was ventilator-free days. MEASUREMENTS AND MAIN RESULTS APC increased plasma protein C levels (P = 0. 002) and decreased pulmonary dead space fraction (P = 0. 02). However, there was no statistically significant difference between patients receiving placebo (n = 38) or APC (n = 37) in the number of ventilator-free days (median [25-75% interquartile range]: 19 [0-24] vs. 19 [14-22], respectively; P = 0. 78) or in 60-day mortality (5/38 vs. 5/37 patients, respectively; P = 1. 0). There were no differences in the number of bleeding events between the two groups. CONCLUSIONS APC did not improve outcomes from ALI. The results of this trial do not support a large clinical trial of APC for ALI in the absence of severe sepsis and high disease severity.