Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in acute lung injury to reduce pulmonary dysfunction (HARP-2) trial : study protocol for a randomized controlled trial

Acute lung injury (ALI) is a common devastating clinical syndrome characterized by life-threatening respiratory failure requiring mechanical ventilation and multiple organ failure. There are in vitro, animal studies and pre-clinical data suggesting that statins may be beneficial in ALI. The Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP-2) trial is a multicenter, prospective, randomized, allocation concealed, double-blind, placebo-controlled clinical trial which aims to test the hypothesis that treatment with simvastatin will improve clinical outcomes in patients with ALI

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

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