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Gordon R. Bernard - One of the best experts on this subject based on the ideXlab platform.
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A case series of Drotrecogin Alfa (activated) in lung transplant recipients.
Transplantation, 2006Co-Authors: Titus L. Daniels, J. S. Dummer, Gordon R. Bernard, Aaron P. MilstoneAbstract:Severe sepsis in lung transplant recipients is a challenging problem and carries a high mortality. Recombinant human activated protein C (Drotrecogin Alfa [activated]) has been approved for use in patients with severe sepsis. Its use has been shown to be safe and impart a survival advantage. However, the safety of Drotrecogin Alfa activated has not been evaluated in lung transplant recipients. We report for the first time on the use of Drotrecogin Alfa activated in six lung transplant recipients. Clinical trials are warranted to further evaluate the use of Drotrecogin Alfa activated in transplant recipients.
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Drotrecogin Alfa activated treatment in severe sepsis from the global open label trial enhance further evidence for survival and safety and implications for early treatment
Critical Care Medicine, 2005Co-Authors: Jean Louis Vincent, Gordon R. Bernard, Jean-françois Dhainaut, William L. Macias, Antonio Artigas, Richard Beale, Christopher J Doig, Christian Putensen, Roberto Fumagalli, Theressa J WrightAbstract:Objective:To provide further evidence for the efficacy and safety of Drotrecogin Alfa (activated) treatment in severe sepsis.Design:Single-arm, open-label, trial of Drotrecogin Alfa (activated) treatment in severe sepsis patients. Enrollment began in March 2001 and day-28 follow-up completed in Janu
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extended evaluation of recombinant human activated protein c united states trial enhance us a single arm phase 3b multicenter study of Drotrecogin Alfa activated in severe sepsis
Chest, 2004Co-Authors: Gordon R. Bernard, Howard Levy, Benjamin D Margolis, Wesley E Ely, Harvey M Shanies, Arthur P Wheeler, Kar Wong, Theressa J WrightAbstract:Study objective To gather additional 28-day all-cause mortality and safety data among adult patients with severe sepsis who were treated with Drotrecogin Alfa (activated). Design Prospective, single-arm, multicenter clinical trial. Setting Eighty-five study sites in the United States and two in Puerto Rico. Participants Adult patients (273 patients) with a diagnosis of severe sepsis, which was defined as a systemic inflammatory response due to acute infection and one or more sepsis-induced organ dysfunctions present for ≤ 48 h, as in the recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial. Interventions Drotrecogin Alfa (activated) [Xigris; Eli Lilly and Company; Indianapolis, IN], 24 μg/kg/h, as a continuous IV infusion for a duration of 96 ± 1 h. Measurements and results The primary end point was all-cause mortality, which was assessed 28 days after the start of the infusion of Drotrecogin Alfa (activated). Serious bleeding was monitored to day 28. Comparisons of mortality were made to treatment groups from two double-blind, placebo-controlled clinical trials (PROWESS United States and the Secretory Phospholipase A2 Inhibitor [sPLA2I] in Severe Sepsis trial) that used similarly defined patient populations from the United States. For the 273 adult patients enrolled in this study, the 28-day all-cause mortality rate was 26.4%. This mortality rate was 6% lower than that observed in the placebo groups in the PROWESS US trial (32.9%) and the sPLA2I trial (33.2%), and was similar to that of the group treated with Drotrecogin Alfa (activated) in the PROWESS US trial (24.4%). One nonfatal intracranial hemorrhage was reported in the Extended Evaluation of Recombinant Human Activated Protein C United States trial (ENHANCE US) [0.35%]. Serious bleeding events during the infusion period occurred in 11 patients (4.0%) compared to 10 patients (2.8%) in the PROWESS US Drotrecogin Alfa (activated) treatment group. Conclusions Despite the limitations associated with comparisons across trials, this study provides confirmatory evidence of the efficacy and safety of Drotrecogin Alfa (activated) documented in the PROWESS trial.
