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1.
Effect of an early resuscitation protocol on in-hospital mortality among adults with sepsis and hypotension: a randomized clinical trial
Andrews B, Semler MW, Muchemwa L, Kelly P, Lakhi S, Heimburger DC, Mabula C, Bwalya M, Bernard GR
Jama. 2017;318((13)):1233-1240.
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Abstract
Importance: The effect of an early resuscitation protocol on sepsis outcomes in developing countries remains unknown. Objective: To determine whether an early resuscitation protocol with administration of intravenous fluids, vasopressors, and blood transfusion decreases mortality among Zambian adults with sepsis and hypotension compared with usual care. Design, Setting, and Participants: Randomized clinical trial of 212 adults with sepsis (suspected infection plus ≥2 systemic inflammatory response syndrome criteria) and hypotension (systolic blood pressure ≤90 mm Hg or mean arterial pressure ≤65 mm Hg) presenting to the emergency department at a 1500-bed referral hospital in Zambia between October 22, 2012, and November 11, 2013. Data collection concluded December 9, 2013. Interventions: Patients were randomized 1:1 to either (1) an early resuscitation protocol for sepsis (n = 107) that included intravenous fluid bolus administration with monitoring of jugular venous pressure, respiratory rate, and arterial oxygen saturation and treatment with vasopressors targeting mean arterial pressure (≥65 mm Hg) and blood transfusion (for patients with a hemoglobin level <7 g/dL) or (2) usual care (n = 105) in which treating clinicians determined hemodynamic management. Main Outcomes and Measures: The primary outcome was in-hospital mortality and the secondary outcomes included the volume of intravenous fluid received and receipt of vasopressors. Results: Among 212 patients randomized to receive either the sepsis protocol or usual care, 3 were ineligible and the remaining 209 completed the study and were included in the analysis (mean [SD] age, 36.7 [12.4] years; 117 men [56.0%]; 187 [89.5%] positive for the human immunodeficiency virus). The primary outcome of in-hospital mortality occurred in 51 of 106 patients (48.1%) in the sepsis protocol group compared with 34 of 103 patients (33.0%) in the usual care group (between-group difference, 15.1% [95% CI, 2.0%-28.3%]; relative risk, 1.46 [95% CI, 1.04-2.05]; P = .03). In the 6 hours after presentation to the emergency department, patients in the sepsis protocol group received a median of 3.5 L (interquartile range, 2.7-4.0 L) of intravenous fluid compared with 2.0 L (interquartile range, 1.0-2.5 L) in the usual care group (mean difference, 1.2 L [95% CI, 1.0-1.5 L]; P < .001). Fifteen patients (14.2%) in the sepsis protocol group and 2 patients (1.9%) in the usual care group received vasopressors (between-group difference, 12.3% [95% CI, 5.1%-19.4%]; P < .001). Conclusions and Relevance: Among adults with sepsis and hypotension, most of whom were positive for HIV, in a resource-limited setting, a protocol for early resuscitation with administration of intravenous fluids and vasopressors increased in-hospital mortality compared with usual care. Further studies are needed to understand the effects of administration of intravenous fluid boluses and vasopressors in patients with sepsis across different low- and middle-income clinical settings and patient populations. Trial Registration: clinicaltrials.gov Identifier: NCT01663701.
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The effect of drotrecogin alfa (activated) on long-term survival after severe sepsis
Angus DC, Laterre P-F, Helterbrand J, Ely EW, Ball DE, Garg R, Weissfeld LA, Bernard GR
Critical Care Medicine. 2004;32((11):):2199-206.
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Abstract
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 trial. Setting: One hundred sixty-four tertiary care institutions in 11 countries. Participants: The 1,690 subjects with severe sepsis enrolled and treated with study drug in PROWESS, of whom 1,220 were alive at 28 days (the end of the original PROWESS follow-up). Interventions: DrotAA (n = 850), 24 mug/kg/hr for 96 hrs, or placebo (n = 840). Measurements and Main Results: Long-term survival data were collected. We had follow-up information on 100% of subjects at 28 days, 98% at hospital discharge, 94% at 3 months, and 93% at 1 yr. The longest follow-up was 3. 6 yrs. Hospital survival was higher with DrotAA vs. placebo (70. 3% vs. 65. 1%, p =. 03). There was no statistically significant difference in duration of survival time or in landmark survival rates in subjects who received DrotAA compared with those who received placebo (median duration of survival = 1113 days vs. 846 days for DrotAA vs. placebo, p =. 10; landmark survival rates for DrotAA vs. placebo, 66. 1% vs. 62. 4% at 3 months [p =. 11], 62. 2% vs. 60. 3% at 6 months [p =. 44], 58. 9% vs. 57. 2% at 1 yr [p =. 49], and 52. 6% vs. 49. 3% at 21/2 yrs [p =. 21]). There was a significant interaction (p =. 0008) between treatment assignment and baseline Acute Physiology and Chronic Health Evaluation (APACHE) II scores, suggesting qualitative differences in treatment effect with severity of illness. Subjects with APACHE II >=25 had better survival time with DrotAA (median duration of survival: 450 vs. 71 days, p =. 0005). Survival rates were also higher at landmark time points (DrotAA vs. placebo, 58. 9% vs. 48. 4% at 3 months [p =. 003], 55. 2% vs. 45. 3% at 6 months [p =. 005], 52. 1% vs. 41. 3% at 1 yr [p =. 002], and 45. 6% vs. 33. 8% at 21/2 yrs [p =. 001]). In the APACHE II <25 group there was no significant difference in survival time or survival rates at landmark time points except at 1 yr (DrotAA vs. placebo, 65. 5% vs. 72. 0% at 1 yr, p =. 04). Conclusions: The acute survival benefit observed in subjects with severe sepsis who received DrotAA persists to hospital discharge. The survival benefit loses statistical significance thereafter. Post hoc analysis suggests the effect of DrotAA varies by APACHE II score with improved long-term survival in subjects with APACHE II scores >=25 but no benefit in those with lower scores. Copyright © 2011 Elsevier B. V. , Amsterdam. All Rights Reserved.
