***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    Input: Introduction In March 2001 , the results of the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis ( PROWESS ) study were published , which indicated a 6.1 % absolute reduction in 28-day mortality .  Drotrecogin alfa ( activated ; DrotAA ) was subsequently approved for use in patients with severe sepsis . Methods In December 2002 , critical care units in Engl and , Wales and Northern Irel and were invited to participate in an audit of DrotAA .  Data for each infusion of DrotAA were linked to case mix and outcome data from a national audit . Use of DrotAA was described and a nonr and omized comparison of effectiveness was conducted . Results 1,292 infusions of DrotAA were recorded in 112 units ; 61 % commenced during the first 24 hours in the unit . The majority ( 77 % ) of patients had  three or more  organs failing ; lung ( 42 % ) and abdomen ( 40 % ) were the most common primary sites of infection . Crude hospital mortality was high ( 45 % ) ; at 28 days , only 18 % had left acute hospital and 19 % were still in the unit . For 30 % , the full 96-hour infusion was not completed ; 24 % of infusions were interrupted ; 8.1 % experienced one or more serious adverse events , of which 77 % were serious bleeding events . Of eight relative risks estimated from individually-matched ( 0.75 to 0.85 ) and propensity-matched ( 0.82 to 0.90 ) controls , seven were consistent with the results of PROWESS . Restricting the analysis to patients receiving DrotAA during the first 24 hours result ed in larger treatment effects ( relative risks 0.62 to 0.81 ) . For all matches , similar patterns were seen across subgroups . No effect of DrotAA was seen for two organs failing or lower severity scores , compared with a significant mortality reduction for three or more organs failing or higher severity scores . Conclusion Use of DrotAA was approximately one in 16 for admissions meeting the definition for severe sepsis and with two or more organs failing . Patients receiving DrotAA  were younger and more severely ill but were less likely to have serious conditions in their past medical history . Nonr and omized estimates for the effectiveness of DrotAA were consistent with the findings of PROWESS . DrotAA appeared not to be effective in patients with less severe disease BACKGROUND We conducted a retrospective evaluation of the overall safety of drotrecogin alfa ( activated ) in surgical patients with severe sepsis enrolled in PROWESS . METHODS A blinded Surgical Evaluation Committee ( SEC ) verified surgical patients as having undergone a significant operative procedure within 30 days prior to enrollment . Serious and treatment-emergent bleeding events , both during the study drug infusion period ( 120 h ) and the entire 28-day study period were analyzed by surgical status and by treatment assignment . Statistical analysis was performed using Fisher 's exact test . RESULTS Serious bleeding rates during infusion in the surgical patients were 3.1 % ( 7/228 ) and 0 % ( 0/246 ) in the drotrecogin alfa ( activated ) and placebo groups , respectively ( p = 0.006 ) . Treatment-emergent bleeding rates during infusion in the surgical patients were 16.7 % ( 38/228 ) and 7.7 % ( 19/246 ) in the drotrecogin alfa ( activated ) and placebo groups , respectively ( p = 0.003 ) . None of the treatment-emergent bleeding events was fatal . Of seven drotrecogin alfa ( activated ) serious bleeding events , six were procedure-related . The serious bleeding rates within each treatment group were statistically indistinguishable between the medical and surgical patients . However , the medical patients had numerically higher treatment-emergent bleeding rates than the surgical patients within each treatment group . Despite this observation , overall surgical patients received more transfusions of red blood cells , of platelets , and of fresh frozen plasma than their medical counterparts . CONCLUSIONS Although treatment of surgical patients with drotrecogin alfa ( activated ) for severe sepsis is associated with a higher incidence of serious bleeding and subsequent treatment- emergent bleeding events , the magnitude of this increase is small and clinical ly acceptable Objective To monitor the use of  drotrecogin alfa activated ( DrotAA ) in Italy and its effects on patients ' health . Design Prospect i ve pharmaco-surveillance program with a parallel non-r and omized control group . Setting The Ministry of Health required all intensive care units ( ICUs ) using DrotAA  to participate in the pharmaco-surveillance program . Our control group was formed of patients eligible for treatment with DrotAA but who had not received it .  