Comprehensive safety analysis of concomitant drotrecogin alfa (activated) and prophylactic heparin use in patients with severe sepsis.
OBJECTIVE
The safety of using heparin concomitantly with drotrecogin alfa (activated) {DrotAA} was explored in the XPRESS study. No heparin effect on mortality was observed. Safety results from that study are explored in more detail.


METHODS
A randomized, double-blind trial of prophylactic heparin versus placebo in severe sepsis patients treated with DrotAA (24 microg/(kg h) for 96 h) was conducted at 224 sites in 20 countries. Patients were randomized 1:1:2 to receive unfractionated heparin (UFH) (5,000 Units twice daily) (n = 511), low-molecular-weight heparin (LMWH) (enoxaparin, 40 mg per day) (n = 493), or placebo (n = 990) every 12 h during the DrotAA infusion.


RESULTS
Bleeding events during the DrotAA infusion period (Days 0-6) were higher in the heparin than placebo groups (10.8 vs. 8.1%; p = 0.049), but serious bleeding events were similar (heparin 2.3% vs. placebo 2.5%; p = 0.72) and central nervous system (CNS) bleeds were rare in both groups (0.3 vs. 0.3%). Fewer heparin patients experienced an ischemic stroke during infusion (0.3 vs. 1.3%; p = 0.018) and 28-day period (0.5 vs. 1.8%; p = 0.009).


CONCLUSIONS
Coadministration of DrotAA with low-dose heparin in severe sepsis patients did not increase incidence of serious bleeding. Fewer ischemic strokes in the heparin group suggest heparin cessation should be avoided during DrotAA infusion.
Levy
Mitchell
M
Rhode Island Hospital and Brown University Medical School, 593 Eddy St., Providence, RI 02903, USA. mitchell_levy@brown.edu
Levi
Marcel
M
Williams
Mark D
MD
Antonelli
Massimo
M
Wang
Dazhe
D
Mignini
Mariano Alejandro
MA
D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects; D000075202:Contraindications; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced; D006493:Heparin / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D008297:Male; D011486:Protein C / Q000008:administration & dosage / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D018805:Sepsis / Q000188:drug therapy*; D012720:Severity of Illness Index
D000890:Anti-Infective Agents; D000925:Anticoagulants; D011486:Protein C; D011994:Recombinant Proteins; D006493:Heparin; C421124:drotrecogin alfa activated