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Drotrecogin Alfa (Activated) for the Treatment of Severe Sepsis and Septic Shock
The American Journal of the Medical Sciences, 2004Co-Authors: Todd W. Rice, Gordon R. BernardAbstract:Coagulopathy and systemic inflammation are almost universal in patients with severe sepsis. Interaction between the two results in an intense inflammatory response and microthrombi formation in the vessels of multiple organs, resulting in organ dysfunction or severe sepsis. Recombinant human activated protein C, also known as Drotrecogin Alfa (activated), possesses anti-inflammatory, antithrombotic, and profibrinolytic properties. Treatment with Drotrecogin Alfa (activated) significantly reduces morbidity and mortality in patients with severe sepsis. An increased risk of bleeding during the infusion was the only side effect experienced. Recent data demonstrate that early administration of Drotrecogin Alfa (activated) is associated with lower mortality rates. Despite concern over its relatively high cost, analysis has demonstrated that recombinant human activated protein C is as cost-effective as other commonly used treatments in the intensive care unit.
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The effect of Drotrecogin Alfa (activated) on long-term survival after severe sepsis.
Critical care medicine, 2004Co-Authors: Derek C. Angus, Eugene W. Ely, Pierre-françois Laterre, Jeffrey Helterbrand, Daniel E Ball, Rekha Garg, Lisa A. Weissfeld, Gordon R. BernardAbstract:Objective:To determine long-term survival for subjects with severe sepsis enrolled in the previous multiple-center trial (PROWESS) of Drotrecogin Alfa (activated) (DrotAA) vs. placebo.Design:Retrospective, cross-sectional, blinded follow-up of subjects enrolled in a previous randomized, controlled t
Pierre-françois Laterre - One of the best experts on this subject based on the ideXlab platform.
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address administration of Drotrecogin Alfa activated in early stage severe sepsis long term follow up one year safety and efficacy evaluation
Critical Care Medicine, 2007Co-Authors: Pierre-françois Laterre, Edward Abraham, Jonathan Janes, Benjamin L Trzaskoma, Nancy L Correll, Frank V BoothAbstract:OBJECTIVE: To demonstrate that Drotrecogin Alfa (activated) has an acceptable safety profile 1 yr from randomization. DESIGN: One-year follow-up of patients participating in a placebo-controlled clinical study of Drotrecogin Alfa (activated) in severe sepsis patients at low risk of death (the ADDRESS study). SETTING: The study was conducted at 516 hospitals in 34 countries. PATIENTS: The study included 2,640 patients. INTERVENTIONS: One-year follow-up was performed as an addendum to the placebo-controlled ADDRESS study. Treatment groups were compared using the chi-square test and Kaplan-Meier estimates. MEASUREMENTS AND MAIN RESULTS: Survival status at 1 yr was obtained for 90% of patients enrolled in the study (n = 2,376). The difference in mortality rate between Drotrecogin Alfa (activated) and placebo patients was numerically smaller at 1 yr (34.2% and 34.0%, respectively, p = .94) than at 28 days (18.5% and 17.0%, respectively, p = .34). In the subgroups defined by organ dysfunction class (single or multiple) and Acute Physiology and Chronic Health Evaluation II score ( or=25), the differences in mortality rate between treatment groups at 1 yr were consistent with those observed at 28 days; no significant differences in mortality rates between treatment groups were observed. No additional serious adverse events were reported during the period between hospital discharge and 1 yr. CONCLUSIONS: No increased risk of death or evidence of harm at 1 yr was associated with Drotrecogin Alfa (activated) administration in patients with severe sepsis at lower risk of death.