Patients and participants The data we collected included basic demographic characteristics , indications , modalities of use , adverse events , and ICU mortality . We identified potentially non-collaborating centres on the basis of data on DrotAA purchasing by hospitals . Measurements and results From 2003 to 2006 , 668 cases of treatment with DrotAA were reported . We estimate that 79.3 % of all patients treated in Italy in this period were recruited . Off-label use was common . Delayed start was the main reason for off-label prescription . Bleeding during infusion occurred in 73 patients ( 10.9 % ) . The ICU mortality was higher in patients with bleeding ( 57.5 vs. 44.9 % ; p = 0.041 ) . Crude ICU mortality was lower in patients receiving DrotAA  than in controls ( 46.4 vs. 54.9 % ; p = 0.0004 ) ; however , multivariate analysis , which adjusted for certain relevant differences , showed that DrotAA treatment was associated with higher mortality after scheduled surgery . Conclusions These results question the way in which the drug is used in everyday clinical practice and its efficacy in a selected subgroup , and reinforce the need for a new , independent , confirmatory trial to reassess the risk-to-benefit ratio of DrotAA 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 Prospect i ve , 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 micro g/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 population s 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 Abstract Introduction : Severe sepsis is the major cause of mortality in intensive care units ( ICUs ) . The BOOST study (= B ( Belgian ) OO ( Open Label ) ST ( Study ) ) is a Belgian open-label trial design ed to pragmatically assess the safety and efficacy of Drotrecogin Alfa ( activated ) ( DAA ) , the only registered treatment in this indication with favourable ratio benefit/risk . Methodology : Adult patients with severe sepsis and 2 or more sepsis-induced organ dysfunctions ( OD ) within the 48-hour period preceding the treatment ( DAA at 24µg/kg/h for 96 hours ) , were included between January 2003 and October 2003 . Platelet count < 30 000/mm3 and increased risk for bleeding were exclusion criteria . Mortality and location were evaluated at 28 and 90 days . Results : Of the 100 included patients , 97 ( median age : 66 years ; men/women : 57/40 ) were treated and completed the study . The predominant infection sites were lung ( 49 % ) and abdomen ( 29 % ) and 35 % had had recent surgery . The mean and median numbers of OD were 3.4 and 3.0 , respectively , and most patients ( 80 % ; 77/97 ) had 3 or more organ failures at baseline , predominantly respiratory ( 95 % ) and cardiovascular ( 87 % ) . The mean APACHE II score was 25.3 ( range : 6 - 53 ) . The 28-day mortality rate was 32.0 % ( 90 % CI : 24.2 - 39.7 ) and increased with the number of OD : from 15 % ( 1.9 - 28.1 ) for 2 ODs , to 71 % ( 52.4 - 88.8 ) for 5 ODs . At day 28 , the 66 surviving patients were located in general ward ( 35 % ) , in the ICU ( 32 % ) or at home ( 30 % ) . The 90-day mortality rate was 42 % ( 90 % CI : 34.0 - 50.5 ) , with most of the survivors ( 73 % ) staying at home . Eight serious adverse events , including 4 bleedings , were reported between study days 2 and 5 , in 5 patients ( 5.2 % ) and led to death in 2 patients ( 2.1 % ) . Conclusion : Despite a higher severity of illness at baseline , this phase IV open-label long-term study in Belgian ICUs shows consistent results with previous studies with DAA . Importantly , most of the surviving patients at day 90 were staying at home Background The purpose of this study was to characterize the usage patterns and clinical outcomes of DAA in Ontario and Quebec over a 1-year period . Methods All hospitals with DAA on formulary in Ontario and Quebec were invited to participate . Consecutive patients who received DAA from 1 March 2003 to 29 February 2004 were identified retrospectively . Demographic , treatment , and outcome variables were collected via chart review . Descriptive statistics on relevant variables were performed , along with logistic regression to determine relevant risk factors for survival and bleeding . Results Thirty-seven sites participated with a total of 261 courses of DAA  administered . The overall mortality rate was 45 % ; age ( > 65 years ) , multiple organ system failure ( > 3 ) , and nosocomial source of sepsis were predictors of mortality , whereas early DAA administration ( < 12 h ) was associated with lower mortality . Serious bleeding events occurred in 10 % of the patients . Only 1 case ( 0.4 % ) of fatal intracranial bleed was observed . Multiple organ system failure ( ≥ 4 ) and relative contraindications to DAA were predictors of bleeding events . InterpretationMortality and bleeding complications associated with the use of DAA were higher than that reported in r and omized trials but similar to other usage data base . This may be due to the higher severity of illness seen in this cohort of patients . Modifiable risks associated with mortality and bleeding , such as time to treatment , and knowledge of relative contraindications should be targets of further research and future educational efforts in order to optimize the risk-to-benefit ratio of DAA RATIONALE Patients with severe sepsis frequently receive prophylactic heparin during drotrecogin alfa ( activated ) ( DrotAA ) treatment due to risk of venous thromboembolic events ( VTEs ) . Biological plausibility exists for heparin to reduce DrotAA efficacy and /or increase bleeding . OBJECTIVES Primary : demonstrate in adult patients with severe sepsis receiving DrotAA treatment  that 28-day mortality was equivalent for patients treated with concomitant prophylactic heparin compared with placebo ; secondary : safety and VTE incidence . METHODS International , r and omized , double-blind , phase 4 , equivalence- design trial ( n = 1994 ) . Patients were eligible if indicated for and receiving DrotAA treatment under the country 's approved label . Study drug ( low molecular weight/un 
    Output:
    
Activated protein C is associated with significant risk of bleeding , so strict inclusion and exclusion criteria should be set prior to administering activated protein