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Rationale: Patients with severe sepsis frequently receive prophylactic heparin during drotrecogin alfa (activated) (DrotAA) treatment due to risk of venous thromboembolic events (VTEs). Biological plausibility exists for heparin to reduce DrotAA efficacy and/or increase bleeding., Objectives: Primary: demonstrate in adult patients with severe sepsis receiving DrotAA treatment that 28-day mortality was equivalent for patients treated with concomitant prophylactic heparin compared with placebo; secondary: safety and VTE incidence., Methods: International, randomized, double-blind, phase 4, equivalence-design trial (n = 1994). Patients were eligible if indicated for and receiving DrotAA treatment under the country's approved label. Study drug (low molecular weight/unfractionated heparin) or placebo (saline) was administered every 12 hours during DrotAA infusion (24 ug/kg/hr for 96 hr). In patients on baseline heparin and randomized to placebo, heparin was stopped., Measurements and Main Results: Twenty-eight-day mortality was not equivalent between treatment groups. Heparin mortality was numerically lower (28.3 vs. 31.9%; p = 0.08). In the prospectively defined subgroup of patients exposed to heparin at baseline, patients receiving placebo experienced higher mortality (35.6 vs. 26.9%; p = 0.005). For safety, significant differences were observed during Days 0-6 for any bleeding event (placebo, n = 78; heparin, n = 105; p = 0.049) and ischemic stroke during Days 0-6 (placebo, n = 12; heparin, n = 3; p = 0.02) and Days 0-28 (placebo, n = 17; heparin, n = 5; p = 0.009). The VTE rate was low, with no statistical difference between groups (0-6 d, p = 0.60; 0-28 d, p = 0.26)., Conclusions: Compared with placebo, concomitant prophylactic heparin was not equivalent, did not increase 28-day mortality, and had an acceptable safety profile in patients with severe sepsis receiving DrotAA. Heparin discontinuation should be carefully weighed in patients considered for DrotAA treatment. XPRESS clinical trial registered with www.clinicaltrials.gov (NCT 00049777). The study ID numbers are 6743; F1K-MC-EVBR.

Objective: To demonstrate that drotrecogin alfa (activated) has an acceptable safety profile 1 yr from randomization., Design: One-year follow-up of patients participating in a placebo-controlled clinical study of drotrecogin alfa (activated) in severe sepsis patients at low risk of death (the ADDRESS study)., Setting: The study was conducted at 516 hospitals in 34 countries., Patients: The study included 2,640 patients., Interventions: One-year follow-up was performed as an addendum to the placebo-controlled ADDRESS study. Treatment groups were compared using the chi-square test and Kaplan-Meier estimates., Measurements and Main Results: Survival status at 1 yr was obtained for 90% of patients enrolled in the study (n = 2,376). The difference in mortality rate between drotrecogin alfa (activated) and placebo patients was numerically smaller at 1 yr (34.2% and 34.0%, respectively, p = .94) than at 28 days (18.5% and 17.0%, respectively, p = .34). In the subgroups defined by organ dysfunction class (single or multiple) and Acute Physiology and Chronic Health Evaluation II score (<25 or >or=25), the differences in mortality rate between treatment groups at 1 yr were consistent with those observed at 28 days; no significant differences in mortality rates between treatment groups were observed. No additional serious adverse events were reported during the period between hospital discharge and 1 yr., Conclusions: No increased risk of death or evidence of harm at 1 yr was associated with drotrecogin alfa (activated) administration in patients with severe sepsis at lower risk of death.

Background: The International Integrated Database for the Evaluation of Severe Sepsis and Drotrecogin alfa (activated) Therapy includes an extensive cohort of surgical patients (1659/4459; 37%). This database broadens the experience reported on a comparatively small set of surgical patients from the pivotal Protein C Worldwide Evaluation in Severe Sepsis trial to examine issues of safety and efficacy in a much larger cohort., Methods: We conducted a retrospective analysis of prospectively defined outcomes from 5 integrated clinical studies of severe sepsis. Multivariable analyses incorporated propensity scores, treatment, and significant baseline risk factors as independent variables in logistic regression models for 2 outcomes: serious adverse events that were observed during infusion and 28-day, all-cause mortality rates. Adjusted odds ratios were calculated for clinically important strata. Multiple subcategories of serious bleeding-event rates are presented., Results: Although surgical patients who were treated with drotrecogin alfa [activated] (DrotAA) experienced a greater proportion of serious bleeding events during the infusion period, most of the patients were treated without fatal consequence. A 10.7% absolute all cause mortality risk reduction (adjusted odds ratio, 0.66; 95% CI, 0.45-0.97) was observed for DrotAA-treated, high-risk (Acute Physiology and Chronic Health Evaluation II, >/= 25) surgical patients. We could not demonstrate a survival benefit in DrotAA-treated, low-risk (Acute Physiology and Chronic Health Evaluation II, <25) surgical patients. When surgical patients were stratified by number of organ dysfunctions, absolute risk reductions were observed in both categories: multiorgan (4.3%) and single (4.5%)., Conclusion: International Integrated Database for the Evaluation of Severe Sepsis and Drotrecogin alfa (activated) Therapy analyses affirmed the favorable benefit/risk profile of DrotAA for surgical patients. The serious adverse event rate that was experienced by surgical patients during the study drug infusion period was 7.5% in the DrotAA-treated group versus 6.3% in the placebo-treated group (odds ratio, 1.41; 95% CI, 0.89-2.25). The clinical benefit of DrotAA therapy paralleled baseline risk of death and substantiated findings from the Protein C Worldwide Evaluation in Severe Sepsis study. Future analyses are needed to evaluate the special relationships among sepsis severity, bleeding management, and the postoperative timing of DrotAA administration.