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steroid use in prowess severe sepsis patients treated with Drotrecogin Alfa activated
Critical Care, 2005Co-Authors: Howard Levy, Pierre-françois Laterre, Becky Bates, Rebecca L. QualyAbstract:Introduction In a study conducted by Annane, patients with septic shock and unresponsive to adrenocorticotropic hormone stimulation receiving low-dose steroid therapy had prolonged survival but not significantly improved 28-day mortality. The present study examines intravenous steroid use in PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) patients meeting the Annane enrollment criteria (AEC). Methods Adrenocorticotropic hormone stimulation tests were not done in PROWESS. Steroids were allowed but their use was not directed. Patients were identified using AEC (all of: randomization to study drug treatment within 8 hours of shock onset; infection, fever, or hypothermia; tachycardia; systolic blood pressure <90 mmHg on vasopressors; mechanical ventilation; and one of urine <0.5 ml/kg per hour, lactic acidosis, or arterial oxygen tension/inspired fractional oxygen <280). We examined steroid use and mortality data; additional analyses were done outside the 8-hour window. Results Steroid-treated patients were older, had higher Acute Physiology and Chronic Health Evaluation scores and more organ dysfunctions, and were more commonly receiving mechanical ventilation. Among patients meeting AEC, regardless of steroid treatment (n = 97), mortality in the placebo and Drotrecogin Alfa (activated) groups was 38% (19/50) and 28% (13/47), respectively (relative risk [RR] = 0.73, 95% confidence interval [CI] 0.41–1.30). When using AEC but excluding the requirement for randomization within 8 hours of shock onset (n = 612), placebo mortality was 38% (118/313) and Drotrecogin Alfa (activated) mortality was 29% (88/299; RR = 0.78, 95% CI 0.62–0.98). Using AEC but excluding the 8hour window and with steroids initiated at baseline and/or infusion (n = 228) resulted in mortality for placebo and Drotrecogin Alfa (activated) groups of 43% (51/118) and 33% (36/110), respectively (RR = 0.76, 95% CI 0.54–1.06).
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steroid use in prowess severe sepsis patients treated with Drotrecogin Alfa activated
16th Annual Congress of the European-Society-of-Intensive-Care-Medicine, 2005Co-Authors: Howard Levy, Pierre-françois Laterre, Becky Bates, Rebecca L. QualyAbstract:Introduction In a study conducted by Annane, patients with septic shock and unresponsive to adrenocorticotropic hormone stimulation receiving low-dose steroid therapy had prolonged survival but not significantly improved 28-day mortality. The present study examines intravenous steroid use in PROWESS ( Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) patients meeting the Annane enrollment criteria (AEC). Methods Adrenocorticotropic hormone stimulation tests were not done in PROWESS. Steroids were allowed but their use was not directed. Patients were identified using AEC ( all of: randomization to study drug treatment within 8 hours of shock onset; infection, fever, or hypothermia; tachycardia; systolic blood pressure < 90 mmHg on vasopressors; mechanical ventilation; and one of urine < 0.5 ml/kg per hour, lactic acidosis, or arterial oxygen tension/ inspired fractional oxygen < 280). We examined steroid use and mortality data; additional analyses were done outside the 8-hour window. Results Steroid-treated patients were older, had higher Acute Physiology and Chronic Health Evaluation scores and more organ dysfunctions, and were more commonly receiving mechanical ventilation. Among patients meeting AEC, regardless of steroid treatment (n = 97), mortality in the placebo and Drotrecogin Alfa ( activated) groups was 38% (19/50) and 28% (13/47), respectively ( relative risk [RR] = 0.73, 95% confidence interval [CI] 0.41 - 1.30). When using AEC but excluding the requirement for randomization within 8 hours of shock onset ( n = 612), placebo mortality was 38% (118/313) and Drotrecogin Alfa ( activated) mortality was 29% (88/299; RR = 0.78, 95% CI 0.62 - 0.98). Using AEC but excluding the 8-hour window and with steroids initiated at baseline and/or infusion ( n = 228) resulted in mortality for placebo and Drotrecogin Alfa ( activated) groups of 43% (51/118) and 33% (36/110), respectively ( RR = 0.76, 95% CI 0.54 - 1.06). Conclusion Patients with severe sepsis from the PROWESS trial who were likely to respond to low-dose steroids according to the AEC were those patients at a high risk for death. However, when using the AEC, regardless of steroid use, patients exhibited a survival benefit from treatment with Drotrecogin Alfa ( activated).
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The effect of Drotrecogin Alfa (activated) on long-term survival after severe sepsis.
