Invited Commentary: Jonathon Truwit, MD, MBA

We're discussing Craig et al, "A Randomized Clinical Trial of HMG-Coenzyme A Reductase Inhibition for Acute Lung Injury (HARP)", in the March AJRCCM. The UK investigators gave 80 mg of simvastatin or placebo to 60 acute lung injury patients for up to 14 days. There were no differences in mortality (30%), ventilator-free days or ICU/hospital stay. However, the one-third of the treated group who were left to analyze after 14 days had significantly lower SOFA organ dysfunction scores. They also had a non-statistically significant improvement in hemodynamics at day 14 (0 of 9 [simvastatin] vs. 3-4 of 10 [placebo] requiring vasopressors or inotropes, p=0.05-0.09), and significantly lower IL-8 in BAL fluid. No adverse events were noted.  (n=60).   Read the article / abstract  

Pulmonary Central: Dr. Truwit, you're the principal investigator of the NHLBI / ARDSNet funded Statins for Acutely Injured Lungs from Sepsis (SAILS) trial, with an intended enrollment of 1,000 patients, according to What are your thoughts on the HARP trial, how does this data from Craig et al fit into the "statins for ALI" story, and the bottom line: is it time to start empirically using statins in patients with acute lung injury?

Jonathon Truwit, MD: Statins reduce inflammation and affect the immune system response to insult.1-4   These advantages are documented in animals with sepsis and acute lung injury (ALI), setting the stage for critically ill patients.5-8   Meta-analyses of retrospective studies suggest potential benefit.9-11

Data regarding stains for patients with acute lung injury is at odds.   Kor et al in a retrospective review did not see any benefit with regard to progression of ALI nor end-organ damage, but did note non-significant trends in reduced mortality and increased ventilator free days (VFD).12   The Irish Critical Care Trials Group  (ICCTG) noted that patients with ALI on statins, compared to those not, had a trend toward reduced mortality.13  

This article by Craig et al, a randomized control trial (RCT) in patients with ALI, suggests statin therapy reduces organ dysfunction at day 14, as measured by SOFA scores.14 Changes in SOFA scores for those receiving simvastatin 80 mg/day v placebo were from 10.2 to 4.2 v 10.4 to 8.8, respectively, p=0.01. This study was too small to demonstrate a difference in mortality, if one exists.  Furthermore, the SOFA score improvement in SOFA scores, must be viewed with caution, as less than 1/3 of patients were evaluable at day 14.   Of note, the frequency of elevated in CK, ALT and AST values was similar in both groups, suggesting a good safety profile.

At this point, statins cannot be recommended as standard therapy for ALI.  While the side effect profile is encouraging, the question of efficacy remains.   Larger RCTs in sepsis and ALI are needed. Kruger and ANZICS have just concluded a study randomizing ICU patients with severe sepsis to atorvastatin or placebo, ACTRN12607000028404.  ICCTG, based on the positive signal form Craig et al14 has initiated a larger RCT, where the primary outcome is Ventilator Free Days (VFDs), ISRCTN88244364.   The NHLBI ARDSNet has launched “Statins for Acutely Injured Lungs from Sepsis (SAILS)”, NCT00979121.  To date, 117 subjects have been enrolled in this RCT between rosuvastatin 20mg (equivalent to 80 mg simvastatin) and placebo studies patients with ALI.  The primary outcome is mortality, but will also examine VFDs amongst other secondary outcome variables.   These studies should provide guidance on use of statin therapy for ALI, treatment and prevention.

Jonathon Truwit, MD, MBA

E. Cato Drash Professor of Medicine

University of Virginia School of Medicine

Sr. Associate Dean for Clinical Affairs

Chief Medical Officer

University of Virginia Health System


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12.  Kor D, Iscimen R, Yilmaz M, Brown M, Brown D, Gajic O. Statin administration did not influence the progression of lung injury or associated organ failures in a cohort of patients with acute lung injury.Intensive Care Med 2009;35:1494–1495.

13.  The Irish Critical Care Trials Group. Acute lung injury and the acute respiratory distress syndrome in Ireland: a prospective audit of epidemiology and management. Crit Care 2008;12:R30.

14.  Craig TR, Duffy MJ, Shyamsundar M, McDowell C, O' Kane C, Elborn JS, McAuley DF. A Randomized Clinical Trial of Hydroxymethylglutaryl-CoA reductase Inhibition for Acute Lung Injury (The HARP study). Am J Respir Crit Care Med. 2010 Sep 24.  [Epub ahead of print]