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

Background

A global, single-arm, open-label trial of Drotrecogin alfa (activated) (DrotAA) in adult patients with severe sepsis was subsequently conducted at 361 sites in 25 countries (ENHANCE, n = 2378). Reported here are 28-day all-cause mortality and safety data.

Methods

Inclusion/exclusion criteria and the definition of serious adverse events (SAE) were similar to PROWESS. Patients at high risk of bleding were excluded from participation. SAE bleeding rates, including intracranial hemorrhage (ICH), during the study drug infusion period (infusion period + 1 day) were determined and the all-cause mortality was assessed at day 28.

Results

Serious bleeding rates and fatal event rates for PROWESS and ENHANCE are presented in Table 1. Overall 28-day mortality: PROWESS placebo = 30.8%, PROWESS DrotAA = 24.7%, ENHANCE DrotAA = 25.3%. As in PROWESS, bleeding was the most common drug-related complication associated with DrotAA. A total 48.9% of SAE bleeding events were adjudicated as procedure-related. In ENHANCE, the ICH rate during infusion was 0.6% (n = 15), of which five (0.2%) were fatal. ICH rates for placebo vs DrotAA in PROWESS were 0% and 0.2% (n = 2, both fatal), respectively. A higher postinfusion rate of serious bleeding was observed in ENHANCE, suggesting a higher overall background bleeding rate, relative to PROWESS.

Table 1 Table

Conclusions

Twenty-eight-day survival was similar in PROWESS and ENHANCE. Serious bleeding events during infusion of DrotAA were slightly more frequent in ENHANCE than in PROWESS; the proportion of fatal bleeding events was the same. However, the background bleeding rate in ENHANCE may have been higher. The ENHANCE safety and efficacy data are highly consistent with PROWESS, and reinforce the favorable benefit–risk profile of DrotAA in patients with severe sepsis.