Critical care medicine, 2004Co-Authors: Derek C. Angus, Eugene W. Ely, Pierre-françois Laterre, Jeffrey Helterbrand, Daniel E Ball, Rekha Garg, Lisa A. Weissfeld, Gordon R. BernardAbstract:Objective:To determine long-term survival for subjects with severe sepsis enrolled in the previous multiple-center trial (PROWESS) of Drotrecogin Alfa (activated) (DrotAA) vs. placebo.Design:Retrospective, cross-sectional, blinded follow-up of subjects enrolled in a previous randomized, controlled t
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clinical review Drotrecogin Alfa activated as adjunctive therapy for severe sepsis practical aspects at the bedside and patient identification
Critical Care, 2003Co-Authors: Pierre-françois Laterre, Xavier WitteboleAbstract:Administration of Drotrecogin Alfa (activated) has been demonstrated to reduce mortality in patients with severe sepsis who are at high risk for death or who have multiple organ dysfunction. This benefit was associated with an increased incidence of bleeding events, but the latter were mainly procedure related. Drug infusion interruptions should be instituted, in accordance with recent recommendations. Monitoring coagulation parameters may help in identifying patients at higher risk for bleeding but it is not indicated to adjust drug dosage. Acute renal failure and hemodialysis are not contraindications to this therapy, and no drug dosage adjustment is indicated. Finally, the type and source of infection, and its anticipated natural history, may determine whether Drotrecogin Alfa (activated) is indicated as well as the timing of its administration.
Derek C. Angus - One of the best experts on this subject based on the ideXlab platform.
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Cost effectiveness of Drotrecogin Alfa (activated) for the treatment of severe sepsis in the United Kingdom.
Anaesthesia, 2005Co-Authors: A. Davies, Chris Chinn, S. A. Ridley, J. Hutton, B. Barber, Derek C. AngusAbstract:Summary Drotrecogin Alfa (activated) is licensed in Europe for the treatment of severe sepsis in patients with multiple organ failure. We constructed a model to assess the cost effectiveness of Drotrecogin Alfa (activated) from the perspective of the UK National Health Service when used in adult intensive care units. Patient outcomes from a 28-day international clinical trial (PROWESS) and a subsequent follow-up study (EVBI) were supplemented with UK data. Cost effectiveness was assessed as incremental cost per life year and per quality adjusted life year saved compared to placebo alongside best usual care. Applying the 28-day mortality outcomes of the PROWESS study, the model produced a cost per life year saved of £4608 and cost per quality adjusted life year saved of £6679. Equivalent results using actual hospital outcomes were £7625 per life year and £11 051 per quality adjusted life year. Drotrecogin Alfa (activated) appears cost effective in treating severe sepsis in UK intensive care units.
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The effect of Drotrecogin Alfa (activated) on long-term survival after severe sepsis.
Critical care medicine, 2004Co-Authors: Derek C. Angus, Eugene W. Ely, Pierre-françois Laterre, Jeffrey Helterbrand, Daniel E Ball, Rekha Garg, Lisa A. Weissfeld, Gordon R. BernardAbstract:Objective:To determine long-term survival for subjects with severe sepsis enrolled in the previous multiple-center trial (PROWESS) of Drotrecogin Alfa (activated) (DrotAA) vs. placebo.Design:Retrospective, cross-sectional, blinded follow-up of subjects enrolled in a previous randomized, controlled t
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Cost-effectiveness of Drotrecogin Alfa (activated) for the treatment of severe sepsis in Germany
Journal of Critical Care, 2003Co-Authors: Aileen R. Neilson, Hilmar Burchardi, Chris Chinn, Johannes Clouth, Heinz Schneider, Derek C. AngusAbstract:Abstract Drotrecogin Alfa (activated) (Xigris; Eli Lilly and Company, Indianapolis, IN) significantly reduced mortality in severe sepsis in the PROWESS trial. We evaluate the cost-effectiveness of Drotrecogin Alfa (activated) as an adjunct to standard therapy from the German healthcare payer’s perspective with respect to patients with 1) severe sepsis and 2) severe sepsis and multiple organ failure the approved European indication. Hospital resource use based on PROWESS was valued using German unit costs. German life-tables and long-term survival assumptions determined life-years gained. European and German healthcare resource use data are examined in the sensitivity analysis. We assumed a unit price of €237.50 for Drotrecogin Alfa (activated). Per patient treated, Drotrecogin Alfa (activated) increased costs by €7,500, and hospital costs by €900 for all patients (€7,400 and €1,500 respectively for the approved indication) and survival by 0.59 life years (0.87 life years respectively for the approved indication). Thus Drotrecogin Alfa (activated) cost €14,100 (€17,700 discounting life years at 3%) per life year gained for all patients (€10,200 and €12,900, respectively, for the approved indication). Testing the unit cost of Drotrecogin Alfa (activated), pattern of resource use, and survival benefit, demonstrated that cost-effectiveness lies well within the range of other life saving interventions in Germany representing good economic value.
