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

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.

CCC 700 6

Critical Care

Compendium

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

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