The Experts below are selected from a list of 2913 Experts worldwide ranked by ideXlab platform
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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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.
Theressa J Wright - One of the best experts on this subject based on the ideXlab platform.
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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.
Pierre-françois Laterre - One of the best experts on this subject based on the ideXlab platform.
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Open Access
2013Co-Authors: Pierre-françois Laterre, Mark D Williams, William L. Macias, Jonathan Janes, David R. NelsonAbstract:Influence of enrollment sequence effect on observed outcomes in the ADDRESS and PROWESS studies of Drotrecogin alfa (activated) in patients with severe sepsi
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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
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 clinical evaluation committee in a large multicenter phase 3 trial of Drotrecogin alfa activated in patients with severe sepsis prowess role methodology and results
Critical Care Medicine, 2003Co-Authors: Jean-françois Dhainaut, Steven P. Larosa, Pierre-françois Laterre, Howard Levy, Gary T Kinasewitz, Darell E. Heiselman, Gary Garber, Bruce R Light, Peter E MorrisAbstract:Objective: In the multinational PROWESS trial, Drotrecogin alfa (activated) significantly reduced mortality rate in patients with severe sepsis compared with placebo. The use of large multiple-enter trials can potentially complicate interpretation of results in severe sepsis populations because of variability in medical attitudes and practices and the frequency of confounding events such as protocol violations. The objective of this study was to perform a blinded, critical, integrated review of data from the 1,690 severe sepsis patients from 164 medical centers enrolled in the PROWESS trial using a Clinical Evaluation Committee. Design: Blinded, critical, integrated review of data. Setting: Participating sites. Patients: The 1,690 severe sepsis patients from 164 medical centers enrolled in the PROWESS trial. Interventions: We performed analyses of the optimal cohort, defined as patients who had full compliance with the protocol, had evidence of an infection, and received adequate anti-infective therapy. We also performed other analyses, including significant underlying disorders, life support measures, and causes of death. Measurements and Main Results: The optimal cohort of 81.4% of the intention-to-treat population [Drotrecogin alfa (activated), n = 695; placebo, n = 680] had similar baseline severity of illness between the two groups, a similar pharmacodynamic effect, and a relative risk of death estimate consistent with that observed in the overall PROWESS trial (0.83, 95% confidence interval 0.69-0.99 vs. 0.806, 95% confidence interval 0.69-0.94). A beneficial effect of Drotrecogin alfa (activated) similarly was observed in patients with significant underlying disorders (0.73, 95% confidence interval 0.57-0.93) who were more severely ill and had a higher percentage of patients forgoing life-sustaining therapy. In contrast with the original investigator determinations, a benefit associated with Drotrecogin alfa (activated) treatment in urinary tract infection adjudicated by the Clinical Evaluation Committee was observed. Conclusions: The survival benefit associated with Drotrecogin alfa (activated) use was consistent with the results of the overall trial regardless of whether patients met criteria of the optimal cohort or had a significant underlying disorder.
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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.
Jean-françois Dhainaut - One of the best experts on this subject based on the ideXlab platform.
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Extended Drotrecogin alfa (activated) treatment in patients with prolonged septic shock.
Intensive Care Medicine, 2009Co-Authors: Jean-françois Dhainaut, Massimo Antonelli, Patrick Wright, Arnaud Desachy, Jean Reignier, Sylvain Lavoue, Julien Charpentier, Mark Belger, Michael Cobas-meyer, Cornelia MaierAbstract:Objective To determine the efficacy and safety of extended Drotrecogin alfa (activated) (DAA) therapy.