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Drotrecogin Alfa (activated) administration across clinically important subgroups of patients with severe sepsis.
Critical Care Medicine, 2003Co-Authors: Eugene W. Ely, Derek C. Angus, Pierre-françois Laterre, Jeffrey Helterbrand, Howard Levy, Jean-françois Dhainaut, Jean Louis Vincent, William L. Macias, Gordon R. BernardAbstract:Objective: To assess the effects of Drotrecogin Alfa (activated) therapy, a recombinant human activated protein C, across clinically relevant subpopulations in a randomized, phase 3, placebo-controlled study of patients with severe sepsis (recombinant human activated protein C worldwide evaluation in severe sepsis [PROWESS]). Design: Univariate and multivariable analysis of prospectively defined subgroups from the PROWESS study. Setting. A total of 164 medical centers in 11 countries. Patients. A total of 1,690 patients with severe sepsis. Measurements and Main Results., We report observed 28-day mortality rates for Drotrecogin Alfa (activated) and placebo patients for subgroups prospectively defined by demographic data, surgical status, type and site of infection, and clinical and biochemical measures of disease severity. We performed subgroup analyses to explore the consistency of the mortality benefit observed in the overall population and performed tests for both quantitative and qualitative interactions. To examine the magnitude of the treatment benefit with Drotrecogin Alfa (activated) across the underlying predicted risk of mortality spectrum, we used stepwise logistic regression on PROWESS placebo patients to generate a predicted risk of mortality model that simultaneously included many clinical and biochemical markers of mortality risk. Because Drotrecogin Alfa (activated) has anticoagulant properties, we also present analyses of bleeding and thrombotic events. Actual mortality rates were lower with Drotrecogin Alfa (activated) compared with placebo for nearly all prospectively defined subgroups. Both univariate and multivariable regression analyses showed a consistent relative risk reduction in 28-day mortality rates for Drotrecogin Alfa (activated). Larger absolute risk reductions were found with Drotrecogin Alfa (activated) in patients with a higher baseline predicted risk of mortality, and actual mortality rates were lower with Drotrecogin Alfa (activated) in all subgroups defined by disease severity measures where a greater than or equal to20% placebo mortality was observed. Although discriminatory power was limited by few observed events, the increased absolute risk of experiencing a serious bleeding event with treatment did not seem to vary according to the baseline predicted risk of mortality. Conclusions. The administration of Drotrecogin Alfa (activated) to patients with severe sepsis was associated with a significant survival benefit that tended to increase with higher baseline likelihood of death. Current data suggest that the increased risk of bleeding does not vary according to likelihood of death.
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Effects of Drotrecogin Alfa (activated) on organ dysfunction in the PROWESS trial.
Critical Care Medicine, 2003Co-Authors: Jean Louis Vincent, Andre C. Kalil, Derek C. Angus, Antonio Artigas, Bruce R. Basson, Hassan H. Jamal, Gerald Johnson, Gordon R. BernardAbstract:Objective To assess morbidity in patients with severe sepsis managed with and without Drotrecogin Alfa (activated). Design Analysis of secondary end points in a prospective, randomized, double-blind, placebo-controlled, multicenter, phase 3 trial (PROWESS). Setting A total of 164 medical institutions in 11 countries. Patients A total of 1,690 consecutive adult patients with severe sepsis. Interventions A 96-hr infusion of Drotrecogin Alfa (activated) (human recombinant activated protein C) or placebo. Measurements and Main Results Sequential Organ Failure Assessment (SOFA) scores for cardiovascular, respiratory, renal, hematologic, and hepatic organ systems were measured for 28 days. Mean cardiovascular SOFA scores were significantly lower for patients treated with Drotrecogin Alfa (activated) compared with placebo patients over this time period (p = .022). Drotrecogin Alfa (activated)–treated patients also showed significantly faster resolution of cardiovascular (p = .009) and respiratory (p = .009) dysfunction and significantly slower onset of hematologic organ dysfunction (p = .041) compared with placebo patients for days 1 to 7. No significant differences in morbidity were observed between treatment groups among 28-day survivors. Conclusion Drotrecogin Alfa (activated) demonstrated significant improvements in organ function compared with placebo in a large phase 3 clinical trial that has shown a mortality benefit in patients with severe sepsis.
