Published ahead of print on June 7, 2007, doi:10.1164/rccm.200612-1803OC Am. J. Respir. Crit. Care Med., Volume 176, Number 5, September 2007, 483-490 A more recent version of this article appeared on September 1, 2007
Submitted on December 13, 2006 Prophylactic Heparin in Patients with Severe Sepsis Treated with Drotrecogin Alfa (Activated)Marcel Levi1*,1 Departments of Vascular Medicine and Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, 2 Rhode Island Hospital and Brown University Medical School, Providence, RI, USA, 3 Lilly Research Laboratories, Eli Lilly, Indianapolis, IN, USA, 4 Division of Pulmonary Sciences and Critical Care Medicine, Denver Health and University of Colorado Health Sciences Center, Denver, CO, USA, 5 Critical Care Center, Sabadell Hospital, Red GIRA G03/063, University Institute Parc Tauli, Autonomous University of Barcelona, Sabadell, Spain, 6 Policlinico Universitario, A. Gemelli Universita Cattolica del Sacro Cuore, Rome, Italy, 7 Guy's and St Thomas's NHS Foundation Trust, London, United Kingdom * To whom correspondence should be addressed. E-mail: m.m.levi{at}amc.uva.nl.
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 to 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 hours). 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, placebo patients 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 days, p=0.60; 0-28 days, p=0.26). Conclusions: Compared to 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. Key words: critical care, recombinant human activated protein C, XPRESS, clinical trial
This article has been cited by other articles:
|
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
