The efficacy of Drotrecogin alfa (activated) during a global, single-arm, open-label trial in adult patients with severe sepsis (ENHANCE): comparisons with PROWESS

Background

Treatment with Drotrecogin alfa (activated) (DrotAA) in a phase 3 clinical trial (PROWESS, n = 1690) was associated with a significant survival advantage and favorable benefit–risk profile compared with placebo in adult patients with severe sepsis. A global, single-arm, open-label trial of DrotAA in adult patients with severe sepsis was subsequently conducted at 361 sites in 25 countries (ENHANCE, n = 2378). Here, the efficacies of DrotAA in ENHANCE and PROWESS were compared, with all-cause mortality at 28 days as the primary study endpoint.

Methods

Inclusion/exclusion criteria were similar to PROWESS. Patients eligible for participation had a known or suspected infection, met three or four criteria defining systemic inflammatory response syndrome and one or more acute sepsis-induced (< 48 hour duration) organ dysfunctions. Patients were classified by the time interval from the first documented organ dysfunction to administration of DrotAA (time-to-treatment), for patients that had received DrotAA within 24 hours (n = 1128) versus > 24 hours (n = 1246) after the first documented organ dysfunction.

Results

Figure 1 shows overall Kaplan–Meier survival curves for PROWESS and ENHANCE (28-day percent mortality shown). Survival curves for patients receiving DrotAA were essentially identical for PROWESS and ENHANCE through 28 days. These results were maintained in patient subgroups of baseline APACHE II score of 25 or more (23.0%, n = 430 vs 27.4%, n = 432) and two or more organ dysfunctions (25.2%, n = 894 vs 28.6%, n = 1110).

Figure 1

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Conclusions

Survival curves for patients receiving DrotAA were similar between the PROWESS and ENHANCE trials. Early treatment was associated with greater mortality benefit. The global ENHANCE reinforces the benefits of DrotAA observed in PROWESS.