Drotrecogin Alfa (Activated)

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Abstract
Drotrecogin alfa (activated) [Xigris®] {DAA}, the recombinant form of human activated protein C, is approved as an adjunctive therapy for patients with severe sepsis (sepsis associated with ≥1 organ system failure [OSF]). In the international, randomised, double-blind, placebo-controlled PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) study, the absolute reduction in 28-day all-cause mortality with intravenous DAA 24 µgg/kg/h for 96 hours plus conventional care versus conventional care alone was 6.1%. Although lacking statistical power, a prospectively planned subgroup analysis of this study suggested that the absolute reduction in mortality increased in patients with a baseline APACHE (Acute Physiology and Chronic Health Evaluation) II score of ≥25 or ≥2 OSFs, with no clear treatment effect in patients with an APACHE II score of ≤24 or 1 OSF. Three fully published cost-effectiveness/cost-utility models of DAA plus conventional care relative to conventional care alone adopted a national healthcare payer’s and/or societal perspective in North America. The base-case (baseline) discounted incremental cost per life-year gained (LYG) with DAA for all patients with severe sepsis was $US15 801–33 300 (year of costing 2000–2002). The results were more favourable for patients with an APACHE II score of ≥25 ($US10 833–19 723 per LYG), but considerably worse for patients with an APACHE II score of ≤24 based on a post hoc reanalysis by the US FDA. Among several fully or partly published cost-effectiveness/cost-utility models that adopted a national healthcare payer’s perspective in continental Western European countries, the base-case (baseline) undiscounted incremental cost per LYG was broadly similar and more favourable for patients with ≥2 OSFs (®9660–11 300; year of costing/publication 1998/1999, 2000, 2002 or 2003) than for all patients with severe sepsis (®13 436–15 071) in those studies that reported both analyses. The DAA acquisition cost accounts for up to 95% of the additional cost of using the drug. In conclusion, DAA is a major advance in the treatment of severe sepsis, based on the significant mortality reduction observed in the PROWESS study. From a hospital/hospital pharmacy perspective, the drug is associated with a high acquisition cost and a small increase in other short-term costs. From a societal or national healthcare payer’s perspective, however, its administration to patients who meet the PROWESS study inclusion criteria, especially individuals with more severe disease (e.g APACHE II score of ≥25 and/or ≥2 OSFs), has a lifetime cost-effectiveness profile that compares well to that of many widely accepted therapies. Severe sepsis (sepsis associated with ≥1 organ system failure [OSF]), is a common, frequently fatal and expensive-to-treat condition. In the US, there are an estimated 751 000 cases of severe sepsis annually, resulting in 215 000 deaths; however, these may be overestimations. In Europe, an estimated 114 000–146 000 deaths each year are attributable to severe sepsis and septic shock; the associated cost is ®5.8–6.7 billion (year of costing not provided). The average hospital cost per patient of conventional care for severe sepsis in the US was estimated at $US22 100 (1995 values) in a large retrospective observational cohort study. The cost was higher in survivors, ICU patients, surgical patients and in patients with ≥4 OSFs than in non-survivors, non-ICU patients, medical patients and in patients with one OSF. The total cost of hospital treatment was estimated to be $US16.7 billion per year from a national healthcare payer’s perspective. Other US studies have reported a similar or higher mean hospital cost per patient; one analysis estimated the 5-year total healthcare charge per patient at $US118 000 (2000 values). A large portion of the hospital cost per patient consists of ICU costs for those admitted. Across continental Western Europe, retrospective estimates of the ICU cost per patient of conventional care ranged from €19 505 in the Netherlands (year of costing not provided) to €28 582 in Austria (2000 values). The major cost drivers measured in these studies included staff, medication and basic bed costs. Severe sepsis imposes a substantial economic burden on society based on estimates of direct plus indirect costs. In studies in Austria and Germany, productivity loss due to mortality accounted for over half the cost of illness and direct costs accounted for approximately one-quarter. Drotrecogin alfa (activated) [DAA] is the recombinant form of human activated protein C (APC), an endogenous protein with antithrombotic, anti-inflammatory and profibrinolytic effects that acts as an important modulator of the systemic response to infection. Plasma levels of protein C, the endogenous precursor of APC, have been shown to be reduced and to inversely correlate with morbidity and mortality outcomes in patients with severe sepsis. The clinical efficacy of DAA as an adjunct to conventional care in the treatment of severe sepsis was demonstrated in the international, randomised, double-blind, placebo-controlled PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) study. The trial included adult patients with a known or suspected infection, ≥3 signs of systemic inflammation and ≥1 acute sepsis-associated OSF within a 24-hour period, but excluded those with an increased risk of bleeding. Patients were randomised to a 96-hour intravenous infusion of either DAA 24 µg/kg/h (n = 850) or placebo (n = 840) starting within 48 hours of the onset of the first sepsis-induced OSF. The primary efficacy endpoint of 28-day all-cause mortality was reduced from 30.8% with placebo to 24.7% with DAA (p < 0.005), corresponding to a 19.4% reduction in the relative...