Jean Louis Vincent - One of the best experts on this subject based on the ideXlab platform.
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Drotrecogin Alfa (activated): The treatment for severe sepsis?
Expert Opinion on Biological Therapy, 2007Co-Authors: Jean Louis VincentAbstract:Severe sepsis is common and increasing in incidence. Mortality rates remain high. Discovery of the link between the coagulation system and the inflammatory response to sepsis led to the development of Drotrecogin Alfa (activated). This recombinant form of the natural anticoagulant, activated protein C, was shown to reduce 28-day mortality from severe sepsis in a large, randomised, placebo-controlled, multi-centre Phase III study. Although subsequent studies have demonstrated that Drotrecogin Alfa (activated) is not of benefit to all patients with severe sepsis, it does reduce mortality rates in patients at a high risk of death. Drotrecogin Alfa (activated) is associated with an increased risk of bleeding. Recent studies have shed light on its mode of action, which is primarily attributed today to cytoprotective effects especially on the endothelium with improved microcirculation. Ongoing studies will help define which patients are most likely to benefit, perhaps with the help of biochemical markers.
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Drotrecogin Alfa (Activated) in the Treatment of Severe Sepsis
Current Drug Safety, 2007Co-Authors: Jean Louis VincentAbstract:Severe sepsis and septic shock are common in the critically ill patient and account for considerable morbidity and mortality not to mention the high associated costs. Advances in our understanding of sepsis pathophysiology and in the important link between the inflammatory response to sepsis and activation of coagulation led to the development and licensing of the first ever, specific, immunomodulatory anti-sepsis drug. Drotrecogin Alfa (activated), a recombinant version of activated protein C, was shown in a large randomized controlled clinical trial to reduce mortality rates from 30.8% in the placebo group to 24.7% in the treatment group, which equated to one additional life saved for every 16 patients treated. Vasopressor requirements and duration of mechanical ventilation were also reduced. Apart from an expected increased risk of severe bleeding, mostly associated with interventions, Drotrecogin Alfa (activated) was not associated with any other adverse reactions. In this article, I will briefly summarize the events leading to the development of Drotrecogin Alfa (activated) including aspects of sepsis epidemiology and pathophysiology and the results of early animal and clinical studies. The results of the large multicenter phase III PROWESS study will then be reviewed, along with results from subsequent open-label studies. Finally, I will focus on the key side effect issue with Drotrecogin Alfa (activated), that of increased bleeding, drawing data from the available clinical studies, and highlighting the contraindications and precautions when prescribing this drug.
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Drotrecogin Alfa (activated) in the treatment of severe sepsis
Expert Review of Anti-infective Therapy, 2006Co-Authors: Jean Louis VincentAbstract:Severe sepsis is a common and frequently fatal condition. Evidence showing a link between the coagulation system and the inflammatory response to sepsis led to the development of Drotrecogin Alfa (activated) as an agent in the treatment of severe sepsis. Recent studies have shown that the mode of action is actually more complex than initially thought. This recombinant form of the natural anticoagulant, activated protein C, has been demonsrated to reduce mortality in a large randomized controlled, Phase III study involving 1690 patients, even though the results of this and subsequent studies and the licensing of Drotrecogin Alfa (activated) have generated considerable debate. Administration of Drotrecogin Alfa (activated) is associated with an increased risk of bleeding and its use is contraindicated in patients with a high risk of bleeding or recent hemorrhagic events.
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Effects of Drotrecogin Alfa activated on microcirculatory alterations in patients with severe sepsis.
