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Simvastatin to reduce pulmonary dysfunction in patients with acute respiratory distress syndrome: the HARP-2 RCT
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McAuley, Daniel F., Laffey, John G., O’Kane, Cecilia M., Perkins, Gavin D., Mullan, Brian, Trinder, Thomas J., Johnston, Paul, Hopkins, Phillip A., Johnston, Andrew J., Murphy, Lynn, McNally, Christine, Agus, Ashley M., McDowell, Clíona and Jackson, Colette (2018) Simvastatin to reduce pulmonary dysfunction in patients with acute respiratory distress syndrome: the HARP-2 RCT. Efficacy and Mechanism Evaluation, 5 (1). pp. 1-80. doi:10.3310/eme05010 ISSN 2050-4365.
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Official URL: http://dx.doi.org/10.3310/eme05010
Abstract
Background
Acute lung injury is a common devastating clinical syndrome characterised by life-threatening respiratory failure requiring mechanical ventilation and multiple organ failure, and is a major cause of morbidity and mortality.
Objective
This study tested the hypothesis that treatment with simvastatin would improve clinical outcomes in patients with acute respiratory distress syndrome (ARDS).
Design
This was a multicentre, allocation-concealed, randomised, double-blind, parallel-group trial.
Setting/participants
Patients in intensive care units were eligible if they were intubated and mechanically ventilated and had ARDS as defined by a partial pressure of arterial oxygen to fraction of inspired oxygen concentration (PaO2 : FiO2) ratio of ≤ 300 mmHg, bilateral pulmonary infiltrates consistent with pulmonary oedema and no evidence of left atrial hypertension.
Intervention
Patients were randomised in a 1 : 1 ratio to receive enteral simvastatin 80 mg or identical placebo tablets once daily for up to 28 days.
Main outcome measures
The primary outcome was the number of ventilator-free days (VFDs) to day 28. Secondary outcomes included the number of non-pulmonary organ failure-free days to day 28, mortality and safety. The biological effect by which simvastatin may modify mechanisms implicated in the development of ARDS was also investigated. A cost-effectiveness analysis was also planned.
Results
The study was completed when 540 patients were recruited with 259 patients allocated to simvastatin and 281 patients to placebo, with 258 patients in the simvastatin group and 279 patients in the placebo group included in the analysis of the primary outcome. There was no significant difference between study groups in mean [standard deviation (SD)] VFDs [12.6 days (SD 9.9 days) with simvastatin and 11.5 days (SD 10.4 days) with placebo; mean difference 1.1, 95% confidence interval –0.6 to 2.8; p = 0.21], non-pulmonary organ failure-free days [19.4 days (SD 11.1 days) with simvastatin and 17.8 days (SD 11.7 days) with placebo; p = 0.11] or in 28-day mortality (22.0% with simvastatin and 26.8% with placebo; p = 0.23). There was no difference in the incidence of severe adverse events between the groups. Simvastatin did not significantly modulate any of the biological mechanisms investigated. Simvastatin was cost-effective at 1 year compared with placebo for the treatment of ARDS, being associated with both a small quality-adjusted life-year (QALY) gain and cost saving.
Item Type: | Journal Article | |||||||||||||||||||||
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Subjects: | R Medicine > RC Internal medicine | |||||||||||||||||||||
Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Clinical Trials Unit Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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Library of Congress Subject Headings (LCSH): | Lungs -- Wounds and injuries -- Treatment -- Great Britain, Intensive care units, Drugs -- Testing | |||||||||||||||||||||
Journal or Publication Title: | Efficacy and Mechanism Evaluation | |||||||||||||||||||||
Publisher: | NIHR Health Technology Assessment Programme | |||||||||||||||||||||
ISSN: | 2050-4365 | |||||||||||||||||||||
Official Date: | February 2018 | |||||||||||||||||||||
Dates: |
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Volume: | 5 | |||||||||||||||||||||
Number: | 1 | |||||||||||||||||||||
Page Range: | pp. 1-80 | |||||||||||||||||||||
DOI: | 10.3310/eme05010 | |||||||||||||||||||||
Status: | Peer Reviewed | |||||||||||||||||||||
Publication Status: | Published | |||||||||||||||||||||
Access rights to Published version: | Open Access (Creative Commons) | |||||||||||||||||||||
Date of first compliant deposit: | 3 April 2018 | |||||||||||||||||||||
Date of first compliant Open Access: | 3 April 2018 | |||||||||||||||||||||
RIOXX Funder/Project Grant: |
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