Design and conduct of the activated protein C and corticosteroids for human septic shock (APROCCHSS) trial
Annals of Intensive Care. 2016;6((1)):43.
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.
The efficacy of activated protein C for the treatment of sepsis: incorporating observational evidence with a Bayesian approach
BMJ Open. 2015;5((1):):e006524.
OBJECTIVE The present study aimed to combine observational evidence with randomised controlled trials (RCTs) by using the Bayesian approach. DATA SOURCES Electronic databases, including PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), ISI Web of Science, EMBASE and EBSCO were searched from inception to January 2014. STUDY ELIGIBILITY RCTs and observational studies (OS) investigating the effectiveness of activated protein C (aPC) on mortality reduction were included for analysis. PARTICIPANTS Patients with sepsis. INTERVENTION aPC. SYNTHESIS METHODS Observational evidence was incorporated into the analysis by using power transformed priors in a Bayesian. Trial sequential analysis was performed to examine changes over time and whether further studies need to be conducted. MAIN RESULTS a total of 7 RCTs and 12 OS were included for the analysis. There was moderate heterogeneity among included RCTs (I(2)=48.6%, p=0.07). The pooled OR for mortality from RCTs was 1.00 (95% CI 0.84 to 1.19). In OS, there was potential publication bias as indicated by the funnel plot and the pooled OR for mortality with the use of aPC was 0.67 (95% CI 0.62 to 0.72). The pooled effect sizes of RCTs were changed by using different power transform priors derived from observational evidence. When observational evidence was used at its 'face value', the treatment effect of aPC was statistically significant in reducing mortality. CONCLUSIONS while RCT evidence showed no beneficial effect of aPC on sepsis, observational evidence showed a significant treatment effect of aPC. By using power transform priors in Bayesian model, we explicitly demonstrated how RCT evidence could be changed by observational evidence. TRIAL REGISTRATION NUMBER The protocol for the current study was registered in PROSPERO (registration number: CRD42014009562).Copyright Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Recombinant human activated protein C in the treatment of acute respiratory distress syndrome: a randomized clinical trial
PLoS ONE. 2014;9((3):):e90983.
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.
Recombinant human activated protein C for the treatment of severe sepsis and septic shock: a study protocol for incorporating observational evidence using a Bayesian approach
BMJ Open. 2014;4((7):):e005622.
INTRODUCTION Activated protein C (aPC) plays a pivotal role in modulating a severe inflammatory response and is thought to be beneficial for patients with sepsis. However, several meta-analyses of randomised controlled trials (RCTs) show that aPC is not significantly associated with improved survival in critically ill patients with sepsis. One suggestion is that these analyses simply ignored observational evidence. The present study aims to quantitatively demonstrate how observational data can alter the findings derived from synthesised evidence from RCTs by using a Bayesian approach. METHODS AND ANALYSIS RCTs and observational studies investigating the effect of aPC on mortality outcome in critically ill patients with sepsis will be included. The quality of included RCTs will be assessed by using the Delphi list. Publication bias will be quantitatively analysed by using the traditional Egger regression test and the Begg rank correlation test. Observational data will be used as the informative prior for the distribution of OR. A power transformation of the observational data likelihood will be considered. Observational evidence will be down-weighted by a power of alpha which takes values from 0 to 1. Trial sequential analysis will be performed to quantify the reliability of data in meta-analysis adjusting significance levels for sparse data and multiple testing on accumulating trials. TRIAL REGISTRATION NUMBER PROSPERO (CRD42014009562). Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Activated protein C attenuates pulmonary coagulopathy in patients with acute respiratory distress syndrome
Journal of Thrombosis and Haemostasis. 2013;11((5):):894-901.
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.
A dream deferred: the rise and fall of recombinant activated protein C
Critical Care. 2013;17((2):):309.
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.
Recombinant human activated protein C as a disease modifier in severe acute pancreatitis: systematic review of current evidence
BACKGROUND The severity of organ failure caused by acute pancreatitis (AP) is the most important determinant of mortality in the disease. Recombinant human activated protein C (Drotrecogin Alfa; Xigris, APC, rhAPC) is the first drug to show a decrease in all-cause mortality due to multiple organ failure caused by sepsis. As the systemic inflammatory response syndrome (SIRS) that causes organ failure in early AP is similar to that caused by severe sepsis, the use of rhAPC in the management of AP has been investigated in experimental and clinical studies which are collated in this review. METHODS A literature review of published material identified from MEDLINE and EMBASE databases, for the period from January 1985 to January 2011, reporting rhAPC usage in AP. RESULTS 3 of 4 experimental studies reported an improvement in outcome in animals with AP given rhAPC. The clinical randomized trial showed no improvement in outcome in the treatment arm. CONCLUSION The experimental evidence of disease amelioration in AP following intervention with rhAPC has not translated to the small clinical RCT. Given that there were only 16 patients in the treatment arm, further clinical evaluation is justified. Copyright Copyright 2012 IAP and EPC. Published by Elsevier B.V. All rights reserved.
Effectiveness and safety of drotrecogin alfa (activated) for severe sepsis: a meta-analysis and metaregression
The Lancet Infectious Diseases. 2012;12((9):):678-86.
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.
Drotrecogin alfa (activated) in adults with septic shock
The New England Journal of Medicine. 2012;366((22):):2055-64.
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.).
Recombinant human activated protein C for severe sepsis in neonates
Cochrane Database of Systematic Reviews.. 2012;:CD005385.
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.