Critical care medicine, 2006Co-Authors: Daniel Backer, Colin Verdant, Marialuisa Chierego, Marc Koch, Antonino Gullo, Jean Louis VincentAbstract:Objective:Microvascular alterations may play an important role in the development of sepsis-induced organ dysfunction. Drotrecogin Alfa activated (DAA) improves outcome in patients with severe sepsis, but its precise mechanism of action is not entirely defined. We investigated whether DAA can influe
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Drotrecogin Alfa activated treatment in severe sepsis from the global open label trial enhance further evidence for survival and safety and implications for early treatment
Critical Care Medicine, 2005Co-Authors: Jean Louis Vincent, Gordon R. Bernard, Jean-françois Dhainaut, William L. Macias, Antonio Artigas, Richard Beale, Christopher J Doig, Christian Putensen, Roberto Fumagalli, Theressa J WrightAbstract:Objective:To provide further evidence for the efficacy and safety of Drotrecogin Alfa (activated) treatment in severe sepsis.Design:Single-arm, open-label, trial of Drotrecogin Alfa (activated) treatment in severe sepsis patients. Enrollment began in March 2001 and day-28 follow-up completed in Janu
Rebecca L. Qualy - One of the best experts on this subject based on the ideXlab platform.
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steroid use in prowess severe sepsis patients treated with Drotrecogin Alfa activated
Critical Care, 2005Co-Authors: Howard Levy, Pierre-françois Laterre, Becky Bates, Rebecca L. QualyAbstract:Introduction In a study conducted by Annane, patients with septic shock and unresponsive to adrenocorticotropic hormone stimulation receiving low-dose steroid therapy had prolonged survival but not significantly improved 28-day mortality. The present study examines intravenous steroid use in PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) patients meeting the Annane enrollment criteria (AEC). Methods Adrenocorticotropic hormone stimulation tests were not done in PROWESS. Steroids were allowed but their use was not directed. Patients were identified using AEC (all of: randomization to study drug treatment within 8 hours of shock onset; infection, fever, or hypothermia; tachycardia; systolic blood pressure <90 mmHg on vasopressors; mechanical ventilation; and one of urine <0.5 ml/kg per hour, lactic acidosis, or arterial oxygen tension/inspired fractional oxygen <280). We examined steroid use and mortality data; additional analyses were done outside the 8-hour window. Results Steroid-treated patients were older, had higher Acute Physiology and Chronic Health Evaluation scores and more organ dysfunctions, and were more commonly receiving mechanical ventilation. Among patients meeting AEC, regardless of steroid treatment (n = 97), mortality in the placebo and Drotrecogin Alfa (activated) groups was 38% (19/50) and 28% (13/47), respectively (relative risk [RR] = 0.73, 95% confidence interval [CI] 0.41–1.30). When using AEC but excluding the requirement for randomization within 8 hours of shock onset (n = 612), placebo mortality was 38% (118/313) and Drotrecogin Alfa (activated) mortality was 29% (88/299; RR = 0.78, 95% CI 0.62–0.98). Using AEC but excluding the 8hour window and with steroids initiated at baseline and/or infusion (n = 228) resulted in mortality for placebo and Drotrecogin Alfa (activated) groups of 43% (51/118) and 33% (36/110), respectively (RR = 0.76, 95% CI 0.54–1.06).
