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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 (activat

OBJECTIVE: To assess the cost-effectiveness of drotrecogin alfa (activated) therapy, which was recently shown to reduce mortality in severe sepsis. DESIGN: Estimates of effectiveness and resource use were based on data collected prospectively as part of a multicenter international trial. Estimates of hospital costs were based on a subset of the patients treated in the United States (33% of all enrolled patients). Lifetime projections were modeled from published sources and tested in sensitivity analyses. Analyses were conducted from the United States societal perspective, limited to healthcare costs, and using a 3% annual discount rate. SETTING: A total of 164 medical institutions in 11 countries. PATIENTS: Adults > or = 18 yrs of age with severe sepsis INTERVENTIONS: Eligible patients were randomly assigned to receive a 96-hr intravenous infusion of drotrecogin alfa (activated) at 24 microg/kg/hr (n = 850) or placebo (n = 840). MEASUREMENTS AND MAIN RESULTS: Base Case: incremental short-term (days 1-28) healthcare costs per day-28 survivor; Panel on Cost-Effectiveness in Health and Medicine Reference Case: incremental lifetime healthcare costs per quality-adjusted life-year. Over the first 28 days (short-term Base Case), drotrecogin alfa (activated) increased the costs of care by $9,800 and survival by 0.061 lives saved per treated patient. Thus, drotrecogin alfa (activated) cost $160,000 per life saved (with 84.7% probability that ratio is <$250,000 per life saved). Projected to lifetime (lifetime Reference Case), drotrecogin alfa (activated) increased the costs of care by $16,000 and quality-adjusted survival by 0.33 quality-adjusted life-years per treated patient. Thus, drotrecogin alfa (activated) cost $48,800 per quality-adjusted life-year (with 82% probability that ratio is <$100,000 per quality-adjusted life-year). Estimates were generally robust to sensitivity analyses, although cost-effectiveness deteriorated to >$100,000 per quality-adjusted life-year if