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.
Trial registration: ClinicalTrials.gov NCT00049777.