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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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the clinical evaluation committee in a large multicenter phase 3 trial of Drotrecogin alfa activated in patients with severe sepsis prowess role methodology and results
Critical Care Medicine, 2003Co-Authors: Jean-françois Dhainaut, Steven P. Larosa, Pierre-françois Laterre, Howard Levy, Gary T Kinasewitz, Darell E. Heiselman, Gary Garber, Bruce R Light, Peter E MorrisAbstract:Objective: In the multinational PROWESS trial, Drotrecogin alfa (activated) significantly reduced mortality rate in patients with severe sepsis compared with placebo. The use of large multiple-enter trials can potentially complicate interpretation of results in severe sepsis populations because of variability in medical attitudes and practices and the frequency of confounding events such as protocol violations. The objective of this study was to perform a blinded, critical, integrated review of data from the 1,690 severe sepsis patients from 164 medical centers enrolled in the PROWESS trial using a Clinical Evaluation Committee. Design: Blinded, critical, integrated review of data. Setting: Participating sites. Patients: The 1,690 severe sepsis patients from 164 medical centers enrolled in the PROWESS trial. Interventions: We performed analyses of the optimal cohort, defined as patients who had full compliance with the protocol, had evidence of an infection, and received adequate anti-infective therapy. We also performed other analyses, including significant underlying disorders, life support measures, and causes of death. Measurements and Main Results: The optimal cohort of 81.4% of the intention-to-treat population [Drotrecogin alfa (activated), n = 695; placebo, n = 680] had similar baseline severity of illness between the two groups, a similar pharmacodynamic effect, and a relative risk of death estimate consistent with that observed in the overall PROWESS trial (0.83, 95% confidence interval 0.69-0.99 vs. 0.806, 95% confidence interval 0.69-0.94). A beneficial effect of Drotrecogin alfa (activated) similarly was observed in patients with significant underlying disorders (0.73, 95% confidence interval 0.57-0.93) who were more severely ill and had a higher percentage of patients forgoing life-sustaining therapy. In contrast with the original investigator determinations, a benefit associated with Drotrecogin alfa (activated) treatment in urinary tract infection adjudicated by the Clinical Evaluation Committee was observed. Conclusions: The survival benefit associated with Drotrecogin alfa (activated) use was consistent with the results of the overall trial regardless of whether patients met criteria of the optimal cohort or had a significant underlying disorder.
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Drotrecogin alfa activated recombinant human activated protein c reduces host coagulopathy response in patients with severe sepsis
Thrombosis and Haemostasis, 2003Co-Authors: Jean-françois Dhainaut, Bruce R. Basson, Gerald Johnson, Benjamin D Margolis, Jose A Lorente, James A Russell, Ross Freebairn, Herbert D Spapen, Hanno Riess, Gary T KinasewitzAbstract:Drotrecogin alfa (activated) improved survival in patients with severe sepsis in PROWESS, a double-blind, study of 1690 adult patients randomized to Drotrecogin alfa (activated) at 24 µg/kg/h (N=850) or placebo (N=840) infused for 96 hours. Pharmacodynamic effects of Drotrecogin alfa (activated) were assessed with 15 prospectively defined systemic biomarkers of hemostasis, inflammation and endothelial injury. The last-obser-vation- carried-forward (LOCF) method of imputation for miss-ing observations was the prospectively defined statistical meth-od. The results were also analyzed with only the observed val-ues without imputation for missing data (repeated measures analysis). With both statistical methods, Drotrecogin alfa (acti-vated)- treated patients demonstrated antithrombotic (reduced markers of thrombin generation and accelerated normalization of anticoagulant factor, protein C and fibrinolytic factors) and anticoagulant (prolonged PT and APTT) effects compared with placebo. A profibrinolytic (reduction in plasminogen activator inhibitor-1) effect was significant only with the LOCF imputa-tion method in observed case and percent change from base-line analyses. An anti-inflammatory (reduction in interleukin-6) effect was significant only with the LOCF imputation method in change from baseline and percent change from baseline analy-ses. Drotrecogin alfa (activated) is a new and promising agent for treatment of patients with severe sepsis. The extensive analysis of systemic biomarkers confirms the previously pub-lished antithrombotic effects. However, the present results using different statistical methods do not provide a strong basis for systemic anti-inflammatory or pro-fibrinolytic effects. These latter two effects may occur at the local or cellular level. The systemic biomarkers reported here might not be the most appropriate approach to demonstrate these potential effects of Drotrecogin alfa (activated).
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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.
Philip S. Barie - One of the best experts on this subject based on the ideXlab platform.
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treatment of strongyloides stercoralis hyperinfection associated septic shock and acute respiratory distress syndrome with Drotrecogin alfa activated in a renal transplant recipient
Transplant Infectious Disease, 2009Co-Authors: Jared M Huston, Soumitra R Eachempati, John R Rodney, C Cayci, Jian Shou, Michael J Goldstein, Sandip Kapur, Dahlene N. Fusco, M Mathew, Philip S. BarieAbstract:: We report a case of Strongyloides stercoralis hyperinfection syndrome in a renal transplant recipient complicated by septic shock, acute respiratory distress syndrome, and Klebsiella pneumoniae superinfection. The patient was treated successfully with Drotrecogin alfa (activated), parenteral ivermectin, albendazole, and piperacillin/tazobactam. This outcome suggests that Drotrecogin alfa (activated) may be useful therapy for transplant recipients who develop severe sepsis or septic shock secondary to potentially lethal opportunistic infections.
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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.
