Nov 082013

Statins have anti-inflammatory and immune-modulating effects, and among critically ill patients, continuing or starting statins have improved soft outcomes in observational and small randomized studies. For example, starting a statin reduced progression of sepsis in ward patients and statins improved organ failure scores in acute lung injury (the HARP trial).

But in their first shot at the big time -- a large multicenter randomized trial -- adding a statin to standard antibiotic therapy for patients with ventilator-associated pneumonia (VAP) in the ICU did not reduce mortality. On the contrary, patients treated with statins had 45% higher mortality (non-significant statistically) and the trial was stopped early for futility. Laurent Papazian et al report the results of their STATIN-VAP study in the October 23/30, 2013 JAMA.

What They Did

In 26 French ICUs, authors randomized 300 patients with ventilator-associated pneumonia not already taking statins to receive 60 mg of daily simvastatin or placebo, started along with antibiotics, and continued throughout their hospital stay up to 28 days. 30 mg simvastatin were given to patients with renal failure. About 10% of patients had taken statins in the previous month, but none were at the time of intubation.

~75% of patients had "probable VAP," with positive cultures from BAL, protected catheter or endotracheal aspirate at accepted CFU cutoffs; about 25% had "possible VAP" with a CPIS score > 4 but without positive cultures. The primary outcome was 28 day mortality, with numerous secondary outcomes.

What They Found

Mortality at 28 days was 21% in patients taking simvastatin and 15% in those taking placebo (a 6% absolute difference, a 45% relative difference with a wide confidence interval crossing 1). Among patients who had never taken statins before, there was an 8% absolute increase in mortality in those given statins compared to placebo.

At this first interim analysis, the trial was stopped for futility.

Statins did not affect any other measured outcome either: there were no differences between groups in antibiotic days, ventilator-free days, ARDS rates, organ dysfunction including renal failure, or the development of new infections.

What It Means

This is the largest and only multicenter randomized trial testing statin therapy for a specific infection in ICU patients. It doesn't negate every previous smaller trial suggesting a protective effect of statins against infections, but it does cast them in a new skeptical light.

Interpretation of previous studies testing statins as preventive or adjunctive therapies for infections is complicated by the fact that most included patients who were already taking statins at the time of enrollment, and (if allocated to the placebo arm) had them stopped at the trial onset. Thus, the observed benefits of statins in some trials could actually have been due to harm in the placebo groups, caused by statin discontinuation.

For now, the scarily large harm signal seen here, though not statistically significant, should cow most physicians considering starting statin therapy as an adjunctive treatment for their patients with ventilator-associated pneumonia, and possibly with any infection in or out of the ICU. This study did not test the continuation of statins in ICU patients taking them for cardiovascular protection; that's a completely separate experimental question, probably deserving of its own trial.

Oh, and this was actually statins' first published shot at the big time. After the pilot HARP trial stoked hopes by showing statins for ARDS could improve organ failure, the Phase 3 randomized, multicenter Statins for Acutely Injured Lungs from Sepis (SAILS) trial testing rosuvastatin vs. placebo was stopped early for futility on October 18, 2013, according to Expect to see those results in a major journal (and on PulmCCM of course) in the next year or so.

Laurent Papazian et al. Effect of Statin Therapy on Mortality in Patients With Ventilator-Associated PneumoniaA Randomized Clinical Trial. JAMA. 2013;310(16):1692-1700. doi:10.1001/jama.2013.280031.

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Statins don’t help in ventilator-associated pneumonia treatment