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steroid use in prowess severe sepsis patients treated with Drotrecogin Alfa activated
16th Annual Congress of the European-Society-of-Intensive-Care-Medicine, 2005Co-Authors: Howard Levy, Pierre-françois Laterre, Becky Bates, Rebecca L. QualyAbstract:Introduction In a study conducted by Annane, patients with septic shock and unresponsive to adrenocorticotropic hormone stimulation receiving low-dose steroid therapy had prolonged survival but not significantly improved 28-day mortality. The present study examines intravenous steroid use in PROWESS ( Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) patients meeting the Annane enrollment criteria (AEC). Methods Adrenocorticotropic hormone stimulation tests were not done in PROWESS. Steroids were allowed but their use was not directed. Patients were identified using AEC ( all of: randomization to study drug treatment within 8 hours of shock onset; infection, fever, or hypothermia; tachycardia; systolic blood pressure < 90 mmHg on vasopressors; mechanical ventilation; and one of urine < 0.5 ml/kg per hour, lactic acidosis, or arterial oxygen tension/ inspired fractional oxygen < 280). We examined steroid use and mortality data; additional analyses were done outside the 8-hour window. Results Steroid-treated patients were older, had higher Acute Physiology and Chronic Health Evaluation scores and more organ dysfunctions, and were more commonly receiving mechanical ventilation. Among patients meeting AEC, regardless of steroid treatment (n = 97), mortality in the placebo and Drotrecogin Alfa ( activated) groups was 38% (19/50) and 28% (13/47), respectively ( relative risk [RR] = 0.73, 95% confidence interval [CI] 0.41 - 1.30). When using AEC but excluding the requirement for randomization within 8 hours of shock onset ( n = 612), placebo mortality was 38% (118/313) and Drotrecogin Alfa ( activated) mortality was 29% (88/299; RR = 0.78, 95% CI 0.62 - 0.98). Using AEC but excluding the 8-hour window and with steroids initiated at baseline and/or infusion ( n = 228) resulted in mortality for placebo and Drotrecogin Alfa ( activated) groups of 43% (51/118) and 33% (36/110), respectively ( RR = 0.76, 95% CI 0.54 - 1.06). Conclusion Patients with severe sepsis from the PROWESS trial who were likely to respond to low-dose steroids according to the AEC were those patients at a high risk for death. However, when using the AEC, regardless of steroid use, patients exhibited a survival benefit from treatment with Drotrecogin Alfa ( activated).
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benefit risk profile of Drotrecogin Alfa activated in surgical patients with severe sepsis
American Journal of Surgery, 2004Co-Authors: Philip S. Barie, Mark D Williams, Stephen F. Lowry, Jill Shwed Mccollam, Becky Bates, Rebecca L. Qualy, Donald E. FryAbstract:Abstract Background The Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial examined the safety and efficacy of Drotrecogin Alfa (activated) (Xigris) in adult patients with severe sepsis. A clinical evaluation committee examined clinical data for each patient enrolled in PROWESS. However, there were no surgeons on the committee, and thus questions remained regarding the safety and efficacy of Drotrecogin Alfa (activated) in surgical patients. Methods Masked to treatment, a Surgical Evaluation Committee adjudicated the presence and type of operation, timing of surgery, infection, and adequacy of source control of surgical patients included in PROWESS. Results Twenty-eight percent of PROWESS cases were confirmed as surgical. The absolute risk reduction for mortality in all surgical patients was 3.2% and 9.1% for patients undergoing intraabdominal procedures. Serious bleeding during the infusion and 28-day period was similar between surgical and nonsurgical patients. Conclusions Consistent with the overall PROWESS results, Drotrecogin Alfa (activated) has a favorable benefit/risk profile in surgical patients.
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Benefit/risk profile of Drotrecogin Alfa (activated) in surgical patients with severe sepsis.
The American Journal of Surgery, 2004Co-Authors: Philip S. Barie, Mark D Williams, Stephen F. Lowry, Jill Shwed Mccollam, Becky Bates, Rebecca L. Qualy, Donald E. FryAbstract:Abstract Background The Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial examined the safety and efficacy of Drotrecogin Alfa (activated) (Xigris) in adult patients with severe sepsis. A clinical evaluation committee examined clinical data for each patient enrolled in PROWESS. However, there were no surgeons on the committee, and thus questions remained regarding the safety and efficacy of Drotrecogin Alfa (activated) in surgical patients. Methods Masked to treatment, a Surgical Evaluation Committee adjudicated the presence and type of operation, timing of surgery, infection, and adequacy of source control of surgical patients included in PROWESS. Results Twenty-eight percent of PROWESS cases were confirmed as surgical. The absolute risk reduction for mortality in all surgical patients was 3.2% and 9.1% for patients undergoing intraabdominal procedures. Serious bleeding during the infusion and 28-day period was similar between surgical and nonsurgical patients. Conclusions Consistent with the overall PROWESS results, Drotrecogin Alfa (activated) has a favorable benefit/risk profile in surgical patients.
