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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. Limitations One possibility for the lack of efficacy relates to the statin and dosage used. It is possible that adverse effects at the simvastatin dosage used outweighed a beneficial effect, although our data suggest that this is unlikely. The heterogenous cohort of patients with ARDS was an attempt to ensure that our findings would be generalisable; however, it may be more appropriate to target potential therapies based on their proposed biological mechanism for a specific population of patients. The assumptions underpinning the economic benefit are based on the analysis of a subgroup of responders. Conclusions High-dose enteral simvastatin, while safe and with minimal adverse effects, is not effective at improving clinical outcomes in patients with ARDS. There was a small gain in QALYs and a cost saving associated with simvastatin. Future work There is a need to confirm if ARDS endotypes that are more likely to benefit from targeted treatment with simvastatin exist. The potential role of simvastatin in the prevention of ARDS in patients at a high risk of developing ARDS has not yet been evaluated. Trial registration Current Controlled Trials ISRCTN88244364. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This study was also funded in the Republic of Ireland by the Health Research Board (HRA_POR-2010-131). In addition, the Health and Social Care Research and Development division of the Public Health Agency in Northern Ireland, the Intensive Care Society of Ireland and REVIVE provided additional funding.

Simvastatin to reduce pulmonary dysfunction in patients with acute respiratory distress syndrome: the HARP-2 RCT