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Effect of Statin Therapy on Mortality in Patients With Ventilator-Associated Pneumonia: A Randomized Clinical Trial
Study Questions:
What is the effect of statin therapy on day-28 mortality in patients with ventilator-assisted pneumonia (VAP)?
Methods:
STATIN-VAP, a randomized, placebo-controlled, double-blind, parallel group, multicenter trial was conducted in 26 intensive care units (ICUs) in France, from January 2010 to March 2013. To detect an 8% absolute reduction in the day-28 mortality rate, planned enrollment was 1,002 patients requiring invasive mechanical ventilation for more than 2 days and having suspected VAP, defined as a modified Clinical Pulmonary Infection Score of 5 or greater. The futility stopping rules were an absolute increase in day-28 mortality of at least 2.7% with simvastatin compared with placebo after enrollment of the first 251 patients. Participants were randomized to receive simvastatin (60 mg) or placebo, started on the same day as antibiotic therapy and given until ICU discharge, death, or day 28, whichever occurred first.
Results:
The study was stopped for futility at the first scheduled interim analysis after enrollment of 300 patients, of whom all but 7% in the simvastatin group and 11% in the placebo group were naïve to statin therapy at ICU admission. Day-28 mortality was not lower in the simvastatin group (21.2%; 95% confidence interval [CI], 15.4%-28.6%) than in the placebo group (15.2%; 95% CI, 10.2%-22.1%; p = 0.10; hazard ratio, 1.45; 95% CI, 0.83-2.51); the between-group difference was 6.0% (95% CI, −3.0% to 14.9%). In statin-naïve patients, day-28 mortality was 21.5% (95% CI, 15.4%-29.1%) with simvastatin and 13.8% (95% CI, 8.8%-21.0%) with placebo (p = 0.054) (between-group difference, 7.7% [95% CI, −1.8% to 16.8%). There were no significant differences regarding day-14, ICU, or hospital mortality rates; duration of mechanical ventilation; or changes in Sequential Organ Failure Assessment (SOFA) score.
Conclusions:
In adults with suspected VAP, adjunctive simvastatin therapy compared with placebo did not improve day-28 survival. These findings do not support the use of statins with the goal of improving VAP outcomes.
Perspective:
Statins are known to have pleiotropic effects that do not seem to contribute to the reduction in coronary heart disease risk. They include anti-inflammatory, immunomodulating, anti-oxidant, and up-regulating of endothelial cell function. The signal that simvastatin in statin-naïve patients was associated with a borderline significant increase in mortality should not infer that statins should be discontinued during serious infections.
Keywords: Pneumonia, Ventilator-Associated, Hospital Mortality, Lipoprotein(a), Hydroxymethylglutaryl-CoA Reductase Inhibitors, Coronary Disease, Organ Dysfunction Scores, Simvastatin, Up-Regulation, Incidence, France, Medical Futility, Confidence Intervals, Endothelial Cells
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