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Neutrophil elastase inhibition in acute lung injury: Results of the STRIVE study

Zeiher, Bernhardt G. MD; Artigas, Antonio MD, PhD; Vincent, Jean-Louis MD, PhD; Dmitrienko, Alexei PhD; Jackson, Kimberley PhD; Thompson, B Taylor MD; Bernard, Gordon MD for the STRIVE Study Group

doi: 10.1097/01.CCM.0000133332.48386.85
Clinical Investigations
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Objective: Neutrophil elastase is believed to be an important mediator of acute lung injury. Sivelestat (ONO-5046, Elaspol) is a small molecular weight inhibitor of neutrophil elastase. The primary objectives of this study were to determine whether sivelestat would reduce 28-day all-cause mortality or increase the number of ventilator-free days (days alive and free from mechanical ventilation from day 1 to day 28) compared with placebo in mechanically ventilated patients with acute lung injury.

Design: Multiple-center, double-blind, placebo-controlled trial administering a continuous infusion of sivelestat at a dose of 0.16 mg·kg−1·hr−1.

Setting: One hundred and five institutions in the United States, Canada, Belgium, Spain, Australia, and New Zealand.

Patients: A total of 492 mechanically ventilated patients with acute lung injury.

Interventions: Patients were randomized in a 1:1 fashion to sivelestat or placebo. Study drug was administered as a continuous infusion for the duration of mechanical ventilation plus 24 hrs for a maximum of 14 days. All patients were managed using low tidal volume mechanical ventilation.

Measurements and Main Results: The study was stopped prematurely at the recommendation of an external Data and Safety Monitoring Board, which noted a negative trend in long-term mortality rate. Final analysis revealed no effect of sivelestat on the primary end points of ventilator-free days (day 1–day 28) or 28-day all-cause mortality. There were 64 deaths in each treatment group within the 28-day study period, and the mean number of ventilator-free days was 11.4 and 11.9 in the sivelestat and placebo treatment groups, respectively (p = .536). There was no evidence of effect on measures of pulmonary function, including Pao2/Fio2, static lung compliance, and time to meeting weaning criteria. There was no difference in adverse events or serious adverse events between treatment groups. A comparison of the Kaplan-Meier 180-day survival curves showed no difference between treatment groups (p = .102), but there was an increase in 180-day all-cause mortality in the sivelestat treatment group compared with the placebo group (p = .006).

Conclusions: Intravenous sivelestat had no effect on 28-day all-cause mortality or ventilator-free days in a heterogeneous acute lung injury patient population managed with low tidal volume mechanical ventilation.

From Eli Lilly and Company (BGZ, AD, KJ), Indianapolis, IN; Critical Care Center (AA), Sabadell Hospital, Parc Tauli University Institute, Cellular Biology and Physiology Department Autonomous University of Barcelona, red Gira, Sabadell, Spain; Department of Intensive Care (J-LV), Erasme Hospital, Free University of Brussels, Brussels, Belgium; Pulmonary/Critical Care Unit (BTT), Department of Medicine, Massachusetts General Hospital, Boston, MA; and Vanderbilt University (GB), Nashville, TN.

Supported by Eli Lilly and Company, Indianapolis, IN.

Address requests for reprints to: Bernhardt G. Zeiher, MD, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285. E-mail: bernie_zeiher@lilly.com

© 2004 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins