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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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2.
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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3.
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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4.
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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Meta-analysis: intravenous immunoglobulin in critically ill adult patients with sepsis
Turgeon AF, Hutton B, Fergusson DA, McIntyre L, Tinmouth AA, Cameron DW, Hebert PC
Annals of Internal Medicine. 2007;146((3):):193-203.
Abstract
BACKGROUND Intravenous immunoglobulin therapy has been proposed as an adjuvant treatment for sepsis. Yet, its benefit remains unclear, and its use is not currently recommended. PURPOSE To evaluate the effect of polyclonal intravenous immunoglobulin therapy on death in critically ill adult patients with sepsis. DATA SOURCES MEDLINE (1966 to May 2006) and the Cochrane Central Register of Controlled Trials (May 2006 edition). STUDY SELECTION All randomized, controlled trials of critically ill adult patients with sepsis, severe sepsis, or septic shock who received polyclonal intravenous immunoglobulin therapy or placebo or no intervention were selected. No restrictions were made for study language or type of publication. Data extraction: Data were independently extracted by 2 investigators using a standardized form. DATA SYNTHESIS The literature search identified 4096 articles, of which 33 were deemed to be potentially eligible. Twenty trials (n = 2621) met eligibility criteria and were included in the analysis. Polyclonal intravenous immunoglobulin therapy was associated with an overall survival benefit (risk ratio, 0.74 (95% CI, 0.62 to 0.89)) compared with placebo or no intervention. In sensitivity analyses, documented survival improved when the analysis was limited to published, peer-reviewed trials (risk ratio, 0.72 (CI, 0.58 to 0.89)) (17 trials (n = 1865)) and blinded trials (risk ratio, 0.61 (CI, 0.40 to 0.93) (7 trials (n = 896)). Severe sepsis or septic shock (risk ratio, 0.64 (CI, 0.52 to 0.79)) (11 trials (n = 689)), receiving a total dose regimen of 1 gram or more per kilogram of body weight (risk ratio, 0.61 (CI, 0.40 to 0.94)) (7 trials (n = 560)), and receiving therapy for longer than 2 days (risk ratio, 0.66 (CI, 0.53 to 0.82)) (17 trials (n = 1847)) were strongly associated with this survival benefit. LIMITATIONS Most trials were published before new developments modifying the care and outcome of critically ill patients with sepsis including early goal-directed therapy and activated protein C treatment, were introduced. CONCLUSIONS A survival benefit was observed for patients with sepsis who received polyclonal intravenous immunoglobulin therapy compared with those who received placebo or no intervention. A large, randomized, controlled trial of polyclonal intravenous immunoglobulin therapy should be performed on the basis of the methodological limitations of the current literature, the potential benefit from this therapy in more severely ill patients, and the potential effect of dosage and duration of this therapy.
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Drotrecogin alfa (activated) in severe sepsis: A systematic review and new cost-effectiveness analysis
Costa V, Brophy JM
BMC Anesthesiology. 2007;7((5):)
Abstract
Background: Activated drotrecogin alfa (human activated protein C, rh APC), is produced by recombinant DNA technology, and purports to improve clinical outcomes by counteracting the inflammatory and thrombotic consequences of severe sepsis. Controversy exists around the clinical benefits of this drug and an updated economic study that considers this variability is needed. Methods: A systematic literature review was performed using Medline, Embase and the International Network of Agencies for Health Technology Assessment (INAHTA) databases to determine efficacy, safety and previous economic studies. Our economic model was populated with systematic estimates of these parameters and with population life tables for longer term survival information. Monte Carlo simulations were used to estimate the incremental cost-effectiveness ratios (ICERs) and variance for the decision analytic models. Results: Two randomized clinical trials (RCTS) of drotrecogin alfa in adults with severe sepsis and 8 previous economic studies were identified. Although associated with statistical heterogeneity, a pooled analysis of the RCTs did not show a statistically significant 28-day mortality benefit for drotrecogin alfa compared to placebo either for all patients (RR: 0.93, 95% CI: 0.69, 1.26) or those at highest risk as measured by APACHE II (greater-than or equal to 25 (RR: 0.90, 95% CI: 0.54, 1.49). Our economic analysis based on the totality of the available clinical evidence suggests that the cost-effectiveness of drotrecogin alfa is uncertain (< 59% probability that incremental cost-effectiveness ratio (ICER) life year gained (LYG) (less-than or equal to) $50,000/LYG) when applied to all patients with severe sepsis. The economic attractiveness of this therapy improves when administered to those at highest risk as assessed by APACHE II (greater-than or equal to 25 (93% probability ICER (less-than or equal to) $50,000/ LYG) but these results are not robust to different measures of disease severity. Conclusion: The evidence supporting the clinical and economic attractiveness of drotrecogin alfa is not conclusive and further research appears to be indicated.
