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
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
References 1. Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 2005;45:89-118. 2. Weitz-Schmidt G. Statins as anti-inflammatory agents. Trends Pharmacol Sci. 2002 Oct;23(10):482-6. 3. Gao F, Linhartova L, Johnston AM, Thickett DR. Statins and sepsis. Br J Anaesth. 2008 Mar;100(3):288-98. 4. Terblanche M, Almog Y, Rosenson RS, Smith TS, Hackam DG. Statins: panacea for sepsis? Lancet Infect Dis. 2006 Apr;6(4):242-8. 5. Jacobson JR, Barnard JW, Grigoryev DN, Ma SF, Tuder RM, Garcia JG. Simvastatin attenuates vascular leak and inflammation in murine inflammatory lung injury. Am J Physiol Lung Cell Mol Physiol. 2005 Jun;288(6):L1026-32. Epub 2005 Jan 21. 6. Merx MW, Liehn EA, Graf J, van de Sandt A, Schaltenbrand M, Schrader J, Hanrath P, Weber C. Statin treatment after onset of sepsis in a murine model improves survival. Circulation. 2005 Jul 5;112(1):117-24. 7. Mueller HC, Hellwig K, Rosseau S, Tschernig T, Schmiedl A, Gutbier B, Schmeck B, Hippenstiel S, Peters H, Morawietz L, Suttorp N, Witzenrath M. Simvastatin attenuates ventilator-induced lung injury in mice. Crit Care. 2010;14(4):R143. Epub 2010 Jul 30. 8. Jain MK, Ridker PM. Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nat Rev Drug Discov. 2005 Dec;4(12):977-87. 9. Janda S, Young A, Fitzgerald JM, Etminan M, Swiston J. The effect of statins on mortality from severe infections and sepsis: a systematic review and meta-analysis. J Crit Care. 2010 Dec;25(4):656.e7-22. Epub 2010 Apr 22. 10. Tleyjeh IM, Kashour T, Hakim FA, Zimmerman VA, Erwin PJ, Sutton AJ, Ibrahim T. Statins for the prevention and treatment of infections: a systematic review and meta-analysis. Arch Intern Med. 2009 Oct 12;169(18):1658-67. 11. Falagas ME, Makris GC, Matthaiou DK, Rafailidis PI. Statins for infection and sepsis: a systematic review of the clinical evidence. J Antimicrob Chemother. 2008 Apr;61(4):774-85. Epub 2008 Feb 7. 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]
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