Heparin prophylaxis did not increase mortality and was beneficial in adults with sepsis receiving drotrecogin alfa

摘要

QuestionnnIn adults with severe sepsis who are receiving drotrecogin alfa (activated) (DrotAA), is co-administration of heparin thromboprophylaxis equivalent to placebo? nnMethodsnnDesign: Randomized, placebo-controlled, equivalence trial (Xigris and Prophylactic HepaRin Evaluation in Severe Sepsis [XPRESS]).nnAllocation: {Concealed}†.*nnBlinding: Blinded (patients, {clinicians, and outcome assessors}†).*nnFollow-up period: 28 days.nnSetting: 224 sites in 20 countries in North, Central, and South America; Europe; Asia; and Australia.nnPatients: 1994 patients who were 18 years of age (mean age 59 y, 59% men), received treatment for severe sepsis, and had multiple organ dysfunction or a relatively high risk for death (i.e., Acute Physiology Age and Chronic Health Evaluation [APACHE] II score 25). Exclusion criteria were heparin contraindication; need for higher heparin dose than that specified in protocol or other anticoagulant medication; creatinine clearance < 30 mL/min; life expectancy < 28 days; and patient, family, or attending physician declining aggressive sepsis therapy.nnIntervention: Unfractionated heparin (UFH), 5000 U subcutaneously twice daily (n = 511), low-molecular-weight heparin (LMWH) (enoxaparin), 40 mg subcutaneously once daily (n = 493), or placebo twice daily (n = 990). All patients received DrotAA at 24 µg/kg per hour for 96 hours. The first study drug injection was given as soon as possible after the DrotAA infusion was started and continued every 12 hours until the DrotAA infusion was completed.nnOutcomes: All-cause mortality. Secondary outcomes included bleeding events, venous thromboembolism, and ischemic stroke.nnPatient follow-up: 97% (intention-to-treat analysis).nnnMain resultsnnAt 28 days, 275 patients had died in the heparin group, and 305 had died in the placebo group. The lower limit of the 90% CI for the absolute risk difference exceeded the prespecified boundaries (Table); therefore, the criteria for equivalence were not met. The Table shows the safety results. nnConclusionnnIn adults with severe sepsis who were receiving drotrecogin alfa (activated), heparin thromboprophylaxis did not increase mortality and was safe with respect to other clinical outcomes.