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Evaluation of the cost-effectiveness of drotrecogin alfa (activated) for the treatment of severe sepsis in the United Kingdom
Green C, Dinnes J, Takeda AL, Cuthbertson BH
International Journal of Technology Assessment in Health Care. 2006;22((1):):90-100.
Abstract
OBJECTIVES The aim of this study was to assess the cost-effectiveness of drotrecogin alfa (activated) compared with best supportive care in a UK cohort of adult intensive-care patients with severe sepsis. METHODS A systematic review of evidence on the clinical- and cost-effectiveness of drotrecogin alfa (activated) was undertaken, and a decision-analytic model was developed to estimate the cost-effectiveness of treatment in the United Kingdom. Trial data from the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study have been synthesized with other data, including UK data on severe sepsis, to estimate the costs and consequences of treatment over time. RESULTS For patients with severe sepsis and multiple organ dysfunction, the estimates of cost per life year and cost per quality-adjusted life year (QALY) are pounds 4931 and pounds 8228, respectively. For patients with severe sepsis alone, the cost per life-year and cost per QALY are pounds 5495 and pounds 9161, respectively. CONCLUSIONS Whereas the therapeutic cost for drotrecogin alfa (activated) appears high (at around pounds 5000 per patient) and the potential impact on the provider budget is considerable, drotrecogin alfa (activated) is clinically effective, represents a cost-effective use of resources, and is a significant advance in the treatment of severe sepsis in patients requiring intensive care.
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Drotrecogin alfa (recombinant human activated protein C) for the treatment of severe sepsis
McCoy C, Matthews SJ
Clinical Therapeutics. 2003;25((2):):396-421.
Abstract
BACKGROUND The search for a life-preserving drug to treat sepsis has increased understanding of the pathogenesis of the process but produced little in the way of successful treatments. The prospective, randomized, double-blind, placebo-controlled, Phase III, multicenter Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial suggested that drotrecogin alfa--recombinant human activated protein C--significantly improved 28-day mortality rates in acute sepsis (P = 0.005). OBJECTIVES The goals of this drug review were to summarize the recent findings regarding the pathogenesis of sepsis and septic shock, as well as the results of select immunomodulator drug trials, and to offer a comprehensive review of the mechanism of action, pharmacokinetic profile, efficacy and safety profile, and pharmacoeconomics of drotrecogin alfa. METHODS The English-language literature was searched using the EMBASE and MEDLINE databases. In EMBASE, the subject headings drotrecogin, activated protein C, and sepsis were used to search publications from 1980 through September 2002. In MEDLINE, the MeSH heading protein C and subject heading sepsis were used to search publications from 1966 through September 2002. Published abstracts of recent meetings and proceedings of the US Food and Drug Administration were also reviewed. RESULTS Drotrecogin alfa mimics the endogenous protein depleted during acute sepsis. Its activity as an antithrombotic, anti-inflammatory, and profibrinolytic agent appears to diminish the negative outcomes of acute sepsis, notably mortality at 28 days. The results of the PROWESS trial support this finding. A bleeding risk was noted during Phase II and III trials despite efforts to exclude those patients at high risk of bleeding. CONCLUSIONS Drotrecogin alfa is the first adjunctive agent for the treatment of sepsis to display clinically and statistically significant effects on mortality rates at 28 days. Many questions remain regarding which patients are ideal candidates for treatment. New research and treatment guidelines are necessary to address these questions.