***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 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BACKGROUND In November 2001 , the Food and Drug Administration ( FDA ) approved drotrecogin alfa ( activated ) ( DrotAA ) for adults who had severe sepsis and a high risk of death . The FDA required a study to evaluate the efficacy of DrotAA for adults who had severe sepsis and a low risk of death . METHODS We r and omly assigned adult patients with severe sepsis and a low risk of death ( defined by an Acute Physiology and Chronic Health Evaluation [ APACHE II ] score < 25 or single-organ failure ) to receive an intravenous infusion of placebo or DrotAA ( 24 microg per kilogram of body weight per hour ) for 96 hours in a double-blind , placebo-controlled , multicenter trial . The prospect ively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion . In-hospital mortality within 90 days after the start of the infusion was measured , and safety information was collected . RESULTS Enrollment in the trial was terminated early because of a low likelihood of meeting the prospect ively defined objective of demonstrating a significant reduction in the 28-day mortality rate with the use of DrotAA .  The study enrolled 2640 patients and collected data on 2613 ( 1297 in the placebo group and 1316 in the DrotAA group ) at the 28-day follow-up . There were no statistically significant differences between the placebo group and the DrotAA group in 28-day mortality ( 17.0 percent in the placebo group vs. 18.5 percent in the DrotAA group ; P=0.34 ; relative risk , 1.08 ; 95 percent confidence interval , 0.92 to 1.28 ) or in in-hospital mortality ( 20.5 percent vs. 20.6 percent ; P=0.98 ; relative risk , 1.00 ; 95 percent confidence interval , 0.86 to 1.16 ) . The rate of serious bleeding was greater in the DrotAA group than in the placebo group during both the infusion ( 2.4 percent vs. 1.2 percent , P=0.02 ) and the 28-day study period ( 3.9 percent vs. 2.2 percent , P=0.01 ) . CONCLUSIONS The absence of a beneficial treatment effect , coupled with an increased incidence of serious bleeding complications , indicates that DrotAA should not be used in patients with severe sepsis who are at low risk for death , such as those with single-organ failure or an APACHE II score less than 25 OBJECTIVES To assess the clinical and cost-effectiveness of drotrecogin alfa ( activated ) for the treatment of adults with severe sepsis in a UK context . DATA SOURCES Electronic data bases . Data from the commercial use of the drug up to April 2002 . Data from the manufacturer su bmi ssion to the National Institute for Clinical Excellence ( NICE ) . REVIEW METHODS A systematic review of the literature and an economic evaluation were undertaken . Data were synthesis ed through a narrative review with full tabulation of results from included studies . RESULTS The evidence on the effectiveness of drotrecogin alfa ( activated ) for the treatment of severe sepsis came primarily from one large pivotal r and omised controlled trial , the PROWESS study . This study demonstrated a statistically significant absolute reduction in 28-day mortality of 6.5 % . Longer term survival benefit was maintained to 90 days . By 9 months , the trend towards increased median survival was non-significant , although the survival curves did not cross . Results presented by the number of organ dysfunctions were not statistically significant , but when mortality rates for those with two or more organ failures were combined , the relative risk of death was significantly lower in those treated with drotrecogin alfa ( activated ) compared with placebo . However , this report highlights a number of considerations relevant to the subgroup analyses reported for the PROWESS study . Published cost-effectiveness studies of treatment with drotrecogin alfa ( activated ) have applied a range of methods to the estimation of benefits , estimating an incremental gain per treated patient of between 0.38 and 0.68 life-years ( for patients with severe sepsis ) . For patients with severe sepsis and multiple organ dysfunction , the manufacturer ( Eli Lilly ) estimated an incremental gain of 1.115 life-years per treated patient , compared to 1.351 life-years per treated patient estimated by the Southampton Health Technology Assessment s Centre ( SHTAC ) . These latter UK analyses are based on a patient group that is more severely affected by disease , where effectiveness is greater and the baseline risk of all-cause mortality is much higher ( SHTAC analysis ) , these factors are associated with the noted difference in effect . The three published cost-effectiveness studies report cost for US and Canadian patient groups ; for those patients with severe sepsis they report the additional cost per patient treated in a range around 10,000 - 16,000 dollars . The manufacturer 's su bmi ssion reports analysis for the UK , based on 28-day survival data in patients with severe sepsis and multiple organ dysfunction ( the European licence indication ) , with the additional mean cost per treated patient estimated to be 5106 pounds . The analysis undertaken by SHTAC , for a UK group of patients with severe sepsis and multiple organ dysfunction , estimates an additional mean cost per patient treated of 6661 pounds . The manufacturer 's su bmi ssion to NICE presents cost-effectiveness estimates for drotrecogin alfa ( activated ) in the UK , in patients with severe sepsis and multiple organ dysfunction , at 6637 pounds per quality -adjusted life-year ( QALY ) based on 28-day effectiveness data , and 10,937 pounds per QALY based on longer term follow-up data . SHTAC developed an independent cost-effectiveness model and estimated a base-case cost per QALY of 8228 pounds in patients with severe sepsis and multiple organ failure ( based on 28-day survival data ) . Simulation results indicate that where the NHS is willing to pay 20,000 pounds per QALY , drotrecogin alfa ( activated ) is a cost-effective use of re sources in 98.7 % of cases . Published economic evaluations report various sensitivity analyses , with results sensitive to changes in the measure of treatment effect , but otherwise studies reported that results were robust to variations in most assumptions used in the cost-effectiveness analysis . CONCLUSIONS Drotrecogin alfa ( activated ) plus best supportive care appears clinical ly and cost-effective compared with best supportive care alone , in a UK cohort of severe sepsis patients , and in the subgroup of more severely affected patients with severe sepsis and multiple organ failure . The introduction of drotrecogin alfa ( activated ) will involve a substantial additional cost to the NHS . The treatment-eligible population in Engl and and Wales may comprise up to 16,570 patients , with an estimated annual drug acquisition cost of over 80 million pounds , excluding VAT . Further research is required on the longer term impact of drotrecogin alfa ( activated ) on both mortality and morbidity in UK patients with severe sepsis , on the clinical and cost-effectiveness of drotrecogin alfa ( activated ) in children ( under 18 years ) with severe sepsis , and on the effect of the timing of dosage and duration of treatment on outcomes in severe sepsis 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 : r and omization 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 r and omization 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 ) result ed 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 ) 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 r and omized , 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 & mgr;g/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 l and mark 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 ; l and mark 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 2½ 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 l and mark 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 2½ yrs [ p = .001 ] ) . In the APACHE II < 25 group there was no significant difference in survival time or survival rates at l and mark 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 T 
    Output:
    
The economic attractiveness of this therapy improves when administered to those at highest risk as assessed by APACHE II ≥ 25 ( 93 % probability ICER ≤ $ 50,000/LYG ) but these results are not robust to different measures of disease severity .