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Systemic host responses in severe sepsis analyzed by causative microorganism and treatment effects of drotrecogin alfa (activated)
Opal SM, Garber GE, LaRosa SP, Maki DG, Freebairn RC, Kinasewitz GT, Dhainaut JF, Yan SB, Williams MD, Graham DE, et al
Clinical Infectious Diseases. 2003;37((1):):50-8.
Abstract
Clinical trials with novel therapeutic agents for severe sepsis have suggested that patients might respond differently depending on causative microorganism. Data from a large, placebo-controlled trial of recombinant human drotrecogin alfa (activated) (DrotAA) were analyzed by type of causative microorganism for treatment-associated differences in mortality, coagulopathy, and inflammatory response. Compared with placebo, mortality rates associated with DrotAA were consistently reduced for each microorganism group (gram-positive bacteria, gram-negative bacteria, mixed bacteria, fungi, other, and unknown microbial etiology), with a stratified relative risk (RR) of 0. 80 (95% confidence interval [CI], 0. 69-0. 94). The greatest reduction in the mortality rate was for Streptococcus pneumoniae infection (RR, 0. 56; 95% CI, 0. 35-0. 88). Levels of coagulation and inflammation biomarkers varied with different pathogens at study entry. Results demonstrate that DrotAA, administered as an adjunct to standard anti-infective therapy, can improve the rate of survival for patients who develop severe sepsis regardless of causative microorganism.
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Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis
Ely EW, Laterre PF, Angus DC, Helterbrand JD, Levy H, Dhainaut JF, Vincent JL, Macias WL, Bernard GR, PROWESS Investigators
Critical Care Medicine. 2003;31((1):):12-9.
Abstract
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 > or = 20% 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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Drotrecogin alfa (activated) treatment of older patients with severe sepsis
Ely EW, Angus DC, Williams MD, Bates B, Qualy R, Bernard GR
Clinical Infectious Diseases. 2003;37((2):):187-95.
Abstract
The incidence of severe sepsis increases dramatically with advanced age, with a mortality rate that approaches 50%. The main purpose of this investigation was to determine both short- and long-term survival outcomes among 386 patients aged >or=75 years who were enrolled in the Protein C Worldwide Evaluation of Severe Sepsis (PROWESS) trial. Subjects who were treated with drotrecogin alfa (activated; DAA) had absolute risk reductions in 28-day and in-hospital mortality of 15. 5% and 15. 6%, respectively (P=. 002 for both), compared with placebo recipients. The relative risk (RR) for 28-day mortality was 0. 68 (95% confidence interval [CI], 0. 54-0. 87), and the in-hospital RR was 0. 70 (95% CI, 0. 56-0. 88). Resource use and patient disposition for DAA-treated patients compared favorably with those for placebo recipients. In addition, long-term follow-up data were available for 375 subjects (97. 2%), and survival rates for DAA recipients were significantly higher over a 2-year period (P=. 02). The incidences of serious adverse bleeding during the 28-day study period in the DAA and placebo groups were 3. 9% and 2. 2%, respectively (P=. 34). There was no interaction between age and bleeding rates (P=. 97). In conclusion, older patients with severe sepsis have higher short- and long-term survival rates when treated with DAA than when treated with placebo but an increased risk of serious bleeding that is not aged related.
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Effects of drotrecogin alfa (activated) on organ dysfunction in the PROWESS trial
Vincent JL, Angus DC, Artigas A, Kalil A, Basson BR, Jamal HH, Johnson G, Bernard GR, Recombinant Human Activated Protein CWorldwide Evaluation in Severe Sepsis Study Group
Critical Care Medicine. 2003;31((3):):834-40.
Abstract
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.
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Drotrecogin alfa (activated) in the treatment of severe sepsis patients with multiple-organ dysfunction: data from the PROWESS trial
Dhainaut JF, Laterre PF, Janes JM, Bernard GR, Artigas A, Bakker J, Riess H, Basson BR, Charpentier J, Utterback BG, et al
Intensive Care Medicine. 2003;29((6):):894-903.