Background: The International Integrated Database for the Evaluation of Severe Sepsis and Drotrecogin alfa (activated) Therapy includes an extensive cohort of surgical patients (1659/4459; 37%). This database broadens the experience reported on a comparatively small set of surgical patients from the pivotal Protein C Worldwide Evaluation in Severe Sepsis trial to examine issues of safety and efficacy in a much larger cohort., Methods: We conducted a retrospective analysis of prospectively defined outcomes from 5 integrated clinical studies of severe sepsis. Multivariable analyses incorporated propensity scores, treatment, and significant baseline risk factors as independent variables in logistic regression models for 2 outcomes: serious adverse events that were observed during infusion and 28-day, all-cause mortality rates. Adjusted odds ratios were calculated for clinically important strata. Multiple subcategories of serious bleeding-event rates are presented., Results: Although surgical patients who were treated with drotrecogin alfa [activated] (DrotAA) experienced a greater proportion of serious bleeding events during the infusion period, most of the patients were treated without fatal consequence. A 10.7% absolute all cause mortality risk reduction (adjusted odds ratio, 0.66; 95% CI, 0.45-0.97) was observed for DrotAA-treated, high-risk (Acute Physiology and Chronic Health Evaluation II, >or=25) surgical patients. We could not demonstrate a survival benefit in DrotAA-treated, low-risk (Acute Physiology and Chronic Health Evaluation II, <25) surgical patients. When surgical patients were stratified by number of organ dysfunctions, absolute risk reductions were observed in both categories: multiorgan (4.3%) and single (4.5%)., Conclusion: International Integrated Database for the Evaluation of Severe Sepsis and Drotrecogin alfa (activated) Therapy analyses affirmed the favorable benefit/risk profile of DrotAA for surgical patients. The serious adverse event rate that was experienced by surgical patients during the study drug infusion period was 7.5% in the DrotAA-treated group versus 6.3% in the placebo-treated group (odds ratio, 1.41; 95% CI, 0.89-2.25). The clinical benefit of DrotAA therapy paralleled baseline risk of death and substantiated findings from the Protein C Worldwide Evaluation in Severe Sepsis study. Future analyses are needed to evaluate the special relationships among sepsis severity, bleeding management, and the postoperative timing of DrotAA administration.

Background: We conducted a retrospective evaluation of the overall safety of drotrecogin alfa (activated) in surgical patients with severe sepsis enrolled in PROWESS., Methods: A blinded Surgical Evaluation Committee (SEC) verified surgical patients as having undergone a significant operative procedure within 30 days prior to enrollment. Serious and treatment-emergent bleeding events, both during the study drug infusion period (120 h) and the entire 28-day study period were analyzed by surgical status and by treatment assignment. Statistical analysis was performed using Fisher's exact test., Results: Serious bleeding rates during infusion in the surgical patients were 3.1% (7/228) and 0% (0/246) in the drotrecogin alfa (activated) and placebo groups, respectively (p = 0.006). Treatment-emergent bleeding rates during infusion in the surgical patients were 16.7% (38/228) and 7.7% (19/246) in the drotrecogin alfa (activated) and placebo groups, respectively (p = 0.003). None of the treatment-emergent bleeding events was fatal. Of seven drotrecogin alfa (activated) serious bleeding events, six were procedure-related. The serious bleeding rates within each treatment group were statistically indistinguishable between the medical and surgical patients. However, the medical patients had numerically higher treatment-emergent bleeding rates than the surgical patients within each treatment group. Despite this observation, overall surgical patients received more transfusions of red blood cells, of platelets, and of fresh frozen plasma than their medical counterparts., Conclusions: Although treatment of surgical patients with drotrecogin alfa (activated) for severe sepsis is associated with a higher incidence of serious bleeding and subsequent treatment- emergent bleeding events, the magnitude of this increase is small and clinically acceptable.