Statins in the Critically Ill

Reviewed and revised 3 October 2014

OVERVIEW

• Statins (HMG CoA reductase inhibitors) are the most widely used drugs for lowering serum cholesterol levels
• Benefits have been shown in many groups including coronary artery disease, stroke, high-risk elderly patients, patients having major surgery and even those with normal lipid levels
• Statins also have anti-inflammatory, anti-oxidant and immune-modulating effects (ie independent lipid-lowering effects) which may attenuate end-organ dysfunction in a number of syndromes
• Among critically ill patients, continuing or starting statins has been associated with improved outcomes in some observational and small randomised trials

POTENTIAL PLEIOTROPIC MECHANISMS OF STATINS

• Increase or alterations in HDL cholesterol
  • NB: “Lipaemia of sepsis”: cytokines induce hyperlipoproteinaemia, which bind and neutralise lipopolysaccharide from bacteria
• Direct antioxidant mechanisms
• Modulates apoptosis and cell proliferation
• Immunomodulatory effects
• Improvement in endothelial and vascular function
• Effects on coagulation

STATINS IN SPECIFIC SYNDROMES

• Statins in ARDS
  • No benefit
  • Evidence: ARDSnet SAILS trial NEJM 2014, HARP-2 trial NEJM 2014
• Statins in VAP
  • No benefit
  • Evidence: STATIN-VAP trial
• Statins in COPD
  • No benefit for prevention of exacerbations in moderate-to-severe COPD
  • Evidence: Criner et al NEJM 2014
• Statins in sepsis
  • Prospective observational cohort studies showed prior statin therapy is associated with decreased rate of severe sepsis and may reduce ICU admissions
  • ANZ-STATInS: phase II MC RCT study – no effect on de novo statin use in severe sepsis
• Statins in SAH
  • No benefit
  • Evidence: STASH trial

EVIDENCE

• Three negative RCTs stopped early due to futility (SAILS, STATCOPE, STATIN-VAP)

SAILS trial: Statins for Acutely Injured Lungs from Sepsis

The National Heart, Lung and Blood Institute ARDS Clinical Trials Network. Rosuvastatin for sepsis-associated acute respiratory distress syndrome. NEJM 2014; 370: 2191-100

• MC RCT
  • ARDSnet centres
  • n = 745 with ARDS
• Intervention
  • Rosuvastatin (40mg load then 20mg maintenance or 10mg if renal impairment) versus placebo
• Outcomes
  • Primary: mortality before hospital discharge home or until study day 60 if still in a health care facility
  • Secondary: ventilator-free days to day 28, organ-failure-free days to day 14
• Results
  • No significant difference 60-day in-hospital mortality
  • Rosuvastatin associated with more renal failure and hepatic failure
  • No increased CK in rosuvastatin group
• Comments
  • No improvement in clinical outcomes and potentially increased hepatic and renal organ dysfunction with rosuvastatin
  • Study stopped due to futility
  • Highly selective: > 7400 eligible with < 10% undergoing randomisation

HARP-2

McAuley DF, Laffey JG, O’Kane CM et al for the Irish Critical Care Trials Group. Simvastatin in the Acute Respiratory Distress Syndrome. NEJM 2014 Sept 20 [Epub ahead of print] PMID: 25268516

• MC RCT
  • UK and Ireland, n = 540
  • Mechanically ventilated and within 48 hrs of onset of ARDS
• Intervention
  • Simvastatin 80mg enterally daily vs placebo for up to 28 days
• Outcomes
  • Primary: number of ventilator-free days to day 28
  • Secondary: number of days free of non-pulmonary organ failure to day 28, mortality at 28 days, safety
• Results
  • No difference in primary or secondary outcomes
  • No difference in subgroup analyses
  • No difference in serious adverse effects
• Comments
  • Similar baseline data except for small (but significant) decrease in P:F ratio in simvastatin group
  • Increased adverse effects (not serious) in statin group: elevated CK and aminotransferase levels
  • Despite promising findings in early-phase clinical trials of statins in ARDS, these have not been translated into improvements in patient-centred outcomes

STATCOPE

Criner CJ et al. Simvastatin for the prevention of exacerbations in moderate-to-severe COPD. NEJM 2014; 370: 2201 – 10

• Prospective MC  RCT, USA and Canada
  • N = 885 with COPD (moderate-to-severe), aged 40–80y
• Intervention
  • Stimvastatin (40mg daily) versus placebo
• Outcomes
  • Primary: annual COPD exacerbation rates
  • Secondary: lung function (spirometry), respiratory-specific quality-of-life (SF-36 and SGRQ)
• Results
  • No difference in mean no of exacerbatons per person-year
  • No difference in time to first exacerbation in COPD patients at high risk for exacerbations
  • No difference in general or disease-specific quality-of-life
• Comments
  • Terminated early due to futility

STATIN-VAP study

Papazian et al. Effect of Statin Therapy on Mortality in Patients With Ventilator-associated Pneumonia: a Randomised Clinical Trial. JAMA 2013; 310 (16): 1692-1700

