Use of an integrated clinical trial database to evaluate the effect of timing of drotrecogin alfa (activated) treatment in severe sepsis

Abstract

Introduction: Several studies have indicated that early identification and treatment of patients with severe sepsis using standard supportive care improves outcomes. Earlier treatment with drotrecogin alfa (activated) (DrotAA) may also improve outcomes in severe sepsis. Using a recently constructed integrated severe sepsis database, our objectives in this study were to describe the influence of baseline clinical characteristics on timing of DrotAA treatment in patients with severe sepsis, to evaluate the efficacy of DrotAA with respect to timing of administration, and to examine the association between early intervention with DrotAA and patient outcomes, using adjustments for imbalances.

Methods: The database comprises data from 4,459 patients with severe sepsis (DrotAA, n = 3,228; placebo, n = 1,231) included in five clinical trials conducted in tertiary care institutions in 28 countries. Placebo data came only from randomized trials, whereas data for the DrotAA group came from randomized (PROWESS) and open-label/observational (ENHANCE) trials.

Results: Increased time-to-treatment with DrotAA was significantly associated with more organ dysfunction, greater need of mechanical ventilation, vasopressor use, or recent surgery. Earlier treatment was associated with higher baseline Acute Physiology and Chronic Health Evaluation (APACHE II) scores. Adjusted and unadjusted survival analyses suggested that compared with placebo, DrotAA treatment provided a potential survival benefit, regardless of time to treatment. Survival curves of DrotAA patients treated early compared with those treated late began to separate at 14 days. By 28 days, patients treated earlier had higher survival than those treated later (76.4% versus 73.5%, p = 0.03). Sepsis-induced multiorgan dysfunction was the most common cause of death followed by refractory shock and respiratory failure. Modeling of the treatment effect, as a function of time to treatment, suggested increased benefit with earlier treatment.

Conclusion: Using an integrated database of five severe sepsis trials and appropriate statistical adjustments to reduce sources of potential bias, earlier treatment with DrotAA seemed to be associated with a lower risk-adjusted mortality than later treatment. These data suggest that earlier treatment with DrotAA may provide most benefit for appropriate patients.

Figure 1

INDEPTH survival curves for placebo-receiving and DrotAA-treated patients by time to treatment. The percentage 28-day survivals are shown parenthetically in the key. Kaplan-Meier survival curves are displayed for therapy groups (namely DrotAA and placebo), as well as for time-to-treatment groups (namely 0 to 24 hours and more than 24 hours). Both DrotAA time-to-treatment curves were significantly different from the placebo time-to-treatment curves. At 14 days, the DrotAA earlier treatment curve (0 to 24 hours) started to diverge from the later treatment curve (more than 24 hours). The difference between the DrotAA earlier and later treatment curves was significant at 28 days (p = 0.03). DrotAA, drotrecogin alfa (activated).

Figure 2

Landmark logistic and Cox regression analysis of DrotAA treatment effect by time to treatment. With the use of logistic (odds ratios for DrotAA versus placebo) and Cox (hazard ratios for DrotAA versus placebo) regression analyses, modeling of the treatment effect as a function of time to treatment was performed. In both analyses there was a trend (logistic regression, p = 0.06; Cox regression, p = 0.07) toward a more beneficial effect with earlier administration of DrotAA (solid line, ratios less than 1 until 36 hours). The most precise estimates of the model were between 12 and 24 hours, as indicated by the narrowest 95% confidence intervals (dashed lines). Outside this range, estimates of benefit were much less precise (that is, wider 95% confidence intervals furthest from the solid line). DrotAA, drotrecogin alfa (activated).