Drotrecogin alfa (activated) in the subgroup of patients with multiple organ dysfunction (MOD) during a global, single-arm, open-label trial in adult patients with severe sepsis (ENHANCE): comparisons with PROWESS

Background

Drotrecogin alfa (activated) (DrotAA) was associated with a significant survival advantage and a favorable benefit–risk profile in a phase 3 clinical trial (PROWESS, n = 1690) in adult patients with severe sepsis. The EMEA approved DrotAA for treatment of adult patients with severe sepsis and multiple organ failure. ENHANCE (n = 2378) was a single-arm, open-label trial of DrotAA in adult patients with severe sepsis. We compared relative efficacies of DrotAA in ENHANCE and PROWESS in the subgroup of patients with MOD.

Methods

Inclusion/exclusion criteria were similar to PROWESS. Patients with MOD in ENHANCE and PROWESS were identified and compared (ENHANCE, n = 2008; PROWESS DrotAA, n = 634; PROWESS placebo [PBO], n = 637). Baseline characteristics, 28-day all-cause mortality, safety, and the effect of time of treatment were assessed.

Results

Age (years), mean (SD): ENHANCE, 60 (17); PROWESS DrotAA, 61 (17); and PBO, 62 (16). Males: ENHANCE, 58%; PROWESS DrotAA, 56%; and PBO, 57%. Recent surgery: ENHANCE, 38%; PROWESS DrotAA, 31%; and PBO, 33%. Organ dysfunctions: ENHANCE, 3.0 (0.9); PROWESS DrotAA, 2.9 (0.9); and PBO, 2.8 (0.9). APACHE, mean (SD): ENHANCE, 22.9 (7.3); PROWESS DrotAA, 25.7 (7.5); and PBO, 25.9 (7.8). Ventilator support: ENHANCE, 86.1%; PROWESS DrotAA, 79.8%; and PBO, 82.9%. Vasopressor support: ENHANCE, 81.7%; PROWESS DrotAA, 71.5%; and PBO, 73.9%. Total SOFA, mean (SD): ENHANCE, 10.3 (3.2); PROWESS DrotAA, 9.7 (3.1); and PBO, 9.6 (3.1). Twenty-eight-day mortality: ENHANCE, 27.1%; PROWESS DrotAA, 26.5%; and PBO, 33.9%. Serious bleeding during infusion: ENHANCE, 3.7%; PROWESS DrotAA, 2.4%; and PBO, 1.3%.

Similar results were observed in the MOD subgroup as in the overall population. ENHANCE MOD patients tended to have lower APACHE scores but greater organ support at baseline compared with PROWESS patients. Mortality was similar for DrotAA-treated patients in ENHANCE and PROWESS, and both were lower than PROWESS placebo patients. Serious bleeding was numerically higher in ENHANCE than in PROWESS. Patients treated within 24 hours of the first organ dysfunction had lower 28-day mortality (25.2%, n = 894) than those treated after 24 hours (28.6%, n = 1110).

Conclusions

Results from the global ENHANCE reinforce the benefit–risk profile of DrotAA observed in the PROWESS MOD subgroup. In addition, earlier treatment (≤ 24 hours) appears to be associated with lower mortality.