• MC RCT, 26 French ICUs
  • N = 300 with VAP who were not already taking statins
• Intervention/ Comparison
  • Simvastatin (60mg or 30mg if renal failure) Vs placebo, commenced in addition to antibiotics
  • Continued throughout hospital stay up to day 28
• Outcomes
  • Primary: 28-day mortality
• Results
  • No difference in mortality: 21% (simvastatin) cf 15% (placebo) but with wide CI crossing 1. Nonetheless – signal for harm…
  • Secondary outcomes: no difference in antibiotic days, ventilator-free days, ARDS rates, organ dysfunction incl renal failure, or development of new infections
• Comments
  • Trial stopped at first interim analysis for futility
  • Largest and only MC-RCT testing statin therapy for a specific infection in the critically ill
  • Previous studies testing statins were complicated by the fact that most included patients who were already taking statins at the time of enrolment: observed benefit of statins in some trials could actually have been due to harm in the ‘placebo’ groups who had their statins discontinued

ANZ-STATInS

Kruger et al. A multicentre randomised trial of atorvastatin therapy in intensive care patients with severe sepsis. Am J Respir Crit Care Med 2013; 187 (7): 743 – 750

• Phase II, MC prospective double-blind placebo-controlled RCT
  • N = 250 critically ill with severe sepsis
• Intervention
  • Aotvastatin (20mg daily) Vs placebo
• Outcomes
  • Primary: IL-6 concentration
  • Secondary: various clinical outcomes (see below)
• Results
  • No difference in IL-6 levels
  • No difference in SOFA score,
  • No difference in mortality at ICU discharge, mortality at hospital discharge, 28- or 90- day mortality
  • No difference in adverse effects
  • Lower cholesterol in atorvastatin group (of course!)
  • Within pre-defined group of 77 prior statin users, those randomised to placebo had greater 28-day mortality cf those who received atorvastatin, but this wasn’t significant at 90-days
• Comments
  • Lack of effect in de novo statin group for primary and secondary outcomes
  • Continued use of atorvastatin in prior statin users was associated with improved 28-day survival
  • Baseline imbalances in age (despite randomisation) – but this was adjusted in analysis

STASH

Kirkpatrick PJ, et al: STASH collaborators. Simvastatin in aneurismal subarachnoid haemorrhage (STASH): a multicentre randomised phase 3 trial. Lancet Neurology 2014 Jul; 13(7): 666-75. PMID: 24837690

• MC RCT, international
  • N = 803, aneurysmal SAH presenting within 96 hrs from ictus
• Intervention
  • Simvastatin 40mg daily vs placebo for up to 28 days
• Outcomes
  • Primary: distribution of modified Rankin Scale score at 6 months
  • Intention-to-treat analysis
• Results
  • No benefit for long- or short-term outcomes
• Comments
  • Cannot recommend treatment with simvastatin during the acute stages of aSAH, despite no safety concerns demonstrated in this trial

References and Links

FOAM and web resources

• PulmCCM — Statins fail for COPD, ARDS (2014)
• PulmCCM — Statins don’t help in ventilator-associated pneumonia treatment (2013)

Journal articles

• Criner GJ, et al; COPD Clinical Research Network; Canadian Institutes of Health Research. Simvastatin for the prevention of exacerbations in moderate-to-severe COPD. N Engl J Med. 2014 Jun 5;370(23):2201-10. PMC4375247
• Drazen JM, Gelijns AC. Statin strikeout. N Engl J Med. 2014 Jun 5;370(23):2240-1. doi: 10.1056/NEJMe1405032. Epub 2014 May 18. PubMed PMID: 24835850. [Free Full Text]
• Kirkpatrick PJ, et al: STASH collaborators. Simvastatin in aneurismal subarachnoid haemorrhage (STASH): a multicentre randomised phase 3 trial. Lancet Neurology 2014 Jul; 13(7): 666-75. PMID: 24837690
• Kruger P, Bailey M, Bellomo R, Cooper DJ, Harward M, Higgins A, Howe B, Jones D, Joyce C, Kostner K, McNeil J, Nichol A, Roberts MS, Syres G, Venkatesh B; ANZ-STATInS Investigators–ANZICS Clinical Trials Group. A multicenter randomized trial of atorvastatin therapy in intensive care patients with severe sepsis. Am J Respir Crit Care Med. 2013 Apr 1;187(7):743-50. PMID: 23348980.
• Kruger PS. Statins: the next anti-endotoxin. Crit Care Resusc. 2006 Sep;8(3):223-6. PMID: 16930109.
• McAuley DF, Laffey JG, O’Kane CM et al for the Irish Critical Care Trials Group. Simvastatin in the Acute Respiratory Distress Syndrome. NEJM 2014 Sept 20 PMID: 25268516
• National Heart, Lung, and Blood Institute ARDS Clinical Trials Network, Truwit JD, et al. Rosuvastatin for sepsis-associated acute respiratory distress syndrome. N Engl J Med. 2014 Jun 5;370(23):2191-200. PMID: 24835849. [Free Full Text]
• Papazian L, Roch A, Charles PE, Penot-Ragon C, Perrin G, Roulier P, Goutorbe P, Lefrant JY, Wiramus S, Jung B, Perbet S, Hernu R, Nau A, Baldesi O, Allardet-Servent J, Baumstarck K, Jouve E, Moussa M, Hraiech S, Guervilly C, Forel JM; STATIN-VAP Study Group. Effect of statin therapy on mortality in patients with ventilator-associated pneumonia: a randomized clinical trial. JAMA. 2013 Oct 23;310(16):1692-700. PMID: 24108510.