Abstract
OBJECTIVE Based on the results of the PROWESS trial the European Agency for the Evaluation of Medicinal Products has recently approved drotrecogin alfa (activated) for treatment of adult patients with severe sepsis and multiple-organ failure. We report study's data on efficacy and safety in patients with multiple-organ dysfunction. DESIGN AND SETTING Randomized, double-blind, placebo-controlled, multicenter trial in 164 medical centers. PATIENTS 1271 patients (75. 2% of the intention-to-treat population, n=1690) with multiple-organ dysfunction at study entry. INTERVENTIONS Drotrecogin alfa (activated) n=634, 24 micro g/kg per hour for 96 h or placebo ( n=637). RESULTS Observed 28-day mortality was significantly lower with drug treatment than with placebo (26. 5%vs. 33. 9%), cardiovascular and respiratory organ dysfunction resolved more rapidly over the first 7 days, and serious bleeding events were more frequent (2. 4% vs. 1. 3%). CONCLUSIONS Treatment with drotrecogin alfa (activated) significantly reduced 28-day mortality and more quickly resolved cardiovascular and respiratory organ dysfunction. The difference in serious bleeding event rates may be clinically significant; however, the overall benefit-risk profile appears favorable.
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Efficacy and safety of recombinant human activated protein C for severe sepsis
Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, et al
New England Journal of Medicine. 2001;344((10):):699-709.
Abstract
BACKGROUND Drotrecogin alfa (activated), or recombinant human activated protein C, has antithrombotic, antiinflammatory, and profibrinolytic properties. In a previous study, drotrecogin alfa activated produced dose-dependent reductions in the levels of markers of coagulation and inflammation in patients with severe sepsis. In this phase 3 trial, we assessed whether treatment with drotrecogin alfa activated reduced the rate of death from any cause among patients with severe sepsis. METHODS We conducted a randomized, double-blind, placebo-controlled, multicenter trial. Patients with systemic inflammation and organ failure due to acute infection were enrolled and assigned to receive an intravenous infusion of either placebo or drotrecogin alfa activated (24 microg per kilogram of body weight per hour) for a total duration of 96 hours. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. Patients were monitored for adverse events; changes in vital signs, laboratory variables, and the results of microbiologic cultures; and the development of neutralizing antibodies against activated protein C. RESULTS A total of 1690 randomized patients were treated (840 in the placebo group and 850 in the drotrecogin alfa activated group). The mortality rate was 30.8 percent in the placebo group and 24.7 percent in the drotrecogin alfa activated group. On the basis of the prospectively defined primary analysis, treatment with drotrecogin alfa activated was associated with a reduction in the relative risk of death of 19.4 percent (95 percent confidence interval, 6.6 to 30.5) and an absolute reduction in the risk of death of 6.1 percent (P=0.005). The incidence of serious bleeding was higher in the drotrecogin alfa activated group than in the placebo group (3.5 percent vs. 2.0 percent, P=0.06). CONCLUSIONS Treatment with drotrecogin alfa activated significantly reduces mortality in patients with severe sepsis and may be associated with an increased risk of bleeding.
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Safety and dose relationship of recombinant human activated protein C for coagulopathy in severe sepsis
Bernard GR, Ely EW, Wright TJ, Fraiz J, Stasek JE Jr, Russell JA, Mayers I, Rosenfeld BA, Morris PE, Yan SB, et al
Critical Care Medicine. 2001;29((11):):2051-9.
Abstract
OBJECTIVES To assess the safety and effect on coagulopathy of a range of doses of recombinant human activated protein C (rhAPC). To determine an effective dose and duration of rhAPC for use in future clinical trials. DESIGN Double-blind, randomized, placebo-controlled, multicenter, dose-ranging (sequential), phase II clinical trial. SETTING Forty community or academic medical institutions in United States and Canada. PATIENTS One hundred thirty-one adult patients with severe sepsis. INTERVENTIONS Intravenous infusion of rhAPC (12, 18, 24, or 30 microg/kg/hr) or placebo for 48 or 96 hrs. MEASUREMENTS AND MAIN RESULTS No significant differences in incidence of serious bleeding events (4% rhAPC, 5% placebo, p >.999) or incidence of serious adverse events (39% rhAPC, 46% placebo, p = 0.422) between rhAPC- and placebo-treated patients were observed. One of 53 rhAPC-treated patients with suitable immunogenicity samples had a low level, transient, non-neutralizing anti-APC antibody response not associated with any clinical adverse event. Significant dose-dependent decreases in both D-dimer (p <0.001) and end of infusion interleukin 6 levels (p =.021) were demonstrated. No statistically significant effects on fibrinogen or platelet counts were observed. A nonstatistically significant 15% relative risk reduction in 28-day all-cause mortality was observed between rhAPC- and placebo-treated patients. CONCLUSIONS rhAPC was safe and well-tolerated and demonstrated a dose-dependent reduction in D-dimer and interleukin 6 levels relative to placebo. The dose of 24 microg/kg/hr for 96 hrs was selected for use in future clinical studies.